Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:11][C:10]([CH3:22])([CH2:12][N:13](C(=O)C(F)(F)F)[CH2:14][CH3:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>C(O)(=O)C>[C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:11][C:10]([CH2:12][NH:13][CH2:14][CH3:15])([CH3:22])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC1(C)CN(C(c2ccccc2)c2ccccc2)C1)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCNCC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Yield: 84.9 %

Procedure:
3.9 g (10 mmol) of 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine in 20 ml of 5% strength sodium hydroxide and 20 ml of ethanol are stirred for one hour at 70° C. The solution is cooled, brought to pH 8 with hydrochloric acid, acidified with acetic acid and evaporated, the residue is extracted with chloroform, the organic phase is dried with anhydrous sodium sulphate, the solvent is evaporated off and 2.5 g (85%) of 1-diphenylmethyl-3-ethylaminomethyl-3-methylazetidine are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2)#[N:2].[OH:23]O.[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2)(=[O:23])[NH2:2]
Reactant: OO
Reactant: N#Cc1cc2c(c(C(=O)OCc3ccccc3)c1)NCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cc2c(c(C(=O)OCc3ccccc3)c1)NCCC2
Reaction time: 7 h
Yield: 41.7 %

Procedure:
To the solution of benzyl 6-cyano-1,2,3,4-tetrahydroquinoline-8-carboxylate (2.5 g) in ethanol (20 ml) was added 35% hydrogen peroxide solution (3 ml) and 6N sodium hydroxide solution (0.33 ml). The reaction mixture was stirred at 40°-45° C. for 7 hours. The resulting precipitate was collected by filtration and washed with ethanol to give benzyl 6-carbamoyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (1.10 g, 41.7%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C1COCC1.CCCCCC>[OH:12][C:13]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
To a solution of 1-methyl-1H-imidazole (2 g) in THF (15 ml) was added 1.59 M n-butyllithium in n-hexane solution (18.4 ml) slowly under ice bath cooling, and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (5.8 g) in THF (15 ml) solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc and was washed with brine, and was dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by silica gel column (CHCl3:MeOH=95:5 to 90:10) to give tert-butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (4.02 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[NH:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11]CC)=O.[CH3:15][S:16]([NH:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C:25]([CH2:30][C:31](O)=[O:32])=[N:26][S:27](=[O:29])(=[O:28])[C:22]=2[CH:21]=1)(=[O:18])=[O:17].CN1CCOCC1.[ClH:43].CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:43].[CH3:14][N:2]([CH3:1])[N:3]1[C@@H:4]2[C@@H:5]([CH2:6][CH2:7][CH2:8]2)[C:9]([OH:11])=[C:30]([C:25]2[NH:24][C:23]3[CH:34]=[CH:35][C:20]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:21][C:22]=3[S:27](=[O:28])(=[O:29])[N:26]=2)[C:31]1=[O:32]
Reactant: CCOC(=O)C1CCCC1NN(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Yield: 52.4 %

Procedure:
Ethyl 2-(2,2-dimethylhydrazinyl)cyclopentanecarboxylate (0.16 g, 0.82 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.27 g, 0.82 mmol) was added followed by N-methylmorpholine (0.19 mL, 1.72 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.86 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The residue was triturated with ethyl acetate to afford the desired product, cis-N-[3-(1-dimethylamino-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide hydrochloride (0.22 g, 0.43 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.48-1.73 (2H, m), 1.88-2.20 (4H, m), 2.82 (6H, s), 3.06 (3H, s), 4.01 (1H, s), 7.49-7.74 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C18H23N5O6S2 469.54, found 470.2 [M+H+].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[F:15][CH:16]([F:20])[C:17](O)=O>O>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:17]([CH:16]([F:20])[F:15])=[N:2][C:3]=2[CH:9]=1
Reactant: O=C(O)C(F)F
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(C(F)F)nc2cc1Cl

Procedure:
To 25 ml of 6 N hydrochloric acid containing 2.22 g of 2-amino-4-chloro-5-sulfamylaniline was added 1.50 g of difluoroacetic acid and the mixture refluxed for 12 hours. The resultant solid was collected by filtration and then added to concentrated ammonium hydroxide to yield the free base which was then suspended in water at 50° C. The solid was then collected by filtration, dissolved in methanol, the methanol brought to a boil, charcoal added, and the suspension filtered through two sheets of filter paper, and then through Celite. Concentration in vacuo provided a brown solid which upon recrystallization from acetonitrile yielded a pink solid, m.p. 233°-235°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)C=O.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=1>C(OCC)(=O)C>[N+:31]([C:23]1[CH:22]=[C:21]([CH2:20][S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])([O-:33])=[O:32]
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CSc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
1.01 g of potassium carbonate and 0.39 mL of thiophenol were added to 10 mL of N,N-dimethylformamide solution containing 1.00 g of methyl 4-(bromomethyl)-2-nitrobenzoate at room temperature and stirred at the same temperature for 7 hours. Ethyl acetate was added to the reaction mixture and insoluble were removed by filtration and water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to obtain 0.70 g of methyl 2-nitro-4-((phenylthio)methyl)benzoate as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Br
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(NCCc2c[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
2.0 g of tryptamine (12.5 mmol) were dissolved in DCM (50 mL) and treated in one portion with triethylamine (1.74 mL. 12.5 mmol, 1 eq) and trityl chloride (3.44 g, 12.3 mmol). The resulting solution was stirred for 24 h at room temperature while protected from light. Volatiles were evaporated and the residue treated with aqueous HCl (1 N). The solid formed was filtered and washed with small portions of ether then dissolved in aqueous sodium hydrogen-carbonate and extracted into DCM. The organic layer was dried and evaporated to give 4.48 g (89% ) of 3-(N-trityl-(2-aminoethyl))-indole, which was used without further purification.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]1[C@@H:16]2[C@H:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25](=[O:27])[CH3:26])[N:23]=3)[CH2:18][C@@:12]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:13]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[CH2:14][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:4]([N:11]1[C@@H:16]2[C@H:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])([CH3:1])[CH3:26])[N:23]=3)[CH2:18][C@@:12]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:13]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:42])([F:43])[F:41])[CH:31]=1)[CH2:14][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 0 °C
Yield: 38.3 %

Procedure:
Methylmagnesium bromide (3.0M solution in THF, 0.7 ml, 2.1 mmol) was added dropwise to a −78° C. solution of (1R*12R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-oxopropyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 1.1 g, 1.7 mmol) in THF (25 ml). The mixture was warmed to 0° C. for 30 minutes then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2.5, 5 and 10% ethyl acetate/iso-hexanes to yield the title compound (0.43 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(Cl)c1Nc1ccccc1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
To a mixture of (2-chloro-3-fluoro-6-nitrophenyl)phenylamine (1.28 g, 4.8 mmol) in MeOH (45 mL) and water (15 mL) were added NH4Cl (1.48 g, 28.8 mmol) and iron powder (1.07 g, 19.2 mmol) and the reaction mixture heated at 90° C. for 2 h. After cooling to RT, the crude mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound (918 mg, 81%). LCMS (Method C): RT 3.46 min [M+H]+ 237.1/239.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:9][CH2:10][CH2:11][C:12]#[N:13]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:3]1
Reactant: CC1CCCNC1
Reactant: N#CCCCCl
Solvent: c1ccccc1
Product: CC1CCCN(CCCC#N)C1
Reaction time: 0.42 h
Yield: 70.3 %

Procedure:
In a solution under reflux of 58.6 ml (0.50 mole) of 3-methylpiperidine in 65 ml of benzene, were run in 25 minutes 27.2 g (0.25 mole) of 4-chlorobutyronitrile Reflux was continued for 2h, the precipitate was removed by filtration and the filtrate brought to dryness under reduced pressure. The residue from the evaporation was purified by distillation under reduced pressure to give 29.2 g (yields=70.3%) of 4-(3-methylpiperidino)-butyronitrile which was in the form of a colourless oil. Boiling point 5-6 mmHg =100° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:28]2)=[O:21])[CH2:13]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Methane sulphonyl chloride (0.009 ml) was added to a solution of Intermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) in dichloromethane (3 ml). The solution was stirred for 5 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a pale yellow gum (0.034 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:27])[CH2:18][N:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20]>>[CH:21]1([N:19]([CH3:20])[CH2:18][CH:17]([OH:27])[CH2:16][NH:15][C:11]([C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=3[NH:3][C:2]=2[CH3:1])=[O:13])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(CC(O)CN)C1CCCCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN(C)C1CCCCC1)CCCC2=O
Yield: 83 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(cyclohexyl(methyl)amino)propan-2-ol 0.39 g (2.1 mmol) were reacted to give 0.30 g (83%) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=1)=[CH:16][CH:15]=3.I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][O:26][CH3:33])[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Reactant: CI
Product: COCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 101 above, with the compound from Example 95 above, 3-(2,4-dichlorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless oil. MS: 484.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].C([Sn](CCCC)(CCCC)[C:21]([O:23]CC)=[CH2:22])CCC.Cl>C(OCC)(=O)C.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:23])[CH3:22]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 6-bromo-2,2,4,4-tetramethyl chroman (see U.S. Pat. No. 6,252,090, 0.9 g, 3.34 mmol) in anhydrous tetrahydrofuran (50 mL) was sparged with argon for 5 min. and treated with dichlorobis(triphenylphosphine)palladium(II) (0.117 g, 0.167 mmol) followed by tributyl(1-ethoxyvinyl)tin (2.41 g, 6.7 mmol). The resulting reaction mixture was heated at 80° C. under argon for 18 h. The reaction mixture was then cooled to ambient temperature and treated with 10% aqueous hydrochloric acid (5 mL) and stirred for 30 min. The reaction mixture was then diluted with ethyl acetate and washed with water (×1) and brine (×1). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-3%% ethyl acetate in hexane as the eluent to afford the title compound as a colorless oil (0.36 g, 46%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](F)=[O:9])=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)C>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]=[N+:16]=[N-:17])=[O:9])=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: [N-]=[N+]=NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
A mixture of 5 grams (24 mmol) of 4-(trifluoromethoxy)benzoyl fluoride, 1.87 grams (29 mmol) of sodium azide, 0.2 grams of 18-Crown-6 ether, and 20 ml. of acetonitrile was stirred at room temperature for two hours under an atmosphere of dry nitrogen. The reaction mixture was diluted with diethyl ether, filtered and concentrated under reduced pressure, with a bath temperature of 40° C., to give the title compound as a turbid oil. IR showed adsorptions at 2280, 2240 and 1695 cm-1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[OH:16][CH:17]([CH2:20][NH2:21])[CH2:18][NH2:19]>>[OH:16][CH:17]([CH2:20][NH:21][CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[OH:9])[CH2:18][NH:19][CH:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)CN
Product: OC(CNC(c1ccccc1)C(O)c1ccccc1)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 55 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mol) and 2-hydroxy-1,3-propanediamine (0.90 g, 0.010 mol) was heated on a steam bath for 18 hours, giving a white solid. The material was triturated with boiling toluene and allowed to cool. The white solid that formed was collected, washed with toluene, and dried under ambient conditions for 18 hours. The solid was then vacuum dried over refluxing toluene for 4 hours to obtain 2.60 g (55% yield); mp 155°-175° C. (undefined).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>C1COCC1>[C:24]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:9]1=[O:18])(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: C=CCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 66.5 %

Procedure:
Charge a 250 mL, single-neck, round-bottomed flask with (4S,5R)-4,5-diphenyloxazolidin-2-one (5.0 g, 21.0 mmol) and THF (300 mL). Stir the mixture at −78° C. and add dropwise BuLi (13.7 mL, 21.9 mmol). Stir the reaction mixture for 0.5 hours and then add pent-4-enoyl chloride (3.71 g, 31.3 mmol). Stir the reaction mixture one hour until TLC shows that the starting material has been consumed. Add water (100 mL) and extract the aqueous with CH2Cl2 (3×250 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (4S,5R)-3-Pent-4-enoyl-4,5-diphenyloxazolidin-2-one (4.49 g, 67%).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][C:12](=O)[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[BH4-].[Na+]>O1CCOCC1>[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CCNCC2

Procedure:
A solution of glacial acetic acid (1.8 g) in dioxan (10 ml) is added to a suspension of 7,8-dimethoxy-1,3,4,5-tetrahydro-2-H-3-benzazepin-2-one (1.3 g, 6 mmol) and sodium borohydride (1.1 g, 3 mmol) in dioxan (20 ml). The resulting mixture is refluxed for 3 hours, evaporated and mixed with water. The mixture is extracted twice with methylene chloride, the extract is concentrated by evaporation and the residue is taken up in ether. After filtering, the ether is eliminated in vacuo. Yield: 1.1 g. Mp: 86°-89° C.