Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[NH:18][C:17]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=2)=[CH:12][CH:11]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([NH:32][C:28]1[CH:27]=[C:26]([C:17]2[NH:18][C:19]3[C:20](=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:16]=2[C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH:31]=[CH:30][N:29]=1)=[O:6]
Reactant: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccnc(N)c3)[nH]c2c1
Reactant: COC(=O)CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Nc1cc(-c2[nH]c3cc(C)cnc3c2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 15.4 %

Procedure:
Chlorocarbonyl-acetic acid methyl ester (129 mg, 0.9 mmole) is added to a solution of 200 mg (0.62 mmole) of 4-[3-(4-Fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-ylamine (prepared following the procedure for example 7) in 3 mL of pyridine at room temperature. After 30 hours at room temperature, Chlorocarbonyl-acetic acid methyl ester (129 mg, 0.9 mmole) is added again to the reaction mixture stirred 12 more hours at room temperature. The reaction mixture is then poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the solid residue is purified by chromatography on silica gel (ethyl acetate) to give 40 mg of N-{4-[3-(4-Fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-yl}-malonamic acid methyl ester as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[NH:8][S:7]1(=[O:34])=[O:33].[C:41](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[N:8]([CH3:41])[S:7]1(=[O:34])=[O:33]
Reactant: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3N(C)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (approx. 0.115 mmol, 50% purity) of the compound from example 99A were initially charged in 5 ml of DMF, 44 mg (0.138 mmol) of cesium carbonate and 8.5 μl (0.138 mmol) of iodomethane were added and the mixture was stirred at RT overnight. Subsequently, another 14.3 μl (0.230 mmol) of iodomethane were added and the mixture was heated to 50° C. overnight. After cooling, the mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 30.9 mg (46% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:26]1[C:27]2[C:34]([Cl:35])=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:35][C:34]1[C:27]2[C:26]([N:19]3[CH2:18][CH2:17][C:16]([CH3:22])([C:14]([NH:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=5)[CH:8]=4)=[O:15])[CH2:21][CH2:20]3)=[N:31][CH:30]=[N:29][C:28]=2[NH:32][CH:33]=1
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]cc(Cl)c23)CC1
Temperature: 130 °C

Procedure:
N-(3-(4-Fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from step B (50 mg, 0.13 mmol), 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine from step C (19 mg, 0.1 mmol), and triethylamine (0.04 mL, 0.3 mmol) were combined in isopropanol (1 mL) and heated at 130° C. for 30 minutes under microwave conditions. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: [C:1]([CH:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:4]([O:6][CH3:7])=[O:5])#[N:2].IC.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:29])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(±)-tert-Butyl 4-(1-cyano-2-methoxy-2-oxoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-C) (1.1 g, 3.07 mmol) was dissolved in acetone (6.14 ml) and then added iodomethane (0.576 ml, 9.21 mmol) followed by potassium carbonate (0.636 g, 4.60 mmol) and stirred at room temperature for 2.5 hours. The reaction was then cooled in an ice bath and quenched with a saturated aqueous solution of ammonium chloride and diluted with DCM. The layers were separated and the organic layer was dried and concentrated to obtain the title compound. MS (ESI+) m/z 373.4 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][CH:30]([C:33]4[N:34]=[C:35]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5C(OCC5C=CC=CC=5)=O)[NH:36][CH:37]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[NH:19][CH:20]=1)=O)C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>CC1C=CC=CC=1C>[NH:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[NH:36][CH:37]=[C:33]([CH:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:19][CH:20]=[C:16]([C@@H:12]5[CH2:13][CH2:14][CH2:15][NH:11]5)[N:17]=4)=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[N:34]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1c[nH]c(-c2ccc(C3CCC(c4c[nH]c([C@@H]5CCCN5C(=O)OCc5ccccc5)n4)CC3)cc2)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: c1cc(C2CCC(c3c[nH]c([C@@H]4CCCN4)n3)CC2)ccc1-c1nc([C@@H]2CCCN2)c[nH]1
Temperature: 140 °C

Procedure:
To a solution of A5′ (2.5 g, 3.5 mmol) in o-xylene (25 mL) in a sealed tube was added ammonium acetate (4.1 g, 53 mmol). The mixture was sealed and heated at 140° C. for 3 h and then cooled to rt. The volatile component was removed in vacuo, and the residue was partitioned between H2O and CH2Cl2, and the organic phase was dried, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography (CH2Cl2/MeOH=9/1 (v/v)) to provide A6′ as a yellow solid (250 mg, 10% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[C:8]2[C:12](=[O:13])[O:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-:15].[Na+]>CO.O.C(Cl)Cl>[C:10]([NH:9][C:8](=[CH:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12]([OH:11])=[O:13])(=[O:15])[CH3:14]
Reactant: [OH-]
Reactant: CC1=NC(=Cc2ccc(Cl)s2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC(=Cc1ccc(Cl)s1)C(=O)O
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution containing 4-(5-chloro-thiophen-2-ylmethylene)-2-methyl-4H-oxazol-5-one (1.5 g, 6.82 mmol) in MeOH (18 mL) is added 1.0 M NaOH (12.0 mL, 12 mmol) at ambient temperature. After 3 h, the reaction mixture is diluted with water (100 mL) and CH2Cl2 (100 mL) and the layers are separated. The basic, aqueous layer is washed with CH2Cl2 and then acidified using 1.0 M HCl (20 mL) to provide a crude solid which is collected on a Buchner funnel. Drying in vacuo provided 1.2 g (75%) of the title compound as a pale brown solid which is used without further purification. 1H NMR (300 MHz, DMSO-d6) δ2.00 (s, 3H), 7.14 (d, J=4.01 Hz, 1H), 7.38 (d, J=4.01 Hz, 1H), 7.63 (s, 1H), 9.28 (s, 1H), 12.73 (br s, 1H) ppm; MS (EI): m/z 245 (M+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH:9][CH3:10])[O:3]1.[CH3:11][N:12]([CH3:24])[S:13]([C:16]1[S:20][C:19]([N:21]=[C:22]=[O:23])=[N:18][N:17]=1)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:11][N:12]([CH3:24])[S:13]([C:16]1[S:20][C:19]([NH:21][C:22]([N:9]([CH2:8][CH:4]2[O:3][CH:2]([CH3:1])[CH2:7][CH2:6][O:5]2)[CH3:10])=[O:23])=[N:18][N:17]=1)(=[O:15])=[O:14]
Reactant: CNCC1OCCC(C)O1
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Solvent: ClC(Cl)Cl
Product: CC1CCOC(CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(4-methyl-1,3-dioxan-2-ylmethyl)-methylamine (6 grams), 5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams) and chloroform (20 ml) were charged into a glass reaction vessel and stirred at room temperature for a period of about 2 hours. The solvent was then stripped off on a rotary evaporator and the residue treated with a mixture of diethyl ethyl (100 ml)/water (50 ml). The ether, layer was isolated and dried. Ether was stripped off an a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N'-(4-methyl-1,3-dioxan-2-ylmethyl)-N'-methylurea as the residue. Melting point 131° C.-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=O)[CH3:15]>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[C:7](=[O:11])[NH:8][C:9]2[CH:10]=[C:2]3[C:3](=[CH:4][C:5]1=2)[CH:15]=[C:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH:1]3
Reactant: CC(=O)c1cccs1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cccs4)cc3cc21

Procedure:
Analogously to Example 1, 6.8 g. (38 mmole) 6-amino-3,3-dimethylindolin-2-one are diazotised and reduced. Into the solution are added dropwise 10.9 g. (85 mmole) 2-acetylthiophene and the oil which separates out is taken up in methylene chloride, dried and evaporated. As crude product, there are obtained 11.2 g. 2-acetylthiophene-(3,3-dimethyl-2-oxoindoline-6-hydrazone) which is further reacted without purification.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>C1COCC1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]([NH:1][C:16]([O:18][CH3:19])=[O:17])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)Cl
Reactant: NC(C(=O)O)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)O)c1ccccc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Amino-(2-fluoro-phenyl)-acetic acid (0.5 g, 2.44 mmol) was dissolved in THF (7 mL) and cooled to 0° C. in an external ice/brine bath. Aqueous sodium hydroxide (12.5M, 0.47 mL, 5.856 mmol) and methyl chloroformate (0.23 mL, 2.948 mmol) were added at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid as an off-white solid. LCMS-ESI+: calc'd for C10H10FNO4: 227.06 (M+); Found: 228.17 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Yield: 80.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) in acetonitrile (8 mL) with 4-(4-bromophenylsulfonyl)morpholine (148 mg) was treated with aqueous sodium carbonate (2M, 0.5 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h under nitrogen. The reaction mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 100:0) to afford the sub-titled compound (240 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[N:7]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[C:11]([C:18]4[NH:26][C:25]5[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=5[CH:19]=4)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:35])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[N:16][C:15]2[C:10]([N:9]=1)=[C:11]([C:18]1[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=1)[CH:12]=[CH:13][CH:14]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 19 %

Procedure:
A solution of tert-butyl 3,3-dimethyl-4-(8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)piperazine-1-carboxylate (27 mg, 0.057 mmol) and TFA (4.36 μl, 0.057 mmol) in DCM (567 μl) was stirred at RT for 20 min. Purification by silica gel (100% DCM to 8% [2 M NH3 in MeOH]/DCM) provided 2-(3-(2,2-dimethylpiperazin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (19% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 2.32-2.35 (m, 1H) 2.66-2.71 (m, 2H) 2.86 (t, J=6.94 Hz, 2H) 2.95-2.99 (m, 1H) 3.44 (td, J=6.75, 2.35 Hz, 2H) 3.60 (t, J=4.9 Hz, 2H) 6.96 (s, 1H) 7.09 (d, J=2.15 Hz, 1H) 7.52 (t, J=7.63 Hz, 1H) 7.73 (d, J=7.04 Hz, 1H) 7.92 (d, J=7.43 Hz, 1H) 8.81 (s, 1H) 11.71 (s, 1H). MS (ESI, pos. ion) m/z: 377.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][O:5][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)CCCC(C)CCO
Reactant: CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCCCCOCCC(C)CCCC(C)C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To 2-L glass flask, 158 g of 3,7-dimethyl-1-octanol, 221 g of 1-bromodecane, 32 g of tetrabutylammonium bromide, and 454 g of aqueous sodium hydroxide (236 g of sodium hydroxide dissolved in 218 g of water) were added, and the mixture was allowed to react under stirring at 70° C. for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH2:11][NH2:12])[CH2:9][CH2:10]2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: N#CC1(c2ccc(Cl)nc2Cl)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: NCC1(c2ccc(Cl)nc2Cl)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 1.50 g of 1-(2,6-dichloro-pyridin-3-yl)-cyclopropanecarbonitrile in dry toluene was added slowly at −10° C. 14.8 mL of diisobutylaluminium hydride. The reaction mixture was stirred at −10° C. for 30 min. Subsequently, 1.90 g of sodium borohydride and 20 ml of methanol were added sequentially. The speed of addition was such as to maintain the temperature of the reaction mixture below −5° C. The resulting reaction mixture was stirred at −10° C. for 30 min before being quenched by the addition of 35 ml of a aqueous saturated solution of sodium potassium tartrate and extracted with three portions of diethyl ether. The organic phases were combined, washed with brine, dried over sodium sulphate, filtered and concentrated. 1.66 g of crude material was obtained as yellow oil which was purified by flash chromatography on silica gel with dichloromethane/methanol (95:5) as a solvent. Thus, 367 mg of C-[1-(2,6-dichloro-pyridin-3-yl)-cyclopropyl]-methylamine was obtained as a colorless oil. 1H-NMR (CDCl3): 7.63 ppm (d, 1H), 7.23 ppm (d, 1H), 2.85 ppm (s, 2H), 1.46 (m, 1H), 0.93 ppm (m, 2H), 0.83 ppm (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[CH:16]=[C:17]([C:37]([O:39][CH3:40])=[O:38])[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:23]=[CH:24][C:25]=3[C:26]=2[N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]3[C:26]4[N:27]=[C:15]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=5)[CH:16]=[C:17]([C:37]([O:39][CH3:40])=[O:38])[C:18]=4[NH:19][C:20]=3[CH:21]=2)[CH2:32][CH2:33]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCCN3CCOCC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OCCN3CCOCC3)ccc12
Temperature: 70 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
A mixture of 3-(trifluoromethyl)phenylboronic acid (51 mg, 0.27 mmol), methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (90 mg, 0.21 mmol), powdered potassium phosphate tribasic (114 mg, 0.539 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol), and Pd(OAc)2 (4.7 mg, 0.021 mmol) in a microwave vial was flushed with nitrogen. THF (1 mL) was added, the vial was capped, and the reaction was heated in a 70° C. oil bath for 18 hr. Additional Pd(OAc)2 (4.7 mg, 0.021 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol) were added, the vial was resealed, and heating was continued for 16 hr. The reaction was filtered and the collected solid was washed with THF. The filtrate was applied onto an SCX column and washed with DCM and then MeOH. Release with 2 N NH3 in MeOH afforded crude methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (107 mg). This was suspended in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial and heated at 80° C. overnight. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aqueous CH3CN; B=10 mM NH4OAc in 95% aqueous CH3CN] over 20 min) followed by removal of the solvents on a SPEEDVAC® gave 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (48 mg, 0.094 mmol, 44% yield) as a yellow solid. MS (ESI) m/z 483.1 (M−H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.51 (1H, s), 8.62 (3H, s), 8.47 (1H, s), 8.16 (1H, d, J=8.55 Hz), 7.92 (1H, s), 7.69-7.83 (2H, m), 7.31 (1H, d, J=1.53 Hz), 6.92 (1H, dd, J=8.70, 1.68 Hz), 4.19 (2H, t, J=5.49 Hz), 3.61 (4H, t, J=4.43 Hz), 2.77 (2H, t, J=5.49 Hz), 2.51 (4H, br. s.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31](OS(C)(=O)=O)C)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=3)=[N:12][CH:13]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CS(=O)(=O)N1CC=C(c2ccc(O)cn2)CC1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)nc2)CC1
Yield: 90.1 %

Procedure:
To a 3-necked flask is added 1′-methanesulfonyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-5-ol (254.3 g, 1.0 mol) followed by 4-(1-methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (396.1 g,1.34 mol) and potassium carbonate (248.8 g, 1.8 mol). Dimethylformamide (3800 mL) is added and the mixture is heated at 80˜90° C. for 6 h. 3810 mL of water are added dropwise at 70˜80° C. The mixture is cooled slowly to 20˜30° C. and filtered. The cake is slurried with 1000 mL of water, concentrated and dried under vacuum to provide 407 g of a solid with 97.13% HPLC purity.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:17]([C:6]1([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)C1CCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one (0.24 g, 1 mmol) (from Example 3b, supra), benzyl bromide (0.21 g, 1.2 mmol), potassium iodide (0.20 g, 1.2 mmol) and potassium carbonate (0.3 g, 2.2 mmol) in acetone (6 mL) was heated at 60° C. for 13 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 3% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one as white prisms. (Yield 0.13 g, 39.2%).