Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([CH:16]=[N:17][OH:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.[CH3:27][O:28][CH2:29][C:30]#[CH:31].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([C:16]2[CH:31]=[C:30]([CH2:29][O:28][CH3:27])[O:18][N:17]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(C=NO)C1
Reactant: C#CCOC
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime (5.3 g, 20 mmol) in 100 ml dry dimethylformamide was added N-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml dry dimethylformamide. The reaction mixture was stirred at room temperature for 1 h. Now methylpropargylether (1.5 ml, 25 mmol) and 2 ml triethylamine was added and the reaction mixture stirred at room temperature overnight. 200 ml water was added and the aqueous phase extracted with 3×50 ml ether. The combined ether extracts were washed with 2×50 ml water, dried over magnesiumsulfate and concentrated in vacuo. The compound was finally purified by column chromatography with methylenechloride/ethylacetate 4:1 as eluent. Yield: 3.5 g. M.p. 60.5°-62° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2)c(Cl)c1Cl
Reaction time: 17 h

Procedure:
To a stirred mixture of 2,3-dichloroanisole (73.5 g., 0.414 mole), 4-bromophenylacetyl chloride (105 g., 0.456 mole) and carbon disulfide (300 ml.) is added portionwise aluminum chloride (60.9 g., 0.456 mole) with cooling at 0°-5° C. The reaction mixture is left at 25° C. for 17 hours, then flushed with nitrogen, and the solid residue treated with crushed ice and 12 N hydrochloric acid (80 ml.) to give 147.7 g. of 2,3-dichloro-4-(4-bromophenyl)acetylanisole which melts at 163°-164.5° C. after crystallization from benzene:hexane, 1:1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]#[N:18])[C:5](=[O:16])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]=1[CH3:8].[CH3:19][Sn](C)(C)C.O.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[C:7]([CH3:8])=[C:2]([CH3:19])[CH:3]=[C:4]([C:17]#[N:18])[C:5]2=[O:16])=[CH:10][CH:11]=1
Reactant: C[Sn](C)(C)C
Reactant: Cc1c(Br)cc(C#N)c(=O)n1-c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(=O)n(-c2ccc(F)cc2)c1C
Temperature: 120 °C
Reaction time: 17 h
Yield: 59.6 %

Procedure:
To a solution of 5-bromo-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (200 mg, 0.651 mmol) in N,N-dimethylformamide (2 mL) were added tetramethyltin (582 mg, 3.255 mmol) and tetrakistriphenylphosphinepalladium(0) (22.3 mg, 0.019 mmol), and the mixture was stirred at 120° C. for 17 hr. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (94 mg, 60%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]=[C:30]=[O:31]
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=C(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=NCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H).
Reaction SMILES: C1(CBr)CC1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:20][C:19]=1[CH3:29])(=[O:17])[CH3:16]>>[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][N:25]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=3)[C:24]2=[O:28])=[N:20][C:19]=1[CH3:29])(=[O:17])[CH3:16]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as describe in Preparation 19, making variations as required to replace cyclopropylmethyl bromide with 4-fluorobenzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 98% yield (3.27 g): 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.07-6.97 (m, 2H), 4.45 (s, 2H), 4.10-4.04 (m, 2H), 3.48-3.37 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 334.1 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]3)[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:28][NH2:29]>CCO>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:11]=[C:12]([NH:25][CH3:26])[N:13]=[C:14]([N:16]4[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]4)[CH:15]=3)=[CH:7][CH:6]=2)[NH:29][N:28]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 42 h
Yield: 72.8 %

Procedure:
A mixture of 2-fluoro-4-[6-[(2S,5R)-2-(hydroxymethyl)-5-methyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]benzonitrile (151 mg, 0.42 mmol) and hydrazine monohydrate (0.41 mL, 8.44 mmol) in EtOH (4 mL) was stirred at 100° C. in a sealed tube for 42 hours. It was then cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (113 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17 (d, J=6.6 Hz, 3H), 2.72-2.93 (m, 4H), 3.37-3.59 (m, 3H), 3.66 (d, J=11.2 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.94-4.74 (bs, 2H), 4.38 (t, J=5.7 Hz, 1H), 5.38 (s, 2H), 6.54 (m, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](=[O:22])[CH3:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].CO>[CH2:18]([C:11]1[CH:10]=[C:9]([C:20](=[O:22])[CH3:21])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:19]
Reactant: [H][H]
Reactant: C=Cc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Yield: 20.8 %

Procedure:
A mixture of 1-[8-(3-fluorophenyl)-5-vinylquinolin-7-yl]ethanone (0.03 g, 0.1 mmol) and 5% palladium on carbon (3 mg) in methanol (1 mL) was treated with hydrogen under balloon pressure, at room temperature, for 3 hours. The mixture was filtered. The filtrate was concentrated and purified on silica gel (eluting with 0 to 10% Ethyl acetate in hexane) to give the desired product (6.1 mg, 20%). LCMS calculated for C19H17FNO (M+H)+: m/z=294.1; Found: 294.1.
Reaction SMILES: [Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])=[N:10]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+].Cl>C(Cl)(=O)C.CO>[Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([N:15]([C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])[C:40](=[O:42])[CH3:41])=[N:10]1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(NC2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(N(C(C)=O)C2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dodecyl 3-{N-[1-(2-chloro-2,4-dimethylphenyl)-4,5-dihydro-5-oxo-1H-pyrazol-3-yl]-amino}-4-methoxy-benzoate (10.5 g, 18.9 mmol) was dissolved in acetyl chloride (50 ml) and acetic anhydride (35 ml) and the solution was heated under reflux for 1.5 hrs. The solution was cooled, then it was slowly poured into ice/water (750 ml) and the resulting sticky solid was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and evaporated to give an oil. Sodium hydroxide (0.8 g, 18.9 mmol) was added to a solution of the oil in methanol (80 ml) and the mixture was stirred at room temperature for 4 hrs. The solution was poured slowly into 3N hydrochloric acid (500 ml), the aqueous liquor was decanted off and the residue was dissolved in ethyl acetate (100 ml). The organic solution was dried (MgSO4) and evaporated to give a glass. The crude material was recrystallized from methanol (50 ml) to give pure product as a white solid, 5.8 g, 51%.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[CH2:31][C:3]1[C:4](=[O:20])[O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Cc1ccccc1Cl

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL, 1.2 mmol), 2-chlorobenzoyl chloride (0.14 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 0.5% MeOH in CH2 Cl2) to provide a solid (0.130 g, 185°-187° C.). 1H NMR (400 MHz, DMSO-d6) δ11.351 (bs, 1H), 7.464-7.282 (m, 11H), 7.054 (t, 1H, J=7 Hz), 6.679 (td, 1H, J=1 Hz, J=7.5 Hz), 5.797 (d, 1H, J=7 Hz), 3.586 (s, 2H), 3.472 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7](=[O:16])[N:8]([CH3:15])[CH2:9][C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.47 g (11 mmol) of N-chlorosuccinimide are heated to 100° for 30 minutes in dimethylformamide. Subsequently, the mixture is poured into water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields 3-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 217°-218°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:43]([N:46]=[C:47]=[O:48])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:47](=[O:48])[NH:46][CH:43]([CH3:45])[CH3:44])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 50 °C

Procedure:
5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.27 mmol, 1.0 equiv) was dissolved in tetrahydrofuran and treated with triethylamine (1.50 equiv) and isopropyl isocyanate (0.4 mmol, 1.50 equiv). The resulting mixture was heated to 50° C. for 18 h. The reaction mixture was concentrated and crude product was purified on silica using gradient elution from ethyl acetate (100%) and ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.70 (3H, s), 0.90 (3H, s), 1.1 (3H, d), 1.25 (3H, d), 1.4 (1H, m), 1.6 (1H, m), 2.30–2.50 (8H, m), 2.70 (2H, m), 3.80–4.00 (3H, m), 3.55 (3H, s), 4.85 (1H, m), 5.30 (2H, br, s), 6.20 (1H, t), 6.80–7.00 (2H, dd), 7.20–7.45 (6H, m), 7.60 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 576 (M+1), UV retention time: 1.58 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C=O.[BH3-][C:32]#N.[Na+]>CO.O>[CH3:2][N:3]([CH3:32])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: [BH3-]C#N
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([O:13][C:14](Cl)=[O:15])([CH3:12])[CH3:11]>O>[C:4]1([NH:3][C:14](=[O:15])[O:13][CH:10]([CH3:12])[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)OC(=O)Nc1ccccc1

Procedure:
Six hundred and seventy (670) pounds of 50 percent aqueous sodium hydroxide solution were added to one hundred and fifty (150) gallons of water contained in a reactor kettle equipped with a stirrer, heating, and cooling means. The temperature was maintained below 60° F., and the solution was continuously stirred. Seven hundred and fifteen (715) pounds of aniline were then added; the temperature was lowered to 50° F. and the pH of the solution was adjusted to between 7.0 and 8.0 and maintained thereat while one thousand and fifty (1050) pounds of isopropylchloroformate were added to form isopropyl N-phenylcarbamate. When 99 to 99.5 percent of the aniline had reacted, the reaction mixture was pumped into a wash kettle and heated with stirring to about 185° to 210° F. until about 95 percent of the isopropyl N-phenylcarbamate had melted. The stirring was stopped, and the mixture was allowed to separate into two phases, the lower of which, i.e., the aqueous salt phase, was drained away. An equal volume of hot water (200° F.) was added to the remaining phase comprised primarily of molten isopropyl N-phenylcarbamate, and the mixture was agitated for 20 minutes, and then allowed to separate into two phases. The upper phase comprising washed molten isopropyl N-phenylcarbamate was pumped into a second wash kettle and washed with 200 gallons of dilute hydrochloric acid solution maintained at 185° F. The washing of the mixture in the second wash kettle was continued, until a 25 milliliter sample of the wash kettle showed that a 1/2 inch cube of solid isopropyl N-phenylcarbamate heated and mixed with 25 milliliters of distilled water gave no color or only a slight bluish tinge when 3 drops of a solution containing 5 grams of calcium hypochlorite per 100 milliliters of water were added to the mixture of water and isopropyl N-phenylcarbamate after the mixture was cooled to ambient temperature (65° F.).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:21]([NH2:25])(=[O:24])[CH:22]=[CH2:23].[Cl-].[NH4+]>CN(C)C=O>[C:21]([CH2:22][CH2:23][N:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)(=[O:24])[NH2:25]
Reactant: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Reactant: C=CC(N)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)CCn1ccc2cc(C(=O)NCC3CCCC3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
A solution of 5-(N-cyclopentylmethylcarbamoyl)indole (A) (1.50 g) in N,N-dimethylformamide (DMF) (5 ml) was added to a stirred slurry of sodium hydride (0.16 g) in DMF (15 ml) maintained at 0° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature for 15 minutes, treated with a solution of acrylamide (0.66 g) in DMF (5 ml), and allowed to stir for 12 hours. The mixture was poured into a cold, saturated aqueous solution of ammonium chloride to give a milky suspension which was extracted with ethyl acetate. The organic phase was washed successively with water and brine, dried (MgSO4), and evaporated. The resulting clear oil was purified by flash chromatography on silica gel (700 ml), eluting with 7:93 v/v methanol:ethyl acetate, to give 1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indole (0.70 g, 36%) as a gummy white foam; NMR (80 MHz, CDCl3): 1.2-2.2(broad m, 9H, cyclopentyl), 2.7(t, 2H, CH2CO), 3.4(dd, 2H, CH2NH), 4.5(t, 2H, CH2CH2CO), 5.4(broad, 2H, CONH2), 6.5(dd, 1H, H3 -indole), 7.2(d, 1H2 -indole), 7.3(d, 1H, H7 -indole), 7.6(dd, 1H, H6 -indole), 8.0(m, 1H, H4 -indole).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[OH:7][CH2:8][CH2:9][N:10]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:11](=[O:33])[NH:12][C@@H:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[C:14](OC1C=CC=CC=1)=[O:15]>O1CCCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:14](=[O:15])[C@@H:13]([NH:12][C:11]([N:10]([CH2:9][CH2:8][OH:7])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1
Reactant: O=C(Oc1ccccc1)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)N(CCO)CCc1ccccc1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)N(CCO)CCc1ccccc1
Yield: 81 %

Procedure:
A solution of 2-(dimethylamino)ethylamine (362 mg) in tetrahydrofuran (3 ml) is added to a solution of phenyl (2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-3-(4-nitrophenyl)propionate (Compound No. 1-35, 392 mg) in tetrahydrofuran (5 ml) under ice cooling, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over andhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 314 mg (81%) of the titled compound (Compound No. 19-1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=O)[CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[ClH:34]>O1CCCC1>[ClH:1].[ClH:34].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:9][CH2:8]2)=[CH:25][CH:26]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1Cl)N1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(CN2CCN(CC=Cc3ccc(Cl)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Chlorobenzyl)-4-(2,4-dichlorocinnamoyl)piperazine (1.0 g, 2.44 mmole) (the compound prepared in Reference Example 1) is dissolved in anhydrous tetrahydrofuran (10 ml), and thereto is added in portions lithium aluminum hydride (0.1 g, 2.63 mmole) at room temperature. After the addition, the mixture is stirred at room temperature for one hour. After adding water in portions, the reaction mixture is neutralized to approximately neutral with 3N hydrochloric acid, and then is extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The resulting oily substance is dissolved in ethanol (5 ml), and thereto is added an ethanol solution (10 ml) of conc. hydrochloric acid (0.5 ml), and the precipitated crystals are separated by filtration. The product is recrystallized from water-ethanol to give the title compound (0.2 g). The product has the same physical properties as those of the compound prepared in Example 1-(1).