Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][O:10][CH2:11][C:12]#[C:13][C:14]([OH:16])=O.CN1CCOCC1.N#N.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1>N1C=CC=CC=1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:14](=[O:16])[C:13]#[C:12][CH2:11][O:10][CH3:9])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]1[C:18]2=[C:19]3[C:25](=O)[CH2:24][CH2:23][C:20]3=[N:21][CH:22]=[C:17]2[O:16][CH2:15]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]1[C:18]2=[C:19]3[C:20]([CH2:23][CH2:24]/[C:25]/3=[CH:3]\[C:1]#[N:2])=[N:21][CH:22]=[C:17]2[O:16][CH2:15]1
Reactant: O=C1CCc2ncc3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C1\CCc2ncc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (757 mg, 4.27 mmol) in tetrahydrofuran (20 mL) was added 65% sodium hydride (137 mg, 3.71 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was added to a solution of 1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-one (500 mg, 2.85 mmol) in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization (ethyl acetate) to give the title compound (337 mg, yield 60%).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].O[C:19]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20]>O>[OH:11][C:10]1[CH:12]=[C:13]([OH:14])[CH:15]=[CH:16][C:17]=1[C:19]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20]
Reactant: CCCCCC(C)(C)O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCC(C)(C)c1ccc(O)cc1O
Reaction time: 8 h

Procedure:
To 100 parts of glacial acetic acid containing 9.8 parts of 98% sulphuric acid was added 22 parts of resorcinol followed by 13 parts of 2-hydroxy-2-methyl-heptane at room temperature. After storing overnight at the same temperature the reaction mixture was poured into 1000 parts of water. The organic phase which separated out, was after decanting off the water, taken up in ether, washed with sodium bicarbonate solution, and finally with water. The ether solution was then evaporated and the residue distilled to give 2-(2,4-dihydroxyphenyl)-2-methyl-heptane (compound of the formula (4)) with a boiling point (b.p.12) of from 202°-204° C. and with the following percentage composition by weight:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:27]=1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8]3[N:7]([C:29](=[O:32])[NH:30][N:31]=3)[C:6]=2[CH:27]=1
Reactant: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 8,9-dichloro-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 6,7-dichloro-2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH:22][C:23]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)=[O:24])([CH3:21])[CH3:20])=[CH:17][CH:18]=1
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Nc1cccc2cnccc12)c1ccc(Cl)cc1
Yield: 34 %

Procedure:
The title compound was prepared using 5-aminoisoquinoline, the product of Example 76B and the procedure described in Example 73B except that THF was used as solvent. The product was recrystallized from ethyl acetate to provide the title compound as a white solid (840 mg, 34%). MS (ESI+) m/z 355 (M+H)+; MS (ESI−) m/z 353 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 1.63 (s, 6H), 7.23 (s, 1H), 7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8, 2H), 7.73 (t, J 9.2, 1H), 7.93 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39 (d, J 8.1, 1H), 8.67 (d, J 6.4, 1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal. Calcd for C19H18ClN3O HCl 0.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82; H, 5.23; N, 10.45.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.Cl.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[CH:6]=[N:5][C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=2[C:2]=1[NH:30][CH:26]1[CH2:27][CH2:28][CH2:29][O:24][CH2:25]1)([O-:10])=[O:9]
Reactant: NC1CCCOC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Temperature: 82 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
A stirred suspension of 4-chloro-5-nitro-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.10 g, 33.0 mmol) in isopropanol (IPA) (100 ml) was treated with tetrahydro-2H-pyran-3-amine hydrochloride (5.0 g, 36.0 mmol) and N,N-diisopropylethylamine (15.0 mL, 84.0 mmol), and stirred at 82° C. for four hours. The mixture was then cooled and left to stand at 5° C. for 2 h. The resulting precipitate was collected by filtration and washed with IPA. Trituration (water) afforded 11.7 g (89%) of 5-nitro-1-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method E, ESI): RT=1.65 min, m+H=403.2; 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=7.6 Hz, 1H), 9.11 (s, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.69-7.56 (m, 2H), 7.60-7.42 (m, 2H), 6.76 (d, J=4.2 Hz, 1H), 4.14 (ddt, J=10.7, 7.1, 3.5 Hz, 1H), 3.98 (dd, J=11.5, 2.7 Hz, 1H), 3.85-3.62 (m, 2H), 3.58 (dd, J=11.5, 6.4 Hz, 1H), 2.27-2.06 (m, 1H), 1.86 (tdt, J=11.8, 7.5, 3.9 Hz, 2H), 1.79-1.63 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)C1C=CC=CC=1.CC(O)=O.[H][H]>CO.[Pd]>[F:15][C:14]([F:17])([F:16])[CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)C1CNCCN1
Reaction time: 12 h

Procedure:
1-Benzyl-3-(trifluoromethyl)piperazine 34a (4.1 mmol) is dissolved in MeOH (50 mL) followed by addition of AcOH (2.0 mL) and 5% mol of Pd/C. The flask is charged with a hydrogen balloon and stirred for 12 h. The mixture is filtered over celite and the filtrate is concentrated to afford 2-(trifluoromethyl)piperazine 35a, which is used without further purification. MS (m/z) (M+1)+: 155.1.
Reaction SMILES: [C:1]([NH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([OH:31])([CH2:24]3)[CH2:22]1)[CH2:28]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][C:21]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][C:23]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:29]3)[CH2:22]1)[CH2:30]2)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C(NC23CC4CC(C2)CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To KH (35%; 0.35 g; 0.003 mole) in THF (8 ml) under N2 and cooled to 0° C. is added N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1 -amine (1 g; 0.0025 mole) of all at once. The reaction is stirred for 5 minutes with ice cooling then at room temperature for an hour, developing into a clear yellow solution. Then 4-(benzoxazol-2-yl)benzyl bromide (0.70 g; 0.0025 mole) is added and the reaction cooled in ice for 10 minutes and stirred at room temperature for 4 hours. Methanol is added to quench any KH, then the reaction is filtered and evaporated to dryness. HPLC is used to purify the product (eluting with 10% ethyl acetate/hexane) to obtain N-trityl-3-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-1-amine (m.p. 174°-177° C.) which is used directly in step D.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27]C2C=CC=C3C(NC(=O)C=23)=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:40]N>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27][NH2:40])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1NC(=O)c2c(OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cccc21
Solvent: ClCCl
Solvent: O
Product: NOCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To a solution of 12.0 g of the (2-tritylaminothiazol-4-yl)methoxyphthalimide in 400 ml of dichloromethane was added 1.161 g of hydrazine hydrate with cooling, and the mixture was stirred at room temperature for 5 hours. The formed precipitates were removed by filtration, the dichloromethane layer was washed with 300 ml of 10% ammonia water three times and then with 300 ml of saturated saline twice, dried on anhydrous magnesium sulfate, and concentrated to dryness to obtain 8.74 g of (2-tritylaminothiazol-4-yl)methoxyamine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1>C(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1
Solvent: O=CO
Product: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Yield: 79.1 %

Procedure:
A solution of 1.27 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyrido[2,3-d]-pyrimidine and 10 mL 88% formic acid were stirred at room temperature. A yellow solid started to form after about 12 hours and after 4 days of stirring, the reaction mixture was filtered. The collected solid was washed well successively with water, methanol, and acetone and was then dried under reduced pressure to give 0.85 g (79%) of the title compound, mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]2[SH:20])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[S:20])[CH3:43]
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc(-c2cnc(S)n2-c2ccc(Cl)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Temperature: 60 °C

Procedure:
To a solution 1-(4-chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazole-2-thiol (1 eq) in DMF is added a 1M solution of lithium bis(trimethylsilyl)amide in THF (1 eq) and ethyl 3-bromopropionate (1 eq) at room temperature. The mixture is heated at 60° C. for 2 hours and cooled to room temperature. The mixture is quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue is purified by chromatography on silica to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid ethyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([F:27])[CH:26]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:28][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(F)cc(Br)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of triphenylphosphine (1.75 g, 6.66 mmol) and 3-bromo-5-fluorophenol (795 mg, 4.16 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (922 mg, 4.58 mmol) in THF (20. mL) was added di-tert-butyl azodicarboxylate (1.53 g, 6.66 mmol) (DBAD) at 0° C. The reaction was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in methanol and purified by preparative-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product (1.09 g, 70%). LCMS (M+Na)+: 396.0, 398.0.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH3:11][C:12](OC(C)=O)=[O:13].C([O-])(O)=O.[Na+]>CC(O)=O>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH3:11])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 3,4-(Methylenedioxy)aniline (8 g, 58.3 mmol) in AcOH (120 ml) was added Ac2O (48 mL). The mixture was stirred for overnight. After reaction, the mixture was poured into saturated NaHCO3 solution, and then filtered. The filtrate was extracted with ethyl acetate to give N-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 95%). LCMS: 180[M+1]+.; 1H NMR (DMSO-d6) δ 2.0 (s, 3H), 5.96 (s, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=1.8 Hz), 9.84 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
2,2,2-trifluoroethanol 7a (7.2 mL, 100 mmol) was dissolved in 300 mL dichloromethane, followed by addition of triethylamine (28 mL, 200 mmol). The reaction mixture was cooled to 0° C. The reaction mixture was warmed and stirred for 16 hours at room temperature after a solution (100 mL) of p-toluene sulfonyl chloride (TsCl) (30 g, 150 mmol) in dichloromethane was dropwise added. Thereafter, the reaction mixture was extracted with dichloromethane (100 mL×3) after 100 mL water were added. The organic extract was washed with saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 7b (25 g, colourless liquid), yield: 98.4%. 1H NMR (400 MHz, CDCl3): δ 7.88-7.76 (m, 2H), 7.44-7.33 (m, 2H), 4.35 (d, 2H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([O:8]C)=[O:7].Cl.O>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
A mixture of methyl 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoate (16.0 g) in 2N aqueous sodium hydroxide solution (65 mL) and methanol (100 mL) was stirred at room temperature for 1 hr, and the mixture was acidified with 6N hydrochloric acid (pH=3-4). Water was added to the reaction mixture, and the precipitate was collected by filtration. The solid was washed with ethyl acetate and water to give the title compound (8.07 g). To the filtrate was added saturated brine, and the mixture was extracted with ethyl acetate/2-propanol. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (4.10 g).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[C@H:15]([CH2:16][CH3:17])[CH2:14][N:13]1[C:18](=[O:32])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[C:22]([O:28][CH3:29])=[C:21]([O:30][CH3:31])[CH:20]=1)=[O:11])C1C=CC=CC=1.[H][H]>>[OH:8][NH:9][C:10]([C@H:12]1[C@H:15]([CH2:16][CH3:17])[CH2:14][N:13]1[C:18](=[O:32])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[C:22]([O:28][CH3:29])=[C:21]([O:30][CH3:31])[CH:20]=1)=[O:11]
Reactant: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)NOCc2ccccc2)cc(OC)c1OC
Reactant: [H][H]
Product: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)NO)cc(OC)c1OC
Yield: 90 %

Procedure:
(+)-trans-1-(3,4-Dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid hydroxyamide was prepared from (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid benzyloxyamide by following Method H in 90% yield. The reaction was conducted at room temperature using a balloon of hydrogen for 1 h. ESMS: 351.6 [M+H]. 1H NMR (300 MHz, CD3OD): 6.93 (s, 1H), 6.90 (s, 1H), 4.80 (m, 1H), 4.48 (m, 1H), 4.32 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.62 (m, 1H), 2.49 (t, 2H), 1.85 (m, 1H), 1.72 (m, 1H), 1.50 (m, 2H), 0.84 (t, 6H)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)C2CCCCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (92 μL, 0.66 mmol) in methylene chloride (20 mL) was added dropwise cyclohexanecarbonyl chloride (67 μL, 0.46 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 10 min and then washed with dilute aqueous sodium hydrogen carbonate. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave 71 mg (45% yield) of the title compound as white crystals: mp 183-184° C.; [α]21D +12° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 355 (56, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([Cl:11])[CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino-3-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:20]([C:19]1[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:5]2
Reactant: Ic1ccc2c(c1)CNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(I)cc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 5-Iodo-2,3-dihydro-1H-isoindole (example A38(a)) and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 539.1 (M+, 100%).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: Nc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2cccc(F)c2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 3-fluoroaniline and DIEA to give 2-(3-fluoro-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 351 (MH+).