Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(CCC(N[C@H](C(N[C@H](C([NH:37][C@H:38]([C:47]([NH:49][C@H](C(N[C@H](C(O)=O)CC(C)C)=O)C(C)(C)C)=[O:48])[CH2:39][C:40]1[CH:45]=CC=C[C:41]=1C)=O)CCC(=O)OC(C)(C)C)=O)CC(=O)OC(C)(C)C)=O)=O)(C)(C)C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.FC(F)(C)C[C@H](N)C(OC)OC>ClCCl>[NH2:37][C@H:38]([C:47]([NH2:49])=[O:48])[CH2:39][CH:40]([CH3:45])[CH3:41]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: COC(OC)[C@@H](N)CC(C)(F)F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.3 g (0.33 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine was dissolved in 15 ml of dichloromethane. 0.22 ml (1.98 mmol) of N-methylmorpholine, 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 45 mg (0.33 mmol) of hydroxybenzotriazole and 217 mg (0.99 mmol) of 3,3-difluoro-1(S)-(dimethoxymethyl)butylamine hydrochloride were added and the solution was stirred at room temperature for 18 hours. The mixture was washed with 2M hydrochloric acid and aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulphate and evaporated. The residue was triturated with diethyl ether and the resulting solid was filtered off and dried. There were obtained 143 g of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[3,3-difluoro-1(S)-dimethoxymethyl)butyl]-L-leucinamide; MS: m/e 1106 [M+Na]+.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])#[N:19]
Reactant: CCCCCN=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCCCCNC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-n-pentyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 130.4°-131.6° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[N+:1]([C:4]1[C:5]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3,5-dinitro-1-carboxy-2-chlorobenzene (53 g) in acetonitrile (500 mL) and triethylamine (100 mL) was added benzylamine at 0° C. in a dropwise fashion. The reaction was allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to afford the crude product, 3,5-dinitro-1-carboxy-2-(benzyl)aminobenzene. The product was dissolved in methanol/12N HCl (400 mL, 3:1, v/v), and was hydrogenated at 60 psi for 3 hours until H2 intake stopped. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-triamino-1-carboxybenzene. To the product in pyridine (400 mL) was added isobutyric anhydride (200 mL), and the reaction mixture was stirred at ambient temperature for 14 hours. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-tri(isopropylcarbonylamino)-1-carboxybenzene. The product was refluxed in methanol/12N HCl (500 mL, 4:1, v/v) for 16 hours to afford the desired product, 2-isopropyl-4-methoxycarbonyl-6-aminobenzimidazole, after removal of the solvents under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (390 mg, 0.78 mmol) from Example 51, Step B in methanol (5 mL) was added 5N sodium hydroxide (0.31 mL, 1.56 mmol). The reaction was stirred at rt 20 h and then at 40° C. for 1 h. The reaction was diluted with water, acidified with 2N hydrochloric acid, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2C=O)cc1
Yield: 59 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) and 2-formylphenylboronic acid. Yield: 59%. 1H NMR (400 MHz, dMSO): δ 0.72-0.75 (d, 6H), 1.49 (s, 6H), 1.65-1.72 (m, 1H), 2.80-2.85 (t, 2H), 7.35-7.44 (m, 5H), 7.47-7.50 (d, 1H), 7.55-7.65 (t, 1H), 7.70-7.75 (t, 1H), 7.85-7.90 (d,1H), 9.9 (s, 1H); MS+H (324).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]#[N:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Si:1]([O:8][C@H:9]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][Br:32])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]#[N:22])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)cc(C#N)n2C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cn1c(C#N)cc2cc(CBr)ccc21)O[Si](C)(C)C(C)(C)C
Yield: 89.9 %

Procedure:
To a stirred solution of 55 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-methyl-1H-indole-2-carbonitrile (0.12 mmol) in carbon tetrachloride (0.5 mL) was added 21.3 mg of N-bromosuccinimide (0.12 mmol) and 1.1 mg of AIBN (0.0065 mmol). The mixture was refluxed for 1 h, then cooled, concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 58 mg of crude (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-(bromomethyl)-1H-indole-2-carbonitrile that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([O-:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)=[CH:5][CH:4]=1.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3c(C(=O)[O-])cccc3c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc3c(C(=O)O)cccc3c2)cn1

Procedure:
To a solution of 6-(6-methoxypyridin-3-yloxy)-1-naphthoate (480 mg, 1.55 mmol) in THF (155 mL) at RT was added 1M aqueous LiOH (31 mL). The reaction was stirred until the reaction was completed. THF was removed in vacuo. The aqueous layer was acidified using 6M aqueous HCl to pH=6-7 and extracted with EtOAc. The aqueous layer was further acidified to pH=5 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=2)[N:7]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=2)[N:7]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1cc(C(C)(C)C)nn1-c1cc(C)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)O)c(Nc2cc(C(C)(C)C)nn2-c2cc(C)ccc2C)n1
Temperature: 40 °C
Yield: 100.2 %

Procedure:
To a solution of ethyl 4-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-2-(methylthio)pyrimidine-5-carboxylate (71 mg, 0.16 mmol) in a mixture of ethanol (0.5 mL) and THF (0.5 mL) was added lithium hydroxide monohydrate (68 mg, 1.6 mmol) in water (1 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid, and the mixture was concentrated to dryness. The crude mixture was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 66 mg (99%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.50 (s, 1H), 8.65 (s, 1H), 7.17 (dd, 2H), 7.12 (s, 1H), 6.83 (s, 1H), 2.68 (s, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.35 (s, 9H); ES-MS m/z 412.2 (MH+); HPLC RT (min) 3.94.
Reaction SMILES: Br[CH:2]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2([CH3:12])[CH:3]1[CH2:4][CH2:5][C:6]2=[O:13]>C(O)C=C>[CH2:10]([O:11][CH:2]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2([CH3:12])[CH:3]1[CH2:4][CH2:5][C:6]2=[O:13])[CH:9]=[CH2:8]
Reactant: CC12CCC(=O)C(Br)C1CCC2=O
Solvent: C=CCO
Product: C=CCOC1C(=O)CCC2(C)C(=O)CCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 4-bromo-7a-methyl-hexahydro-indene-1,5-dione 1 (prepared according to the procedure described in J. Org. Chem. 2001, 66, 626.) (2.44 g, 10 mmol), molecular sieves of 4 Å (2.5 g) and silica gel (2.5 g) in allyl alcohol (20 mL) was added Ag2O (2.55 g, 11 mmol) at room temperature. The reaction mixture was stirred at room temperature in the dark for 8 h. The reaction mixture was filtered through a mixture of Celite® and silica gel. The solvent was removed under reduced pressure to yield the title compound as a crude yellow oil.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]#N)[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-:20].[K+].Cl.[OH-:23].[Na+]>O>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]([OH:23])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-c2ccc(C#N)c(=O)[nH]2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1

Procedure:
A mixture of 92.5 g (0.37 mol) of 6-(3-acetylaminophenyl)-1,2-dihydro-2-oxonicotinonitrile, 185 g of potassium hydroxide, and 740 ml of water is heated at 105° for 30 hrs. The cooled reaction mixture is poured into 285 ml of concentrated hydrochloric acid and ice. The pH of the suspension is adjusted to 5.0 with aqueous sodium hydroxide solution and the solid filtered, washed with water, and dried to give 81.2 g of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid. ##EQU49##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:2]2[N+:3]([O-:11])=[CH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Solvent: CCO
Product: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A mixture of 2-chloro-4-nitropyridine-1-oxide (75 g, 0.43 mol) and 1-(4-methoxyphenyl)-methanamine (125 g, 0.91 mol) in ethanol (1 L) was heated at reflux for 5 h. The reaction was allowed to cool to room temperature and cooled in a freezer overnight. The resulting cold mixture was filtered. The isolated solid was further slurried in methanol (100 mL) and filtered to give N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (51.62 g, 40% yield) as an orange solid. LCMS: (FA) ES+ 276; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.34 (dd, J=6.5, 0.8 Hz, 1H), 8.27 (t, J=6.7, 6.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 4.52 (d, J=6.6 Hz, 1H), 3.70 (s, 1H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(C(=O)NNC(=O)c2ccccc2)c1C
Reaction time: 24 h
Yield: 91 %

Procedure:
First, 9.4 g (69.0 mmol) of benzoylhydrazine and 50 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 13.0 g (77.1 mmol) of 2,3-dimethylbenzoyl chloride and 10 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 16.9 g of a white solid of 1-(2,3-dimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 91%. A synthesis scheme of Step 1 is shown in (d-1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:44])=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccc4)cc2)CCO3)cc1
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-(phenylthiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) in dichloromethane (30 ml) was added 70% m-chloroperbenzoic acid (0.046 g) at the temperature ranging from -20 to -10° C., and the mixture was stirred for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenylsulfinylmethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 108) (0.11 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1>>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:19]=[C:18]5[C:14]([CH:15]=[CH:16][NH:17]5)=[CH:13][CH:12]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:19]=2)[CH:15]=[CH:16]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc3cc[nH]c3c2)nc1Nc1ccc2cc[nH]c2c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to yield N2,N4-bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.39 min.; purity: 85%; MS (m/e): 359 (MH+).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]2)[CH:2]=1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(-n2nnc(C(=O)O)n2)c1

Procedure:
This intermediate was prepared from m-tolylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added ethanol (6.4 mL) followed by a solution of NaOH (0.483 g, 12.1 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 NHCl (22.8 mL), and the mixture stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×4 mL) and dried in a vacuum oven at 45° C. overnights to give 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.51 (bs, 1H), 10.68 (bs, 1H), 8.30 (t, J=1.8, 1H), 8.14 (dt, J=7.7, 1.4, 1H), 7.99 (ddd, J=7.8, 2.0, 1.1, 1H), 7.70 (t, J=7.8, 1H), 7.27 (m, 1H), 6.94-6.82 (m, 3H); MS (ESI) m/z 294 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(Cc2ccccn2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound. ES-MS m/e (%): 458.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]=[C:3]1[C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][CH:15]([OH:38])[CH2:16][NH:17][CH2:18][CH:19](CC2C=CC=CC=2)[O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28](=[O:30])[NH2:29])[CH:22]=2)=[CH:11][CH:10]=1>CO.[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:38])[CH2:16][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28](=[O:30])[NH2:29])[CH:22]=2)=[CH:39][CH:40]=1
Reactant: Cn1c(-c2ccc(OCC(O)CNCC(Cc3ccccc3)Oc3ccc(O)c(C(N)=O)c3)cc2)cccc1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)cccc1=O

Procedure:
A solution of 5.2 g of 1-[4-(1,6-dihydro-1-methyl-6-oxo-2-pyridyl)-phenoxy]-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-N-benzylethylamino]-2-propanol in 100 ml of methanol is hydrogenated under normal conditions in the presence of 1 g of palladium-on-carbon catalyst (5%). The hydrogenated mixture is filtered with suction, the filtrate is concentrated to dryness by evaporation and the residue is washed with ethyl acetate. Recrystallisation from isopropanol yields pure 1-[4-(1,6-dihydro-1-methyl-6-oxo-2-pyridyl)-phenoxy]-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-2-propanol having a melting point of 148°-150°.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:25]2[CH2:24][CH2:23][N:22]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[CH:21]([CH3:20])[CH2:26]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
64 mg (44%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 2-methyl-1-m-tolylpiperazine (59 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([OH:18])=O.C(Cl)(=O)C(Cl)=O.ClCCl.CN(C=O)C>Cl[Ti](Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:9]1[CH:10]([CH2:15][C:16]2=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccccc1C1CCCCC1CC(=O)O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetic acid (0.300 g, 1.21 mmol), oxalyl chloride (0.13 mL, 1.45 mmol), and dichloromethane (6.0 mL) and catalytic DMF (0.1 mL) at room temperature. After 1 hour at 0° C. added TiCl4 (0.33 mL, 3.0 mmol) and reaction gradually warmed to room temperature. After 3 hours, quenched reaction with 5N HCl and added ethyl acetate. Separate layers, wash with brine, and dry over anhydrous sodium sulfate. Concentrate and flash chromatograph using 0 to 20% ethyl acetate/hexanes eluent to yield the titled compound (0.198 g, 72%). TLC Rf=0.4 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.6 (d, 1H, J=7.0 Hz), 7.3 (m, 1H), 7.0 (m, 1H), 3.8 (s, 3H), 3.2 (m, 1H), 2.9 (m, 1H), 2.4 (m, 2H), 1.9 (m, 1H), 1.6 (m, 7H).