Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=[CH:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 93.3 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylvinyl)indol-1-ylmethyl]-3-methoxybenzoate (1.11 g) in methanol (10 ml) was treated with 10% (w/w) palladium on carbon (0.28 g) and shaken under 3.45 bars of hydrogen for 24 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (1.04 g, 94%) as a grey foam, mp 58°-60°.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[O:9])=[CH:6][CH:5]=1)[CH3:2].[CH2:28]([O:30][C:31]1[CH:43]=[CH:42][C:34]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH:32]=1)[CH3:29]>>[CH2:1]([N:3]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]2([N:35]([C:34]3[CH:42]=[CH:43][C:31]([O:30][CH2:28][CH3:29])=[CH:32][CH:33]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:13])[O:9]2)=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CCOc1ccc(Nc2ccccc2)cc1
Product: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(CC)Cc4ccccc4)cc3)OC(=O)c3ccccc32)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 2 but employing 5.4 g of 2-[4-(ethylbenzylamino)benzoyl]-benzoic acid and 3.1 g of 4-ethoxy-N-phenylaniline there was obtained 7.5 g of 3-[4-(ethylbenzylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide, m.p. 163°-173° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>COCCOC.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.O>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A suspension of tert-butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.04 g), phenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium (0.42 g) and sodium carbonate (0.77 g) in 1,2-dimethoxyethane (25 mL)-water (25 mL) was stirred at 105° C. for 12 hr. After cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.97 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:27][CH3:28])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+]=[N-])[O:17][C:16]3=[O:24])=[CH:11][C:10]=2[F:25])[CH2:5][CH:4]1[F:26]>[Pd].C(OCC)(=O)C>[CH3:28][O:27][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH2:21])[O:17][C:16]3=[O:24])=[CH:11][C:10]=2[F:25])[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
The suspension of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-azide (25.2 mmol) and 10% palladium on carbon (1.0 g) was in ethyl acetate (150 ml) was stirred at a room temperature under hydrogen atmosphere for 10 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified on silica gel column chromatography to provide title compound in 76% yield.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:12]1([N:11]2[C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([C:31]#[N:32])=[CH:3][CH:4]=3)=[CH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[N:10]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cc3ccc(Br)cc3)n(C3CCCCC3)n2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 651 mg 5-(4-bromobenzyl)-1-cyclohexyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step C Example 11, 95.7 mg zinc cyanide, 62.9 mg tetrakis(triphenylphosphine)palladium(0) in 2.5 mL DMF was heated under nitrogen in 80° C. oil bath for 24 hours. Evaporate most of DMF. The residue was purified on silica gel using 1 and 3% MeCN in methylene chloride to give the title compound as a yellow foam. 1H NMR (CDCl3, 600 MHz) δ 7.78˜7.81 (m, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.215 (d, J=8.3 Hz, 2H), 6.25 (s, 1H), 4.09 (s, 2H), 3.83 (tt, J=3.9 & 11.7 Hz, 1H), 1.96˜2.03 (m, 2H), 1.85˜1.89 (m, 2H), 1.73˜1.77 (m, 2H), 1.68˜1.71 (m, 1H), 1.23˜1.33 (m, 3H). LC-MS: 2.63 min. (M+H=426).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:16]([CH2:17][C:18]([O:20]CC)=[O:19])=[C:15]([CH3:23])[N:14]=[C:9]12.CO>O>[C:18]([CH2:17][C:16]1[N:8]2[CH:7]=[CH:6][C:5]3[C:10]([C:9]2=[N:14][C:15]=1[CH3:23])=[CH:11][CH:12]=[CH:13][C:4]=3[Cl:3])([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1c(C)nc2c3cccc(Cl)c3ccn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CC(=O)O
Yield: 74.2 %

Procedure:
A solution of sodium hydroxide (1.25 g) in water (5 ml) was added to a mixture of 7-chloro-3-ethoxycarbonylmethyl-2-methylimidazo[2,1-a]isoquinoline (4.75 g) and methanol (48 ml) and the mixture was refluxed for 1.5 hours. After being cooled, the mixture was evaporated in vacuo and 1N hydrochloric acid (31.4 ml) was added to the residue under ice-cooling. The resulting precipitate was collected by filtration, washed with water, dried in a desiccator and washed with a mixture of ethanol and methanol to give 3-carboxymethyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]([NH2:36])=O)=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:39])=O.Cl>ClCCl>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:19]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]#[N:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(N)=O)s3)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C#N)s3)ccc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Add 5-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl)thiophene-2-carboxamide (79 mg, 0.16 mmol) and phosphoryl chloride (13 mL, 139.9 mmol) to a round bottom flask under nitrogen. Warm the resulting mixture to 100° C. and stir for 15 min. Cool the mixture to room temperature and concentrate in vacuo to give a yellow residue. Carefully quench the resulting residue with methanol and load onto an SCX acidic ion exchange column. Flush the column with methanol then elute desired material with 2M ammonia in methanol. Concentrate the ammonia containing eluent in vacuo to give a pale yellow solid. Dissolve the resulting solid in dichloromethane and treat with HCl (1M in ether, 5 mL). Concentrate in vacuo to obtain the title compound (81.5 mg, 0.16 mmol) 1H NMR (d6-DMSO) δ 0.82-0.73 (m, 1H), 1.33-1.23 (m, 4H), 2.88-2.80 (m, 2H), 3.36-3.31 (m, 5H), 3.81 (s, 3H), 4.23-4.19 (m, 2H), 6.73-6.63 (m, 2H), 6.87-6.77 (m, 2H), 7.15-7.09 (m, 1H), 7.41-7.36 (m, 1H), 7.62-7.54 (m, 1H), 7.87-7.77 (m, 3H), 8.09-8.05 (m, 1H), 10.58-10.45 (m, 1H).
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:6]=[C:7]2[C:13]([CH:14]=O)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1.C(=O)(O)[O-].[Na+]>CO>[Br:4][C:5]1[CH:6]=[C:7]2[C:13]([C:14]#[N:2])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (46 mg) was added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde obtained by the method of described in WO 2004/101565 (150 mg) in methanol (1.0 ml) under nitrogen atmosphere, and the mixture was stirred at room temperature for one hour. After azeotropic distillation with toluene, thionyl chloride (118 μl) was added to a suspension of the residue in toluene (2 ml), and the mixture was stirred at 80° C. for 16 hours and at 100° C. for 8 hours. After leaving to cool to room temperature, saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (88 mg).
Reaction SMILES: [K].[CH3:2][C:3]([OH:6])([CH3:5])[CH3:4].[I:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:18]CC(=O)C[CH2:14]2)[CH:12]=1.[Cl-].C[S+](C)(C)=O.CCOC(C)=O>CS(C)=O>[I:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:5][C:3]3([O:6][CH2:4]3)[CH2:2][CH2:14]2)[CH:12]=1
Reactant: CC(C)(C)O
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CCC3(CC2)CO3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methyl-propan-2-ol potassium (466 mg; 4.15 mmol; 1.2 eq.) was added in one portion to a solution of 4-(4-Iodo-pyrazol-1-yl)-cyclohexanone (1.02 g; 3.50 mmol; 1.0 eq.) and trimethylsulfoxonium chloride (531 mg; 4.13 mmol; 1.2 eq.) in DMSO (50 mL). The reaction mixture was stirred at RT for 16 h. It was then poured into EtOAc. Organic phase was separated and washed with brine (three times), dried over magnesium sulfate, filtered and concentrated to give the title compound a white solid (813 mg, 76%). 1H NMR (300 MHz, DMSO) δ 8.01 (d, J=0.5 Hz, 1H), 7.52 (d, J=0.5 Hz, 1H), 4.41-4.26 (m, 1H), 2.66 (s, 2H), 2.13-1.85 (m, 6H), 1.34-1.21 (m, 2H). MS (ESI+): 305.1.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol (68 mg, 50% yield). Rfsm=0.72; Rfp=0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457, found 457.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (388 mg, 1.83 mmol) was added to a DCE solution (2 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (330 mg, 0.92 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (186 mg, 0.92 mmol), and AcOH (0.21 mL, 3.66 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:8]=2)[O:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:8]=2)[O:3]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 40 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
550 mg of (RS)-methyl 4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoate, dissolved in 40 ml THF/10 ml H2O/10 ml methanol, was treated with 600 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 10 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 40 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 20 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by trituration in acetonitrile, providing 510 mg of a pale yellow solid, m.p. 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2C=[CH:25][CH:24]=[CH:23][C:20]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:29]([O:32]CC)(=[O:31])[CH3:30]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:20]=[CH:23][CH:24]=[CH:25][C:30]=2[C:29]([OH:32])=[O:31])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:15])[CH3:16])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Nc2cc(Nc3ccccc3C#N)c(Cl)cn2)n(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccccc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (80 g, 218 mmol) was dissolved in 1,4-dioxane (1.5 L) and 1 M NaOH (1500 mL, 1500 mmol) was added. The suspension was refluxed overnight. After cooling to RT, ethyl acetate (1 L) was added and layers were separated. The water layer was washed with 1 L of ethyl acetate. Both organic layers were combined and backwashed with 0.1 M NaOH (1 L) until no product was observed in organic. The organics were then discarded. Combined aqueous were then washed with 1 L of ethyl acetate. The water layer was then acidified with acetic acid (very slowly to ph˜7). The solid was filtered and 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (67 g, 165 mmol, 76% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.57 Hz, 6H) 2.11 (s, 3H) 4.41 (quin, J=6.57 Hz, 1H) 5.96 (s, 1H) 6.83 (s, 1H) 7.09 (ddd, J=8.02, 5.12, 3.03 Hz, 1H) 7.40 (1H) 7.52-7.61 (m, 2H) 7.91-8.16 (m, 2H) 8.55 (s, 1H) 10.17 (brs, 1H) 13.64 (brs, 1H); HPLC Rt=2.35 min, MS (ESI): [M+H]+=386.1.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].[OH-].[Na+].CC(OC)(C)C>O>[CH2:1]([O:8][C:9]([NH:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCCC(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CSCCC(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
51 ml benzyloxycarbonyl chloride was dripped into a solution of 50 g (0.34 mole) DL-methionine amide in 200 ml water at 5-20° C., during which the pH was maintained at 7-9 with sodium hydroxide solution. A slimy precipitate formed immediately which became finely crystalline upon the addition of 200 ml MTBE. After the end of the addition the mixture was agitated 30 min further at room temperature. The precipitated, colorless crystals were then filtered off, washed with a little MTBE and recrystallized out of 700 ml toluene. After filtering off, washing with toluene and drying, 67 g (69%) Nαbenzyloxycarbonyl-DL-methionine amide with a melting point of 120-122° C. was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])[O:29][CH:30]=1>>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1/[CH:32]=[CH:31]/[C:28]1[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=2)[N:27]=1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 62.3 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol(204 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (223 mg).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH:11]=O)=[C:9](Cl)[N:8]=[CH:7][N:6]=1.[N+](C)([O-])=O.C(=O)=O.C(N(CC)CC)C>CO>[Cl:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]2[NH:2][N:3]=[CH:11][C:10]=12
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: NN
Agent: O=C=O
Solvent: C[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Clc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
Hydrazine hydrate (2.0 ml, 41 mmol) was slowly added to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (7.2 g, 41 mmol) in MeOH (150 ml)-60° C. (nitromethane-dry ice bath) followed by triethylamine (6.8 mL, 49 mmol). The mixture was allowed to warm to rt and stirred for 2 h. MeOH was removed in vacuo and water (150 mL) was added. The mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered through a glass funnel. Removal of solvent gave 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (4.45 g, 71%). MS (ESI, pos. ion) m/z: 155 [M+H]+