Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27][OH:28]>>[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27][O:28][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)cc3Cl)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 2,4-dichlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=509 (M++1); Rt=5.07 min; 1H-NMR 400 MHz (CDCl3): δ 5.60 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.21 (m, 6H), 7.38-7.42 (m, 1H), 7.60 (d, J=9 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:27][OH:28]>C(O)C>[OH:28][NH:27][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:8]3[CH:25]=[CH:26][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)=[NH:24]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C#N)CC3)cn2)cc1
Reactant: NO
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C(=N)NO)CC3)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-carbonitrile (92 mg, 0.248 mmol) in ethanol (0.8 mL) was added 50% hydroxylamine solution (0.2 mL). The mixture was stirred at 60° C. for 4 hours, allowed to cool to room temperature and concentrated under reduced pressure to give the title compound (98 mg, yield 98%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[F:20][CH:21]([F:24])[CH2:22]I>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:22][CH:21]([F:24])[F:20])[CH:13]=[CH:12]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: FC(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccc(Br)cc2ccn1CC(F)F
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
Under nitrogen atmosphere, 44 mg of 60% sodium hydride was added at room temperature to 2 ml solution of dimethylformamide with 49 mg of 6-bromo-2H-isoquinoline-1-one and the mixture was stirred for 30 min. Then, 169 mg of 2,2-difluoroethyliodide was added and stirred at room temperature for 6 hours. Cold water was added to the reaction solution, the products were extracted with chloroform. Chloroform layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (chloroform/methyl alcohol=10/1) to obtain 41 mg of the above compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:23])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl[CH2:31][C:32](=O)[CH3:33]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:31]=[C:32]([CH3:33])[N:24]=2)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nc(C)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 16.3 %

Procedure:
A solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-thioacetamide (0.44 g) and chloroacetone (0.30 g) in ethanol (30 ml) was heated under reflux for 7 hours and then evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-10% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with petroleum ether (b.p. 60°-80° C.) and dried to give the title compound (78 mg), m.p. 107°-110° C.
Reaction SMILES: [C:1]([C:9]1[C:10]([F:18])=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C@@H:25]([NH2:27])[CH3:26])[CH3:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C@@H:25]([NH:27][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[F:18])[CH3:26])[CH3:21]
Reactant: CCOC(=O)C[C@H](C)N
Reactant: O=Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)C[C@H](C)NCc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 48 h
Yield: 41.6 %

Procedure:
Step 1 To a solution of 3-benzoyl-4-chloro-2-fluoro-benzaldehyde (Intermediate 10, 337 mg, 1.29 mmol) in dichloroethane (5 ml) was sequentially added (S)-3-amino-butyric acid ethyl ester hydrochloride (237 mg, 1.41 mmol), triethylamine (0.196 ml, 1.41 mmol), sodium triacetoxyborohydride (818 mg, 3.86 mmol) and glacial acetic acid (0.159 ml 2.57 mmol). The mixture was stirred for 2 days then dilute sodium bicarbonate was added. After stirring for 10 minutes, the mixture was extracted with ethyl acetate. The organic liquors were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by silica chromatography eluting with 20-100% ethyl acetate/petroleum ether furnishing (3S)-3-(3-benzoyl-4-chloro-2-fluoro-benzylamino)-butyric acid ethyl ester as a colourless oil (203 mg). MS: [M+H] 378
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[CH:8]=[O:9]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:1])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of TiCl4 (9.48 g, 50 mmol) and methylmagnesiumbromide (20.80 ml, 52 mmol, 2.5 M solution in THF) in THF (400 ml) was stirred at −30° C. when 3-bromo-5-nitro-benzaldehyde (9.20 g, 40 mmol) was added as solid. The mixture was stirred for 1 h at −30° C. As the reaction was not complete, the reaction was cooled to −78° C. and 0.65 eq. methylmagnesium bromide and 0.625 eq. TiCl4 were added and stirring was continued at −30° C. This procedure was repeated again to add 0.325 eq. methylmagnesium bromide and 0.313 eq. TiCl4. After complete conversion the reaction was cooled to −78° C. and quenched by addition of 500 ml cold water. 500 ml dichloromethane were added and the reaction was allowed to warm to r.t. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellowish oil. 1H-NMR (360 MHz, CDCl3): 8.20 (s, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 4.95 (q, 1H), 1.45 (d, 3H).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:10]([OH:18])=[C:9]([O:19][CH3:20])[C:8]=1[O:21][CH3:22])(=[O:5])[CH3:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:3]([O:6][C:7]1[C:8]([O:21][CH3:22])=[C:9]([O:19][CH3:20])[C:10]2[O:18][C:15]([CH2:17][Br:1])([CH3:16])[CH2:14][C:11]=2[C:12]=1[CH3:13])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: C=C(C)Cc1c(C)c(OC(C)=O)c(OC)c(OC)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CBr)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Bromine (1.9 g) was added to a solution (40 ml) of 4-acetoxy-2,3-dimethoxy-5-methyl-6-(2-methyl-2-propenyl)phenol (3.0 g) and sodium acetate (1.0 g) in acetic acid, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=85:15 to 4:1) to obtain the title compound (2.5 g, 65%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([NH:7][C:8](=[O:32])[C@@H:9]([C@H:11]2[O:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=3)[C:12]2=[O:31])[OH:10])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>CCOCC>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][CH2:15][O:16][C@H:11]([C@@H:9]([OH:10])[C:8]([NH:7][C:6]3[CH:33]=[CH:34][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:32])[C:12]2=[O:31])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To compound 26-4 (1.65 g), was added trifluoroacetic acid (10 mL) with anisole (0.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour then Et2O was added into the mixture to precipitate. The precipitate was collected by filtration and washed with Et2O. Then the precipitate was solved in water and the solution was basified with sat. NaHCO3 aq. The precipitate was collected by filtration and washed with H2O to obtain compound 26-5 (1.2 g) as a pale brown amorphous solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:23])([F:22])[C:14]1[N:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1COCC1>[F:23][C:13]([F:22])([F:12])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:8][O:21]2)=[CH:18][N:19]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([N:14]([CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:27](=O)[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH2:18]1)[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl.[OH-].[Na+]>C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([N:14]([CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)[CH2:18]1)[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(Cc1ccccc1)CC1Cc2ccccc2N(C(=O)CCc2ccc(-c3ccccc3)cc2)C1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)CC1Cc2ccccc2N(CCCc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 401.2 %

Procedure:
3-(N-Benzyl-N-methylamino)methyl-1-[3-(4-biphenylyl]propanoyl)-1,2,3,4-tetrahydroquinoline oxalate (0.800 g) was converted into a free form, which was dissolved in THF (5 ml). 1M Borane-THF complex (3 ml) was added to the reaction mixture, which was heated under reflux for 30 minutes, then left standing for cooling. Water (0.5 ml) and 6N hydrochloric acid (2 ml) were added to the reaction mixture, which was stirred at room temperature for 12 hours. The reaction mixture was made basic by adding 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/50). A methanol solution (3 ml) of oxalic acid dehydrate (149 mg) was added to a methanol solution (10 ml) of the residue, which was concentrated. Ethyl acetate was added to the residue, and the precipitates were collected by filtration to give the entitled compound (3.130 g) as an amorphous powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:14]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[O:20][CH2:21][C:22]1[N:31]([CH3:32])[C:30](=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(N(CC)CC)C>ClCCl>[CH3:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:14]([CH2:15][O:16][C:17]2[CH:36]=[CH:35][CH:34]=[C:19]([O:20][CH2:21][C:22]3[N:31]([CH3:32])[C:30](=[O:33])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:18]=2)[C:13]=1[CH:12]=[O:11]
Reactant: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1C=O
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (2.5 mL, 1.75 M in CH2Cl2) is added, dropwise, DMSO (80 mL). On complete addition, a solution of 2-[3-(2-hydroxymethyl-3-methyl-1 benzyloxy)-phenoxymethyl]-3-methyl-3H-quinazolin-4-one (120 mg, 0.28 mmol, example 101) in dichloromethane (1 mL) is added dropwise. This solution is stirred for 5 min then triethylamine (276 mL, 2 mmol) is added in one portion. The cold bath is removed and stirring continued for 10 min. The mixture is then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound as a solid. MS (ESI) 415 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19](C=O)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C2ON=C(C3N=CC([CH2:45][NH:46][CH:47]4[CH2:50][CH:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:45][NH:46][C@@H:47]4[CH2:50][C@H:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=[N:20][CH:21]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CNC4CC(C(=O)O)C4)cn3)no2)cc1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(C=O)nc3)no2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)nc3)no2)cc1

Procedure:
The title compound was prepared from 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine-2-carbaldehyde by procedures analogous to those described in Examples (1A-1B) for the preparation of 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]2[S:15][CH:14]=[C:13]([Br:16])[C:8]=2[C:9](Cl)=[N:10][CH:11]=1)(=O)C.[NH4+:17].[OH-]>O1CCOCC1>[NH2:17][C:9]1[C:8]2[C:13]([Br:16])=[CH:14][S:15][C:7]=2[C:6]([CH2:5][OH:4])=[CH:11][N:10]=1
Reactant: CC(=O)OCc1cnc(Cl)c2c(Br)csc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncc(CO)c2scc(Br)c12
Yield: 84 %

Procedure:
A mixture of Example 277D (3.1 g, 9.7 mmol), concentrated NH4OH (62 mL), and dioxane (62 mL) was heated to 150° C. in a sealed tube for 36 hours, filtered, and concentrated to provide a soid which was triturated with water (20 mL), collected and dried to give 2.1 g (84% yield) of the desired product. MS (ESI(+)) m/e 258.9, 260.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:17]2[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([NH2:12])[N:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2cc(C)nc(N)n2)CC1

Procedure:
A solution of 4-piperidinecarboxylic acid ethyl ester (6.6 g), 2-amino-4-chloro-6-methylpyrimidine (5.0 g) and triethylamine (4.2 g) in ethanol (50 ml) is stirred at 90° C. for 3 hours. Ethanol is evaporated under reduced pressure, and the residue is dissolved in chloroform, and washed with water. The organic layer is concentrated under reduced pressure to give the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(O)CCC>[CH:13]1([N:16]2[CH2:21][CH2:20][N:19]([C:2]3[S:3][C:4]4[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Reactant: C1CN(C2CC2)CCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: N#Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 43 %

Procedure:
A suspension of 2-chlorobenzothiazole-6-carbonitrile (3.5 g, 18 mmol), 1-cyclopropylpiperazine (3.63 g, 28.8 mmol) and ammonium chloride (0.96 g, 18 mmol) in butan-1-ol (112 mL) was heated at reflux for 48 h. The solvent was removed under reduced pressure and the residue was diluted with water (30 mL). The mixture was made alkaline with potassium carbonate and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were concenrated to give a residue which was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 2.2 g (43 5) of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carbonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)[O-])cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.2 g (10 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylate in 150 mL methanol was mixed with a solution of 1.5 g lithium hydroxide in 20 mL water and stirred for 24 hours at room temperature. Then the mixture was diluted with 50 mL of water, the alcohol was distilled off and the aqueous phase was washed with ethyl acetate. After acidification with dilute hydrochloric acid, the mixture was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulfate and the solvent was distilled off. Yield: 2.1 g beige solid (70% of theory); Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[NH2:2].OO.[OH-].[Na+].C(OO)=[O:18]>CS(O)(=O)=O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][OH:18])=[O:11])(=[O:3])[NH2:2]
Reactant: O=COO
Reactant: NC(=O)NCCCCCC(=O)O
Agent: CS(=O)(=O)O
Agent: OO
Agent: [Na+]
Product: NC(=O)NCCCCCC(=O)OO
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
17.4 g (0.1 mol) of N-carbamoyl-6-aminohexanoic acid are dissolved in 50 g of methanesulfonic acid and the solution is cooled to 15° C. 12 g (0.3 mol) of hydrogen peroxide (85% strength by weight) are added dropwise with cooling at such a rate that the internal temperature can be maintained between 15° and 20° C. The mixture is subsequently stirred at 18° C. for a further 10 minutes, then cooled down to 0° C. and adjusted to pH 3 with aqueous sodium hydroxide solution (33% strength by weight). 65 g of sodium hydroxide solution are used. After stirring for 20 minutes at 0° C. the precipitated peroxycarboxylic acid is filtered off with suction, washed with ice-water and dried at 40° C. under an aspirator vacuum.
Reaction SMILES: [CH2:1]([C:4](=[N:11][NH:12]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH3:3].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([CH:4]([NH:11][NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH3:3]
Reactant: CCCCCCC(CCC)=NNC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(CCC)NN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
39.41 g (145.7 mmol) of tert-butyl N′-(1-propyl-heptylidene)-hydrazinecarboxylate are dissolved in a mixture of 100 ml of THF and 150 ml of methanol and, after 10.65 g (169 mmol) of sodium cyanoborohydride have been added, the mixture is stirred for 1 hour at room temperature. 100 ml of 6N HCl are added dropwise in the course of 30 minutes and, after the addition has ended, the mixture is refluxed for 1 hour. The mixture is neutralized with 6N NaOH solution, then, after the non-aqueous solvents have been removed, extracted three times with dichloromethane, and, after the mixture has been dried over sodium sulphate, the solvent is removed in vacuo. This gives 23.90 g (95%) of a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1
Reactant: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (655.5 mg, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A44. A solution of 4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (254.1 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B44. Solution B44 was added to Solution A44 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (97.8 mg, 30%) as a white solid: MS (ESI) M+1=441.1.