Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:47])[CH2:9][CH2:10][C@H:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C@H:34]([OH:45])[C@H:35]4[O:41][CH:39]([OH:40])[C@H:38]([OH:42])[C@@H:37]([OH:43])[C@@H:36]4[OH:44])[CH:29]=3)=[CH:24][C:23]=2[OH:46])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(#N)C.O.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:47])[CH2:9][CH2:10][C@H:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C@H:34]([OH:45])[C@@H:35]([OH:41])[C@@H:36]([OH:44])[C@H:37]([OH:43])[C@@H:38]([OH:42])[CH2:39][OH:40])[CH:29]=3)=[CH:24][C:23]=2[OH:46])=[CH:6][CH:7]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@H](O)[C@H]4OC(O)[C@H](O)[C@@H](O)[C@@H]4O)c3)cc2O)N1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO)c3)cc2O)N1c1ccccc1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose (7.1 mg, 0.01 mmol) was dissolved in 80:20 acetonitrile-water (1 mL). Sodium borohydride (0.4 mg, 0.01 mmol) was added at room temperature and the reaction was stirred for 30 min monitoring by LCMS. Upon completion, the reaction was diluted with 80:20 acetonitrile:water (3 mL) then filtered through a Whatman 0.45 μM glass microfiber filter and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol (1.4 mg, 22% yield). 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.37-6.89 (m, 16H), 5.08 (d, J=2.4 Hz, 1H), 4.97-4.95 (m, 1H), 4.60 (t, J=6.0 Hz, 1H), 3.92 (m, 1H), 3.76-3.56 (m, 6H), 2.01-1.82 (m, 4H) ppm; MS [M−OH]+ 629.8.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:27]#[N:28])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>C(OCC)(=O)C>[C:27]([CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1)[CH2:4][OH:3])#[N:28]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC(C#N)CO)cc2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
Ethyl 2-cyano-3-{4-[2 (4-methylsulfonyloxypbenyl)ethoxy]phenyl } propanoate A mixture of compound (a) (1.69 g; 4.07 mmole) and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (2.06 g; 8.14 mmole) was slowly heated to more than 190° C. under vacuum and thereafter allowed to cool to room temperature. The crude product was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 2:1 to 1:1) as eluant to give 1.55 g (yield 91%) of the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][N:15]([CH3:29])[C:16]([C:18]1[S:19][CH:20]=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=12)=[O:17].[I:30]I>C1COCC1>[CH3:13][O:14][N:15]([CH3:29])[C:16]([C:18]1[S:19][C:20]([I:30])=[C:21]2[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=12)=[O:17]
Reactant: CON(C)C(=O)c1scc2c1CCC(C)(C)C2
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)c1sc(I)c2c1CCC(C)(C)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of diisopropylamine (11.02 g, 109 mmol) in THF (400 mL) is added n-butyl lithium (72.7 mL, 109 mmol, 1.5 M in pentane) at 0-5° C. The solution is cooled to −78° C. and a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (23 g, 91 mmol) in THF (100 mL) is added. Upon complete addition, the mixture is stirred for 20 min at −78° C. before a solution of iodine (30 g, 119 mmol) in THF (100 mL) is added. Stirring is continued at −78° C. for 30 min. The reaction is quenched by slowly adding a 1:1 mixture of water/methanol (20 mL). The solution is diluted with water (400 mL) and extracted with diethyl ether (3×100 mL). The combined organic extracts are washed with 10% aq. citric acid solution and brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with DCM to afford 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (18 g) as a brownish oil; LC-MS: tR=1.09 min, [M+1]=380.21.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.CO[C:23]([CH2:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[O:26].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1([CH2:29][CH3:30])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: CCC(=CC(=O)OC)OC
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A mixture consisting of 5-benzyloxytryptophol (24.0 g, 0.090 mol), methylene chloride (600 mL), methyl 3-methoxy-2-pentenoate (16.8 g, 0.177 mol) and borontrifluoride etherate (2 mL) is stirred at room temperature for 3 hours. The reaction mixture is washed with 5% NaHCO3 (2×200 mL), water (2×200 mL) and once with brine (200 mL), dried (MgSO4), filtered and concentrated to give 38.0 g crude product. The crude product is flash chromatographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 29.0 g pure title compound, m.p. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:23][C:24]#[C:25]C>>[CH2:20]([O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[C:23]#[C:24][CH3:25]
Reactant: CC#CCBr
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Product: CC#CCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-butyne by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17]3[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]=2[CH:24]=1.[BH4-].[Na+]>CO.O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH:18]=3)[C:7]=2[CH:24]=1
Reactant: C[n+]1ccc(C2=Cc3ccccc3Oc3ccc(Br)cc32)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC=C(C2=Cc3ccccc3Oc3ccc(Br)cc32)CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A stirred suspension of 4-(8-bromodibenz[b,f]oxepin-10-yl)-1-methylpyridinium iodide (2.7 g) in methanol (50 ml) was treated with sodium borohydride (1.04 g) and 15 ml of water. The mixture was stirred at ambient temperature for thirty minutes and then was diluted with 175 ml of water. The resulting solid was filtered off, washed with water and then was dissolved in dichloromethane (100 ml). The organic solution was washed with water, then was dried (potassium carbonate) and evaporated in vacuo. A solution of the residual solid in ethyl acetate (75 ml) was treated with a solution of maleic acid (0.64 g) in ethanol (5 ml). The crystalline product was recovered in two crops to give a total yield of 2.0 g of 4-(8-bromodibenz[b,f]oxepin-10-yl)-1,2,3,6-tetrahydro-1-methylpyridine, (Z)-2-butenedioate (1:1) salt, mp 186°-188°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([NH:57][C:58]4[S:59][CH:60]=[CH:61][N:62]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Nc1nccs1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (14 mg, 0.045 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.3 mL) was added HATU (30 mg, 0.079 mmol) at 0° C. under argon. After stirring at 0° C. for 5 min, 2-aminothiazole (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at rt for 5 min and 50° C. for 30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methyl-N-(thiazol-2-yl)butanamide (Example 114, 9 mg, 0.02 mmol, 44% yield) as a white solid. MS found: (M+H)+=395. 1H-NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, s) 7.67 (1H, s) 7.58 (2H, dd, J=8.90, 4.83 Hz) 7.53 (1H, d, J=9.16 Hz) 7.40-7.46 (1H, m) 7.25 (1H, s) 7.14 (2H, t, J=8.65 Hz) 6.87 (1H, s) 2.81 (2H, s) 1.51 (6H, s).
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])=[CH:19][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 2.32 g t-butyl N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate in tetrahydrofuran was added dropwise under ice-cooling to a tetrahydrofuran solution of Grignard reagent prepared from 5.2 g of 1-bromo-4-fluorobenzene and 1 g magnesium. The mixture was stirred at 5° C. for 2 hours, then poured into an aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The extract was purified by silica gel column, to give 2.6 g of t-butyl N-{(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamate as colorless oil. This product was treated with 4 N hydrochloric acid/ethyl acetate, to give 1.73 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[NH:13][C:12]3[C:14]4[CH2:15][C:16]([CH3:26])([CH3:25])[O:17][C:18]=4[C:19]([C:21]([O:23]C)=O)=[CH:20][C:11]=3[N:10]=2)=[C:6]([CH3:27])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[NH:13][C:12]3[C:14]4[CH2:15][C:16]([CH3:25])([CH3:26])[O:17][C:18]=4[C:19]([C:21]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=4)=[O:23])=[CH:20][C:11]=3[N:10]=2)=[C:6]([CH3:27])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(C)ccnc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccnc(Cl)c1Nc1nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 56.3 %

Procedure:
Under inert atmosphere to a solution of methyl 2-((2-chloro-4-methylpyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-48, 0.200 g, 0.516 mmol) in dry toluene was added 3-trifluoromethyl aniline (0.124 g, 0.774 mmol) and trimethyl aluminium (2.0 M solution in toluene) (0.037 g, 0.516 mmol). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on neutral alumina eluting with 40.0% Acetone: petroleum ether to afford 0.150 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.24 (s, 3H), 3.08 (s, 2H), 7.45-7.37 (m, 3H), 7.59 (t, J=7.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 8.15 (d, J=4.2 Hz, 1H), 8.33 (s, 1H), 9.93 (s, 1H), 11 (bs, 1H); MS [M+H]+: 516.35.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[C:11]([CH3:35])[CH:12]=[C:13]([C:21]5[C:22]6[C:27]([CH:28]=[C:29]7[C:34]=5[CH:33]=[CH:32][CH:31]=[CH:30]7)=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Br:38]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.O>[Br:38][C:28]1[C:29]2[C:34]([C:21]([C:13]3[C:14]4[C:20]5=[C:19]6[C:17](=[CH:16][CH:15]=4)[CH:18]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]6[CH:8]=[CH:9][C:10]5=[C:11]([CH3:35])[CH:12]=3)=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:33][CH:32]=[CH:31][CH:30]=2
Reactant: BrBr
Reactant: Cc1cc(-c2c3ccccc3cc3ccccc23)c2ccc3cc(C(C)(C)C)cc4ccc1c2c43
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2c3ccccc3c(Br)c3ccccc23)c2ccc3cc(C(C)(C)C)cc4ccc1c2c43
Temperature: 40 °C
Yield: 50.9 %

Procedure:
Under a nitrogen atmosphere, Intermediate Compound 1 (6 g, 13.4 mmol) was dissolved in 100 ml of dioxane. An aqueous solution prepared by dissolving 0.75 g (13.4 mmol) of potassium hydroxide in 5 ml of distilled water was added to the solution, and 2.56 g (16.1 mmol) of bromine were dropped to the mixture. After the resultant had been stirred on an oil bath heated to 40° C. for 30 minutes, 9.7 g (3.08 mmol) of a 5% sodium thiosulfate solution were added to the resultant, and the whole was stirred at 20° C. for an additional 2 hours. After having been filtrated, the resultant was washed with methanol and recrystallized from toluene (twice). The resultant was dried in a vacuum under heat, whereby 3.6 g of Intermediate Compound 2 were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:23])[CH2:20][C:21]#[CH:22].O>C(NCC)C.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:22][C:21]#[C:20][N:19]([CH3:23])[CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCNCC
Product: CN(C)C#CCc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
1-(tert-Butoxycarbonyl)-5-iodoindole (1.00 g, 2.91 mmol) was dissolved in diethylamine (20 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (163 mg, 0.233 mmol), cuprous iodide (44.4 mg, 0.233 mmol) and 1-dimethylamino-2-propyne (0.628 mL, 5.82 mmol), followed by stirring at 80° C. for 7.0 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=19/1) to obtain 1-(tert-butoxycarbonyl)-5-(3-dimethylamino-2-propyn-1-yl)indole (0.78 g, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(OCC)(O[CH2:16][CH3:17])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:16]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (9.9 g, 0.063 mol) and diethyl sulfate (12.17 g, 0.079 mol) in DMF (100 mL) was added K2CO3 (17.39 g, 0.126 mol). The resulting mixture was stirred at 80° C. for 90 min and then cooled to rt. The reaction mixture was diluted with H2O (200 mL) and extracted with 25% EtOAc in hexanes (2×100 mL). The combined organic phases were washed with brine (100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give 11.5 g (98%) of 53 as an orange-yellow solid. 1H NMR (60 MHz, CDCl3): δ 8.8-7.7 (m, 1H), 6.6-6.2 (m, 2H), 4.0 (q, 2H), 1.4 (t, 3H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: Nc1ccccc1
Solvent: CO
Product: N#CNC(=Nc1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and aniline (0.27 g, 2.9 mmol) dissolved in methanol (5 ml) was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g). Elution with chloroform-methanol (100:1) gave the object compound, which was further crystallized from methanol-diethyl ether to give N-cyano-N'-phenyl-4-pyridinecarboximidamide (0.32 g, 1.4 mmol, yield: 54%) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20]OC2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[C:33]1([C:39]2[CH:46]=[CH:45][C:42]([CH2:43][OH:44])=[CH:41][CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:44][CH2:43][C:42]2[CH:41]=[CH:40][C:39]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:46][CH:45]=2)[CH2:14][CH2:13]1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(-c3ccccc3)cc2)CC1

Procedure:
Compound 23 was prepared in a similar manner to compound 7, substituting the commercially available 4-phenylbenzylalcohol for 2-propanol in part C. MS (M+1)=488.42
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N[C@H](CCO)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@H](CCO)C(=O)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a suspension of D-Homoserine (2.5 g, 20.99 mmol) and K2CO3 (5.8 g, 41.98 mmol) in DMSO (30 mL) was added 2-chloro-3-methyl-4-fluorobenzonitrile (3.56 g, 20.99 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (200 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a beige solid (3.39 g, 60%): 1H NMR (400 MHz, δ in ppm) 7.49 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.06 (br d, J=9 Hz, 1H), 4.49-4.41 (m, 1H), 3.83-3.80 (m, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 1H) and 2.18-2.09 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:42]([N:45]=[C:46]=[O:47])([CH3:44])[CH3:43].C(N(CC)CC)C.ClCCl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:46]([NH:45][CH:42]([CH3:44])[CH3:43])=[O:47])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with isopropyl isocyanate/triethylamine/dichloromethane as described in Example 93 to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 0.98 (3H, d), 1.1 (3H, d), 1.35-1.42 (1H, m), 1.90-1.95 (1H, m), 2.4 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.3-3.4 (1H, m), 3.50-3.63 (6H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.05 (1H, br d), 5.45 (1H, d), 6.18 (2H, s), 6.92 (2H, d), 7.0 (1H, d), 7.18 (2H, d), 7.22 (1H, s), 7.3 (2H, d), 7.58 (1H, d); MS: 678 (MH+); C32H43N3O11S.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:6]=[CH:7]2)[CH:13]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: COc1cccc(I)c1
Product: COc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-methoxybenzene: ESMS m/e: 257.9 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(CN3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.9 %

Procedure:
A mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.200 g, 1.09 mmol), 4-bromomethyl-biphenyl (0.322 g, 1.303 mmol) and potassium carbonate (0.300 g, 2.17 mol) in dry N, N-dimethyl formamide (6 mL) was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The separated organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a colorless syrup (0.42 g). Purification by flash chromatography using a solvent gradient of 0 to 5% ethyl acetate in hexane afforded a white foam that was crystallized from ethyl acetate/hexane to afford the title compound (0.261 g, 68%) as a white crystalline solid, m.p. 135-137° C.