Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.[N+]([O-])(O)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:33][CH2:32]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:31]5[CH2:32][CH2:33][CH:34]([C:37]([N:39]6[CH2:43][CH2:42][CH2:41][CH2:40]6)=[O:38])[CH2:35][CH2:36]5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Reactant: O=C(C1CCNCC1)N1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(N5CCC(C(=O)N6CCCC6)CC5)cc4s3)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (35 mg, 0.081 mmol), piperidin-4-yl(pyrrolidin-1-yl)methanone nitrate salt (39.5 mg, 0.162 mmol), sodium tert-butoxide (31.0 mg, 0.323 mmol), and BINAP (1.0 mg, 1.61 mmol) in toluene (1 mL) was added Pd2(dba)3 (4.5 mg, 5 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to rt, diluted with water (3 mL), and extracted with EtOAc (3×4 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 100% EtOAc) to afford (1-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone (6 mg, 10.66 μmol, 13% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.2 Hz, 2H), 7.57 (dd, J=8.9, 2.3 Hz, 1H), 7.23-7.18 (m, 1H), 7.09-7.03 (m, 1H), 5.47-5.37 (m, 1H), 4.28-4.18 (m, 2H), 3.78-3.62 (m, 4H), 3.58-3.48 (m, 4H), 2.77 (t, J=12.1 Hz, 2H), 2.55-2.46 (m, 1H), 2.45-2.40 (m, 2H), 2.24-2.14 (m, 2H), 2.12-1.82 (m, 10H), 1.64-1.58 (m, 2H), 0.97 (td, J=7.3, 2.5 Hz, 3H). LCMS (m/z)=535 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C)C=O>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 82.2 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil 92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, 4-methylbenzylbromide (426 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(4-methyl-benzyl)-3-nitro-1H-pyrazole (316 mg, 82%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 2.36 (3H, s), 5.32 (2H, s), 6.87 (1H, d, J=2.3 Hz), 7.19 (4H, s), 7.34 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:15])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2Br)=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:15])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][C:21]=1[Cl:23])=[O:4]
Reactant: COC(=O)c1c2cccc(Br)c2nn1C
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 35a (0.750 g, 2.79 mmol), 2,4-dichlorophenyl boronic acid (1.06 g, 5.57 mmol), 10 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine) palladium(0) (0.097 g, 0.084 mmol), and 10 mL of a 2 M aqueous Na2CO3 solution was stirred at 85° C. overnight, then allowed to cool. Ethyl acetate (50 mL) was added, and the mixture was washed with 30 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow oil. Column chromatography (0→10% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35b: 0.582 g; 62%; m.p. 128-131) as a white solid:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3]C1.C(C[C:10]([O:12][CH2:13][CH3:14])=[O:11])#N.C(=O)C>C(O)(=O)C.O>[C:6](/[C:5](=[CH:4]\[CH3:3])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:1]
Reactant: CCOC(=O)CC#N
Reactant: C1CCNCC1
Agent: CC=O
Solvent: O
Solvent: CC(=O)O
Product: C/C=C(\C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 cm3 of piperidine are added dropwise to a solution of 64 cm3 of ethyl cyanoacetate and 34 cm3 of acetaldehyde in 80 cm3 of acetic acid. After stirring for 20 hours at ambient temperature, the reaction mixture is diluted with 200 cm3 of water and extracted with ether (3×200 cm3). The combined organic phases are washed with water and then dried over sodium sulphate and evaporated. Distillation under reduced pressure (97° C./10 torr) of the residue obtained allows 40.44 g of the expected product to be obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([CH3:27])=[CH:10][C:11]([CH3:26])([CH3:25])[NH:12]2)(=[O:4])[CH:2]=[CH2:3].[CH2:28](Br)[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][CH2:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([CH3:27])=[CH:10][C:11]([CH3:26])([CH3:25])[N:12]2[CH2:30][CH:29]=[CH2:28])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCc1c(-c2ccccc2OC)ccc2c1C(C)=CC(C)(C)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1c2ccc(-c3ccccc3OC)c(COC(=O)C=C)c2C(C)=CC1(C)C
Temperature: 60 °C
Reaction time: 96 h
Yield: 41 %

Procedure:
A mixture of 5-acryloyloxymethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 1-7, 50 mg, 0.14 mmol), allylbromide (111 μL, 1.28 mmol) and potassium carbonate (78 mg, 0.56 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 60° C. for 4 days. After cooling down, it was diluted with ethyl acetate (25 mL). The whole was washed with water (30 mL, twice) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (23 mg) as a pale yellow oil. (Yield 41%)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.036 g, 0.1 mmol), 3-fluoro-benzoyl chloride (14.6 μL, 0.12 mmol) and triethylamine (18.1 μL, 0.13 mmol)) in methylene chloride (2 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 455 as a tan solid in 85.4% yield. LCMS m/z (%)=487 (M+H79Br, 97), 489 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 9.71 (bs, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.66 (s, 1H), 7.63-7.57 (m, 1H), 7.46 (t, J=8.7 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.45-4.21 (m, 2H), 3.68 (s, 3H), 3.51-3.42 (m, 2H and water), 3.43-3.20 (m, 2H), 2.93-2.60 (m, 2H), 1.97-1.68 (m, 4H).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:13]=1[N+:20]([O-:22])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(-c2ccccc2)s1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1sc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
2-Ethoxalylamino-5-phenylthiophene (2.75 g, 10 mmol) was dissolved in 20 ml of acetic anhydride, cooled to -15° C., and treated with a solution of 0.63 ml (10 mmol) of fuming nitric acid dissolved in 5 ml of acetic acid over a period of 30 minutes. After 10 minutes at this temperature, the solvents were evaporated, and traces of acetic acid were removed by stripping with toluene. The solid residue was suspended in 50 ml of ethanol, and 50 ml of water was slowly added. The mixture was stirred overnight, and the precipitate was isolated by filtration to yield 2.62 g (82%) of 2-ethoxalylamino-5-phenyl-3-nitrothiophene, melting at 139°-144° C. 1H-NMR (DMSO-D6, δ): 1.3 (t, 3H), 4.4 (q, 2H), 6.9 (t, 1H), 7.0 (t, 2H), 7.8 (d, 2H), 8.0 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl.[Br:15]Br>[Fe]>[Br:15][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:10])([F:11])[F:1])=[CH:5][CH:6]=1
Reactant: FC(F)(F)Oc1ccccc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Trifluoromethoxybenzene 6c (11.35 g, 70 mmol) was dissolved in 3.57 mL liquid bromine, followed by addition of iron (0.24 g). The reaction mixture was stirred for 16 hours at 100° C. 450 mL of dichloromethane were added and the organic extract was washed with 6 M hydrochloric acid (140 mL), 10% sodium hydrogen sulfite solution (140 mL) and saturated sodium chloride solution (140 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-bromo-4-(trifluoromethoxy)benzene 6d (14.1 g, yellow solid), yield: 83.8%. 1H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.11-7.09 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)-2-hydroxyethanone (18 mg, 0.048 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (18 mg, 0.062 mmol) followed by formation of the dihydrochloride salt to afford the desired product (9.1 mg, 33%) as an off-white solid. 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.13 (s, 2H), 5.78-5.68 (m, 1H), 4.91 (s, 2H), 3.10 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.49-2.42 (m, 2H), 2.10-2.00 (m, 3H), 1.76-1.66 (m, 2H), 1.48-1.36 (m, 2H).; ESI MS m/z 503 [M+H]+; HPLC>99% (AUC), tR=9.40 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1>[Cu]>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])=[CH:10][C:11]=1[F:16]
Reactant: Oc1ccccn1
Reactant: Nc1ccc(Br)cc1F
Agent: [Cu]
Product: Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
The process described in patent US2005/0215599, i.e. copper catalyzed N-arylation of 2-hydroxypyridine with 4-bromo-2-fluoroaniline suffers from a major safety issue.
Reaction SMILES: [Na].[C:2]1([C:8]2[N:9]=[C:10]([CH2:19]P(=O)(OC)OC)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([C:28]1[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)=O>CO.O>[C:2]1([C:8]2[N:9]=[C:10]([CH:19]=[CH:26][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)OC
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)COc1ccc(C=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reaction time: 0.17 h

Procedure:
Sodium metal (570 mg, 25 mg atom) was dissolved in methanol (50 mL) and dimethyl [(4,5-diphenyl-2-oxazolyl)methyl]phosphonate (7.80 g, 22 mmol) added. The mixture was stirred for 10 minutes before adding methyl (4-formylphenoxy)acetate (4.00 g, 20 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with water and a yellow solid filtered off and air dried to give crude product (3.80 g, 44%). This was combined with 3.50 g from a previous experiment and recrystallized twice from methanol to afford analytically pure methyl [4-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate, m.p. 122°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33]C)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h

Procedure:
220 mg (0.46 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylic acid amide is dissolved in 5.0 ml of dichloromethane and mixed with 9.2 ml of a 1N boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding methanol. The solvent is removed in a vacuum, the residue is taken up in saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-100%), 60 mg (28% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=3)=[CH:27][N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OCCn1cc(-c2ccc(Cl)nc2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(-c4cn(CCO)nn4)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-[4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl]ethanol (72 mg, 0.32 mmol) as starting materials.
Reaction SMILES: C(OCC)C.C([O:8][C:9](=O)[CH2:10][C:11]1([CH2:31][C:32](O)=[O:33])[S:15][C:14]2[CH:16]=[C:17]3[S:21][C:20]([CH2:26][C:27](O)=[O:28])([CH2:22][C:23](O)=[O:24])[S:19][C:18]3=[CH:30][C:13]=2[S:12]1)C.C(O)C>O>[OH:28][CH2:27][CH2:26][C:20]1([CH2:22][CH2:23][OH:24])[S:19][C:18]2[CH:30]=[C:13]3[S:12][C:11]([CH2:31][CH2:32][OH:33])([CH2:10][CH2:9][OH:8])[S:15][C:14]3=[CH:16][C:17]=2[S:21]1
Reactant: CCOC(=O)CC1(CC(=O)O)Sc2cc3c(cc2S1)SC(CC(=O)O)(CC(=O)O)S3
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: OCCC1(CCO)Sc2cc3c(cc2S1)SC(CCO)(CCO)S3
Temperature: 25 °C

Procedure:
A dry flask under argon atmosphere was charged with diethyl ether (2600 ml) and LiAlH, (21.2 g 0.56 mol). Benzo[1,2-d:4,5-d']bis(1,3)dithiole-2,2,6,6-tetraacetic acid ethyl ester (80.2 g, 0.139 mol) was added and the mixture was refluxed for 26 h. The mixture was cooled to ambient temperature and ethanol (165 ml) was carefully added followed by water (410 ml). The ether was decanted off and the white precipitate was stirred with water (3300 ml) to give a slurry. After acidification with hydrochloric acid the slurry was filtered and the crude product was washed with water and dried. Yield: 55.0 g (97%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>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.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
2,4-Dichloropyrimidine (50.0 g, 333 mmol) and 1-ethynyl-4-fluorobenzene (40.0 g, 333 mmol) were added to triethylamine (200 mL) at 25° C. To the reaction mixture were added dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol) and copper iodide (1.0 g, 5.2 mmol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 h. The residue was partitioned between water (400 mL) and dichloromethane (400 mL). The organic layer was washed with water (2×400 mL), dried (MgSO4) and evaporated under reduced pressure to give an oil. Flash chromatographic purification on silica gel with 0 to 50% ethyl acetate/hexanes as eluant gave 69.5 g of the title compound as a light brown solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:21]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1cccc(C2(O)CCCN(C(=O)CCc3ccccc3)C2)c1

Procedure:
The compound of Example 53 was prepared according to the general preparation protocol A from 3-phenyl-propionyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[C:12]=[O:13]>C1COCC1>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:13]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cc1ccccc1CN=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)n1[nH]c2ccccc2c1=O

Procedure:
105 mg (0.78 mmol) of 1H-indazol-3-ol were reacted in 3 ml of THF with 138.3 mg (0.94 mmol) of 1-isocyanatomethyl-2-methylbenzene to give 3-oxo-1,3-dihydroindazole-2-carboxylic acid 2-methylbenzylamide. 50 mg (178 μmol) of this compound were stirred in 3 ml of pyridine with 40 mg (355 μmol) of triethylamine and 43 mg (266 μmmol) of 4-methylpiperidine-1-carbonyl chloride at room temperature for 7 h. Addition of a further 120 mg of 4-methylpiperidine-1-carbonyl chloride and 100 mg of triethylamine in 3 portions was followed by stirring again for 7 h, concentration and purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 48 mg (66%), M+H+: 407.15.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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]>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1ncc2ccnc(-c3cnn(C)c3)c2n1
Yield: 112.8 %

Procedure:
A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33, 480 mg, 2.268 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (940 mg, 4.52 mmol) and Pd(dppf)Cl2.DCM (100 mg, 0.122 mmol) was dissolved in THF (15 mL) and 2M sodium carbonate in water (5 mL) and heated to 65° C. for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 4% MeOH in DCM to give the title compound (658 mg, quant).