Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CS(=O)(=O)Oc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2OS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methanesulfonyloxybenzoic acid (0.30 g, 1.4 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (10 mL) was heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.49 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.47 mmol) and triethylamine (98 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (55%) of the title compound as white crystals: mp 144-145° C.; [α]21D -7.1° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (10, M+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of benzyl (1S,2S,3S,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3.1.0]hexan-3-ylcarbamate (2.0 g, 5.540 mmol) in THF (20) at room temperature was added 1 M tetrabutylammonium fluoride in THF (55 mL, 55.4 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (1.2 g, 92%) as a white solid. MS (ES+) C14H17NO3 requires: 247, found: 230 [M+H−H2O]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:19]#[N:20])[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:21]>C1COCC1>[ClH:21].[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:19][NH2:20])[CH:10]3[CH2:18][CH:14]4[CH2:13][CH:12]([CH2:17][CH:16]2[CH2:15]4)[CH2:11]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(C2(C#N)C3CC4CC(C3)CC2C4)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cccc(C2(CN)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 2-(3-ethylphenyl)-2-adamantanecarbonitrile (265 mg, 1 mmol) in dry THF (5 mL) under argon was treated with 1-M BH3 in THF (3.3 mL, 3.3 mmol), refluxed for 2 h, cooled to room temperature, treated with 6-M HCl (10 mL), refluxed for 0.25 h, cooled to room temperature and extracted with CHCl3 (2×10 mL). The combined extracts were washed with water (2×5 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc-MeOH (9:1)] to give the title compound (258 mg, 85%) as a white solid: mp 89-90° C.; IR νmax (Nujol)/cm−1 3395, 2922, 1603, 1489, 1458, 1376, 1100, 797, 734 and 713; NMR δH (400 MHz, DMSO-d6) 1.19 (3H, d, J 7.5 Hz), 1.41-1.57 (2H, m), 1.60-1.75 (6H, m), 1.89 (1H, s), 2.06-2.15 (2H, m), 2.46-2.64 (5H, m), 3.05 (2H, s) and 7.02-7.33 (7H, m); Anal. Calcd for C19H28ClN.0.2 H2O: C, 73.74; H, 9.25; N, 4.53. Found: C, 73.90; H, 9.28; N, 4.53.
Reaction SMILES: [OH:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:12].C(=O)([O-])[O-].[Ba+2].S([O-])([O-])(=O)=O.[Ba+2]>C(O)C.O>[OH:1][C:2]1([C:9](=[O:12])[NH2:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CN1CCC(O)(C#N)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: O
Product: CN1CCC(O)(C(N)=O)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
The compound 4-hydroxy-4-cyano-1-methylpiperidine (36.4 g, 0.26 mole) was gradually added to sulfuric acid (80 ml), under external cooling. The mixture was maintained at room temperature for 41 hours, then was added to powdered ice (30 g). The resulting solution was neutralized with barium carbonate (376 g) to pH 8-9 and after addition of water the resulting barium sulfate was separated and washed with methanol. The filtrate was concentrated under reduced pressure. The product, 4-hydroxy-4 -carbamoyl-1-methylpiperidine (28.16 g, 0.18 mole, 69% yield), crystallized from ethanol as a white solid (mp. 180° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([OH:38])[CH:33]1[OH:39]>CS(C)=O>[OH:39][CH:33]1[CH:34]([OH:38])[CH2:35][CH2:36][CH2:37][CH:32]1[NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CCCC(O)C1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Product: O=C(NC1CCCC(O)C1O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid (300 mg, 0.84 mmol.) and 1,1′-carbonylbis(1H-imidazole) (177 mg, 1.1 mmol) were suspended in DMSO (4 ml). The mixture was allowed to stir overnight (12 hr) at room temperature. 3-aminocyclohexane-1,2-diol (racemic 27/28) (110 mg, 0.84 mmol) was then added. The mixture was stirred for another 12 h at room temperature. The mixture was separated by preparative HPLC to afford two products, racemic amide (3) and racemic esters (4). LC/MS [Method A: rt: 6.01 min; m/z: 472 (M+1)]. Chiral HPLC [7.10 min, 13.12 min].
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:11]([CH3:20])[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:33]=1)[C:27](N(OC)C)=[O:28]>>[Br:21][C:22]1[CH:33]=[C:26]([C:27]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C@H:11]([CH3:20])[CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:3]=2)=[O:28])[CH:25]=[N:24][CH:23]=1
Reactant: C[C@H](COC1CCCCO1)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 5-iodo-7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 17) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a brown oil in 66% yield, 215 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH:18](C#N)[C:19]([O:21]CC)=O)([C:16]#[N:17])[C:7]1=[O:26].Br.C(O)(=[O:34])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:19](=[O:21])[NH:17][C:16]2=[O:34])[C:7]1=[O:26]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)C1(C#N)C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccc(F)cc21
Agent: Br
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(F)cc12

Procedure:
A solution of ethyl 2-[1-(3,4-dichlorobenzyl)-3-cyano-5-fluoro-2-oxo-3-indolinyl]-2-cyanoacetate (E) (2.0 g.) in 48% w/v hydrogen bromide in acetic acid (25 ml.) was heated under reflux for 3 hours. The solution was evaporated to half volume and poured into water (20 ml.). The mixture was extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with water (2×50 ml.), brine (50 ml.), dried (MgSO4) and evaporated. The residual solid was recrystallised from 2-propanol/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-fluoro-spiro[pyrrolidine 3,3'-indoline]-2,2',5-trione (0.49 g.), m.p. 253°-254° C.
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)#[CH:18]>>[CH3:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2][C:18]#[C:17][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(-c2ccccc2C=CI)c1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: Cc1cccc(-c2ccccc2C=CC#Cc2ccc(C(=O)O)cc2)c1
Yield: 23.5 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 2.10 g (6.55 mmol) of 2-(2-iodovinyl)-3'-methylbiphenyl obtained in Example 21(b) with 1.05 g (6.55 mmol) of methyl 4-ethynylbenzoate, 520 mg (22%) of the expected compound are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14](=O)[NH:15][N:16]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[N:15]=[N:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: CC(=O)Oc1ccccc1-c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1ccccc1-c1ccc(Cl)nn1
Reaction time: 8 h

Procedure:
A mixture of 6-(2-acetoxyphenyl)-3(2H)pyridazinone (22.4g) and phosphoryl chloride (90 ml) was stirred and warmed at 55°-60° for 40 minutes. The phosphoryl chloride was removed under reduced pressure at 50° and the residual oil was poured on to ice (200 g). The mixture was allowed to stand overnight at 5° and was filtered to give 3-chloro-6-(2-acetoxyphenyl)pyridazine (23.1 g m.p. 131°-133.5°. A sample recrystallised from ethanol had m.p. 137°-138°.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]([NH2:25])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:33][C:14]1[N:15]([CH2:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:25])[N:10]=[C:9]([NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:17]=2
Reactant: Nc1nc(NCC2CCCCC2)nc2c1ncn2CC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(NCC2CCCCC2)nc2c1nc(Br)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(cyclohexylmethyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (90 mg) in dry chloroform (1 mL) at room temperature was added NBS (46 mg) in one go. The dark brown reaction was stirred at RT for 1 hour. The reaction was diluted with DCM (15 mL) and washed with water (5 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][S:9](=[O:14])(=[O:13])[C:8]=2[CH:15]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][S:9](=[O:14])(=[O:13])[C:8]=2[CH:15]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)CCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)S(=O)(=O)CCO2
Yield: 46.4 %

Procedure:
0.917 g 6-Nitro-2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide (from g)) were hydrogenated in a mixture of 20 ml THF and 20 ml MeOH with 0.90 g 5% Pd—C at atmospheric hydrogen pressure for 90 min. at room temperature. The catalyst was filtered off, the filtrate evaporated and the residue chromatographed on silica to yield 370 mg of the title compound.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C1(C)C=CC=CC=1>[OH-].[Na+].O>[C:1]([N:5]([C:21]([C:17]1[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=1)=[O:22])[NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)NNC(=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C(=O)N(NC(=S)c2ccccc2)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
N'-t-butyl-N-(thiobenzoyl)hydrazine (ca. 1 g), m-toluoyl chloride (approx. 0.7 g) and 50% aqueous sodium hydroxide (6 drops) were mixed in 1 ml water and 10 ml toluene at 23° C. After stirring for 3 hours, ether-hexane was added and the product was isolated by filtration (0.25 g): m.p. 165°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:11]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]2)=[O:17])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(OC)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(OC)cc2)CC1
Yield: 52381 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (42.0 mmol) of ethyl 3-[(4-methoxyphenyl)amino]-3-oxopropanoate, 14.54 grams (105.0 mmol) of anhydrous potassium carbonate, 30 milliliters of dimethylformamide and 7.9 grams (42.0 mmol) of 1,2-dibromoethane were reacted for a period of 12 days to give 5.74 grams (22.0 mol) of ethyl 1-(4-methoxyphenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 89.5° C.-91.0° C. The total yield was 56 percent. NMR analysis of the product indicated the following:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:5]2[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1cccs1
Product: O=C(O)Cc1ccc(C(=O)c2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 1, thiophene-2-acetic acid and p-chlorobenzoyl chloride were reacted to obtain 5-(p-chlorobenzoyl)-thiophene-2-acetic acid melting at 165° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO.C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:20][NH:19][C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
A mixture of 4-benzyloxybenzoic acid (0.780 g, 3.42 mmol), tert-butyl carbazate (0.443 g, 3.35 mmol), Et3N (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) and 1-hydroxybenzotriazole hydrate (0.778 g, 5.76 mmol) in N,N-dimethylformamide (27 mL) was stirred at room temperature for 2 days. The reaction was concentrated and diluted in dichloromethane. The organic phase was washed twice with water, dried with MgSO4 and concentrated. The residue was purified on column chromatography (silica gel, 5% MeOH in CH2Cl2) and tert-butyl 2-[4-(benzyloxy)benzoyl]hydrazine carboxylate (0.998 g, yield: 85%) was identified by NMR spectroscopy.
Reaction SMILES: C[C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.C([N:18](CC)CC)C.FC1C=CC=CC=1[N+]([O-])=O>CN(C)C=O>[CH3:8][CH:5]1[NH:6][CH2:7][CH2:2][N:3]([C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:18])[CH2:4]1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Reactant: CCN(CC)CC
Agent: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Product: CC1CN(c2ccccc2N)CCN1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2(R),5(S)-Dimethyl-1-N-benzyl-piperazine (6.0 g, 29 mmol) was dissolved in dimethylformamide (100 mL), and triethylamine (6.4 mL, 44 mmol) and the mixture was placed under nitrogen. To the solution was added 2-fluoro-nitrobenzene (3.5 mL, 31 mmol). The reaction was heated at 100° C. for 72 hours The solution was evaporated in vacuo and redissolved in ethyl acetate (100 mL). The solution was then washed with saturated sodium bicarbonate solution (100 mL) and saturated brine solution (100 mL). The separated organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The crude product was then purified by flash chromatography, eluting with ethyl acetate/methanol/triethylamine 85:10:5. The product (8.2 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Yield (5.2 g, 87%)
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=1)P(OCC)(=O)OCC.[Li]CCCC.P(=O)([O-])[O-].[Cl:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([C:34]3=O)[CH2:32]1)[CH2:38]2>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]([O:2][CH3:1])=[C:36]2[CH:37]3[CH2:39][CH:33]4[CH2:32][C:31]([Cl:30])([CH2:40][CH:35]2[CH2:34]4)[CH2:38]3)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: O=C1C2CC3CC1CC(Cl)(C3)C2
Reactant: CCOP(=O)(OCC)C(OC)c1ccc(Cl)c(OC)c1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC1CC(Cl)(C3)C2)c1ccc(Cl)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Phosphonate 4 (3.2 g, 10 mmol) was dissolved in 30 ml dry THF under argon and cooled to -78° C. Dropwise addition of nBuLi (2.3M, 4.4 ml, 10.1 mmol) generated a yellow-orange phosphonate ylid. After stirring the ylid solution for 10 min, 5-chloro-2 adamantanone (1.75 g, 9.5 mmol), dissolved in 8 ml THF, was added dropwise to the ylid at -78° C. The reaction was slowly warmed to room temperature over 45 min and refluxed for 2 h. Upon cooling, the THF was stripped in vacuo and the product was partitioned between EtOAc/hexanes (1:1) and dilute NaHCO3. The organic layer was dried over NaHCO3. The organic layer was dried over Na2SO4, stripped of solvent and purified on silica gel (2-4% EtOAc/hexanes) to give 3.3 g (96%) of enol ether 5 as a colorless, viscous gum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCI
Yield: 100.1 %

Procedure:
To 112 ml of a solution of 13.38 g of ethyl 6-bromohexanoate in acetone, 26.97 g of sodium iodide was added and heated to reflux for 18 hours. The reaction solution was cooled, filtered to remove insolubles and washed with acetone. The filtrate was concentrated and, after addition of water, extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to provide 16.21 g of the objective compound as red-yellow oil.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CCN(CC)CC>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CCN(CC)CC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 65.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.092 g, 0.28 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.051 g, 0.31 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM38-35) (0.068 g, 64%). 1NMR (CDCl3) δ 7.32 (d, J=6.7 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=7.2 Hz, J=10.8 Hz, CH2), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H), 2.33 (dd, J=6.1 Hz, J=2.1 Hz, 1H), 2.12 (t, J=4.7 Hz, 1H), 2.01-1.78 (m, 2H), 1.58-1.40 (m, 5H), 1.38-1.13 (m, 9H), 0.92-0.84 (m, 6H); 13C NMR (CDCl3) δ 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8, 60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=371.3.
Reaction SMILES: [CH2:1]([C@H:3]1[N:13]2[C@@H:7]([S:8][CH2:9][CH2:10][C@H:11]([NH:15]C(=O)OC(C)(C)C)[C:12]2=[O:14])[CH2:6][CH2:5][CH2:4]1)[CH3:2].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[NH2:15][C@H:11]1[CH2:10][CH2:9][S:8][C@H:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[N:13]2[C:12]1=[O:14]
Reactant: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (4S,7R,10aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (52 mg, 0.16 mmol) in DCM (1 mL) was added TFA (1.0 mL, 13 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under high vacuum to afford (4S,7R,10aS)-4-amino-7-ethylhexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one trifluoroacetate (54 mg, 0.16 mmol, 100% yield) as an oil. Anal. Calcd. for C11H20N2OS m/z 228.3. found: 229.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: C1COCCN1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CN4CCOCC4)cc3)cc2n1

Procedure:
The title compound was prepared from morpholine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 141-152° C.; LC-MS: 442 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: O1CC1CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=O)[NH:9]2.[CH2:16](O)[CH3:17]>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1CC(=O)N2>[NH2:9][CH:8]1[CH2:17][CH2:16][C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7]1
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Reactant: CCO
Agent: Cl
Agent: O=C1Cc2c(cccc2OCC(O)CNC2CCc3ccccc3C2)N1
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)-2-oxoindoline (20.3 g, see JP 49-094666) and 2-aminotetralin (14.81 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxoindolin-4-yloxy)-propanamine hydrochloride is obtained ((i): R=H, Ar=radical 36, and the chain is attached to position 2 of the tetralin moiety).