Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:14]=1)[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A DMF (4 mL) solution containing Na2CO3 (60 mg, 0.57 mmol), 4-chloro-2-fluoro-1-nitrobenzene (100 mg, 0.57 mmol) and methyl 4-hydroxybenzoate (87 mg, 0.57 mmol) was stirred at room temperature for 8 hours. HPLC analysis indicated ca. 85% product. The reaction solution was stirred for an additional 2 hours at 40° C. The solution was then diluted with ethyl acetate and washed with 1N NaOH. The organic phase was washed with water (3×), brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.1 Hz, 2H); 8.01 (d, J=8.2 Hz, 1H); 7.31-7.27 (m, 1H); 7.11-7.07 (m, 3H); 3.95 (s, 3H). LCMS1 3.66 min. (M+H)=308.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]\[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]\[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: O=C(O)/C=C\Cl
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C\Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-3-chloroacrylic acid (5.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol), cooled to 0° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49 g, 0.78 mmol, 50% solution of EtOAc). The resulting mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (15 mg, yield: 63%). 1H NMR (400 MHz, CDCl3) δ X; MS (ESI): 551.0 [M+H]+.
Reaction SMILES: C1(N2C(=O)C3=CNC4[CH:14]=[C:15]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)C=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]3[C:33]([C:38](=[O:48])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[N:40]=3)=[CH:34][NH:35][C:36]=2[CH:37]=1.CN1CCNCC1>>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:48])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:15][CH2:14]5)[CH:29]=[CH:30][C:31]=4[C:32]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Reactant: Nc1ccc2c3nn(-c4ccc(Cl)cc4)c(=O)c-3c[nH]c2c1
Agent: CN1CCNCC1
Product: CN1CCN(c2ccc3c4nn(-c5ccc(Cl)cc5)c(=O)c-4c[nH]c3c2)CC1

Procedure:
The title compound was prepared following the procedure for 14a using 13b and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.39 (3H, s), 2.67 (4H, brm), 3.40 (4H, brm), 7.01 (1H, d, J=2.47 Hz), 7.34 (1H, dd, J=9.07, 2.47 Hz), 7.46 (2H, dd, J=6.87, 2.20 Hz), 8.09 (2H, dd, J=7.14, 1.92 Hz), 8.19 (1H, d, J=9.07 Hz), 8.51 (1H, s). m/z 394.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12]OC(OC)(OC)C>CCOC(C)=O>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: COC(C)(OC)OC
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
To 5,6-dichloronicotinic acid (2.2 g) was added 1,1,1-trimethoxyethane (4.3 mL), followed by irradiation with microwave at 120° C. for 15 minutes. The reaction mixture was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4 and the vehicle was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=85:15 to 80:20) to obtain methyl 5,6-dichloronicotinate (2.2 g) as a white solid.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:15]([Cl:23])=[CH:16][C:17]([C:18]#[N:19])=[CH:20][C:21]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(/N=C/c2cncc(F)c2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.0 g, 12.0 mmol), 4-amino-3,5-dichlorobenzonitrile (2.25 g, 12.0 mmol) and triethylamine (5.0 mL, 36.1 mmol) in DCM (48 mL) was added titanium tetrachloride (1M in DCM, 7.2 mL, 7.2 mmol) dropwise over 20 minutes. The reaction mixture was stirred for 20 minutes, warmed to room temperature, and stirred for a further 30 minutes. The resultant mixture was concentrated to dryness under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][N:17](CC3C=CC=CC=3)[CH2:16]2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][NH:17][CH2:16]2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CN(Cc3ccccc3)CC2O)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CNCC2O)n1

Procedure:
A suspension of [6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester I-3 (0.002 mol) and 10% Pd—C (0.7 g) in MeOH (30 mL) was stirred at 45° C. under hydrogen overnight. Then, the catalyst was removed by filtration and washed with MeOH (30 mL). The filtrate was concentrated to give II-1. Most of the product was used in the next reaction without further purification (100%). Some was purified by column chromatography (silica gel, CH2Cl2:MeOH:Et3N, 6:30:0.1) to determine NMR and mass spectrum.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:21]3[CH:22]=[C:17]([CH3:16])[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(NC(C)=O)c(C)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ncc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1C

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[ClH:16]>>[Cl:16][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 2.19 g (0.0104 mole) of methyl 2-(4hydroxymethylphenoxy)propionate and 3.00 g (0.0823 mole) of 36% hydrochloric acid was stirred for fifteen minutes at room temperature. The reaction mixture was then poured into ice-water, and the resulting mixture was extracted with diethyl ether. The extracts were combined and washed in succession with water and a saturated aqueous solution of sodium bicarbonate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a colorless liquid. This liquid was placed on a column of silica gel and eluted with methylene chloride. After the product-containing fractions were combined and the solvent evaporated under reduced pressure, 1.6 g of methyl 2-(4-chloromethylphenoxy)propionate was isolated as a colorless liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][C:12](=O)[C:13]([OH:15])=[O:14]>[NH4+].[OH-].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[NH:8]2
Reactant: O=C(O)C(=O)Cc1c(F)cccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c(F)cccc2[nH]1
Yield: 21.6 %

Procedure:
A solution of 32 (4.8 g, 31 mmol) in 4% NH4OH (60 mL) was added to a suspension of ferrous hydroxide that was prepared from ferrous sulfate heptahydrate (52.45 g, 188.7 mmol) and concentrated NH4OH (23 mL) in water (200 mL). The mixture was maintained at the boiling point for five minutes. The ferric hydroxide was separated by filtration and washed repeatedly with dilute NH4OH and water. The filtrate was acidified with dilute HCl. The resulting solid was collected by filtration to afford 1.2 g (22%) of 4-fluoro-1H-indole-2-carboxylic acid (34) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: c1ccoc1
Reactant: COCCCCCC(=O)O
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCCCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In 50 ml of toluene were dissolved 7.31 g (0.05 mole) of 6-methoxyhexanoic acid, 4.43 g (0.065 mole) of furan and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 8.83 g of 2-(6-methoxyhexanoyl)furan.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: CN1CCCC[C@H](N)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
(S)-3-Amino-1-methylazepan-2-one hydrochloride (0.112 g, 0.627 mmol) was dissolved in triethylamine (0.238 mL, 1.71 mmol) and N,N-dimethylformamide (3 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 253 mg, 0.570 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by flash chromatography on a silica gel column, eluting with 60% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (If) (208 mg, 78%). Mass spec: 471 (M+1). 1H NMR (CDCl3) δ 9.15 (br, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.21 (m, 1H), 6.99 (m, 2H), 6.92 (m, 1H), 4.91 (ddd, 1H), 4.21 (d, 2H), 3.67 (dd, 1H), 3.22 (dd, 1H), 3.04 (s, 3H), 2.35 (m, 1H), 2.21 (m, 1H), 2.05-1.81 (m, 3H), 1.54 (m, 1H), 1.45 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: CS[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2>[Ni].C(O)C>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[CH:11]2
Reactant: CSc1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2[nH]ccc2c1
Reaction time: 1.5 h

Procedure:
Combine moist Raney nickel (330 g), 2-methylthio-5-trifluoromethyl-1H-indole (33.8 g, 146.2 mmol) and absolute ethanol (850 ml) and stir. After 1.5 hours, filter the mixture through celite and wash the celite with ethanol (500 ml). Evaporate the filtrate to dryness, add toluene (20 ml) and evaporate and dry to give 5-trifluoromethylindole: mp=55–60° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>>[Br:1][C:2]1[N:7]=[C:6]2[C:5]([C:11](=[O:13])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCNc1cccc(Br)n1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=C1CCNc2nc(Br)ccc21
Temperature: 75 °C
Yield: 34 %

Procedure:
3-(6-Bromo-pyridin-2-ylamino)propionic acid (5.0 g) was combined with Eaton's reagent (100 mL) in a ratio of 5 g 3-(6-bromo-pyridin-2-ylamino)propionic acid per 100 mL Eaton's reagent. The resulting mixture was heated at 75° C. for 2.5 hours. Ice cold water (50 mL) was added to the reaction mixture, followed by aqueous NaOH (50% w/w) to pH 12. The mixture was then extracted twice with ethyl acetate (200 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel chromatography using a gradient of 0-80% ethyl acetate/hexane as the eluting solvent to give the title compound as a yellow solid (34% yield). M.p. 196-197° C., LCMS: m/z=227.26 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 2.57 (t, J=7.2 Hz, 2H), 3.34-3.49 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.96 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(C)=CC=CC=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 86 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 12 g of sodium carbonate in 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., 0.1 mol % of a catalyst solution prepared as described in Example 2 was added. After the reaction was complete, 50 ml of xylene were added and the organic phase was separated off. Distillation gave 18.1 g of 2-cyano-4'-methylbiphenyl (b.p. 140° C./mbar).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:5]2[N:6]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:7][CH2:8][CH2:9]/[C:10](=[N:11]/[C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)/[C:4]=2[CH:3]=1.CC1C=C(C)C2N(C(OCC3C=CC=CC=3)=O)CCC=C(NC3N=NN(C)N=3)C=2C=1.C1(C)C=CC=CC=1>>[CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:5]2[N:6]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)/C(=N\c1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Agent: Cc1cc(C)c2c(c1)C(Nc1nnn(C)n1)=CCCN2C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)[C@@H](Nc1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
Charge an autoclave with a mixture of (Z)-benzyl 7,9-dimethyl-5-(2-methyl-2H-tetrazol-5-ylimino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate and (E)-benzyl 7,9-dimethyl-5-(2-methyl-2H-tetrazol-5-ylamino)-2,3-dihydro-1H-benzo[b]azepine-1-carboxylate (4.04 g, 10 mmole), S-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl((S)-BINAP, 60 mg, 96.3 μmoles), KI (415 mg 24 mmoles, KI can be deleted if desired) and di chloro-bis((1,2,5,6 eta)-1,5-cyclooctadiene)diiridium (Ir2Cl2(COD)2 (927 mg 40.2 μmoles). Purge the autoclave with nitrogen. While maintaining an oxygen free environment, add degassed toluene (50 mL, 472.8 mmol) and seal the autoclave. Heat to 100° C. under 500 psi H2 for 66 h. Cool the reaction mixture to RT and vent. Filter the solids and collect the organic mixture. Wash the organic mixture with water (2×25 mL); dry over Na2SO4, and filter. Collect the filtrate and remove the solvent under vacuum to provide the title compound (3.99 g, 88.7% ee by HPLC).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([NH2:17])[CH:4]=[N:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:17][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)[N:28]=1
Reactant: Cn1ncc(N)c1N1CCNC(C(F)(F)F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.4 %

Procedure:
To a solution of (±)-1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-amine (300 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (516 mg, 1.73 mmol), HATU (0.54 g, 1.73 mmol) in DMF (15 mL) was added TEA (1.1 mL). The reaction mixture was stirred at 25° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-2-(2,6-difluorophenyl)-4-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (380 mg, 52%) as white solid. MS (ESI) m/z: 588 (M+1+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:19][CH2:20][CH3:21].C(O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCC2=O)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCC1(c2cccc(OC)c2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 2-(3-methoxy-phenyl)-cyclohexanone (2.04 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added over 10 min to a mixture of sodium hydride (0.29 g, 12.0 mmol) in N,N-dimethylformamide (4 mL), the temperature being kept below 30° C. The reaction mixture was stirred at 20-25° C. for 2 h. A solution of 1-iodo-propane (1.17 mL, 12.0 mmol) in N,N-dimethylformamide (2 mL) was added over 10 min at 20-25° C. The mixture was stirred for 18 h, and then, ethanol (2 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with water, and dried over sodium sulfate. Solvents were removed under reduced pressure and the remaining oil was purified by column chromatography on silica gel using heptane/diethyl ether (4:1, v/v) as eluent to give the title compound (0.74 g, ca. 30%) as pale-yellow oil. MS ISP (m/e): 247.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:32])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 41A (100 mg, 0.30 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (69 mg, 0.42 mmol) to yield 75 mg (56%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]C)=[CH:8][CH:7]=1.B(O[O-])=[O:15].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](=[S:12]=[O:15])[CH2:8][CH:7]=1
Reactant: CSc1ccc(OCCCCl)cc1
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S=C1C=CC(OCCCCl)=CC1

Procedure:
The title compound is prepared by treating 1-(3-chloropropoxy)-4-methylthiobenzene with sodium perborate in glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (181.5 mg, 1 mmol, intermediate A-2) and DDQ (227 mg, 1 mmol) in dioxane (3 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was treated with satd. aq. NaHCO3 solution, and then extracted with ethyl acetate (2×10 mL). The organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo to afford a crude product which was then purified by silica gel flash chromatography to give title compound (108 mg, 60%) as a white solid. MS: 180.0 (M+H+).