Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[C:14](=[CH:25][N:26]([CH3:29])[C:27]=3[CH3:28])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1.S(=O)(O)[O-:33].[Na+]>C(O)(=O)C>[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[CH:27]([CH3:28])[N:26]([CH3:29])[C:25](=[O:33])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: Cc1c2c(cn1C)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: O=S([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1C2=C(CN=C(c3ccccc3Cl)c3cc(Cl)ccc32)C(=O)N1C
Reaction time: 1 h

Procedure:
In one portion, 0.7 ml (5.9 mmol) of a 30% hydrogen peroxide solution was added to 33 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.8 g (5.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting solution was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and basififed with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Crystallization from ethyl aceatate gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1,2-dimethylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 207°-208° C.
Reaction SMILES: [CH3:1][N:2]([C:13](=[O:38])[C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=2[CH3:27])[CH:17]=[CH:16][C:15]=1[O:34]C(=O)C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][N:2]([C:13](=[O:38])[C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=2[CH3:27])[CH:17]=[CH:16][C:15]=1[OH:34])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:8]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 58.8 %

Procedure:
N-Methyl-N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.138 g, 0.260 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) to obtain the titled compound (0.075 g, 0.153 mmol, 59%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH2:13])=[CH:8][CH:7]=1)=O.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C@@H:18]1[CH2:13][C@H:12]1[C:9]1[CH:8]=[CH:7][C:6]([NH2:5])=[CH:11][CH:10]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
Trifluoroacetic anhydride (10.3 mL, 73.9 mmol) was added to a solution of 4-aminostyrene (8.00 g, 67.2 mmol) and pyridine (8.1 mL, 100.8 mmol) in 100 mL of dichloromethane at 0° C. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under vacuum and purified by chromatography (silica gel, hexane:ethyl acetate) to give 10.89 g (75%) of 2,2,2-trifluoro-N-(4-vinylphenyl)acetamide (VIII-3) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.52 (d, J=8.61 Hz, 2H), 7.42 (d, J=8.61 Hz, 2H), 6.67 (dd, J=10.99 Hz, 17.58 Hz, 1H), 5.73 (d, J=17.58 Hz, 1H), 5.27 (d, J=10.80 Hz, 1H). (2R)-4-tert-Butyl-2-{1-[(4R)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-oxazole (VIII-A) (0.147 g, 0.501 mmol) prepared as described by Evans et al., J. Am. Chem. Soc. 1991, 113, 726-728, was added to a suspension of copper (I) trifluormethanesulfonate-toluene complex (2:1) in 15 mL of chloroform at room temperature. After 1.5 hours the mixture was added to a solution of 2,2,2-trifluoro-N-(4-vinylphenyl)acetamide (10.77 g, 50.1 mmol) in 200 mL of chloroform. A small amount (2-3 mL) of a solution of ethyl diazoacetate (7.8 mL, 74.1 mmol) in 100 mL of chloroform was added. The mixture was carefully warmed with a heat gun until gas evolution and a color change from green to yellow occurred. The remaining ethyl diazoacetate solution was added dropwise over two hours. The solvent was evaporated. The crude product (˜3:1 trans VIII-4/cis VIII-5) was dissolved in 150 mL of methanol and potassium carbonate (13.8 g, 100.2 mmol) and 50 mL of water were added. The mixture was stirred at room temperature overnight. Methanol was evaporated and the residue was extracted between dichloromethane and water. The organic phase was evaporated and the residue was purified by chromatography on silica gel with an ethyl acetate gradient (5 to 30%) in hexanes to give 1.02 g (10% yield) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=8.24 Hz, 2H), 6.59 (d, J=8.42 Hz, 2H), 4.14 (quartet, J=7.14 Hz, 2H), 3.59 (br s, 2H), 2.41 (m, 1H), 1.75 (m, 1H), 1.50 (m, 1H), 1.26 (t, J=7.14 Hz, 3H), 1.21 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=2)O1>>[CH3:11][N:9]1[CH2:10][C:5]2[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:3][C:2]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=3)=[N:7][C:6]=2[CH2:8]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(N)=O)cc2)nc2c1CN(C)C2

Procedure:
Method as intermediate 5 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[C:30]2[C:25](=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.Cl.ClC1C2C(=C(S(Cl)(=O)=O)C=CC=2)C=CN=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[CH:23][N:22]=[C:21]2[Cl:20])(=[O:33])=[O:32])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
According to the method of Example 1, Step A, a solution of N-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) and triethylamine (335 μl) in dichloromethane (3 ml) was added with a solution of (1-chloro-5-isoquinolyl)sulfonyl chloride (524 mg, prepared from (1-chloro-5-isoquinolyl)sulfonyl chloride hydrochloride according to the method of Japanese Patent Unexamined Publication (Kokai) No. 63-2980) in dichloromethane (3 ml) with stirring and ice cooling and stirred at room temperature for 20 hours. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate twice and with saturated brine. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries), and then the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (640 mg).
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:17]([O:19][C:20](=[O:38])/[C:21](/[CH3:37])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:37])[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:3][N:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:12]1)=[O:38])[CH3:18]
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (27 g, 113.7 mmol) and (E)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (19 g, 62.4 mmol) in CH2Cl2 (50 mL), cooled to 0° C., was added trifluoroacetic acid (1.0 M in CH2Cl2, 22.8 mL, 22.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then another molar equivalent of N-methoxymethyl-N-(phenylmethyl)tri-methylsilylmethylamine (14.8 g, 62.4 mmol) added over 10 minutes. Stirring was continued for 3 hours, then the CH2Cl2 was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1.0 N aqueous HCl (2×50 mL), water, 1.0 N aqueous NaOH solution, water, and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a pale yellow oil. Chromatography on silica gel (9:1, hexanes:ethyl acetate) provided the product as an amber oil (16.7 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ (ppm); 7.39-7.23 (m, 5H, aromatic), 6.91 (s, 1H, aromatic), 6.78 (m, 2H, aromatic), 4.75 (m, 1H), 4.18 (q, 2H, OEt), 3.86 (m, 1H), 3.81 (s, 3H, OCH3), 3.75 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.20 (d, 1H, J=9.5 Hz), 3.01 (m, 1H), 2.91 (m, 1H), 2.51 (d, 1H, J=9.5 Hz), 1.93-1.58 (M, 8H, cyclopentyl), 1.28 (t, 3H, OEt), 0.9 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A stirred solution of 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (310 mg, 1 mmol) in anhydrous tetrahydrofuran (2 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (3 ml, 3 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour and heated to reflux for another 5 hours. The reaction mixture was added with cold water (5 ml) and 1N hydrochloric acid (2 ml) dropwise, the mixture was stirred for 5 minutes, adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[2-(2-diethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (300 mg) as a brown oil which was used as such.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=[O:24]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:18][C:19]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]([N:15]=[N+:16]=[N-:17])=[O:24]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccc(Cl)c1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (3.00 mL) was added 2,3-dichlorocinnamic acid (3.00 g) to a room temperature suspension in benzene (20 mL) and triethylamine (2.50 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound (1.77 g) having the following physical data.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:34].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)(=[O:34])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidine-4-sulfinyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 223 (86 mg, 0.19 mmol) in DCM (7 mL) was added TFA (74 μL, 0.953 mmol) followed by a slow addition of a solution of m-CPBA (43 mg, 0.248 mmol) in DCM (2 mL) and the resulting mixture was stirred for 3 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further column chromatography purification (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 224 as a white solid (69 mg, 77%). LCMS: RT 2.08 min [M+H]+ 467.1. 1H NMR (DMSO, 400 MHz): δ 8.95 (1H, d, J=2.41 Hz), 8.40 (1H, d, J=4.98 Hz), 7.96 (1H, s), 7.80 (1H, s), 7.70 (1H, dd, J=8.62, 2.44 Hz), 7.29 (1H, d, J=8.62 Hz), 7.09 (1H, dd, J=5.05, 1.56 Hz), 4.65-4.55 (4H, m), 3.24-3.15 (1H, m), 2.83 (2H, bd, J=11.14 Hz), 2.70-2.60 (1H, m), 2.41 (3H, s), 2.09 (2H, t, J=11.51 Hz), 1.88 (2H, d, J=12.14 Hz), 1.54-1.41 (2H, m), 0.90 (6H, d, J=6.55 Hz)
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:14]C(=O)C)[CH:10]=2)[N:5]=1.Cl>>[ClH:2].[ClH:1].[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:14])[CH:10]=2)[N:5]=1
Reactant: CC(=O)Nc1ccc2nc(CCl)ccc2c1
Agent: Cl
Product: Nc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 192.6 %

Procedure:
To the N-[2-(chloromethyl)-6-quinolinyl]acetamide hydrochloride (900 mg, 3.32 mmol) obtained in Reference Example 6 was added 5N hydrochloric acid (17 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with tetrahydrofuran to obtain the titled compound (849 mg) as powders.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:20]3[C:15](=[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]1)[C:6]([CH3:27])=[C:5]2[C:28]([O:30]C)=[O:29].BrC1C(C)=C(C(OC)=O)C2C(=CC=C(F)C=2)N=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:20]3[C:15](=[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]1)[C:6]([CH3:27])=[C:5]2[C:28]([OH:30])=[O:29]
Reactant: COC(=O)c1c(C)c(N2CCc3c(-c4ccccc4)cccc32)nc2ccc(F)cc12
Agent: COC(=O)c1c(C)c(Br)nc2ccc(F)cc12
Solvent: CCO
Product: Cc1c(N2CCc3c(-c4ccccc4)cccc32)nc2ccc(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Methyl 6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)quinoline-4-carboxylate: A mixture of 2-bromo-4-carbomethoxy-6-fluoro-3-methylquinoline, obtained in step 1D, (5.96 g, 20.00 mmol), and the product of step 1H (3.90 g, 20.00 mmol) in absolute ethanol (100 mL) was stirred at reflux for 65 h. The mixture was allowed to cool to room temperature and the solid filtered to provide the desired product (6.64 g, 16.09 mmol) in 80.4% yield as a yellow solid, mp=213°-215° C.; NMR(CDCl3): 6.52-7.93 (m, 11H), 4.18 (t, 2H), 4.10 (s, 3H), 3.23 (t, 2H), 2.45 (s, 3H); IR(KBr): 2860, 1728; Mass spectrum: m/z 413.1 (M+H).
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Agent: [K+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O

Procedure:
A 17.1 g portion of the compound of Example 64, prepared in successive reactions, was hydrolyzed with 5.8 g of potassium hydroxide, substantially as shown in Example 58, to obtain 15.5 g of the desired product, m.p. 215°-218°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][C:10]([CH3:13])([CH3:12])[O:11][C:5]2=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C.O>C1COCC1>[CH3:12][C:10]1([CH3:13])[O:11][C:5]2[C:6](=[N:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=2)[CH:8]=[CH:9]1
Reactant: CC1(C)C=Cc2nc(Br)ccc2O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=Cc2nc(C=O)ccc2O1
Reaction time: 0.58 h
Yield: 23 %

Procedure:
To a solution of 23 (200 mg, 0.83 mmol) in anhydrous THF (5 mL) at −78° C. was added BuLi (2.5M, 0.35 mL) and stirred for 35 minutes, then DMF (0.08 mL, 0.1 mmol) was added dropwise. The reaction was stirred at −78° C. for 30 additional minutes. Water (3 mL) was added to quench the reaction and was extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography; 20:1 Hx/EtOAc. To give the product as a yellowish solid (23% yield). 1H NMR δ 1.53 (s, 6H), 6.01 (d 1H, J=10.4), 6.58 (d, 1H, J=10.4), 7.13 (d, 1H, J=8.4), 7.77 (d, 1H, J=8.4), 9.93 ppm (s, 1H). 13C NMR δ 28.8, 78.7, 123.0, 123.3, 123.4, 136.3, 145.8, 153.7, 191.9 ppm
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.[CH:21]12[NH:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][O:23][CH2:22]2.C(N(C(C)C)CC)(C)C>C(#N)C.C(Cl)Cl.Cl.C(OCC)C>[ClH:1].[CH:25]12[N:28]([CH2:2][C:3]3[N:7]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=4)[N:6]=[N:5][N:4]=3)[CH:21]([CH2:27][CH2:26]1)[CH2:22][O:23][CH2:24]2
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2nnnc2CN2C3CCC2COC3)cc1C(F)(F)F
Temperature: 85 °C
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a solution of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 1.70 g, 5.91 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (Intermediate 27, 0.884 g, 5.91 mmol) in acetonitrile (25 mL) was added di-isopropylethylamine (2.06 mL, 11.8 mmol). The reaction was heated to 85° C. and stirred for 6 hours. The reaction was cooled and the solvent removed under vacuum. The residue was partitioned between DCM (100 mL) and water (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The DCM layers were combined and the solvent removed. The residue was purified by silica chromatography (Biotage SP4, eluting a gradient of ethyl acetate in iso-hexane) to yield a colourless gum. The product was dissolved in a minimum of DCM before the addition of 1N HCl in diethyl ether (10 mL). The solvent was removed from the resulting suspension. The solid obtained was triturated with diethyl ether (5 mL), the ether decanted and the solid dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (1.43 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CCCCc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of compound 77 (158 mg, 0.83 mmol), NH4Cl (666 mg, 12 mmol) and Iron Powder (463 mg, 8.3 mmol) in water (5 mL) and CH3OH (5 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 78 (100 mg, 75%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ8.04 (s, 1H), 6.90-7.00 (m, 2H), 3.53 (br s, 2H), 2.83 (t, 2H, J=7.1 Hz), 2.36 (t, 2H, J=7.1 Hz), 2.02-2.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5](O)[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].C(O)(=O)C(C)C>>[CH3:1][C:2]([CH3:10])([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4]
Reactant: CC(C)C(O)C(C)(C)CO
Solvent: CC(C)C(=O)O
Product: CC(C)CC(C)(C)CO

Procedure:
Saturated trisubstituted alchols, such as 2,2,4-trimethyl-1-pentanol, have been produced for decades via several different proesses. In British Patent Specification 1,288,615, published Sept. 13, 1972 and issued to B. Yeomans, 2,2,4-trimethyl-1-pentanol is produced by a multi-step process that involves the esterification of 2,2,4-trimethylpentane-1,3-diol with isobutyric acid to produce 3-hydroxy-2,2,4-trimethylpentyl-1 isobutyrate, dehydration of the saturated hydroxyl ester to the unsaturated 2,2,4-trimethylpentenyl-1 isobutyrate, hydrogenation of the unsaturated ester to the saturated 2,2,4-trimethylpentyl-1 isobutyrate over a noble metal hydrogenation catalyst, and saponification of this saturated ester to 2,2,4-trimethyl-1-pentanol. In this reference the 2,2,4-trimethyl-1-pentanol is obtained by the saponification of the ester, not by a reduction process.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O.C(OCC)C>[CH2:13]([O:12][C:5]1[C:4]([F:3])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(F)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1cccc(F)c1OCc1ccccc1

Procedure:
To a suspension of sodium hydride (688 mg, 28.7 mmol) in dimethylformamide (20 ml) on ice bath was bit by bit added 3-fluorosalicylaldehyde (2.68 g, 19.1 mmol) with stirring. After dropwise adding benzyl bromide (2.73 ml, 22.9 mmol), the mixture was stirred under ice cooling for 30 minutes, stirred at room temperature for 2 hours, mixed with water and the product was shaken with diethyl ether (60 ml×2). The extracts were washed with 10% aqueous sodium carbonate solution, dilute hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate and concentrated in vacuo to remove the solvent to give 2-benzyloxy-3-fluorobenzaldehyde as an oily material.