Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]([F:40])([F:39])[C:13]1[CH:14]=[C:15]([CH2:23][C:24]([N:26]2[C@@H:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][O:28][C:27]2=[O:38])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.I[CH3:42].[Cl-].[NH4+]>O1CCCC1>[O:25]=[C:24]([N:26]1[C@@H:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][O:28][C:27]1=[O:38])[C@H:23]([C:15]1[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=[C:13]([C:12]([F:11])([F:39])[F:40])[CH:14]=1)[CH3:42]
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 19.3 mL) was added slowly to a stirred, cooled (−78° C.) solution of (4S)-3-[3,5-bis(trifluoromethyl)benzeneacetyl]-4-(phenylmethyl)-2-oxazolidinone (Description 36, 7.25 g, 16.8 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred at −78° C. for 1 hour. Iodomethane (21 mL, 33.6 mmol) was added and the mixture was stirred at −78° C. for 30 minutes, at 0° C. for 1 hour, then at room temperature overnight. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane:EtOAc (90:10 increasing to 85:15), to give the title compound as a colorless oil (5.14 g, 69%). 1H NMR (360 MHz, CDCl3) δ 7.84 (2H, s), 7.78 (1H, s), 7.38–7.27 (3H, m), 7.23–7.21 (2H, m), 5.26 (1H, q, J 7.0 Hz), 4.68–4.64 (1H, m), 4.19–4.15 (2H, m), 3.34 (1H, dd, J 3.3, 13.3 Hz), 2.83 (1H, dd, J 9.5, 13.3 Hz), and 1.60 (3H, d, J 7.0 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc(C(N)=O)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred, cooled (0° C.) solution of 3′-methoxybiphenyl-3-carboxylic acid amide (0.57 g; 2.5 mmol) in dry CH2Cl2 (28 mL), under N2 atmosphere, a 1M solution of BBr3 in CH2Cl2 (6.4 mL) was added. The mixture was stirred at room temperature for 1 h, quenched with 2N Na2CO3 and extracted with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification of residue by column chromatography (cyclohexane/EtOAc 2:8) gave the desired product as an amorphous solid. Yield 91%. Mp: 148-51° C. (after digestion with i-Pr2O). MS (EI): m/z 213 (M+, 100%). 1H NMR (CDCl3/d6-DMSO): δ 6.06 (br s, 1H); 6.59 (m, 1H); 6.85 (m, 2H); 7.01 (t, 1H); 7.23 (t, 1H); 7.35 (br s, 1H); 7.45 (m, 1H); 7.60 (m, 1H) 7.88 (s, 1H); 8.80 (s, 1H) ppm. IR (Nujol): 3314, 3141, 1669, 1630, 1607, 1577 cm−1.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([C:21]1[C:30]([C:31]#[N:32])=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:40]=[CH:41]/[CH:42]=O)[CH:27]=2)[N:22]=1)[CH:18]([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[C:21]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:22][C:23]2[C:28]([C:29]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[CH:27][C:26](/[CH:40]=[CH:41]/[CH:42]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:25][CH:24]=2)#[N:32]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/C=O)cc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.90 g, 10.2 mmol) in tetrahydrofuran (50 ml) was added sodium hydride (60% in oil, 408 mg, 10.2 mmol) at 0° C. and the mixture was stirred for 10 min. To the reaction mixture was added 2-isobutyl-4-(4-methylphenyl)-6-[(1E)-3-oxoprop-1-en-1-yl]quinoline-3-carbonitrile (3.00 g, 8.47 mmol). The temperature of the mixture was raised to room temperature and the mixture was stirred for 10 min. The reaction mixture was diluted with a mixture of tetrahydrofuran and ethyl acetate, washed successively with 2N aqueous sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals. The crystals were washed with diisopropyl ether to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (2.71 g, yield 75%) as yellow crystals. The solvent of the mother liquor was removed under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (320 mg, yield 9%) as yellow crystals.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[CH:22]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 402.39 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:39]=[CH:38][C:29]2[NH:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([CH3:36])([CH3:35])[C:28]=2[CH:27]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[N:7][C:2]([NH:25][C:26]2[CH:39]=[CH:38][C:29]3[NH:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([CH3:36])([CH3:35])[C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2Nc2nc(Cl)ncc2Cl)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-c4nc(C(F)(F)F)c[nH]4)n3)cc21
Yield: 26.5 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-(4-trifluoromethyl-1H-imidazol-2-yl)-phenyl]-amine (50.0 mg, 0.134 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (27.0 mg, 0.132 mmol) and 10-Camphorsulfonic acid (31.0 mg, 0.133 mmol) were suspended in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The reaction mixture was then reduced under nitrogen and the crude residue was isolated and purified by prep HPLC to afford 18.95 mg (26%) of the desired product as a TFA salt. LC/MS (ESI): 558.26. 1H NMR (400 MHz, DMSO, d6) δ 9.46 (s, 1H), 9.39 (s, 1H), 8.96 (m, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.97 (m, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 7.21 (m, 1H), 6.91 (d, 1H, J=8.59 Hz), 2.16 (m, 2H), 1.98 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[S:14]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 84.5 %

Procedure:
A 500 mL eggplant-shaped flask was charged with diethylene glycol 13 (15.0 mL, 155 mmol) and pyridine (300 mL), and p-toluenesulfonyl chloride (68.0 g, 351 mmol) was gradually added thereto in an ice bath. The mixture was stirred for 4 hours in the ice bath. Thereafter, a 1-L Erlenmeyer flask containing ice was charged with the reaction solution, and a concentrated hydrochloric acid (220 mL) was added thereto in the ice bath to adjust its pH to 4. The reaction mixture was subjected to suction filtration, and thereafter the residue was dissolved in chloroform. The mixture obtained was dried over anhydrous magnesium sulfate and concentrated, to give a product 12 (54.4 g, 131 mmol) in the form of a white solid (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18]([N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)c1
Yield: 26.5 %

Procedure:
1-(2-(1-(3,5-Dimethoxyphenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (300 mg, 1.62 mmol), N,N-diisopropylethylamine (418 mg, 3.24 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 21 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (231 mg, 27% yield). 1H NMR (400 MHz, CDCl3): δ 9.30 (d, 1H), 7.59 (d, 1H), 6.48 (s, 2H), 6.33 (s, 1H), 6.13 (d, 1H), 5.68 (s, 1H), 4.44 (m, 1H), 3.43 (m, 4H), 3.25 (m, 2H), 3.20 (m, 2H), 1.59 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C27H34F3N3O5: 537.25; Observed: 560.3 (M++Na).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.S(=O)(=O)(O)O.O.[C:20](=O)([O-])[O-].[K+].[K+]>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:20])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1n[nH]c2ncccc12
Temperature: 70 °C

Procedure:
2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetic acid (317 mg a crude) was dissolved in 15 mL methanol, and concentrated sulfuric acid 0.5 mL was added dropwise. It was heated to 70° C. and reacted for 12 hours. The reaction was monitored to be complete by LC-MS. 50 mL water was added, and the pH was adjusted to be weak basic with potassium carbonate. Methanol was rotate evaporated. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotate evaporated to dryness to obtain a light yellow solid 250 mg, at a yield over two steps of 73.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[N:56][CH:55]=[N:54]1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][N:53]2[CH:57]=[N:56][CH:55]=[N:54]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1nc[nH]n1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (k) the (3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with [1,2,4]triazol and sodium hydride in N,N-dimethylformamide to yield the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 784 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8])([CH3:4])[CH3:3].[C:14](#[N:16])[CH3:15]>>[O:5]=[C:2]([NH:8][C@H:7]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:13])[CH2:9][CH:10]([CH3:11])[CH3:12])[CH2:1][CH2:15][CH:14]1[CH2:9][CH2:7][C:6](=[O:13])[NH:16]1
Reactant: CC#N
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)C[C@H](NC(=O)CCC1CCC(=O)N1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of 7.0 g (0.05 mol) of dihydro-1H-3,5(2H,6H)dioxopyrrolizidine in 150 ml of acetonitrile is treated with 14.05 g (0.075 mol) L-Leucine 1,1-dimethylethyl ester. The mixture is refluxed 24 hours. The solution is concentrated under reduced pressure and the resulting oil is chromatographed over silica gel using elution with 2.5% methanol in dichloromethane. After concentration at reduced pressure, the oil is rechromatographed over silica gel using 19:1 dichloromethane:methanol. The eluate is concentrated at reduced pressure and heated at 80° C. to yield N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)-propyl]-L-leucine, 1,1-dimethylethyl ester as an analytically pure oil with the following characteristic proton NMR spectrum: 1H-NMR(CDCL3) 0.92(d, 6H), 1.42 (s, 9H), 1.4-1.9 (m, 5H), 2.2-2.4 (m, 7H), 3.5-3.8 (m, 1H), 4.2-4.5 (m, 1H), 6.25-6.5 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.[Mn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1-c1ccc(F)cc1
Agent: [Mn]
Solvent: ClCCl
Product: Cc1nc(C=O)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol is dissolved in methylene chloride. Mangan (IV) oxide is added and the reaction mixture is stirred at room temperature for 3 days. The suspension is filtered through a dicalite speed plus pad and the desired compound (4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.O>C(OC(C)=O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([O:25][C:5]([CH3:10])([CH3:6])[CH3:4])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (˜2.78 mmol) in t-BuOAc (14 mL) was added 70% perchloric acid (HClO4) (334 μL, 5.56 mmol). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 7.62 (m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59 (s, 3H), 1.19 (t, J=7 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([CH3:33])=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:28](OCC)=[O:29])[S:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]>C(O)C>[Cl:3][C:4]1[C:5]([CH3:33])=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH2:28][OH:29])[S:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(CO)n3)n2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Sodium borohydride (14.21 mg, 0.376 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-ethyl 4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate (86 mg, 0.188 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to 7 and the mixture was evaporated. DCM and a few drops of methanol were added and the crude product was washed with 1M Na2CO3 and with water. Yield 89%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 2.53 (s, 3H), 4.23 (dd, 1H), 4.40 (dd, 1H), 4.49 (m, 1H), 4.75 (d, 2H), 6.21 (t, 1H), 6.62 (d, 1H), 7.64 (dd, 1H), 7.82 (dd, 1H), 7.85 (d, 1H), 8.13 (s, 1H), 8.43 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=O)C.[NH4+].[OH-]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.150 g, 2.01 mmol) in MeOH (100 mL) was added 28% aq. NH4OH solution (0.7 mL). The mixture was stirred at RT for 20 h. The solid was collected via filtration and dried under vacuum to give tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.800 g, 1.51 mmol, 75%). HPLC retention time 6.57 mins.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:35])=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:35])=[N:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(OC(C)C)ccc1Br
Product: Cc1nc(OC(C)C)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-bromo-6-isopropoxy-2-methyl-pyridine (Intermediate 25) in analogy to Example 1a): MS (ISP): 453.2 and 455.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26](Br)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)C1=O
Yield: 22.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 250 mg, 1.412 mmol) was reacted with 5-bromo-indole-1-carboxylic acid tert-butyl ester (0.499 g, 1.691 mmol), 1,4-dioxane (15 mL), copper iodide (0.0080 g), trans-1,2-diamino cyclohexane (0.0241 g, 0.2110 mmol) and potassium carbonate (0.389 g, 2.818 mmol) to afford the crude product. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 125 mg of 5-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-indole-1-carboxylic acid tert-butyl ester (24% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Li+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.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>[CH3:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)cc1-c1ccccc1

Procedure:
To a suspension of product from step B (14 g; 47 mmol), 2M Na2CO3 (61.1 ml; 122.2 mmol) phenylboronic acid (6.3 g; 51.7 mmole) and LiCl (3.98 g; 94 mmol) in toluene (400 ml), was added, under argon atmosphere, a solution of tetrakis(triphenylphosphine)palladium (1.01 ml; 1.88 mmol) in THF (150 ml). The mixture was refluxed overnight, washed with 2N, NaOH and saturated NaCl. The organic phase was evaporated and the residue purified by flash chromatography (AcOEt/Petroleum ether: 95/5) to give methyl 4-methyl-2-phenylbenzoate as an oil (10.44 g; 98%).