Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=2)=[N:6][CH:7]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:21][N:20]=1)=[O:24])([CH3:39])[CH3:35]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 5-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridine-2-carboxylic acid (82 mg, 0.25 mmol) and TBTU (88 mg, 0.27 mmol) in DMF (1.2 mL) was added DIPEA (213 μL, 1.25 mmol). Then isopropylamine (23 μL, 0.27 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (57 mg, 62%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.Cl[S:16]([OH:19])(=O)=[O:17].C([N:22](CC)CC)C.P(Cl)(Cl)(Cl)=O.O.N.Cl>ClC(Cl)C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:16]([NH2:22])(=[O:19])=[O:17])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cn2nc(Cl)ccc2n1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Product: NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazine (6.00 g, 27.1 mmol) was dissolved in 1,1,2,2-tetrachloroethane (60.0 ml), and chlorosulfonic acid (97%, 2.80 ml, 40.7 mmol) was added to the solution with stirring at room temperature. The mixture was heated for 8 hours under reflux and then cooled to room temperature, and triethylamine (4.39 g, 43.4 mmol) and phosphorus oxychloride (7.47 g, 48.7 mmol) were added dropwise thereto. The reaction mixture was heated at 120° C. for 3 hours with stirring and then cooled to 50° C., and water (150 ml) was added thereto. After the reaction solution was partitioned, the aqueous layer was extracted twice with chloroform, and the organic layers were combined, washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were dissolved in acetonitrile (100 ml) and stirred at room temperature, during which ammonia water (14 M, 9.00 ml, 126 mmol) was added thereto. The reaction solution was stirred at room temperature for 2 hours, poured into ice-water (400 ml) and adjusted to pH 2 with conc. hydrochloric acid, to precipitate crystals which were then filtered and washed with water. The crystals were dried and then purified by silica gel chromatography (ethyl acetate:chloroform=1:9→1:4→1:2), to give the title compound as colorless crystals. The yield was 3.80 g (46.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:12][CH2:13][C:14](=[O:16])[CH3:15]>CC(C)=O>[Br-:12].[O:16]=[C:14]([CH3:15])[CH2:13][N+:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: CC(=O)CBr
Reactant: COC(=O)c1ccc(C)nc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C)[n+](CC(C)=O)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of methyl 6-methylnicotinate (1.00 g, 6.60 mmol) and bromoacetone (1.00 g, 7.30 mmol) in acetone (3 mL) was refluxed overnight, cooled to room temperature, and decanted. The resulting solid was dried under vacuum to provide approximatelyl.47 g the desired product as a solid, which was used directly in the next step without further purification.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:48]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:47]1[CH:48]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([B:25]([OH:27])[OH:26])=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:50]=[CH:51][CH:52]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Yield: 64 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 39D (1.07 g, 1.84 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 39E (640 mg, 64%) as a tan foam. 1H NMR (400 MHz, CD3OD) δ ppm 1.14 (t, J=7.15 Hz, 3 H) 2.65-2.86 (m, 2 H) 2.99 (t, J=7.15 Hz, 2 H) 4.05 (q, J=7.15 Hz, 2 H) 4.19-4.35 (m, 2 H) 4.93-5.14 (m, 3 H) 6.98 (d, J=7.70 Hz, 1 H) 7.12-7.33 (m, 8 H) 7.34-7.45 (m, 2 H) 7.45-7.59 (m, 1 H) 9.14 (s, 1 H)
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1.[Li]CCCC.B(OC)(OC)[O:24]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:24]
Reactant: COB(OC)OC
Reactant: CCCCCC1CCc2ccc(F)c(F)c2O1
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
52.4 g (about 0.22 mol) of crude 7,8-difluoro-2-pentylchroman are initially introduced in 400 ml of THF, and 150.7 ml (0.24 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 3 h at this temperature, 26.8 ml (0.24 mol) of trimethyl borate are added dropwise, and the batch is warmed to room temperature. 55 ml of dilute acetic acid (about 30%) are added, and 57 ml of hydrogen peroxide soln. (35%) are carefully added to the batch. When the addition is complete, the mixture is stirred for 17 h at room temperature. Water is added, and the batch is acidified using HCl. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1.Cl[C:25]([O:27][CH:28]([Cl:30])[CH3:29])=[O:26].CCCCCC.CCOC(C)=O>ClCCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:25]([O:27][CH:28]([Cl:30])[CH3:29])=[O:26])[CH2:15][CH2:16]1
Reactant: Cc1cc(N2CCN(Cc3ccccc3)CC2)c(C)cc1C=O
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCCCCC
Product: Cc1cc(N2CCN(C(=O)OC(C)Cl)CC2)c(C)cc1C=O
Yield: 63.7 %

Procedure:
The 4-(2,5-dimethyl-4-formylphenyl)-1-benzylpiperazine (9 g, 29 mmol) was dissolved in anhydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) was added. The solution was refluxed for 30 minutes or until TLC analysis indicated the disappearance of the starting material. The product was just slightly less polar than the starting material by TLC using hexane/EtOAc (3/1). Dichloroethane was evaporated and the residue was chromatographed using gradient hexane/EtOAc (10/0 to 8/2) to give the product (6 g, 64%) as an oil.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]CCCC(C1C=CC(F)=CC=1)=O>C1(C)C=CC=CC=1.[I-].[K+]>[ClH:13].[C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Agent: c1ccc(C23CNCC2C3)cc1
Solvent: Cc1ccccc1
Product: Cl

Procedure:
A mixture of 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane (Example 9), 20.1 g of γ-chloro-p-fluorobutyrophenone and 10 mg of potassium iodide in 100 ml of toluene is refluxed for 24 hours. Filtration gives 11.6 g of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 166°-167° C. Evaporation of the filtrate gives a brown oil which is combined with 2 N hydrochloric acid and chloroform. The crystals which form in the chloroform layer are collected by filtration and recrystallized from ethanol to give 3.10 g of 3-[3-(p-fluorobenzoyl)propyl]-1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride as pale tan crystals, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([N:8]([C:32]1([CH3:41])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)[CH2:9][C@H:10]([O:28][C:29](=[O:31])[CH3:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([N+:25]([O-])=O)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](O)CN(CC2C=CC=CC=2)C2CC3C(=CC(CC)=C(CC)C=3)C2)C=CC=1OCC1C=CC=CC=1>>[NH2:25][C:13]1[CH:12]=[C:11]([C@@H:10]([O:28][C:29](=[O:31])[CH3:30])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:32]2([CH3:41])[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40]2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c(N)c1
Reaction time: 6 h

Procedure:
The title compound is prepared from acetic acid (R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethyl ester (2.90 g) by an analogous procedure to that used to prepare (R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica; n-hexane/ethyl acetate 2:1 Rf=0.60).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN.Cl>C(O)C.O>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 6-nitrobenzo[d]thiazole (1.64 g, 9.10 mmol) in ethanol (16 mL) was added hydrazine hydrate (2.66 mL, 54.6 mmol). The resulting dark solution was stirred overnight at room temperature. The mixture was then diluted with water and slowly acidified with 3 M HCl, giving a yellow suspension. The mixture was then extracted with dichloromethane. The combined organics were dried, filtered, and concentrated, giving a yellow solid, used directly in the subsequent reaction. 1H NMR (DMSO-d6) δ 8.09 (brs, 1H), 7.87 (d, J=8.7 Hz, 1H), 6.74 (d, J=9.0 Hz, 1H), 6.27 (brs, 2H); MS-EI: (m/z, %) 170 (M+, 100), 140 (28), 124 (35).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[BrH:18].[Br:19]Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[Br:18][CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=2)[C:13]1=[O:17].[Br:18][C:12]1([Br:19])[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=2)[C:13]1=[O:17]
Reactant: O=C1CCc2cc(-c3cccc(Cl)c3)ccc21
Reactant: BrBr
Reactant: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3cccc(Cl)c3)cc2CC1(Br)Br
Product: O=C1c2ccc(-c3cccc(Cl)c3)cc2CC1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.42 g (10 mmol) of 5-(3-chlorophenyl)indan-1-one are dissolved in 30 ml of glacial acetic acid and, after addition of 10 μof a 48% strength HBr solution in water, treated dropwise while stirring with a solution of 0.77 ml (15 mmol) of bromine in 7 ml of glacial acetic acid. After the reaction mixture has been stirred at room temperature for 3 h, it is poured into a mixture of 100 g of ice with 70 ml of water and 100 mg of NaHSO3 and stirred. The resulting suspension is extracted by shaking with 200 ml of dichloromethane, and the organic phase is then washed with water (3×100 ml), dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel with toluene/ethyl acetate 50/1. 2-Bromo-5-(3-chlorophenyl)indan-1-one is obtained with a melting point of 110° C., in addition to a little 2,2-dibromo-5-(3-chlorophenyl)indan-1-one.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)(=[O:13])[CH3:12]>[O-]CC.[Na+]>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[CH3:10]
Reactant: CC(=O)c1nccs1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a sodium ethoxide solution (prepared from 150 ml of ethanol and 4.2 g of sodium) at 0° C., a mixture of diethyl oxalate (22.98 g) and acetylthiazole (20.07 g) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours and concentrated. The residue was treated with 100 ml of water and neutralized with 6N HCl. Filtration afforded 25.8 g of 2,4-diketo-4-(thiazol-2-yl)butyric acid ethyl ester as brown solids. NMR: 1.46 (t, 3H), 4.49 (q, 2H), 7.27 (s, 1H), 7.65, 8.04 (2d, 2H, thiazolyl H's).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
4-Acetylaniline (0.159 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. 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 (chloroform:methanol=1:2) to obtain the titled compound (0.160 g, 0.326 mmol, 61%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[F:16])[NH2:12].[H][H]>[Pd]>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C@H:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: [H][H]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COC(=O)C(C)=O
Agent: [Pd]
Product: COC(=O)[C@H](C)Nc1ccc(F)c(Cl)c1

Procedure:
Methyl pyruvate (1-1, 42.082 g, 412.201 mmol) and 3-chloro-4-fluoroaniline (1-2, 15.000 g, 103.50 mmol) were combined in a dry pressure tube, and dissolved in cyclohexanes (400 mL). The resulting solution was treated with 10% palladium on activated carbon (7.500 g), and reacted under high pressure hydrogen gas (50 bar) for 24 h. Upon completion, the reaction mixture was filtered through celite and washed 5 times with 40 mL portions of cyclohexanes. The filtrate was concentrated under vacuum. The crude residue was purified by flash column chromotography (SiO2, 0-100% EtOAc/hexanes gradient) to give methyl N-(3-chloro-4-fluorophenyl)alaninate (1-3). 1H NMR (300 MHz, CDCl3) δ 6.94 (dd, J=8.8, 8.8 Hz, 1H), 6.60 (dd, J=6.0, 3.0 Hz, 1H), 6.42 (dd, 8.8, 6.7, 3.0 Hz 1H), 4.13 (q, J=7.0 Hz, 1H), 3.75 (m, 3H), 1.47 (d, J=6.7 Hz, 3H). MS 332.2 found, 332.6 (M+H+) required.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH3:18][N:19]=[C:20]=[O:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:12])[S:10][N:19]([CH3:18])[C:20]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN=C=O
Reactant: Cc1ccc(N=C=S)cc1
Agent: Cl
Agent: [K+]
Product: Cc1ccc(-n2c(=O)sn(C)c2=O)cc1

Procedure:
Reagents: 4-Methylphenyl isothiocyanate (0.88 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), methyl isocyanate (0.38 ml, 6.5 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([S:12]CCCC)[CH2:9][CH2:10][CH3:11]>>[C:2]1([S:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CCCCSCCCC
Product: CCCCSc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (310 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.26–7.09 (m, 5H; Hb, Hb′, Hc, Hc′, Hd), 2.88–2.82 (t, J=4.0, 2H; He), 1.60–1.46 (m, 2H; Hf), 1.42–1.30 (m, 2H; Hg), 0.88–0.82 (t, J=3.9, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 136.9 (C1), 128.7 (C3′, C3, C2, C2), 125.5 (C4), 33.1 (C5), 31.1 (C6), 21.9 (C7), 13.6 (C8). Anal. Calcd. for C10H14S: C, 72.23; H, 8.49; S, 19.28; Found C, 71.97; H, 8.67; S, 19.07.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]1=[O:25]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]([N:15]2[C:16](=[O:25])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:23]2=[O:24])=[C:2]([F:1])[CH:7]=1
Reactant: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1N
Temperature: 80 °C
Yield: 86.2 %

Procedure:
Iron powder (1.22 g) was suspended in a 5% aqueous acetic acid solution, followed by heating at 80° C. A solution of 2-[2-fluoro-4-nitro-5-(2-propynyl)aminophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.75 g) in a mixture of acetic acid (2.2 ml) and ethyl acetate (2.2 ml) was dropwise added to the suspension, and the resultant mixture was heated at 70° C. for 3 hours. After removal of the precipitate by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-[4-amino-2-fluoro-5-(2-propynyl)aminophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). m.p., 182.2° C.
Reaction SMILES: [Cl-].[Cl-].[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:11]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH2:16][NH+:15]([CH2:23][CH2:24][NH+:25]([CH3:27])[CH3:26])[CH2:14][CH2:13][N:12]3[C:28]=2[CH:29]=1)(O)=[O:4].[N:36]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[CH:30]1([C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:3]([NH:45][S:42]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)(=[O:44])=[O:43])=[O:4])=[CH:29][C:28]=3[N:12]3[CH2:13][CH2:14][N:15]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:11]=23)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C[NH+](C)CC[NH+]1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2C1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N4CCOCC4)cc32)-c2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To 11-carboxy-14-cyclohexyl-6-[2-(dimethylammonio)ethyl]-5,6,7,8-tetrahydroindolo-[2,1-a][2,5]benzodiazocin-6-ium dichloride (1 eq) (prepared from the product described in Example 20, Step 5, by iterative freeze drying in the presence of aqueous HCl) in DCM (0.06 M) was added morpholine-4-sulfonamide (1.5 eq), EDCI (1.5 eq) and DMAP (1.5 eq). The solution was stirred at RT overnight. The solvent was evaporated in vacuo and the crude was purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1 TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (31%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([OH:42])[C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2.Br[CH2:86][C:87]([O:89]C)=[O:88].CI>>[C:40]([C:38]1[CH:37]=[CH:36][C:26]2[NH:27][C:23]([CH:22]([C:3]3[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[C:8]4[C:4]=3[CH:5]=[CH:6][NH:7]4)[O:42][CH2:86][C:87]([OH:89])=[O:88])=[N:24][C:25]=2[CH:39]=1)#[N:41]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Reactant: COC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Solvent: CI
Product: Cc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) as described in Example 68 using methyl 2-bromoacetate as electrophile instead of methyl iodide. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 11.00 (br.s, 1H) 7.97 (s, 1H) 7.64 (d, J=8.33 Hz, 1H) 7.51-7.54 (m, 1H) 7.21 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.48-6.51 (m, 2H) 4.14 (A of AB, J=16.55 Hz, 1H) 3.99 (B of AB, J=16.55 Hz, 1H) 2.42 (s, 3H) 2.40 (s, 3H). HRMS calcd. for C21H18N4O3 (M+H)+ 375.1452. found 375.1465.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.COC1C=CC2CC(CC(OCC)=O)C3C=CC=CC=3CC=2C=1>CO.C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2cc(F)ccc21
Agent: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC1Cc2ccc(O)cc2Cc2cc(F)ccc21

Procedure:
According to the procedure of Preparation 10 (g), except substituting ethyl (±)-10,11-dihydro-7-fluoro3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a white solid following silica gel chromatography (1% MeOH/CH2Cl2): MS (ES) m/e 315.0 (M+H)+, 332.0 (M+NH4)+.