Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([NH2:21])=[C:15]([CH2:22][CH3:23])[CH:14]=1)[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH2:24]([C:26]([CH3:28])=O)[CH3:25]>[Pt].O1CCCC1>[CH:24]([NH:21][C:16]1[C:17]([CH2:19][CH3:20])=[CH:18][C:13]([CH2:1][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][CH:1]([CH2:2][CH3:3])[CH3:13])=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:14][C:15]=1[CH2:22][CH3:23])([CH2:26][CH3:28])[CH3:25]
Reactant: CCc1cc(Cc2cc(CC)c(N)c(CC)c2)cc(CC)c1N
Reactant: CCC(C)=O
Agent: [Pt]
Solvent: C1CCOC1
Product: CCc1cc(Cc2cc(CC)c(NC(C)CC)c(CC)c2)cc(CC)c1NC(C)CC
Temperature: 110 °C
Yield: 86 %

Procedure:
4,4′-Methylenebis(2,6-diethylbenzeneamine) (3 g), Pt(S)/C (0.3 g), Amberlyst-15 (0.3 g), methyl ethyl ketone (25 g), and tetrahydrofuran (THF; 25 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 90 psig (7.22×105 Pa) of H2 at 22° C. The reaction mixture was then heated at 100-120° C. under 125 psig (9.63×105 Pa) of H2 for 5 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (180° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of 4,4′-methylenebis(2,6-diethylbenzeneamine), and an 86% yield of N,N′-di-sec-butyl-4,4′-methylenebis(2,6-diethylbenzeneamine).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(CO)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 5.4 %

Procedure:
Pd(PPh3)2Cl2 (5 mg, 0.007 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(hydroxymethyl)phenylboronic acid (17 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 2′-amino-6-(4-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.16 mg, 5%). 1H-NMR (MeOD): 2.42 (m, 1H), 2.57 (m, 1H), 3.31 (m, 3H), 4.15 (s, 2H), 5.83 (m, 1H), 7.09 (m, 1H), 7.28 (m, 1H), 7.38 (m, 4H), 7.47 (m, 3H), 7.56 (m, 1H), 7.61 (m, 1H).
Reaction SMILES: [C:1]1([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]3[C:22]=2[CH:21]=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=[CH:18]3)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:37]1(C(Cl)=O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44]C=2)[CH:40]=[CH:39][CH:38]=1.C(OC1C=CC=C2C=1C=CC(OC(=O)C)=C2)CCCC>C(Cl)Cl>[C:1]1([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]3[C:22]=2[CH:21]=[C:20]([O:23][C:24]([C:25]2[C:46]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:42]=[CH:43][CH:44]=2)=[O:26])[CH:19]=[CH:18]3)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2cc(OC(C)=O)ccc12
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: CCCCCOc1cccc2cc(OC(C)=O)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2cc(OC(=O)c3cccc4ccccc34)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Acetic acid 8-(naphthalene-1-carbonyl)-5-pentyloxynaphthalen-2-yl ester: To a stirred suspension of anhydrous aluminium chloride (4.42 g, 33.09 mmol) in anhydrous DCM (290 mL) at 0° C. under nitrogen is added dropwise a solution of naphthoyl chloride (3.7 mL, 24.8 mmol) in anhydrous DCM (35 mL). After 15 min, a solution of acetic acid 5-pentyloxynaphthalen-2-yl ester (4.5 g, 16.54 mmol) in anhydrous DCM (70 mL) is added, and the reaction mixture is allowed to warm to room temperature and stir for 20 h. The mixture is washed with saturated sodium hydrogen carbonate solution, the phases separated and the DCM removed under reduced pressure. The residue is taken up in diethyl ether and washed with water, dried (MgSO4) and the solvent removed under reduced pressure. Purification by chromatography on silica gel (1–3% ethyl acetate in cyclohexane) affords the desired product (4.8 g, 68%) and naphthalene-1-carboxylic acid 8-(naphthalene-1-carbonyl)-5-pentyloxynaphthalen-2-yl ester (2.1 g), arising from naphthoyl replacement of the acetyl group.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nccc2ccccc12
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a 200 ml-three-necked flask, 3.40 g (25.0 mmole) of 4-methylphenyl-boronic acid (made by Aldrich Co.), 4.09 g (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 mol of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.80 g (yield=51.1%) of 1-(4-methylphenyl)isoquinoline.
Reaction SMILES: C(Cl)(=O)C.C(O)C.Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.O=[C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:22][C:21]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Add acetyl chloride (8.5 mL, 120 mmol) to absolute ethanol (30 mL) and stir for 1 h. Add 4-methoxyphenylhydrazine hydrochloride (1.74 g, 10 mmol) and N-(4-oxo-cyclohexyl)-isobutyramide (Preparation 2) (1.83 g, 120 mmol) and reflux with stirring for 56 h. Cool to room temperature, dilute with ethyl acetate (100 mL) and wash with sodium bicarbonate solution (2×50 mL), brine, dry (MgSO4), filter and concentrate in vacuo. Dissolve the residue in dichloromethane and pass over a silica pad, eluting with 20% ethyl acetate/dichloromethane to obtain 2.32 g of a solid. Triturate the solid in diethyl ether with a small amount of dichloromethane, filter and dry under house vacuum to obtain 2.14 g (75%) of an off-white solid. MS (ES): m/z 287 (M+1), 285 (M−1); 1H NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.13 (d, 1H, J=8.8 Hz), 6.85 (s, 1H), 6.64 (dd, 1H, J=8.8, 2.2 Hz), 4.02 (m, 1H), 3.75 (m, 3H), 2.90 (dd, 1H, J=15.0, 5.3 Hz), 2.78 (m, 2H), 2.42 (m, 2H), 1.96 (m, 1H), 1.79 (m, 1H), 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[O:15]1CC[CH2:17][CH2:16]1.C(Cl)(=O)C>O>[Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][C:16](=[O:15])[CH3:17]
Reactant: C1CCOC1
Reactant: CC(C)(CO)CBr
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC(C)(C)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-2,2-dimethyl-1-propanol (5 mL) and triethylamine (15 mL) was added tetrahydrofuran (50 mL), acetyl chloride (3.8 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give acetic acid (3-bromo-2,2-dimethyl-1-propyl)ester (8.37 g). The obtained acetic acid (3-bromo-2,2-dimethyl-1-propyl)ester (8.37 g) were added sodium sulfite (5.05 g) and water (20 mL), and the mixture was stirred with heating under reflux for 20 hr. To the reaction mixture was added concentrated hydrochloric acid (5.81 mL), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, neutralized with 4N aqueous sodium hydroxide solution (20.5 mL), and the mixture was concentrated to about 10 mL. The precipitated precipitate was collected by filtration, and the filtrate was concentrated. To the obtained residue was added phosphorus pentachloride (18.35 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Into the reaction mixture was poured ice water, and the mixture was extracted with dichloromethane. The solvent was evaporated from the organic layer to give crude 3-chloro-2,2-dimethylpropane-1-sulfonyl chloride (3.99 g). Using the obtained crude 3-chloro-2,2-dimethylpropane-1-sulfonyl chloride (3.99 g) and ethyl 4-aminobenzoate (3.21 g) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (127 mg) was obtained.
Reaction SMILES: [Br-].[C:2]1([P+:8]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[C:2]1([P:8]([CH2:9][C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH3:14])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc([P+]2(c3ccccc3)Cc3ccccc3-c3ccccc3C2)cc1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccccc1CP(c1ccccc1)c1ccccc1

Procedure:
4 g (9.0 mmol) of 6,6-diphenyl-6,7-dihydro-5H-dibenzo-[c,e]phosphepinium bromide are suspended in 70 ml of absolute toluene under protective gas and reacted with 680 mg (18 mmol) of lithium aluminum hydride using a method analogous to Example 5.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([C:12]([NH:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[N:10]=[C:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:8]1)=[N+:2]=[N-:3].I[CH3:35].[H-].[Na+]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([C:12]([N:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:35])=[O:13])[N:10]=[C:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)ONC(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.061 g, 0.13 mmol) and iodomethane (0.18 g, 1.3 mmol) in DMF (4 mL) was added sodium hydride (0.006 g, 0.26 mmol). After stirring at 0° C. for 30 minutes and then at room temperature for 1 hour, the mixture was partitioned between ethyl acetate (10 mL) and saturated NH4Cl (5 mL). The organic layer was washed with water (2×5 mL), dried and concentrated under reduced pressure to provide the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH:13][C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:9]1.O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH:13][C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][C:10]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[N:9]1
Reactant: CCOC(=O)c1cccnc1Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cccnc1Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Temperature: 40 °C
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-{[1-(2-chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}nicotinate (410 mg, 0.94 mmol) in a mixture of ethanol (4 mL) and THF (4 mL) was added lithium hydroxide monohydrate (115 mg, 2.74 mmol) in water (8 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, and the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid solution (the mixture turned cloudy). The solid was filtered off and washed with more water. The solid was dried in a vacuum oven at 60° C. to give 380 mg of the desired product (99%). 1H NMR (300 MHz, CD2Cl2) δ 10.18 (s, 1H), 8.45 (dd, 1H), 8.24 (dd, 1H), 7.87 (dd, 2H), 7.47-7.62 (m, 4H), 7.23 (s, 1H), 7.12 (t, 2H), 6.85 (dd, 1H); ES-MS m/z 351.2 (MH+); HPLC RT (min) 2.58.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([I:13])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][O:25][CH3:26])=[C:6]([I:13])[CH:5]=1
Reactant: COC(=O)c1cc(I)c(O)c(OC)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1c(I)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 4-hydroxy-3-iodo-5-methoxybenzoic acid methyl ester (4.6 g) in chloroform (30 mL) were successively added diisopropylethylamine (3.88 g) and chloromethyl methyl ether (1.88 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with ethyl acetate, 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with solvent (hexane:ethyl acetate=3:1, v/v) to give the title compound (2.70 g).
Reaction SMILES: [Si](Cl)(Cl)(Cl)Cl.[CH2:6]=[CH:7][CH3:8].[C:9]([OH:12])(=[O:11])[CH3:10]>C(OC(=O)C)(=O)C>[C:9]([O:12][CH2:6][CH:7]([O:12][C:9](=[O:11])[CH3:10])[CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: C=CC
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 160 °C

Procedure:
2 g silicon tetrachloride were dissolved together with 2 g cuprous chloride and 2 g cupric chloride in 500 ml glacial acetic acid and 50 ml acetic anhydride. This solution was saturated with propylene and with compressed air at 40 atmospheres, and then heated to 160°C. Distillation resulted in the preparation of 4.6 g propylene glycol diacetate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH2:28][NH2:29])[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:36](OC(=O)C)(=[O:38])[CH3:37]>O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH2:28][NH:29][C:36](=[O:38])[CH3:37])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CN)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1nc(CNC(C)=O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 92.9 mg (0.22 mmol) sample of 5-[4′-[(5-butyl-3-methylamine-1H-1,2,4-triazol-1-yl)methyl]-(1,1′-biphenyl-2-yl]-1H-tetrazole hydrochloride from Example 27 was dissolved in 5 ml of water and the pH was adjusted to 9 with 1M potassium carbonate (K2CO3). The solution was cooled to 0° C. and 0.22 ml of 1M K2CO3 was added followed by 0.22 mmol of acetic anhydride. Additional K2CO3 was added as needed to maintain a pH of 9. At 30 min intervals, this addition was repeated until analytical reverse phase chromatography showed that all starting material has been consumed. The pH was adjusted to three with 1N HCl and extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the product lyophilized from acetonitrile/water providing 36 mg (39%) of N-[[5-butyl-1-[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]acetamide as a colorless solid: NMR (CDCl3) δ0.80 (t, J=8 Hz, 3H), 1.18–1.37 (m, 2H), 1.47–1.64 (m, 2H), 1.94 (s, 3H), 2.63 (t, J=8 Hz, 2H), 4.22 (d, J=8 Hz, 2H), 5.18 (s, 2H), 6.95 (d, J=8 Hz, 2H), 7.04–7.21 (m, 2H), 7.44 (d, J=8 Hz, 1H), 7.50–7.66 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 431 (42), 207 (100); HRMS. Calc'd for M+H: 431.2308. Found: 431.2271.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CO.O1CCCC1.O>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
To a solution of methyl 5-bromo-6-(3-(trifluoromethyl)phenoxy)nicotinate (610 mg, 1.62 mmol) in methanol (4.00 mL), tetrahydrofuran (THF) (4 mL) and water (2.000 mL) was added LiOH (117 mg, 4.87 mmol) at rt. The reaction mixture was stirred at rt for 3 h, quenched with HCl and concentrated. Purification via ISCO system (ethyl acetate/petroleum ether=1/10) afforded the title product (600 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH-].[K+]>O1CCCC1.CO>[F:1][C:2]1[C:3]([NH:40][CH2:41][C:42]2[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide was dissolved in a mixture of tetrahydrofuran and methanol. A solution of aqueous potassium hydroxide (50% w/v) was added to the reaction mixture, and the combined mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (0-100% [10% methanol in ethyl acetate] in hexanes) to afford 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide. 1H-NMR (250 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.53-8.41 (m, 3H), 8.09 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.60 (dd, J=7.5, 1.5 Hz, 1H), 7.52 (dd, J=14.0, 2.0 Hz, 1H), 7.33-7.21 (m, 3H), 7.17 (d, J=1.6 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.01 (broad s, 1H), 4.42 (d, J=6.6 Hz, 2H), 3.80 (s, 3H), 2.89 (s, 12H), 2.59 (s, 12H); MS: m/z 496.3 (M+H+).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[Na+].[Cl-:17].CCOCC>OP(O)(O)=O.O.[O-]S([O-])(=O)=O.[Cu+2].[Cu](Cl)Cl>[Cl:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: [Cu+2]
Agent: O=N[O-]
Solvent: O
Solvent: CCOCC
Product: Clc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
2-Amino-6-chlorobenzothiazole (15.7 g, 85 mmol) in H3PO4 (85%)(470 ml) was heated to 100 degrees and dissolved. Then clear solution was cooled and vigorously stirred by mechanical stirrer. NaNO2 (17.6 g, 255 mmol) in water (30 ml) was added slowly keeps the temperature below 0 degrees. Separately a solution of CuSO4/5H2O(85 g), NaCl (107 g) in water (350 ml) was cooled to −5 degrees and stirred by mechanical stirrer. After Potassium Iodide Starch paper's color was disappeared Diazonium solution was keeping cold and added slowly to the copper chloride solution with vigorous stirring. The reaction Mixture was allowed to warm to room temperature. After 1-hour water (1L) and ether (1L) were added to the reaction mixture and extracted twice. Organic layer was washed by water and dried over anhydrous MgSO4 and concentrated.Crude residue was purified by silica gel chromatography (H/A=4/1, 180 g of silica gel) to provide title compound 363 (7.46 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[O:11]
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1cc(F)cc(F)c1
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 3′,5′-difluoroacetophenone (3 g, 19.2 mmol) (Lancaster Synthesis) in dioxane (30 mL) was added dropwise a solution of bromine (3.67 g, 23 mmol) in dioxane (75 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3,5-difluorophenyl)ethanone as a colorless oil (2.9 g, 64% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[C:17](=[O:16])[CH2:18][N:19]([CH3:20])[C:11]1=[S:12])[CH3:2]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(C)c1N1C(=O)CN(C)C1=S
Yield: 60 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 8.9 g of 2-ethyl-6-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.5 g of triethyl amine, and 250 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.45 g) as a peach solid, m.p. 106°-108° C. Anal. Calcd. for C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.52; H, 6.61; N, 11.29. Mass spectrum (+ESI, [M+H]+) m/z 269/271.