Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]([O:16]CC)=[O:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
Ethyl 2-(4-fluoro-N-methylphenylsulfonamido)acetate (2.27 g) was dissolved in THF (20 mL) and 0.5 N LiOH solution (20 mL) was added. The mixture was stirred at room temperature for 5 h. Solvents were evaporated and the residue was dissolved in water, filtered and acidified with hydrochloric acid. The white solid was filtered to give [(4-fluoro-benzenesulfonyl)-methyl-amino]-acetic acid (1.68 g). LRMS calcd for C9H10FNO4S (m/e) 247.0; obsd 246.1 (ES−).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].[CH2:11]([NH:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)[CH3:12].O>C(OCCO)C>[CH2:11]([N:13]1[C:14]2[N:15]=[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:17]=[CH:18][C:19]=2[CH:20]=[C:8]([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:9]1=[NH:10])[CH3:12]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: N#CCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: CCn1c(=N)c(-c2cccs2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 2-thiopheneacetonitrile (168 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added, and the reaction heated at 120° C. for 2 hours, resulting in a dark brown solution. Upon cooling, the solution was poured into water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 370 mg (85%) of (8-ethyl-7-imino-6-thiophen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 204°-205° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CNCCOC
Product: COCCN(C)CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and N-(2-methoxyethyl)methylamine (TCI America) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2[(M+H)+] 557.2352, observed 557.2357.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1.O.O1[CH2:35][CH2:34]OCC1>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>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:35]2[CH:34]=[N:4][CH:3]=[CH:2][N:1]=2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(Br)c2)c1N
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(-c3cnccn3)c2)c1N
Yield: 63 %

Procedure:
A solution of 3-[5-amino-4-(3-bromobenzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide (60 mg), 2-tributyltinpyrazine (120 uL) and tetrakis(triphenylphosphine)palladium(0) (30 mg) in 1,4-dioxane (0.8 mL) was heated under microwave radiation at 160° C. for 25 min. Water (3 ml) was added and the mixture was extracted with ethyl acetate (4 mL×2). Evaporation of the solvent and purification by preparatory TLC (EtOAc: MeOH=10:1) gave the desired product (38 mg, 63%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 439.27 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][N:13](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[CH:3][C:4]=1[Cl:11])(=[O:10])[CH3:9]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: CC(=O)c1ccc(C#N)cc1Cl
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 59 mg of zinc, 528 mg of zinc cyanide, 2.1 g of 1-(4-bromo-2-chlorophenyl)ethanone and 367 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 10 ml N,N-dimethylacetamide is stirred for 4 h at 160° C. The reaction mixture is allowed to cool down to room temperature and stirred for 14 h at room temperature. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (n-hexane/ethyl acetate, 85/15 (v/v)) to yield the title compound.
Reaction SMILES: CN(/C=[N:5]/[C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([NH:36][S:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)(=[O:39])=[O:38])=[CH:8][N:7]=1)C.Cl>O1CCOCC1>[NH2:5][C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([NH:36][S:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:39])=[CH:8][N:7]=1
Reactant: COc1cc(-c2csc3c(NS(=O)(=O)c4cccs4)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(NS(=O)(=O)c4cccs4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 13 h
Yield: 43.7 %

Procedure:
N-(4-{4-{[(1E)-(dimethylamino)methylene]amino}-7-[(thien-2-ylsulfonyl)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (prepared by reaction 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 with 2-thiophenesulfonyl chloride according to General Procedure G) (0.021 g, 0.033 mmol) was dissolved in dioxane (1 mL), and aqueous hydrochloric acid (6 M, 1 mL) was added. The mixture was stirred at 50° C. for 13 h, cooled to ambient temperature, and quenched with aqueous sodium carbonate (1 M, 10 mL). The mixture was extracted with methanol/dichloromethane (1:9, 3×20 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) afforded the title compound as a white foam (0.0085 g, 45%): 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (br, 1H), 9.49 (s, 1H), 7.97 (d, 1H), 7.80 (m, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.47 (s, 1H), 7.40 (m, 1H), 7.37 (s, 1H), 7.34 (m, 2H), 7.17 (s 1H), 7.14 (d, 1H), 7.07 (m, 2H), 5.35 (br, 2H), 4.03 (s, 3H), 3.90 (s, 3H); MS: (M−H)−588.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:28][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCNCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCNCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
A mixture of 2-(3-fluoro-5-piperazin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 0.43 mmol), lithium hydroxide hydrate (0.18 g, 4.3 mmol), water (2 mL) in methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-fluoro-5-piperazin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (49 mg, 30%) as a white solid: LC/MS m/e calcd for C22H26FN3O2 (M+H)+: 384.5, observed: 384.1.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:6][CH:5]=[C:4]([CH2:25][OH:26])[N:3]=1.C([O-])(=O)C.[K+].[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34].CCOCC>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.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>[OH:26][CH2:25][C:4]1[N:3]=[C:2]([CH:34]=[CH:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CCCCCCCCOc2ccc(CO)nc2Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2C=CC(=O)OC(C)(C)C)cc1
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-6-hydroxymethyl-[8(4-methoxyphenyl)octyloxy]pyridine (5.00 g, 11.8 mmol) in DMF (22.8 ml) and water (1.2 ml) were added potassium acetate (3.00 g, 30.6 mmol), tetra-n-butylammonium iodide (4.36 g, 11.8 mmol), bis(triphenylphosphine)palladium dichloride (0.33 g, 0.47 mmol) and t-butyl acrylate (6.16 g, 48 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 45 min. The mixture was cooled and added to water (250 ml). The product was extracted into ethyl acetate (2×60 ml). The combined extracts were washed with water (100 ml), 5% sodium chloride solution (2×100 ml), then dried and evaporated. The product was obtained by flash column chromatography using silica and 10% ether in dichloromethane. Yield 4.29 g, 77%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1

Procedure:
4-Phenylimidazole was treated with ethyl 8-bromooctanoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 56°-57° C., Found: C, 72.8; H, 8.4; N, 9.0%; C19H26N2O2Requires: C, 72.6; H, 8.3;N, 8.9%
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=2[CH:24]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH:21][CH2:22][C:23]3[CH:40]=[CH:39][C:26]4[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=4[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Reactant: O=Cc1ccc2c(c1)CCC(=O)N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)CCC(=O)N4Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205 g) was added to a methanol solution (10 ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H, 5H)-dione (0.213 g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (0.400 g) as a white amorphous. 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.77-2.81 (2H, m), 2.96-3.00 (2H, m), 3.40 (3H, s), 3.73 (2H, s), 3.74-3.83 (1H, m), 3.81 (2H, s), 4.12-4.17 (1H, m), 5.17 (2H, s), 6.83 (1H, d, J=8.3 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.16 (1H, d, J=1.6 Hz), 7.19-7.25 (6H, m), 7.27-7.33 (2H, m)
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][OH:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 6 h
Yield: 85.7 %

Procedure:
A solution of 17.15 g (50 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 4.40 ml (75 mmol) of propargylalcohol in 32 ml of toluene and 64 ml of triethylamine was heated under nitrogen to 80-5° C. with 175.4 mg (250 μM) of bis(triphenylphosphine)palladium (II) chloride and 8.6 mg (4.5 μM) of copper (1) iodide. After 6 hours, the solid was filtered off and washed with dichloromethane. The solution was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl, sodium bicarbonate solution, and water. The ethyl acetate was removed in vacuo, the residue (15.46 g) was dissolved in dichloromethane and filtered through 60 g of silica gel to give the title compound (13.64 g, 85.8%), mp 165-9° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CCO>[C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a stirred suspension of 420 mg (0.71 mmol) of (RS,SR)-2-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-isoindole-1,3-dione in 50 mL of EtOH, was added 0.10 mL (2.13 mmol, 3 eq) of hydrazine hydrate. The reaction mixture was heated to 80° C. for 3 hours, before it was partitioned between EtOAc and aqueous HCl 1N. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with CH2Cl2/MeOH 95:5 afforded 210 mg (64%) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine light brown solid, MS: 461 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH:18]([CH2:21][CH3:22])[CH2:17][NH:16][C:15](=[O:23])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:21]([CH:18]1[CH2:17][NH:16][C:15](=[O:23])[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:11]=[CH:10]4)[NH:20][C:19]1=2)[CH3:22]
Reactant: Nc1ccccc1
Reactant: CCC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CCC1CNC(=O)c2cc(-c3cccc4ccc(Nc5ccccc5)nc34)[nH]c21
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(2-chloroquinolin-8-yl)-7-ethyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 22; 0.075 g, 0.230 mmol) and aniline (0.105 ml, 1.151 mmol) was treated with LHMDS (1.0 M in THF; 1.151 ml, 1.151 mmol) at RT. After 2 h, the reaction was concentrated, then dissolved in DMSO and treated with TFA (0.089 ml, 1.151 mmol). This material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.055 mmol, 23.85% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (1H, br. s), 9.53 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.96 (1H, dt, J=7.5, 0.6 Hz), 7.53-7.67 (3H, m), 7.39 (2H, t, J=7.8 Hz), 7.29 (1H, t, J=7.6 Hz), 7.03-7.15 (2H, m), 6.86-6.95 (2H, m), 3.46-3.61 (1H, m), 3.06-3.21 (1H, m), 2.58-2.71 (1H, m), 1.15-1.32 (2H, m), 0.66 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 383.0 (M+H)+. A portion of this material was resolved by chiral SFC (Chiralpak IC (21×250 mm, 5 μm); additive in supercritical fluid CO2 was 50% MeOH with 20 mM NH3; 60 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers (R)-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 25) and (S)-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one. (Example 26).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=O)[CH2:3][CH2:2]1.[NH2:17][CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)O>>[C:27]1([C:18]2[N:17]=[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[O:9][C:19]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1

Procedure:
Starting from 1.08 g of mono-tert-butyl piperidine-1,4-dicarboxylate and 1 g 2-amino-1,2-diphenyl-ethanol the product may be prepared as described in the literature (cf. Tet. 2001, 4867). The product is purified by chromatography (method B). 560 mg are obtained in the form of an oil. Analytical HPLC-MS (method A): RT=1.72 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:13][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:10][N:5]2[C:6](=[O:9])[C:7]=1[F:8].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[F:8][C:7]1[C:6](=[O:9])[N:5]2[CH2:10][CH2:11][C@@H:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:4]2=[N:3][C:2]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=c1c(F)c(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: C1COCCN1
Solvent: CC#N
Product: O=c1c(F)c(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reaction time: 8 h

Procedure:
The product can be prepared according to the procedure described in Example 16, stage b, but using 1 g of (8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one in 5 ml of acetonitrile, and 1.6 ml of morpholine. After a period overnight at 65° C., 1.1 g of (8S)-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: OCCc1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
6-(2-Hydroxyethyl)-indole (72.5 mg, 0.45 mmol) was mixed with Et3N (126 mg, 1.35 mmol) in 2 ml of dichloromethane at 0 to 5° C. Methane sulfonyl chloride (61.6 mg, 0.54 mmol) was added and the mixture stirred for 1 hr, diluted with dichloromethane, washed with brine, dried and concentrated to give 107 mg of the title compound (quantitative yield).
Reaction SMILES: N1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1.N>>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=c1cccn[nH]1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2CCCC2=O)cc1

Procedure:
The title compound was prepared using the procedure described in Example 35B substituting pyrrolidin-2-one for pyridazin-3(2H)-one and substituting the product from Example 35A for the product from Example 34F. 1H NMR (300 MHz, CD3OD) δ 0.89-0.96 (m, 1H), 1.01-1.08 (m, 1H), 1.22 (d, J=6 Hz, 3H), 1.25-1.30 (m, 1H), 1.48-1.55 (m, 1H), 1.8-1.89 (m, 4H), 2.03-2.27 (m, 4H), 2.57 (t, J=6 Hz, 2H), 2.65-2.74 (m, 1H), 3.22 (q, J=6 Hz, 1H), 3.33-3.40 (m, 1H), 3.89 (t, J=6 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 299 (M+H)+.