Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[C:19]([NH2:26])=[C:20]([NH2:25])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[C:19]2[NH:26][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:25][C:20]=2[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc(Cl)c(Cl)c4[nH]3)cc2)S1

Procedure:
4,5-Dichloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,4-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)OC(=O)Cl
Product: Cc1c(N2CCN(C(=O)OC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and isopropyl chloroformate to give isopropyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 1.14-1.22 (m, 6H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.27-3.31 (m, 4H), 3.54 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 4.81 (m, 1H) 6.49 (br s, 1H), 7.13-7.18 (m, 1H), 7.29 (d, J=5.2 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 8.34 (s, 1H). Mass Spectrum (ESI) m/e=527.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C.CCOC(C)=O>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:31]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5, 100 mg) in N,N-dimethylacetamide (2 ml) were added methyl-6-chloro-nicotinate (68 mg) and cesium carbonate (256 mg). The mixture was stirred at room temperature for 3 h. Methyl-6-chloro-nicotinate (23 mg) was added and the mixture was stirred overnight and then diluted with EtOAc. Water was added. The mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (103 mg) as a colorless solid. MS (m/e)=519.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc2c(c1)CCN(c1ccc(N)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of 2-(4-aminophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.205 g, 0.46 mmol) and TEA (0.060 g, 0.6 mmol) in 1 mL of CH2Cl2 at 0° C. was treated with acetyl chloride (0.043 g, 0.55 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 (0.5 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×2 mL). The combined organic layer was dried over MgSO4 then concentrated. The crude product was purified by column chromatography to provide the title compound (0.195 g, 87% yield). ES−MS, (m/z) 493 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3].Cl[CH2:18][C:19]#[N:20]>CN(C)C=O>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH3:16])=[C:11]([C:13]([O:15][CH2:18][C:19]#[N:20])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: N#CCCl
Reactant: CCn1ncc2nc(C(=O)O)c(C)nc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CCn1ncc2nc(C(=O)OCC#N)c(C)nc21

Procedure:
9.12 g. of the sodium salt of 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.04 mol.), 3.33 g. of chloroacetonitrile (0.056 mol.) and 90 ml. of dimethyl-formamide are stirred at 70°-80° for 12 hours. After vacuum removal of the dimethylformamide, the residue is stirred with 200 ml. of ether and filtered. The ethereal filtrate is evaporated and the residual 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid, cyanomethyl ester is recrystallized from hexane, yield 3.76 g. (38%), m.p. 83°-84°. A polymorphous form melts at 111°-112°.
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.[CH2:17]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(#N)C>[CH2:17]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCCNC(=O)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCCNc1nc(Cl)ncc1Br)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 860 mg (3.8 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.2 ml (8.5 mmol) of triethylamine in 6 ml of acetonitrile is mixed at 0° C. with 1.0 g (3.7 mmol) of (5-amino-pentyl)-carbamic acid-benzyl ester. The reaction mixture is slowly heated to room temperature while being stirred by removal of the ice bath. After 60 hours, it is mixed with water and then extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is formed is purified by chromatography (hexane/ethyl acetate 1:1). 1.2 g (2.8 mmol, corresponding to 77% of theory) of the product is obtained.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)/[C:13]3=[N:12][C:11]=2[C:34]([O:36]C)=[O:35])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)/[C:13]3=[N:12][C:11]=2[C:34]([OH:36])=[O:35])=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc2n(c1-c1ccc(F)cc1)CCC/C2=C\c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C2\CCCn3c2nc(C(=O)O)c3-c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A 2 N sodium hydroxide solution (1 mL) was added to a solution of methyl 3-(4-fluorophenyl)-8-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (172 mg) in methanol (4 mL), and the reaction solution was heated under reflux for nine hours. The reaction solution was left to cool to room temperature, and 2 N hydrochloric acid (1 mL) was added to the reaction solution. The solid precipitated in the reaction solution was collected by filtration and washed with diethyl ether to obtain 167 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.Cl.[CH3:22][N:23]1[CH:27]=[N:26][C:25]([CH2:28][NH2:29])=[N:24]1>C(N(CC)CC)C.CN(C=O)C>[CH:17]1([C:3]2[C:2]([NH:29][CH2:28][C:25]3[N:26]=[CH:27][N:23]([CH3:22])[N:24]=3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: Cn1cnc(CN)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(CNc2nn3c(-c4ccccc4)nnc3cc2C2CCC2)n1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (144 mg, 0.52 mmol) and C-(1-methyl-1H-1,2,4-triazol-3-yl)methylamine hydrochloride (300 mg, 2.0 mmol) in triethylamine (1 ml) and dry DMF (1 ml) was stirred and heated at 100° C. in a sealed tube for 20 hours. Upon cooling the volatiles were removed in vacuo, and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatograhy on silica gel, eluting with 2%→5%→10% methanol-dichloromethane to give, in order of elution:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[ClH:23].O1CCOCC1.C(OC(C)C)(C)C>ClCCl>[ClH:23].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCO3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: c1cc2c(c(N3CCNCC3)c1)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a 50 mL flask, Tert-butyl 4-(benzo[d][1,3]dioxol-4-yl)piperazine-1-carboxylate (1.145 g, 3.74 mmol) was combined with dichloromethane M (20 ml) to give a colorless solution. Hydrochloric acid solution, 4M in dioxane (9.34 ml, 37.4 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. 15 ml of Diisoproylether were added and the mixture was stirred for 5 min at 0° C. The precipitate was collected by filtration, washed with 2 ml of diisopropylether and dried to yield the title compound as a white solid (0.955 grs, 100%). MS (ISP) m/z=207.4 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:28]([CH3:29])=[N:27][C:26]([NH2:30])=[N:25]1>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:28]([CH3:29])=[N:27][C:26]([NH:30][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:25]1
Reactant: Cc1nc(N)nn1-c1ccc(Cl)cc1Cl
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nc(C)n(-c4ccc(Cl)cc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine (prepared in analogy to Gazzetta Chimica Italiana 29, 105 (1899)). The title compound was obtained as a slightly brownish solid (Yield=54%). MS ISP (m/e): 424.2 & 426.0 (100 & 76) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[F:23])[C:17](O)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.NC1C=C(C=CC=1F)C([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)=O.N1C=CC=CC=1>CO.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=4)[CH:20]=[CH:21][C:22]=3[F:23])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: Nc1cc(C(=O)NCc2ccc(F)c(F)c2)ccc1F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 3) (1.4 g, 5.81 mmol) and thionyl chloride (8.48 ml, 116 mmol) was heated at 100° C. for 1.5 hrs. The mixture was concentrated in vacuo. 3-Amino-N-(3,4-difluorobenzyl)-4-fluorobenzamide (step 1) (1.4 g, 5.00 mmol) and pyridine (16.65 ml) was added and the resulting suspension was stirred at RT for 1 hour. EtOAc and MeOH were added and the mixture was filtered. The white solid was dried to afford the title compound;
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([C@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([F:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](Cn1ccc2c1-c1cc(F)ccc1C2)N=[N+]=[N-]
Yield: 37.7 %

Procedure:
0.51 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.51 g of (S)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.64 ml of triethylamine in 40 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 711 mg of sodium azide and the reaction mixture was heated to 50° for 16 hours while stirring. After cooling, the solution was poured into 110 ml of water and extracted twice with 110 ml of ethyl acetate each time. The combined organic phases were washed once with 90 ml of water and once with 90 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 631 mg (38%) of (R)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([NH:26][C:27](=[O:32])C(Cl)(Cl)Cl)[CH:22]=[CH:21][CH:20]=2>>[NH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([NH:26][C:27]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=1)=[O:32])[CH:22]=[CH:21][CH:20]=2
Reactant: NCc1ccc(N2CCCCC2)cc1
Reactant: Nc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2cn1
Product: Nc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 1B using 4-(1-piperidinyl)benzylamine and the product from Example 150A instead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.22 (s, 1H), 7.87 (d, 1H, J=8 Hz), 7.46 (d, 1H, J=8 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.07 (t, 1H, J=8 Hz), 6.91 (d, 2H, J=8.4 Hz), 6.82 (t, 1H, J=6 Hz), 6.70 (s, 1H), 5.91 (s, 2H), 4.22 (d, 2H, J=6 Hz), 3.10 (m, 4H), 1.70-1.45 (m, 6H). MS (ESI) 376 (M+H)+. Anal. Calcd for C22H25N5O.0.1H2O: C, 70.04; H, 6.73; N, 18.56. Found: C, 69.66; H, 6.50; N, 18.55.
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:17][NH:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>O1CCOCC1.[Cu]I>[Cl:30][C:29]1[CH:28]=[CH:27][C:16]([CH2:17][NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:15][C:14]=1[I:1]
Reactant: [I-]
Reactant: C[C@@H](NCc1ccc(Cl)c(Br)c1)c1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NCc1ccc(Cl)c(I)c1)c1ccccc1
Temperature: 115 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
To a mixture of sodium iodide (0.19 mL, 4.6 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.034 g, 0.24 mmol), (R)—N-(3-bromo-4-chlorobenzyl)-1-phenylethanamine 75 (0.762 g, 2.3 mmol), and copper(I) iodide (0.025 mg, 0.13 mmol) was added in dioxane (2.5 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min and heated to 115° C. in a sealed tube. After 15 h, the reaction mixture was diluted with EtOAc and the organic phase was washed with dilute NH4OH (1×), brine (1 x), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(4-chloro-3-iodobenzyl)-1-phenylethanamine 77 (0.737 g, 84% yield) as a colorless oil. Mass spectrum: calculated for C15H15ClIN 371.0. found 372.1 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([CH2:29][OH:30])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:15]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16].[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:47][CH2:48][CH3:49])[C:41]=1[N:42]1[CH:46]=[CH:45][CH:44]=[CH:43]1)[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:47][CH2:48][CH3:49])[C:41]=1[N:42]1[CH:46]=[CH:45][CH:44]=[CH:43]1)[CH2:37][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:15](=[O:16])[C:14]2[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:12]([O:11][CH2:10][CH:9]([OH:8])[CH2:29][OH:30])[CH:13]=2)[CH2:19][CH2:20]1)[CH3:32]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: COc1cc(OCC(O)CO)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), crude rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide trifluoroacetate (example 175b) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as yellow oil. MS: 568.5 (MH+).
Reaction SMILES: N.O1CCOCC1.C([N:10](CC)CC)C.[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[N:28]2[CH3:47])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1)#[N:16]>>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[N:28]2[CH3:47])=[C:21]([S:23]([NH2:10])(=[O:25])=[O:24])[CH:22]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(N)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Under an atmosphere of argon protective gas, a 0.5 M solution of ammonia in dioxane (4000 μl, 2021 μmol; 10 eq.) and triethylamine (20.4 mg, 202 μmol; 1 eq.) were added to 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (100 mg, 202 μmol) at room temperature, and the mixture was stirred for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (56 mg, 58% of theory).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](O)Cc1ccccc1
Yield: 561.6 %

Procedure:
A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDCl3); δ7.36-7.20 (m, 5 H), 4.47 (ddd, J=5, 6, 7 Hz, 1 H), 3.78 (s, 3 H), 3.14 (dd, J=5, 14 Hz, 1 H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:18]3[CH2:20][CH2:21][CH:22]([CH2:24]Br)[O:23][C:17]=3[CH:16]=[CH:15][C:14]=2[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(OCC)(=O)C.CO.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:18]3[CH2:20][CH2:21][CH:22]([CH2:24][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[O:23][C:17]=3[CH:16]=[CH:15][C:14]=2[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc3c(c2c1C(=O)OCc1ccccc1)CCC(CBr)O3
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1[nH]c2ccc3c(c2c1C(=O)OCc1ccccc1)CCC(CN1CCCC1)O3
Reaction time: 18 h
Yield: 39.9 %

Procedure:
7-Bromomethyl-2-methyl-3,7,8,9-tetrahydro-pyrano[3,2-e]indole-1-carboxylic acid benzyl ester (0.160 g, 0.390 mmol, 1 eq) was suspended in dry acetonitrile (10 mL) under Ar. Potassium iodide (catalytic) was added followed by the addition of pyrrolidine (0.125 mL, 1.50 mmol, 3.75 eq). The reaction mixture was stirred and heated to reflux. The reaction was followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 18 hours, the reaction was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate /methanol/triethylamine 87/10/3. 0.063 g (40% yield) of the indole-pyrrolidine was obtained as a white solid. This was converted to the .HCl salt, LC/MS (ESI+) 405 (M+1), Anal. (C25H28N2O3.HCl.0.2 DMF) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CON
Reactant: O=CCc1ccc(F)cc1
Agent: Cl
Product: CON=CCc1ccc(F)cc1
Yield: 43 %

Procedure:
Reaction of 4-fluorophenylacetaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (43% yield). 1HNMR indicated a 1:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.51 (2H, d, J=6.7 Hz, CH2), 3.66 (2H, d, J=5.5 Hz, CH2), 3.88 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.79 (1H, t, J=5.5 Hz, CH), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics), 7.45 (1H, t, J=6.7 Hz, CH).