Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:8])([OH:7])[CH2:5][CH3:6])[CH3:3].C[Li].Cl[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].O>O1CCCC1.C(OCC)C>[C:12](=[O:13])([O:14][CH2:15][CH:16]=[CH2:17])[O:7][C:4]([CH3:8])([CH2:5][CH3:6])[CH:2]([CH3:3])[CH3:1]
Reactant: CCC(C)(O)C(C)C
Reactant: C=CCOC(=O)Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CCOC(=O)OC(C)(CC)C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of 11.62 grams (0.1 mole) of 2,3-dimethylpentan-3-ol in 75 milliliters of anhydrous tetrahydrofuran at 0° C was added one equivalent of methyllithium in diethyl ether, followed by 12.1 grams (0.10 mole) of allyl chloroformate in 25 milliliters of anhydrous tetrahydrofuran. During both additions the temperature was maintained at 0° C. After the last addition was complete the reaction mixture was stirred for about 18 hours and allowed to warm to ambient temperature. The reaction mixture was poured into water, and then extracted with ether. The ether solution was washed four times with water and dried over magnesium sulfate. Removal of solvent under reduced pressure yielded 18.27 grams (93.1% crude yield) of a yellow oil. Vacuum distillation gave 10.79 grams of 2,3-dimethylpent-3-yl allyl carbonate, b.p. 59°-60° C/0.15 mm.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].O.B1([O-])O[O:19]1.O.O.O.O.[Na+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH2:12][CH2:13][OH:19])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7]
Reactant: C=CCC(C)(CO[Si](C)(C)C(C)(C)C)OC
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(CCCO)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2-methoxy-2-methylpent-4-en-1-yl)oxy]dimethylsilane (2.45 kg, 10.04 mol) in THF (3.5 L) at <5° C. was added BH3 in THF (1M solution, 11.05 L, 11.05 mol) via a funnel while maintaining the reaction temperature at <15° C. The reaction mixture was stirred for 30 minutes and quenched with water (11.75 L, 652 mol). To the stirred mixture was added sodium perborate tetrahydrate (4.64 kg, 30.2 mol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was then filtered, and the filter cake washed with 14 L MTBE. The combined organic layers were washed with brine/water (7 L/3 L). The aqueous layer was extracted with MTBE (14 L). The combined organic layers were sequentially washed with 18.75 L of 5% aqueous sodium thiosulfate/brine/water (10 L/5 L/3.75 L) and then concentrated in vacuo to provide crude material. Flash column chromatography (multiple runs) eluted with 0% to 100% DCM in heptane, then 1% to 50% EtOAc in DCM provided the desired alcohol. 1H NMR (300 MHz, CDCl3): δ 3.65-3.59 (m, 2 H); 3.47 (dd, J=23.9, 10.1 Hz, 2 H); 3.24 (s, 3 H); 2.21-2.07 (m, 1 H); 1.63-1.54 (m, 4 H); 1.05-0.70 (m, 9 H); 0.04 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:5][C:4]=1F)#[N:2].Cl.[NH2:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1.[H-].[Na+].CC(O)=O>CS(C)=O>[C:1]([C:3]1[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)=[CH:5][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)C[C@@H](Nc1cc(F)c(C#N)c(F)c1)C(N)=O
Reactant: Cc1cc(N)sn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C#N)sn1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of (R)-2-(4-cyano-3,5-difluorophenylamino)-4-methylpentanamide (92 mg, 0.34 mmol) and 5-amino-3-methylisothiazole hydrochloride (70 mg, 0.46 mmol) in DMSO (2 mL), NaH (60% in mineral oil, 80 mg, 2.00 mmol) was added. H2 gas evolved. The mixture was stirred at 130 C for 1 h. After being acidified with HOAc (1.0 mL), the mixture was purified by HPLC to give (R)-2-(4-cyano-3-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (38 mg).
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11])[C:3]([Cl:6])([Cl:5])[Cl:4].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([NH:7][C:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11])[O:20][CH2:19][C:18]([F:22])([F:21])[F:17]
Reactant: OCC(F)(F)F
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(OCC(F)(F)F)C(Cl)(Cl)Cl)c1ccccc1O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of N-(1,2,2,2-tetrachloroethyl) salicylamide (30 g) in toluene (100 ml) is added dropwise at less than 10° C. to a solution of 2,2,2-trifluoroethanol (10 g) and pyridine (18.6 g) in toluene (150 ml). After the addition, the mixture is stirred at room temperature for a while, and the contents are washed with water and a 1% aqueous solution of sodium hydrogen carbonate. The toluene layer is dehydrated, and the toluene is evaporated under reduced pressure to give the desired N-[2,2,2,-trichloro-1-(2,2,2,-trifluoroethoxy) ethyl]-salicylamide (26 g) represented by the foregoing formula as a colorless viscous mass. This compound gradually solidifies and shows a melting point of 78° to 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([CH:40]=2)[NH2:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:39][C:38]3[CH:40]=[C:34]([CH:31]4[CH2:32][CH2:33]4)[CH:35]=[CH:36][C:37]=3[F:41])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1cc(C2CC2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C4CC4)ccc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 22.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.090 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.93-0.96 (m, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.13 (s, 2H), 6.80 (s, 1H), 7.14-7.50 (m, 5H), 8.24 (t, J=7.8 Hz, 1H), 10.07 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 509.23.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7]Br.[C-:10]#[N:11].[K+]>CCO.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7][C:10]#[N:11]
Reactant: [C-]#N
Reactant: BrCc1c(Br)csc1Br
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Br)csc1Br
Yield: 85.4 %

Procedure:
To a solution of 2,4-dibromo-3-(bromomethyl)thiophene (1.00 g, 3.00 mmol) in EtOH (10 mL) was added a solution of potassium cyanide (0.29 g, 4.5 mmol) in H2O (0.5 mL). The mixture was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc was dried (MgSO4) and the solvent removed. The residue was recrystalized from EtOH to yield (2,4-dibromothien-3-yl)acetonitrile (0.72 g, 86%). mp 75.5-77° C.; 1H NMR (500 MHz, DMSO-d6) δ: 3.94 (s, 2H), 7.94 (s, 1H). MS (EI) m/z 279/281/283 (M+.). Anal. Calcd for C6H3Br2NS: C, 25.65; H, 1.08; N, 4.99. Found: C, 26.04; H, 1.18; N, 4.86.
Reaction SMILES: O1CCOCC1.[NH2:7][CH:8]([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36](Cl)=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>O>[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:7][CH:8]([CH3:20])[CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=4)[NH:12][N:11]=3)=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(N)Cc1n[nH]c2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Cc1n[nH]c2ccc(O)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a mixture of dioxane and water (4:1, 10 mL) was added 3-(2-aminopropyl)-1H-indazol-5-ol (0.10 g, 0.36 mmol), 9-fluorenylmethoxycarbonyl chloride (0.13 g, 0.54 mmol) and sodium bicarbonate (0.9 g, 0.54 mmol). The reaction mixture poured into dilute sodium bicarbonate and the resulting mixture extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated to a residue that was purified by chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[C:11]([O:15][C:16](=[O:19])[CH2:17][Zn+])([CH3:14])([CH3:13])[CH3:12].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[CH:7]=[N:6][C:5]=1[Cl:8]
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cnc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added 5-bromo-2,3-dichloropyridine 184-1 (113 mg, 0.50 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (1.2 mL, 0.60 mmol), Pd(dba)2 (14 mg, 0.025 mmol), Q-phos (36 mg, 0.05 mmol) and THF (1.5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 70° C. overnight. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(5,6-dichloropyridin-3-yl)acetate 184-3. MS m/z 262.1 (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:12]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[CH2:32]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=1[O:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:33]>O1CCCC1>[CH2:32]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=1[O:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:11]2[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=2)[CH2:39]1)[CH3:33]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (2.91 kg, 22.5 mol) was added to a mixture of ethyl 2-chloropyrimidine-5-carboxylate (1.20 kg, 6.43 mol) and (R)-3-(2-ethoxyphenoxy)piperidine D-tartrate (2.63 kg, 7.07 mol) in tetrahydrofuran (12.0 L) at 55° C., at a rate maintaining a temperature of 50-60° C. The mixture was held at that temperature for 1 hour, then was cooled to 30° C. The mixture was then partitioned between water (8.4 L) and 2-methyltetrahydrofuran (16.8 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and then was concentrated by distillation under reduced pressure. Tetrahydrofuran (12.0 L) and methanol (6.0 L) were added to the residue, and then an aqueous 8M potassium hydroxide solution was added at a rate to maintain the temperature below 55° C. The mixture was held at 50-55° C. for 1 hour, then was cooled to 30° C., and was partitioned between ethyl acetate (18.0 L) and aqueous 3M hydrochloric acid solution (8.86 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and was then distilled to a low volume. Ethyl acetate (22 L) was added and the resulting solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (25 L). The mixture was cooled to and held at 57° C. for 2 hours as crystallization initiated. n-Heptane (8.83 L) was added while maintaining temperature at 55-60° C. After 30 min, the slurry was cooled to 20-25° C. and was held at that temperature for 11 hours. The crystals were collected by filtration, rinsing with 2:1 ethyl acetate:n-heptane (8.0 L), to afford after drying (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1.69 kg). MS (ES+) 344.3 (M+H). The mother liquors were concentrated and the resulting residue was recrystallized from ethyl acetate (4.2 L), with the addition of n-heptane (2.1 L) after crystallization initiated, to afford after filtering and drying an additional portion of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (0.370 kg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([OH:42])=O)([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:87][S:88]([CH:91]6[CH2:93][CH2:92]6)(=[O:90])=[O:89])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:87][S:88]([CH:91]4[CH2:93][CH2:92]4)(=[O:90])=[O:89])=[O:42])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (56) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=756 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3-1.4 (m, 9H), 1.5-1.6 (m, 2H), 1.6-1.65 (m, 1H), 1.75-1.9 (m, 5H), 2.2-2.3 (m, 1H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 2H), 2.6-2.7 (m, 1H), 2.75-2.85 (m, 1H), 3.15-3.25 (m, 1H), 3.8 (d, J=11.2 Hz, 1H), 4.15 (s, 3H), 3.25 (dd, J=11.15 Hz, J=4.5 Hz, 1H), 4.7 (t, J=7.1 Hz, 1H), 5.2 (t, J=10.4 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 (br s, 1H), 7.1 (s, 1H), 7.21 (d, J=9.5 Hz, 1H), 7.6 (s, 1H), 8 (d, J=9.5 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:15]1([NH:7][C:2]2[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 110 °C
Yield: 95.4 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), bromobenzene (2.36 g, 15 mmol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After cooling the flask including the reactant mixture to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10) to produce 3.51 g of colorless N-phenylbiphenyl-2-amine liquid.
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[F:6][C:7]([F:21])([F:20])[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19]>O.C(O)(=O)C.C(#N)C.O>[Cl:1][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][C:7]([F:6])([F:20])[F:21])[CH:10]=1)[O:17][CH2:16][CH2:15][C:14]2=[O:19]
Reactant: O=C1CCOc2c(OC(F)(F)F)cccc21
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C1CCOc2c(OC(F)(F)F)cc(Cl)cc21
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of calcium hypochlorite (15.4 g, 72.4 mmol) in water:acetic acid (65:5) was added a solution of 8-trifluoromethoxychroman-4-one (4.2 g, 18.1 mmol; from step (iv) above) in acetonitrile (20 mL), whereafter the reaction mixture was stirred overnight. The mixture was diluted with water and extracted with ether (3 times) and EtOAc (once). The combined organic layer was washed with water, dried (Na2SO4) and evaporated, yielding 4.2 g (87%) of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:35])[CH3:34])=[O:13].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:34])[CH3:35])=[O:13]
Reactant: COC(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)cn(C(C)C)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)O)cc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 4-[4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-3-methyl-1-(1-methylethyl)-1H-indol-6-yl]benzoate (30 mg, 0.062 mmol) in MeOH (2 mL) and THF (1 mL) was 3N NaOH (0.031 mL, 0.185 mmol). The reaction was heated at 50° C. for 12 h, at which time it was allowed to cool to ambient temperature and treated with acidic ice water to bring pH to 6. The solid was filtered and washed several times with water and an 8:2 mixture of acidic (pH2) ice water:MeOH. Purification by reverse phase Gilson HPLC (10-80%, acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the title compound (12 mg, 0.024 mmol, 39.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br. s., 1H) 11.48 (br. s., 1H) 8.23 (t, J=5.05 Hz, 1H) 8.02 (d, J=8.34 Hz, 3H) 7.87-7.94 (m, 4H) 7.38 (s, 1H) 7.32 (d, J=1.52 Hz, 1H) 5.87 (s, 1H) 4.91 (quin, J=6.63 Hz, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.24 (s, 3H) 2.18 (s, 3H) 2.11 (s, 3H) 1.44 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 486.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH:29]C(OCCCC)=O)[C:7]=2[CH:39]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH2:29])[C:7]=2[CH:39]=1
Reactant: CCCCOC(=O)NCC(=O)NCC(=O)N[C@H]1CCc2cc(OC)c(OC)c(OC)c2-c2ccc(OC)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@@H](NC(=O)CNC(=O)CN)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 65 %

Procedure:
A solution of N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-(butoxycarbonylamino)acetylamino]acetamide (0.9 g; 0.64 mmol) in dichloromethane (6 ml) was treated with TFA (6 ml) at ambient temperature for 0.5 hour. After evaporation to dryness, the residue was neutralised to pH 6.5 with solid sodium hydrogen carbonate and purified on reverse phase silica eluting with a gradient of 30-40% methanol/ammonium carbonate buffer (2 g/1, pH 7). The appropriate fractions were evaporated to dryness and triturated in ether to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([CH:25]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:26][C:27]#[N:28])[Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)C.O>[Si:8]([O:7][CH:25]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:26][CH2:27][NH2:28])([C:21]([CH3:23])([CH3:24])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](OC(CC#N)c1ccncc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC(CCN)c1ccncc1)(c1ccccc1)c1ccccc1
Reaction time: 0.13 h

Procedure:
Lithium aluminum hydride (299 mg, 7.87 mmol) was suspended in anhydrous diethyl ether (10 ml) under a nitrogen atmosphere, a solution of the obtained 3-(t-butyldiphenylsiloxy)-3-(4-pyridyl)propionitrile (1.00 g, 2.59 mmol) in anhydrous diethyl ether (15 ml) was added dropwise to the suspension under ice-cooling with stirring over eight minutes, and the mixture was stirred at room temperature for 75 minutes. Ethyl acetate (15 ml) was added to the reaction mixture under ice-cooling, water (0.28 ml), a 15% aqueous sodium hydroxide solution (0.28 ml) and water (0.85 ml) were added thereto successively, and the whole was stirred at room temperature for 10 minutes. The reaction mixture was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the target compound (180.0 mg, yellow oily matter, 17.8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][N:9]=1.[Br:20]C1C=CC=CC=1C(C1C=CC=CC=1[N+]([O-])=O)=O.NC1C=CC=CC=1C(C1C=CC=CC=1Br)=O>>[Br:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Reactant: O=C(c1ccccc1Br)c1ccccc1[N+](=O)[O-]
Agent: Nc1ccccc1C(=O)c1ccccc1Br
Product: O=C1CN=C(c2ccccc2Br)c2ccccc2N1

Procedure:
To make the 6-(o-bromophenyl) product one can follow the procedure shown by Sternbach et al., J. Med. Chem. 6, 263 (1963), for the preparation of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepin-2-one using the Sandmeyer reaction followed by catalytic hydrogenation of the resulting 2-bromo-2'-nitrobenzophenone. This product, 2-amino-2'-bromobenzophenone, can be substituted in the process described by Sternbach et al. to produce 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepin-2-one.