Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:13][O:14][C:15]([C:17]1[CH2:22][NH:21][CH2:20][CH2:19][CH:18]=1)=[O:16].Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:13][O:14][C:15]([C:17]1[CH2:22][N:21]([CH2:2][CH2:3][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:20][CH2:19][CH:18]=1)=[O:16]
Reactant: BrCCC1CCc2ccccc21
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CCC2CCc3ccccc32)C1
Reaction time: 12 h

Procedure:
4.5 g (20 mmol) of 1-bromo-2-(indan-1-yl)-ethane are dissolved in 20 ml of toluene and added, at room temperature, to a solution of 4.9 g of guvacoline hydrobromide (20 mmol) and 5.7 g (44 mmol) of N,N-diisopropyl-N-ethylamine in 15 ml of dimethylformamide. The mixture is stirred at 45° under nitrogen for 12 hours. The solvents are then substantially removed under reduced pressure. The residue is rendered acidic with 2N hydrochloric acid and the aqueous solution is extracted with diethyl ether. The acidic aqueous phases are rendered basic with saturated sodium bicarbonate solution and extracted by shaking with diethyl ether. The organic phases are separated off, washed with saturated sodium chloride solution and dried over magnesium sulphate. 1-[2-(indan-1-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is obtained.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1[CH:45]=[CH:44][CH:43]=[N:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][N:46]([C:41]4[N:40]=[CH:45][CH:44]=[CH:43][N:42]=4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: c1cnc(N2CCNCC2)nc1
Product: Cc1ccccc1-c1nc(N2CCN(c3ncccn3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 48.8 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-(pyrimidine-2-yl)piperazine (30.0 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrimidine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine (48.1 mg, 49%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26](C3CCCCO3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].CO>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Yield: 48.7 %

Procedure:
2-Methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol) was treated with Trifluoroacetic Acid (0.30 mL, 3.9 mmol) in Methylene chloride (1.5 mL, 23 mmol) at r.t. for 16 hours. The solvent and TFA were removed by purging with N2. The residue was treated with Potassium carbonate (82 mg, 0.59 mmol) in Methanol (2.0 mL, 49 mmol) at r.t. for 3 hours. The solvent was removed and the residue was suspended in 5% MeOH/DCM, filtered. The filtrate was purified by chromatograph in a 8 g AnaLogix column using MeOH/DCM (0/100 to 10/90) to afford a solid product (0.012 g, 48.7% yield). LCMS: (FA) ES+ 387, ES− 385. 1H NMR (400 MHz, d6-DMSO) δ 10.39 (σ, 1H), 10.03 (σ, 1H), 8.71 (σ, 1H), 7.99-8.01 (m, 2H), 7.82 (s, 1H), 7.43-7.50 (m, 4H), 2.75 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[N+:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=1)([O-:26])=[O:25]
Reactant: NS(=O)(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(C2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1

Procedure:
A solution of 4-(4-piperidinyl)benzensulphonamide [the product of Example 2(iii)] (0.46 g) and 2-chloro-4-nitropyridine (0.30 g) in pyridine (10 ml) was heated under reflux for 5 hours and then evaporated. The residue was partitioned between dichloromethane and 10% aqueous sodium carbonate solution. The aqueous layer was extracted several times with dichloromethane nd the combined organic extracts were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel. Elution with dichloromethane/methanol (99:1) first gave impurity followed by the pure product. The product-containing fractions were combined and evaporated to give the title compound, (0.15 g), m.p. 215°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C1C=C[C:37]2N(O)N=[N:40][C:38]=2C=1.C(Cl)CCl.Cl.C(N)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:40][CH2:38][CH3:37])=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:32])([F:31])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (394 mg, 0.74 mmol), HOBT (199 mg, 1.47 mmol), EDC (211 mg, 1.47 mmol), ethylamine hydrochloride (119 mg, 1.47 mmol) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexane) to yield the title compound (100 mg, 24%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:23]2[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]2)[N:11]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1Cl
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3Cl)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 2-chloroaniline and 3,5-dimethylpyrazole. Mp. 210.4-217.1° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 9.89 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 4.84 ml of benzyl chloride are reacted. The title compound is obtained as a white solid. Rf=0.53 (1:1 EtOAc-heptane); Rt=4.96.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5](/[N:8]=C/N(C)C)=[N:6][CH:7]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N)=N>N1C=CC=CC=1>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C=Nc1ccccc1
Agent: N=CN
Solvent: c1ccncc1
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
To a solution of N-[4-(7-amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.020 g, 0.040 mmol) in pyridine (1.1 mL) at 0° C. was added phenyl isocyanate (0.0043 mL, 0.040 mmol). The mixture was allowed to warm to ambient temperature, and was stirred at ambient temperature for 12 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel, which had been deactivated with triethylamine (10% by volume of silica gel used), using methanol/dichloromethane as the mobile phase, to afford an intermediate that was then subjected to General Procedure M for formamidine hydrolysis to yield the title compound (0.007 g, 32%) as an off-white foam: 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.06 (d, 1H), 7.73 (m, 2H), 7.60 (d, 1H), 7.49 (d, 2H), 7.36 (s, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 7.00 (t, 1H), 6.10 (br, 2H), 4.04 (s, 3H), 3.93 (s, 3H); MS: (MH)+ 563.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone of melting point 147.5°-148.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 67.3 %

Procedure:
In 30 ml of ethanol is dissolved 17 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate, and 4.5 g of acetic acid is added to the solution. Sodium cyanoborohydride (3 g) is added to the mixture at room temperature with stirring, followed by stirring at room temperature for 3 hours, and 500 ml of water is added to the reaction mixture, which is extracted with methylene chloride. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue is purified by silica-gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 11.5 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate as a colorless oily material.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[OH:13][C:14](O)([CH3:20])[C:15](=O)[CH2:16]CC.C1COCC1>C(N(CC)CC)C>[C:14]([C:15]1([CH3:16])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:13])[CH3:20]
Reactant: CCCC(=O)C(C)(O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3 dihydroxyethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to −78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].Cl[C@H](C1C=CC(Cl)=CC=1)C[NH3+].CC(C)([O-])C.[Na+].[CH3:38][C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41](S(C)(=O)=O)[N:40]=1.O>CN(C=O)C>[CH3:45][C:43]1[CH:44]=[C:39]([CH3:38])[N:40]=[C:41]([O:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [NH3+]C[C@H](Cl)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL three neck flask with stirring arrangement, (1 gm) (R)-2,4-dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.622 gm) sodium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25° C. were taken and stirred for 5 min. (0.604 gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was stirred at room temperature for 4 hours and subsequently dumped into cold water and aqueous layer was washed with toluene. Aqueous layer was collected and acidified with HCl to adjust pH to 2. Solid white material was precipitated. Solid white material was precipitated. The solid so obtained was filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:5])[CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>ClCCl>[C@H:2]([NH:5][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][Cl:13])[CH:16]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@@H](C)N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)NC(=O)c1cccc(CCl)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of (R)-butan-2-amine (14.77 mmol, 1.478 mL, 1,081 g) and triethylamine (15.48 mmol, 2.157 mL, 1.566 g) in dichloromethane was added dropwise to a stirred solution of 3-(chloromethyl)benzoyl chloride (14.07 mmol, 2 mL, 2.66 g) in dichloromethane at room temperature. Upon complete addition the reaction was stirred for 2 hours, after which time the solvent was removed under vacuum and ethyl acetate (100 mL) added. The organic solution was then washed with water (200 mL), dried over sodium sulphate and concentrated under vacuum to give the title compound (2.47 g) as a cream solid. MS (ESI) m/z 226.3[M+H]+
Reaction SMILES: [ClH:1].[ClH:2].[C:3]1([C:10]2[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=2)[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[N+:17]([O-])([O-])=O.[K+].S(=O)(=O)(O)O>>[Cl:1][C:8]1[CH:6]=[CH:5][C:4]2[NH:17][C:16]3[C:10]([C:3]=2[CH:9]=1)=[CH:11][C:12]([Cl:2])=[CH:13][CH:15]=3
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Clc1ccc2[nH]c3ccc(Cl)cc3c2c1

Procedure:
Reaction of benzidine dihydrochloride (CAS 531-85-1) with potassium nitrate and sulfuric acid gives compound 1 (Zhurn. Obsh Khim., 1944, 14, 1019). Reaction of compound 1 with iron and hydrochloric acid leads to compound 2 (Zhurn. Obsh Khim., 1944, 14, 1019). Reaction of compound 2 with sulfuric acid affords 9H-carbazole-2,7-diamine 1-1 (Zhum. Obsh Khim., 1944, 14, 1019).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[H-].[Na+].I[CH3:35]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:35])[C:5]=1[N:12]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(CO)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cccc(C(=O)OC)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 28 %

Procedure:
To a solution of 0.200 g (0.452 mmol) of the product of Example 336 in 5.0 mL of dry THF was added 0.022 g (0.543 mmol) of 60% sodium hydride followed by 0.028 mL of iodomethane. The reaction was stired at room temperature for 18 h and then diluted with ethyl acetate. The organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc to provide 0.057 g (28%) of the methyl ether as ayellow solid. Electrospray Mass Spec: 457.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1.[NH2:20][C:21]1([CH:27](C)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C=CC=NC1.[CH:34]1[CH:39]=[N:38][C:37]2N(O)N=N[C:36]=2[CH:35]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([NH:20][CH:21]([C:36]2[CH:37]=[N:38][CH:39]=[CH:34][CH:35]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:19])[CH2:12]1
Reactant: On1nnc2cccnc21
Reactant: CCOC(=O)C(C)C1(N)C=CC=NC1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CC(C(=O)O)CC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cc([N+](=O)[O-])ccc2C)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-methyl-5-nitrophenyl)-5-oxopyrrolidine-3-carboxylic acid (5 g), ethyl 3-amino-3-pyridylpropanoate and HOAt in DMF at 0° C. was added i-Pr2NEt, followed by EDCI, in portions. The reaction mixture was then warmed up to room temperature and stirred overnight. The reaction solution was diluted with EtOAc and the organic phase was washed with saturated NaHCO3 and NaCl aqueous solution. The organic layer was dried over Na2SO4, concentrated in vacuo. The crude product was purified by flash column chromatography with 10% MeOH/EtOAc as eluent. A yellow solid was obtained. MS (ES+): 427.5 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.ClCCl>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
A mixture of 0.89 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 9 cm3 of dioxane to which had been added 1.41 cm3 of 5N aqueous sodium hydroxide solution was stirred for 18 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3.3 cm; mass 56 g), elution first was carried out with a dichloromethane/methanol (95/5 by volume) mixture. A fraction of 100 cm3 was first collected and then 16-cm3 fractions. Fractions 1 to 36 were separated. Elution was subsequently carried out with a dichloromethane/methanol (75/25 by volume) mixture. A first fraction of 200 cm3 a second of 150 cm3, and then a third of 100 cm3 were obtained. The latter two were combined and concentrated as above. The residue obtained was taken up in dichloromethane and filtered. The filtrate was evaporated as above and then the new residue obtained was triturated in 25 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture. The product which crystallized was filtered off and washed with 2 times 10 cm3 of the same mixture and then 3 times 10 cm3 of pentane. 0.53 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of solid with a cream color melting at 106° C.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][O:46][CH2:47][C:48](Cl)=[O:49]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][N:22]([C:48](=[O:49])[CH2:47][O:46][CH3:45])[CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)COC)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Methoxyacetyl chloride (0.03160 mL, 0.3465 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. LC/MS-m/z+469.2 (M+H)+.