Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[C:14]([O:34]C(=O)C)=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[C:14]([OH:34])=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2O)=C(C)C1=O
Yield: 67.2 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline (0.075 g, 0.145 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.048 g, 0.0975 mmol, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:33]2[C:41]3[C:36](=[CH:37][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:40]=3)[CH2:35][CH2:34]2)=[O:32])[CH:27]=[CH:28][CH:29]=1.C([O-])(O)=O.[Na+].N#N>O1CCOCC1.O.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[C:3]2[C:10]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:33]([C:31](=[O:32])[CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:34][CH2:35]4)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To 1,1-dimethylethyl 3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (200 mg, 0.543 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (246 mg, 0.652 mmol) dissolved in 1,4-Dioxane (4 mL) was added Sat NaHCO3 (2 mL). The mixture was then bubbled N2 gas for 10 minutes then added Pd(Ph3P)4 (62.8 mg, 0.054 mmol) then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was let cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to give an amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane using a gradient of 0 to 10% MeOH in DCM for 30 minutes to isolate 1,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (197 mg, 0.366 mmol, 67.3% yield) as a amber color solid. LC-MS (ES) m/z=539.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.18 (m, 2H), 7.60 (s, 1H), 7.37 (s, 1H), 7.28 (d, J=8.34 Hz, 1H), 7.20-7.26 (m, 1H), 7.06-7.15 (m, 3H), 5.76 (s, 1H), 5.46-5.56 (m, 1H), 4.33 (d, J=8.08 Hz, 4H), 4.21 (t, J=8.46 Hz, 2H), 3.93 (s, 1H), 3.83 (s, 2H), 3.22 (t, J=8.21 Hz, 2H), 2.31 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:11]>>[Br:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1
Reactant: N
Reactant: CSc1cc(Br)nc(Br)c1
Product: CSc1cc(N)nc(Br)c1
Temperature: 140 °C

Procedure:
A mixture of 0.500 g 2,6-dibromo-4-methylsulfanyl-pyridine and 10 ml 25% aqueous ammonia was heated in an autoclave to 140° C. for 24 h. The solvent was evaporated and the residue was purified by chromatohraphy on silica gel with heptane:ethyl aceate=1:1 to yield 0.300 g of the title compound as white crystals. MS (ISP) M+H+=219.1; 221.1
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.CCO.Cl.C([Cl:36])(=O)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[O:20][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1.[ClH:36]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2cc(Cl)cc(Cl)c2)c2ccccc2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCO
Product: Clc1cc(Cl)cc(O[C@H](c2ccccc2)[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester (14.0 g, 33.1 mmol) was dissolved in EtOH (100 mL, 2 mol). Into the mixture was added an HCl solution prepared by the slow addition of acetyl chloride (23.6 mL, 331 mmol) into EtOH (50 mL, 860 mmol) at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, EtOAc (200 mL) was added, followed by removal of most of the solvent. EtOAc (50 mL) was added, the solution was heated to 75° C. for 15 minutes, cooled to room temperature, filtered and dried to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (10.5 g, >99% purity).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7](C)[C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.Cl.O1CCOC[CH2:20]1>>[NH2:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[C:12]([CH3:20])[CH:13]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-acteylamino-2-methyl-3-nitro-benzoic acid (4.8 g, 20.2 mmol) and 6 M HCl (aq) (150 mL) in 120 mL dioxane was stirred for 15 min at 105° C. The mixture was cooled, filtered and washed with water.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[C:21]([CH3:29])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:30]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[CH3:29][C:21]1[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([CH2:1][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:30][C:7]=3[CH:8]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)ccc2[nH]ccc12
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C)CC4)ccc3o2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (800 mg, 2.04 mmol) in a mixture of CH2Cl2 (40 mL) and NMP (5 mL) at room temperature under nitrogen was added N-methylpiperazine (613 mg, 6.12 mmol) followed by glacial acetic acid (674 mg, 11.22 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (2.38 g, 11.22 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 5 h. The reaction mixture was partitioned between CH2Cl2 and aqueous 1N HCl. The aqueous layer was washed with CH2Cl2 and treated with aqueous 1N NaOH whereupon solids precipitated. The solids were collected and dissolved in CH2Cl2. The solution was washed with water thrice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (MeOH/CH2Cl2, 6% to 7.5%) to give 560 mg (58%) of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl}nicotinonitrile as a yellow solid. HPLC retention time: 5.9 min.(g); melting range: 162-165° C. (decom.); and HRMS: 477.24093.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[F:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:10][C:11]1[N:16]=[CH:15][C:14]([N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: OB(O)c1ccc(F)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Two reactions were set up in parallel. For each of them, to a solution of 5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 11.71 mmol) in dry dichloromethane (100 mL), (6-fluoro-3-pyridinyl)boronic acid (1.980 g, 14.05 mmol), copper(II) acetate (2.126 g, 11.71 mmol) and pyridine (1.420 mL, 17.56 mmol) were added. The reaction was left under stirring under air atmosphere at room temperature overnight. The two reaction mixtures were combined and the solid was filtered off. The resulting solution was washed with water (90 mL). The aqueous phase was extracted twice with dichloromethane (twice 90 mL). The organic phases were combined and washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent afforded a residue which was purified by silica gel chromatography (Biotage system, 100 g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 65/35 to 50/50 to afford the title compound as a white solid (1.27 g).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH2:9][CH2:8][N:7](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:6][C:5]=2[N:4]=1.[ClH:39]>CO.O1CCOCC1>[ClH:39].[F:38][C:2]([F:1])([F:37])[C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2

Procedure:
A solution of the product (145 mg) from Step A in 0.5 mL of methanol and 2.5 mL of 4.0M hydrogen chloride in dioxane was kept at room temperature for 3 h. The reaction mixture was concentrated under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a light red powder. LC/MS 275.1 (M+1).
Reaction SMILES: [Br-:1].[Li+].[OH:3][C@@H:4]1[C@H:8]2[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:7]2[O:6][CH2:5]1.C(Cl)Cl>CN(C=O)C>[Br:1][C@H:11]1[CH2:10][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:8]2[C@@H:4]([OH:3])[CH2:5][O:6][C@H:7]12
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](Br)[C@H]2OC[C@H](O)[C@H]21
Temperature: 130 °C
Yield: 52.6 %

Procedure:
Lithium bromide (11.51 g, 132 mmol) was added to a stirred solution of tosylate (35b) (5.28 g, 13.2 mmol) in anhydrous DMF (75 mL) and the mixture heated at 130° C. for 4 hours. The black solution was left to cool to ambient temperature then reduced in vacuo. The residue was taken into DCM (100 mL) and washed with H2O (100 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a black tar (Yield 3.3 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 5:95 to 30:70 gave bromide (111) (2.14 g, 52.6%) as a pale green solid. TLC (Rf=0.4, EtOAc:heptane 3:1), analytical HPLC main peak, Rt=9.34 min., HPLC-MS 252.1/254.1 [M+H−56]+, 308.1/310.1 [M+H]+; 330.0/332.0 [M+Na]+; [α]D22−90.2° (c=2.33, CHCl3); δC (125 MHz, CDCl3) 28.35/28.44 ((CH3)3C), 48.26/48.75 (BrCHCH), 53.48/54.14 (BocNCH2), 67.78/68.29 (BocNCH), 75.48/75.63 (OCH2CHOH), 75.24/76.08 (OCH2CHOH), 80.78/81.07 ((CH3)3C quarternary), 87.01/87.85 (BrCHCH), 153.83/154.61 (Boc C═O).
Reaction SMILES: C([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[N:11][CH:12]=[C:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:14]=1)C1C=CC=CC=1.[ClH:30].NCCS.Cl>>[ClH:30].[ClH:30].[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:10]2[C:9]([OH:8])=[CH:14][C:13]([S:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][N:11]=2)[S:25][CH:26]=1
Reactant: Cc1csc(Nc2ncc(SCc3ccccn3)cc2OCc2ccccc2)n1
Agent: Cl
Agent: NCCS
Product: Cc1csc(Nc2ncc(SCc3ccccn3)cc2O)n1
Yield: 95 %

Procedure:
A 250 mL round-bottomed flask was charged with 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-2-ylmethylthio)pyridin-2-amine (prepared in Example 46, 6.6 g, 16 mmol), 2-aminoethanethiol hydrochloride (2.7 g, 24 mmol), and 6M HCl (125 mL). The reaction was heated to reflux for 3 hours. The reaction was concentrated on rotary evaporator to about 40 mL and the resultant solids were removed by filtration. The filtrate was further concentrated and the resultant solids were removed by filtration. This procedure was repeated. The solids were combined to afford the title compound (4.6 g, 73% yield) as a white solid. 1H NMR (DMSO-d6) δ 11.63 (bs, 1H), 8.75 (m, 1H), 8.32 (td, 1H), 7.82 (d, 1H), 7.77 (m, 2H), 7.35 (d, 1H), 6.92 (d, 1H), 4.50 (s, 2H), 2.34 (s, 3H). Mass spectrum (apci) m/z=331.1 (M+H-2HCl).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=1)[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>ClCCl>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:28](=[O:29])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:17]=2)[CH:6]=1)[CH3:20]
Reactant: CCOC(OCC)c1cc(-c2ccc(N)cc2)nn1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(OCC)c1cc(-c2ccc(NC(=O)OCc3ccccc3)cc2)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109 %

Procedure:
4-[5-(Diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]aniline (Intermediate 10, 5.9 g, 21.5 mmol), and pyridine (4 ml, 50 mmol) were dissolved in dichloromethane (25 ml) at 0° C. Benzyl chloroformate (3.8 ml, 26.7 mmol) was added slowly over 5 minutes and the resulting mixture was stirred at 0° C. for 30 min. The mixture was diluted with dichloromethane and washed with 1M HCl, saturated NaCl, then dried over sodium sulfate and evaporated give the title compound as a thick light orange oil (9.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](COCC[Si](C)(C)C)[C:9]([CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1[N:30]=[C:29]([N:31]2[CH2:37][C:36]3[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=3[O:34][CH2:33][CH2:32]2)[C:28]2[CH2:27][C:26]([CH3:46])([CH3:45])[CH2:25][CH2:24][C:23]=2[N:22]=1>>[CH3:19][C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([C:39]1[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:29]4[C:28]5[CH2:27][C:26]([CH3:45])([CH3:46])[CH2:25][CH2:24][C:23]=5[N:22]=[C:21]([CH3:20])[N:30]=4)[CH2:37][C:36]=3[CH:38]=1)[CH:3]=2
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Reactant: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as acetate salt according to the method of example 5 by using 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 35) and [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 followed by SEM deprotection. 1H NMR (400 MHz, methanol-d4): 8.52 (d, 1H), 8.05 (d, 1H), 7.63 (d, 1H), 7.50 (dd, 1H), 7.09 (d, 1H), 4.73 (s, 2H), 4.33 (m, 2H), 4.00 (m, 2H), 2.75 (t, 2H), 2.64 (s, 3H), 2.47 (s, 2H), 2.41 (s, 3H), 1.96 (s, 3H), 1.66 (t, 2H), 0.91 (s, 6H); MS (EI) for C27H30N6O: 455 (MH+).
Reaction SMILES: FC(F)(F)C1C=C2C(=CC=1)[N:8](CC1C=CC=C(F)C=1)C(C(O)=O)=C2.[CH:25]1([N:31]=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38]CC[CH2:35]2)[CH2:30][CH2:29][CH2:28]CC1.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:35][C:34]1[N:33]=[C:32]2[CH:28]=[C:29]([NH2:8])[CH:30]=[CH:25][N:31]2[C:39]=1[CH3:38]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(N)ccn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 150.3 %

Procedure:
To a solution, stirred at 20° C. under an inert atmosphere, of 1 g (2.96 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid (WO 2006/072736) in 70 mL of DMF are added 0.74 g (3.56 mmol) of dicyclohexylcarbodiimide (DCC) and 0.48 g (3.56 mmol) of 1-hydroxybenzotriazole hydrate (HOBT). The reaction mixture is stirred at room temperature for 30 minutes. 0.7 g (4.45 mmol) of 2,3-dimethylimidazo[1,2-a]pyrid-7-ylamine, obtained according to the protocol described in step 14.4, and 100 mg of dimethylaminopyridine (DMAP) are then added to the reaction mixture. After stirring for 12 hours at 50° C., the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 50 mL of water and 50 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. The product is isolated after successive purifications by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 50 mg of the expected product are thus obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.CC(C)([O-])C.[K+]>C(O)CCC>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1ccc2cc(CCn3ccnc3)ccc2c1

Procedure:
A mixture of imidazole (1.02 g, 0.015 mol), 2-(2-bromoethyl)naphthalene (3.53 g, 0.015 mol) and potassium tert-butoxide (1.68 g, 0.015 mol) in dry butan-1-ol (100 ml) was stirred and heated under reflux for 29 h.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](OCC)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[F:17])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>ClCCl>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[F:17])[N:3]=1
Reactant: CCOC(=O)c1cc2c(F)cccc2nc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc2c(F)cccc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
A solution of quinolinecarboxylate (obtained in Stage 83f; 1.8 g; 6.7 mmol) in dichloromethane (40 ml) under argon is treated dropwise with diisobutylaluminium hydride (1M in dichloromethane; 20 ml; 20 mmol) at ambient temperature maintained at 10° C. by an ice-cooled water bath. The reaction mixture is agitated for 1 hour at ambient temperature, then poured onto a solution of sodium and potassium tartrate at 20% (200 ml). The resulting mixture is agitated vigorously for 1 hour, then filtered on celite. The filtrate is extracted with dichloromethane (2×100 ml). The combined extracts are washed with water and with a saturated solution of sodium chloride, then dried over magnesium sulphate and concentrated. Purification of the residue by chromatography at medium pressure (SiO2, CH2Cl2/MeOH, 98/2) yields 450 mg of a white solid (m.p.: 176° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([Cl:11])[CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino-3-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[H-].[Na+].I[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][N:6]2[CH3:16]
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.