Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[C:7]([F:15])=[C:8]([C:11]([F:14])=[CH:12][CH:13]=1)[CH:9]=[O:10]>C1COCC1>[Cl:5][C:6]1[C:7]([F:15])=[C:8]([CH:9]([OH:10])[CH:1]=[CH2:2])[C:11]([F:14])=[CH:12][CH:13]=1
Reactant: O=Cc1c(F)ccc(Cl)c1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1c(F)ccc(Cl)c1F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 100 mL dry round bottom flask containing vinylmagnesium bromide (1 M in THF) (24 mL, 24.00 mmol) under Ar at 0° C. was added 3-chloro-2,6-difluorobenzaldehyde (3.2 g, 18.13 mmol) in THF (10 mL) dropwise. The reaction was stirred for 1 h and quenched with 1 N HCl to pH 2. The mixture was extracted with Et2O (3×). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to yield the desired product (3.71 g, 100%) as pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.34 (ddd, J=8.9, 8.1, 5.8 Hz, 1H), 6.90 (td, J=9.2, 1.7 Hz, 1H), 6.23 (dddt, J=17.2, 10.4, 5.8, 1.2 Hz, 1H), 5.60 (dd, J=7.6, 6.7 Hz, 1H), 5.40-5.31 (m, 1H), 5.28 (dt, J=10.2, 1.2 Hz, 1H), 2.38 (dt, J=8.3, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]([CH3:27])[C:20]2=[O:28].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]([CH3:27])[C:20]3=[O:28])[CH:4]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ccc2ncn(C)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Tert-butyl 4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenylcarbamate 26 (3.0 g, 7.89 mmol) was added to 50 mL of 10% TFA in DCM. After 1 hr, the reaction mixture was neutralized with 75 mL saturated Na2CO3, extracted into EtOAc (3×100 mL), dried over MgSO4 and concentrated in vacuo to yield the desired product (2.078 g, 7.41 mmol, 94% yield). 1H NMR (300 MHz, D6 DMSO): δ 7.91 (s, 1H), 7.71 (d, 1H, J=2.7 Hz), 7.61 (s, 1H, J=8.8 Hz), 7.37 (dd, 1H, J=2.7 Hz, J=8.8 Hz), 7.31 (s, 1H), 7.03 (d, 1H, J=8.0 Hz), 6.67 (d, 1H, J=2.3 Hz), 6.40 (dd, 1H, J=2.4 Hz, J=8.0 Hz), 5.80 (br s, 1H), 3.63 (s, 3H), 2.16 (s, 3H), 1.64 (s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz, D6 DMSO): δ 160.73, 146.90, 144.88, 142.13, 138.84, 132.85, 131.08, 130.76, 126.96, 125.08, 122.78, 118.25, 115.49, 110.06, 34.87, 18.51. ESMS: m/z 281.2 [MH]+
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=1>>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([OH:14])=[C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=C1CCCCC1
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
A mixture of methylene cyclohexane (0.96 g, 10 mmoles), p-bromophenol (1.73 g, 10 mmoles) and acid resin (Dowex 50x12-150 mg) is heated at 80° C. for 16 hours. The residue is purified by silica gel chromatography (eluant: 50/50 mixture of CH2Cl2 /hexane). On evaporation of the solvents 0.50 g (19% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol in the form of a yellowish oil is obtained.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:38])[C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1>>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([CH2:6][NH:38][C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:32]=3[CH:31]=[N:30][N:29]4[C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)([OH:5])[C:7]([F:8])([F:9])[F:10])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: COc1ccc(-n2ncc3c(N)cccc32)cc1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Product: COc1ccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cccc5c4OCC5)C(F)(F)F)cccc32)cc1

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-[4-(methyloxy)phenyl]-1H-indazol-4-amine (Intermediate 3).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([Si](C)(C)C)[N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[CH:14][N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1cn(C2CCC3(CC2)OCCO3)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.1 %

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]-triazole (1.60 g, 5.68) in 41 mL of dry THF was treated by a 1M solution of tetrabutylammonium fluoride in THF (9.0 mL, 9.0 mmol). The resulting mixture was stirred for 48 h at room temperature under nitrogen. It was diluted with EtOAc, washed with saturated aqueous ammonium chloride, water and brine, dried over Na2SO4 and concentrated to give 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,3]triazole (1.06 g, 89%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:18])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2. 1]octan-2-one (Description 30; 6.9 g, 21.8 mmol) was taken up a mixture of methanol (100 ml) and THF (30 ml). To this suspension was added sodium borohydride (0.5 g, 13 mmol). The mixture was stirred for 30 minutes then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 35 and 50% ethyl acetate/iso-hexanes afforded the title compound (4.8 g, 70%).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])=[C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:19]=1)[CH3:51]
Reactant: CCOC(=O)CI
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(O)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OCC(=O)OCC)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 1-[5-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (100 mg, 0.19 mmol) and potassium tert-butoxide (0.21 mL, 1 M, 0.21 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 minutes. Ethyl 2-iodoacetate (0.027 mL, 0.23 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and aqueous HCl solution was added until the pH was about 7. The organic layer was dried over sodium sulfate and removed in vacuo. The crude material was purified by eluting through a short pad of silica gel column to afford the title compound (100 mg, 86% yield). MS (ESI) [m/e, (M+H)+]=605.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.30-7.41 (m, 8H), 2.68-5.46 (m, 18H), 2.20-2.61 (m, 3H), 0.70-1.74 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH3:16][C:17]([CH3:19])=O>>[CH2:16]([O:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:17]1[CH:19]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: Oc1c(F)cccc1Cl
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cccc(Cl)c1OCc1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-6-fluorophenol (25 g, 170 mmol), acetone (200 ml), K2CO3 (47.08 g, 340 mmol) and bensylbromide (22.31 ml, 187 mmol) was heated at 65° C. for 16 h. The solution was filtered and evaporated. Water (100 ml) was added, and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to dryness to give the title compound (32.3 g). MS m/z (rel. intensity, 70 eV) 236 (M+, 2), 117 (4), 92 (8), 91 (bp), 65 (13).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]>CO>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CO
Product: Cc1ccc(C(=O)COc2cc(C)cc(C)c2C)cc1
Yield: 75 %

Procedure:
Using 2,3,5-trimethylphenol and 2-bromo-1-(4-methylphenyl)ethanone, the title compound was synthesized in the same manner as in Reference Example 159. Yield 75%. Melting point: 94-95° C. (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][Br:18])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cccc23)cc1
Yield: 57.2 %

Procedure:
A mixture of 15.7 g (0.065 mole) of 3-(4-chlorophenyl)-7-methyl-2,1-benzisoxazole, 11.6 g (0.065 mole) of N-bromosuccinimide, 0.5 g of dibenzoylperoxide and 400 ml of carbon tetrachloride was heated at reflux while being illuminated by a flood lamp for 3 hr. The mixture was filtered and the filtrate was concentrated to give a solid as residue. The solid was recrystallized three times from acetonitrile to yield 12.0 g (58%) of crystals, m.p. 153°-155° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=12.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]1=[C:7]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(c1)c(-c1ccccn1)c1n2CCCCC1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccn1)c1n2CCCCC1

Procedure:
The above compound was prepared from 7,8,9,10-tetrahydro-11-(2-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:13]1[C:12]([I:1])=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:10][N:9]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Temperature: 80 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
N-iodosuccinimide (0.6 g, 2.59 mmol) was added to a solution of diethyl 3,5-pyrazoledicarboxylate (0.5 g, 2.35 mmol) in CHCl3 (10 mL) and the mixture was stirred at 80° C. for 24 hours. Then more of N-iodosuccinimide (0.6 g, 2.59 mmol) was added and the mixture was stirred at 100° C. for 48 hours more. Then the mixture was stirred at room temperature for 5 days. Then the mixture was treated with a saturated solution of Na2S2O3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (0.83 g, 90% yield).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 337 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][NH2:13]>>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: COc1ccc(C=O)c(F)c1
Product: COc1ccc2cn[nH]c2c1
Yield: 59 %

Procedure:
A mixture of 2-fluoro-4-methoxybenzaldehyde (1 g, 6.5 mmol) and hydrazine (7 mL) was heated to reflux for 4 h. The mixture was extracted with CH2Cl2. The combined organic layers were washed with water, brine, concentrated in vacuo, and purified by column chromatography (elution with PE/EtOAc=5:1) to afford 6-methoxy-1H-indazole (intermediate 42) (568 mg, 59%) as a yellow solid. HPLC: 99%, RT 2.159 min. MS (ESI) m/z 149.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([NH2:16])[C:6]=2[CH:17]=1.[IH:18].CS[C:21]1[NH:22][CH2:23][CH2:24][N:25]=1.CCOCC>C(O)C>[IH:18].[NH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[N:16][CH:7]1[C:6]2[CH:17]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: NC1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: Brc1ccc2c(c1)C(N=C1NCCN1)c1ccccc1C=C2

Procedure:
6.90 grams (0.024 mole) of 3-bromo-5H-dibenzo[a,d]cycloheptene-5-ylamine, 2.95 grams (0.012 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 65 milliliters of absolute ethanol were stirred together and refluxed for 28 hours. At the end of this period, the solvent was evaporated under reduced pressure and the residue triturated with five 100 milliliter portions of diethyl ether to obtain a purified residue. The purified residue was dissolved in 20 milliliters of absolute ethanol and 300 milliliters of ether added thereto whereupon a solid precipitated. The mixture was stirred thoroughly, the solvent decanted to obtain a residue which was placed on a Still-silica column and eluted with 5 percent methanol in chloroform. The eluted fractions were examined by thin layer chromatography (TLC), the homogeneous TLC fractions combined, and the solvent then vaporized to obtain the desired N-(2-imidazolidinylidene)-3-bromo-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product as residue. The product was crystallized from chloroform to obtain purified product, m.p. 240°-241° C. (dec.). Elemental analyses were as follows: Calc'd for C18H17BrIN3 : C, 44.84; H, 3.55; N, 8.72. Found: C, 44.75; H, 3.48; N, 8.46.
Reaction SMILES: [C:1]([O:4][C:5]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH:7]=[CH2:8])[CH3:6])(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].O.C(=O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:6])([CH2:9][CH2:10][CH:11]([Cl:15])[C:12]([CH3:14])=[CH2:13])[CH:7]=[CH2:8])(=[O:3])[CH3:2]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: [O-]Cl
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: C=CC(C)(CCC(Cl)C(=C)C)OC(C)=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 177.7 %

Procedure:
A stirred mixture of linalyl acetate (39 g, 0.2 mol), 65% calcium hypochlorite (22 g, 0.1 mol), water (70 mL) and dichloromethane (700 mL) was cooled to 10° C. and solid carbon dioxide was added until an exotherm was no longer observed upon addition. After stirring for an additional 1 h at 10° C., the organic layer was separated and washed successively with a solution containing 5% sodium bicarbonate and 1% sodium bisulfite (100 mL), and then with brine (100 mL). The organic layer was dried, the solvent evaporated, and the residue distilled to yield 41 g of 3-acetoxy-6-chloro-3,7-dimethyl-1,7-octadiene, bp 75°-80° C. (0.5 mm). IR (film) 1740, 1370, 1250, 920 cm-1. NMR (CDCl3) δ1.53 (3H, s), 1.8 (3H, bs), 1.8-2.4 (2H, m), 4.33 (1H, m), 4.84-5.33 (4H, complex) 6.0 (1H, dd).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9](=[O:38])(=[O:37])[N:8]([CH3:39])[C:7]=2[CH:40]=1.S([O-])(=O)(=O)C.[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][C:13]([NH:12][CH:11]1[CH2:10][S:9](=[O:37])(=[O:38])[N:8]([CH3:39])[C:7]2[CH:40]=[C:3]([CH2:2][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:4]=[CH:5][C:6]1=2)=[O:36])(=[O:25])=[O:24]
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Reactant: C1CCNCC1
Agent: CS(=O)(=O)[O-]
Product: CN1c2cc(CN3CCCCC3)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O

Procedure:
The title compound was prepared from N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 12, Step D) via its mesylate and addition of piperidine by a method similar to that described in Example 12, Step E. MS (+ESI, m/z): 647 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:23](N(OC)C)=[O:24]>>[CH3:33][O:32][C:30]1[CH:29]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:31]=1)[C:23]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:24]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1cc(OC)cc(C(=O)N(C)OC)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)cc2C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 3,5-dimethoxy-N-methoxy-N-methylbenzamide. It is crystallized from diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:31])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 59.2 %

Procedure:
A 500 ml round bottom flask equipped with nitrogen inlet and magnetic stirrer is charged with 40 g (0.132 mol) of product from Example 2 and 24.97 g (0.233 mol) of 2.6-lutidine. To this is slowly added (exothermic) 185 ml (1.98 mol) of phosphorous oxychloride. The flask is fitted with a condenser and the mixture is heated to reflux. After refluxing for 18 hours the material is cooled, concentrated, and the mixture was poured into 150 g of ice slowly. The ice mixture was then poured into 200 ml of 10% HCl (aqueous) and extracted twice with ether. The combined ether layers were washed with 10% NaOH (aqueous), dried (MgSO4), and concentrated in vacuo affording a black oil. The residue was kugelrohr distilled at 67 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 85° C.) afforded 25.15 g (60%) of product, nD25 1.4185.
Reaction SMILES: C(C1C=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.[CH3:25][C:26]1[O:27]C=C(CCl)[N:30]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[N:30]=[C:26]([CH3:25])[O:27][CH:23]=2)[CH:10]=1
Reactant: Cc1nc(CCl)co1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2coc(C)n2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-methyl-4-chloromethyl-1,3-oxazole instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: O=C(CBr)c1cnccn1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cnccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-(bromoacetyl)pyrazine (prepared according to the method of F. H. Case et al., J. Am.Chem.Soc., 1956, 78, 5842).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc[nH]n3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
6-Methoxy-3-(1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (4.7 g, 0.017 mol) and POCl3 (60 ml) were sealed in 3 different bottles (20 ml). The mixture was heated at 150° C. for 15 minutes under microwave irradiation. The mixture was concentrated, the residue was treated with 15 ml MeOH and stirred for 2 hours at room temperature. The solid was collected and dried to give product (3.4 g, 68% yield). LC-MS: 275 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 56 h
Yield: 98.9 %

Procedure:
To a solution of ethyl(RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without further purification.