Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH3:20][Mg]Br>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([OH:16])[CH3:20]
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone (0.67 g, 2.5 mmol) in anhydrous THF (10 mL) at −78° C. was added a solution of methylmagnesium bromide (3.0 M in diethyl ether, 2.5 mL, 7.5 mmol) under nitrogen. The reaction mixture was slowly warmed to rt, stirred under nitrogen for 12 hours, and quenched with a saturated aqueous ammonium chloride solution (40 mL). Ethyl acetate (50 mL) was added, the organic layer was separated, and dried (MgSO4). After removal of the solvent, the residue was purified via silica gel chromatography (hexane:ethyl acetate/7: 1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol as yellow oil: MS (EI) m/z 287/289 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)([OH:21])[CH3:22])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 g, 4.6 mmol) in DMF (10 mL) was stirred at RT for 5 min. NaH (60%, 933 mg, 23.33 mmol) was added and the reaction mixture was stirred at RT for 10 min. 3-(2-methyloxiran-2-yl)pyridine (1.26 g, 9.34 mmol) was added to the reaction mixture and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-water and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by column chromatography using silica gel: 100-200 mesh and 10% MeOH/DCM/1 mL NH4OH to obtain 600 mg of 1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.74 (s, 1H), 8.54 (d, 1H), 7.71 (d, 1H), 7.26 (s, 1H), 7.27 (m, 1H), 7.19 (d, 1H), 6.96 (d, 1H), 4.26 (dd, 2H), 2.91 (m, 2H), 2.9 (m, 4H), 2.74 (m, 2H), 2.44 (s, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers II-135a-b.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)[CH3:12]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][N:16]1[C:17](=[O:18])[N:13]([CH2:11][CH3:12])[N:14]=[N:15]1
Reactant: BrCCBr
Reactant: CCn1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nnn(CCBr)c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 parts of sodium carbonate in 5 parts of water and 18 parts of N,N-dimethylformamide were added dropwise a solution of 22.5 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one in 5 parts of water and 27 parts of N,N-dimethylformamide at about 40° C. Upon completion, stirring was continued overnight at 40° C. The organic phase was separated, dried and distilled, yielding 9.8 parts (22%) of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one; bp. 110° C. at 0.1 mm pressure (interm. 47).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([O:17][CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[O:16].[NH2:26][C:27]([CH3:31])=[CH:28][C:29]#[N:30]>C(O)C>[C:29]([C:28]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:16])=[C:23]([CH3:24])[NH:26][C:27]=1[CH3:31])#[N:30]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1
Reactant: CC(N)=CC#N
Solvent: CCO
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OCC2CCC2)=C(C)N1

Procedure:
66 mg (0.19 mmol) of cyclobutylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 16 mg (0.19 mmol) of 3-aminobut-2-enenitrile in 3 ml of ethanol and heated under reflux under argon for 24 h. The suspension is allowed to cool and filtered with suction, and the remaining solid is washed with methanol. 45 mg (57% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:12]([N:15](C(C)C)CC)([CH3:14])[CH3:13].C(N)(C)C>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH:12]([CH3:14])[CH3:13])=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(F)c(C(=O)O)c1
Solvent: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)c1cc(N)ccc1F
Yield: 619.6 %

Procedure:
A solution of 5-amino-2-fluorobenzoic acid (300 mg, 1.9 mmol), diisopropylethylamine (1 ml, 5.8 mmol), and isopropylamine (0.3 ml, 3.9 mmol) in acetonitrile was heated to 110° C. in microwave for 45 min. This reaction was repeated 5 times and the crude products combined then concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/dichloromethane (0% to 10% v/v) to afford the title compound as a yellow solid (2.31 g). HPLC retention time 3.93 min. Mass spectrum ES+) m/z 197 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[N:8]=[C:7]1[CH:15]=O)(=[O:5])=[O:4].[N:18]1[C:27]2[CH:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]3=[O:43])[CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:17])[S:3]([N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:28]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]1[C:34](=[O:43])[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]1=[O:42])[CH:26]1[C:27]2[N:18]=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:23][CH2:24][CH2:25]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1c(C=O)nc2c1CCCC2
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
To a solution of 2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide (0.3991 g, 1.5 mmol) and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (0.4424 g, 1.3 mmol) in CH2Cl2 (13 mL) was added sodium triacetoxyborohydride (0.5539 g, 2.6 mmol), and the reaction stirred at room temperature for 22 hours. Saturated NaHCO3 (20 mL) was added and the aqueous phase was extracted with CH2Cl2 (2×100 mL), and the combined organic extracts were washed with brine (1×75 mL), dried (NaSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2—MeOH—NH4OH) provided 0.4564 g (52%) of 2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a yellow foam. 1H NMR (CDCl3) δ 1.28 (t, 2H, J=9 Hz), 1.49-1.52 (m, 2H), 1.74-1.81 (m, 6H), 1.91-2.00 (m, 1H), 2.11-2.20 (m, 1H), 2.50-2.73 (m, 7H), 2.92 (s, 2H), 2.95 (s, 4H), 3.52-3.57 (m, 2H), 4.17-4.22 (m, 2H), 4.32-4.37 (m, 1H), 4.81 (s, 1H), 6.95-6.98 (m, 1H), 7.27-7.28 (m, 1H), 7.68-7.70 (m, 2H), 7.79-7.82 (m, 2H), 8.32 (d, 1H, J=3 Hz).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (59.6 mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol) in methylene chloride (468 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (36.7 mg, 0.206 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (35.2 mg, 0.374 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with ethyl acetate (50 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide (25.0 mg, 34%) as a cream solid: mp 101-102° C.; EI-HRMS m/e calcd for C20H21F3N2OS (M+) 394.1327, found 394.1321.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[C:28]#[N:29])=[CH:23][CH:24]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)C#N)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 156e (191 mg, 0.30 mmol) and lithium hydroxide•1 water (126 mg, 3.0 mmol) in i-propanol/THF (1:1, 8 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and diluted with water (10 mL). It was then extracted with dichloromethane (3×20 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 156 (30 mg, 17%) as a pale yellow solid. MS-ESI: [M+H]+ 594.3. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.79-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 4.92 (bs, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 1.67 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4cccnc4)c(C)c3C)C[C@H]2C)cn1
Yield: 5.9 %

Procedure:
4,5-Dimethyl-3-((R)-3-methyl-piperazin-1-yl)-6-pyridin-3-ylmethyl-pyridazine (350 mg, 1.18 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (243.7 mg, 1.41 mmol) are added to a microwave vial followed by NMP (7 mL) and triethylamine (0.49 mL, 3.54 mmol). The vial is sealed and irradiated in the microwave at 145° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2) to afford the title compound (30 mg, 6%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[F:47][CH2:48][C@@H:49]([NH2:51])[CH3:50]>ClCCl.O.C(N(CC)CC)C>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:51][C@@H:49]([CH3:50])[CH2:48][F:47])=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@H](N)CF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CF)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and 1-hydroxybenzotriazole (61.5 mg) were dissolved in dichloromethane (4 mL). While this solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, a mixture of (2S)-1-fluoro-2-propylamine hydrochloride (32.0 mg), triethylamine (56.0 μL) and dichloromethane (2 mL) was added and the resulting mixture was stirred at room temperature for further 8 hours. Following addition of water, the dichloromethane layer was collected. The dichloromethane layer washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-(4-[N-[(2S)-1-fluoro-2-propyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (34.0 mg) as a white powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.O.[Sn](Cl)[Cl:29]>O.Cl>[ClH:29].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[NH2:1]
Reactant: COc1ccc(CCNS(=O)(=O)c2ccc(N)cc2)cc1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCNS(=O)(=O)c2ccc(NN)cc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of sodium nitrite (0.8 g) in water (20 ml) was added dropwise to a stirred suspension of the product of stage (ii) (3.5 g) in a mixture of concentrated hydrochloric acid (100 ml) and water (100 ml) keeping the temperature below -5° C. The resulting solution was stirred at about -5° C. for 30 min, when a solution of tin (II) chloride dihydrate (13 g) in concentrated hydrochloric acid (100 ml) was added. The resulting suspension was allowed to warm to room temperature over 1 h. The solid was filtered off, washed with ether, and dried in vacuo to give a solid (3.0 g). A sample (2 g) was crystallised from a mixture of methanol and isopropyl acetate to give the title compound as a solid (0.9 g) m.p. 208°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to the procedure described-in Example I, 3,5-dichloroaniline was reacted with methyl chlorocarbonyl(dimethoxy)acetate, prepared as described in Example LXV Part A, employing triethylamine as the acid acceptor in methylene chloride solution. The methyl 3-[(3,5-dichlorophenyl)amino]-2,2-dimethoxy-3-oxopropanoate product (2.31 grams, 0.007 mole) was obtained as colorless crystals having a melting point of 160° C.-164° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(N(CC)CC)C.[C:8](=[N:11][OH:12])([NH2:10])[CH3:9].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[C:8](=[N:11][OH:12])([NH2:10])[CH3:9].[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)([O-:12])(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(N)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 130.5 %

Procedure:
Triethylamine (3 ml, 2.18 g, 0.022 mol) was added to acetamide oxime (1.5 g, 0.02 mol) in tetrahydrofuran (THF) (45 ml). To the mixture, p-toluenesulfonyl chloride (Tosylchloride, TsCl) (4.2 g, 0.022 mol) was added in small portions (generating heat intensively). The mixture was allowed to react at room temperature for 45 mins. and the precipitates were collected by filtration. THF was distilled off under reduced pressure, and water was added to the resultant residue. The residue was extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and isopropyl ether was added to the residue to separate crystals. The crystals were filtered off is and dried to give acetamide-oxime-tosylate (3.2 g, yield; 69.2%).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:35][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])([CH3:33])[CH3:34])=[CH:28][CH:27]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 65 %

Procedure:
The title compound was prepared in a yield of 65% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-(4-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: CO[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O.F[C:30](F)(F)C(O)=O>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:3]3[C:4](=[C:20]([CH3:30])[CH:21]=[CH:22][CH:23]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1CNCC(O)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Product: COc1ccc(C2CNCc3c(C)cccc32)cc1OC

Procedure:
900 mg of α-[[(2-methoxybenzylamino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto 0.21 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 60 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation 3 times, and after adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was recrystallized from ethyl acetate-n-hexane, giving 440 mg of 4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 86°-88° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[N:19]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: C=CCCN[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCN(C(=O)C=C)[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Acryloyl chloride (47 mg, 0.50 mmol) was added at 0° C. to a solution of trans-(2-but-3-enylamino-cyclohexyl)-carbamic acid tert-butyl ester (123 mg, 0.46 mmol) and triethylamine (51 mg, 0.51 mmol) in dichloromethane (3 ml), and the reaction mixture was allowed to reach room temperature over 3 h. After partitioning between dichloro-methane and 10% aq. citric acid solution, the organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (103 mg, 70%). Light yellow solid, MS (ISP) 323.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[NH:9][C:10]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=NO)[CH2:17][CH2:16]4)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:33]>ClCCl>[N:1]1([CH2:7][C:8]2[NH:9][C:10]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:33])[CH2:17][CH2:16]4)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: ON=C1CCc2cc(-c3nc(CN4CCNCC4)[nH]c3-c3ccncc3)ccc21
Solvent: ClCCl
Product: O=C1CCc2cc(-c3nc(CN4CCNCC4)[nH]c3-c3ccncc3)ccc21

Procedure:
A solution of the product of Step 1 (0.350 g, 0.74 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was stirred at room temperature for 3 hours. The solution was concentrated and the residue co-evaporated with dichloromethane. The residue was dissolved in water (10 ml) and the solution was neutralised with sodium carbonate solution. The solvent was evaporated in vacuo and the resulting solid was dried over phosphorus pentoxide to give title compound which was used in the next step; MS(AP+) m/e 374 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH2:14]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncnc(Cl)n2)CC1

Procedure:
A solution of 4-N-Boc-aminomethylpiperidine (25 g, 120 mmol), 2,4-Dichloro-1,3,5-Triazine (20 g, 140 mmol) and DIPEA (77.4 g, 600 mmol) in CH3CN (300 ml) was stirred at room temperature for 2 hours. Water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue that was purified using normal phase chromatography, eluting with petroleum ether containing 30% ethyl acetate to give tert-butyl (1-(4-chloro-1,3,5-triazin-2-yl)piperidin-4-yl)methylcarbamate as an off white solid (30.0 g).