Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11]COC.O.Cl.[O-]S([O-])(=O)=O.[Ca+2]>CO.C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COCOc1ccc(/C=C/c2ccc(S(=O)(=O)N3CCOCC3)cc2)cc1OCOC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(/C=C/c2ccc(O)c(O)c2)cc1)N1CCOCC1
Reaction time: 45 h
Yield: 91 %

Procedure:
N{4-[2-(3,4-Di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonyl} morpholine (0.6 g, 1.3347 mmol) was dissolved in a mixed solvent of MeOH (100 mL) and CH2Cl2 (60 mL). The homogeneous solution was bubbled with argon gas. Water (0.2 g, 11.11 mmol) and concentrated hydrochloric acid (0.9 mL, 10.8 mmol) were added and stirred for 45 hours. The solvents were removed by evaporation and the solid residue was washed with water for several times. The solid was dried under high vacuum in the presence of Drierite providing 0.4388 g of N-{4-[2-(3,4-dihydroxyphenyl)-trans-vinyl]benzenesulfonyl}-morpholine as a yellowish solid (1.214 mmol, yield 91.0%). 1H NMR (Acetone-D6 and DMSO-d6, 300.16 MHz) δ (ppm) 9.05 & 9.03 (2s, 0.64H), 8.81 & 8.79 (2s, 0.65H), 7.81 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.32 (d, J=16.3 Hz, 1H), 7.13-7.04 (m, 2H), 6.96 (dd, J=8.2 & 1.9 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 3.68-3.65 (m, 4H) and 2.94-2.91 (m, 4H). MS (ESI) m/z: 362 (M+1)+, 384 (M+23)+ and 745 (2M+23)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2Cl)c1
Yield: 86.4 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 2-chlorothiophenol (145 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3,5-dimethylphenyl 2-chlorophenyl sulfide (215 mg, 87% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.5 (hexane/ethyl acetate=50/1). 1H NMR (CDCl3, 300 MHz) δ 7.32-7.36 (m, 1 H), 7.05-7.10 (m, 4 H), 6.97 (s, 1 H), 6.88-6.92 (m, 1 H), 2.30 (s, 6 H). 13C NMR (CDCl3, 75 MHz) δ 139.5, 137.4, 132.7, 131.7, 131.5, 130.6, 129.8, 129.6, 127.3, 126.9, 21.6. IR (neat, cm−1) 3060, 3037, 2950, 2917, 2860. MS (EI) m/z (relative intensity) 250 (30), 248 (100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[N:14]=[C:15]([CH2:30][CH2:31][CH2:32][CH3:33])[N:16]=[C:17]([NH:18]CC3C=CC(OC)=CC=3OC)[C:12]=2[NH:11][N:10]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:30]([C:15]1[N:16]=[C:17]([NH2:18])[C:12]2[NH:11][N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:13]=2[N:14]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCCBr)c2n1
Reactant: C1CCNC1
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Example 7 from 3-(7-bromoheptyl)-5-butyl-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and pyrrolidine
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[H-].[Na+].[CH3:25]N(C)C=O>O1CCCC1>[C:1]([N:8]([CH3:25])[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Following the procedure of Boger and Yohannes (J. Org. Chem. 53, 487 (1988), a solution of N-BOC-4-iodophenylalanine (391 mg, 1 mmol) and methyl iodide (156 μL, 2.5 mmol) in tetrahydrofuran (5 mL) at 0° C. was added 60% sodium hydride in oil suspension (100 mg, 2.5 mmol). The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 16 hr. Added dimethylformamide (1 mL) and additional methyl iodide (156 μL, 2.5 mmol) and 60% sodium hydride (100 mg, 2.5 mmol) and heated at 75° C. overnight. The reaction was worked up as described in the reference to yield N-BOC-N-methyl-4-iodophenylalanine.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncccc4c3O2)cc1
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4ncccc4c3O2)C1
Temperature: 77.5 °C

Procedure:
(2R)-2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.50 g, 1.34 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.72 g, 3.65 mmole) were combined in 60 mL of DMSO and heated at 75-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated sodium bicarbonate solution. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate and concentrated to an oil in vacuum. This was column chromatographed on silica gel using first ethyl acetate to elute impurities and then 3% methanol in ethyl acetate to elute 0.110 g of the product as a light yellow solid. This was recrystallized from ethanol to give 0.050 g of the (S)-enantiomer of the title compound as a light yellow solid hemihydrate (m.p. 217° C.).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][C:7]=1[CH:14]=[CH2:15])(=[O:4])=[O:3].Cl.[C:17]1([C:23](=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:7]=1[CH:14]=[CH2:15])(=[O:4])=[O:3]
Reactant: O=C(O)C(=Cc1ccccc1)c1ccccc1
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: Cl
Product: C=Cc1cc(CNC(=O)C(Cc2ccccc2)c2ccccc2)ccc1NS(C)(=O)=O
Yield: 68 %

Procedure:
4-Methanesulfonylamino-3-vinylbenzylamine and HCl salt (131 mg, 0.499 mmol) were reacted with 2,3-diphenyl-acrylic acid (115 mg, 0.512 mmol) prepared by the reported procedure to give N-(4-methanesulfonylamino-3-vinyl-benzyl)-2,3-diphenyl-propionamide (146 mg, 68%).
Reaction SMILES: C([CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(O)=O.[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].C(OO)(=O)C>[Ru](I)I.C1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[C:9]([O:12][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(C(=O)O)N1
Agent: I[Ru]I
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC(=O)N1
Yield: 34.9 %

Procedure:
1.15 g (10 mmol) of 4-carboxyazetidine-2-one (MW 115) was added with 0.905 g (11 mmol) of anhydrous sodium acetate, 3.2 g of acetic acid, 2.8 g of ethyl acetate and 0.433 g (1 mmol) of benzene ruthenium diiodide, cooled to 10°-15° C., then added dropwise 8.25 g of acetic acid solution containing 22% peracetic acid over one hour while stirring. A further 15 hour stirring was carried out at the same temperature, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane/ethyl acetate=1/1 by volume) to obtain 0.45 g of 4-acetoxyazetidine-2-one (yield: 35%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:5]1([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[N:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Brc1ccc(-n2cc3c(n2)CCN(Cc2ccccc2)CC3)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-n2cc3c(n2)CCNCC3)cc1

Procedure:
A solution of 2-(4-bromophenyl)-6-(phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 14) (49 mg, 0.13 mmol) in ethanol (5 ml) with palladium (10% Pd/C Paste) as a catalyst (10 mg) was stirred under an atmosphere of hydrogen overnight. The next day, the resulting mixture was filtered through celite and to afford the title compound which may be used without further purification (D46). MS (ES+) m/e 214 [M+H]+
Reaction SMILES: ClC1SN=NC=1CN1C2=CN=C(C(OCC)=O)C=C2C=C1.N1C2=CN=C(C(OCC)=O)C=C2C=C1.ClC1SN=NC=1CCl.[CH2:44]([O:46][C:47]1[S:51][N:50]=[N:49][C:48]=1[CH2:52][N:53]1[C:57]2=[CH:58][N:59]=[C:60]([C:62]([OH:64])=O)[CH:61]=[C:56]2[CH:55]=[CH:54]1)[CH3:45].[OH-].[Na+].ClC1C(F)=C(C(F)=CC=1)CN1C2=CN=C(C([NH:83][OH:84])=O)C=C2C=C1.Cl.NO>C(O)C>[CH2:44]([O:46][C:47]1[S:51][N:50]=[N:49][C:48]=1[CH2:52][N:53]1[C:57]2=[CH:58][N:59]=[C:60]([C:62]([NH:83][OH:84])=[O:64])[CH:61]=[C:56]2[CH:55]=[CH:54]1)[CH3:45]
Reactant: CCOc1snnc1Cn1ccc2cc(C(=O)O)ncc21
Reactant: O=C(NO)c1cc2ccn(Cc3c(F)ccc(Cl)c3F)c2cn1
Agent: CCOC(=O)c1cc2cc[nH]c2cn1
Agent: CCOC(=O)c1cc2ccn(Cc3nnsc3Cl)c2cn1
Agent: Cl
Solvent: CCO
Product: CCOc1snnc1Cn1ccc2cc(C(=O)NO)ncc21

Procedure:
Ethyl 1-(5-chloro-[1,2,3]thiadiazol-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate and 5-chloro-4-chloromethyl-[1,2,3]thiadiazole in a manner similar to step (a) of example 1. 1H NMR (DMSO-d6) δ: 8.99 (s, 1H), 8.36 (s, 1H), 7.85 (d, 1H, J=3.0 Hz), 6.75 (d, 1H, J=3.0 Hz), 6.04 (s, 2H), 4.32 (q, 2H, J=7.0 Hz), 1.32 (t, 3H, J=7.0 Hz). LCMS (API-ES, M+H+): 323.0. (b) 1-(5-Ethoxy-[1,2,3]thiadiazol-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(5-chloro-[1,2,3]thiadiazol-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1 using sodium hydroxide as base and anhydrous ethanol as solvent. 1H NMR (DMSO-d6): δ: 9.01 (s, 1H), 8.35 (s, 1H), 7.85 (d, 1H, J=3.0 Hz), 6.75 (d, 1H, J=3.0 Hz), 5.86 (s, 2H), 4.36 (q, 2H, J=6.8 Hz), 1.42 (t, 3H, J=6.8 Hz). LCMS (API-ES, M+H+): 305.0. (c) 1-(5-Ethoxy-[1,2,3]thiadiazol-4-ylmethyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(5-ethoxy-[1,2,3]thiadiazol-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) 6; 11.15 (s, 1H), 8.88 (s, 2H), 8.19 (s, 1H), 7.73 (d, 1H, J=3.0 Hz), 6.66 (d, 1H, J=3.0 Hz), 5.81 (s, 2H), 4.32 (q, 2H, J=6.8 Hz), 1.39 (t, 3H, J=6.9 Hz). LCMS (APCI, M+H+): 320.1. HRMS calcd for C13H14N5O3S (M+H) 320.0817, found 320.0823. HPLC: 100% purity.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22][CH3:23])[C:10]=1[C:11](Cl)=[O:12].O>ClCCl>[OH:4][CH2:3][C:2]([NH:1][C:11](=[O:12])[C:10]1[C:14]([O:22][CH3:23])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:9]=1[O:8][CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Reactant: CC(C)(N)CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 3.7 ml (37.22 mmol) 2-amino-2-methyl-1-propanol in 42 ml dichloromethane under nitrogen at 0° C., was added dropwise a solution of 5 g (18.61 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoyl chloride in 12 ml dichloromethane. The temperature rose to 7° C. The mixture was stirred at room temperature for 4 hours. The mixture was poured onto 75 ml water. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 5.66 g (yield: 94.6%) of the title compound as a yellow solid. MS (m/e): 322.2 (M+H').
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@@H:30]([NH2:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([NH:32][C@@H:30]([CH3:31])[C:29]([F:34])([F:33])[F:28])=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1c1ccn2ncc(C(=O)O)c2n1
Reactant: C[C@H](N)C(F)(F)F
Product: C[C@H](NC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12)C(F)(F)F

Procedure:
Prepared according to the method of Example 212, Step F, using 54(2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 219, Step F) and (S)-1,1,1-trifluoropropan-2-amine. The title compound was obtained as a white solid (5.4 mg, 31% yield). MS (apci) m/z=467.1 (M+H).
Reaction SMILES: [H-].[K+].[C:3]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=3)([CH3:6])([CH3:5])[CH3:4].[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39](Cl)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:25]=[CH2:26].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39]([CH:11]1[C:10]2[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)([CH2:40][CH3:41])[CH2:42][CH3:43])[CH:25]=[CH2:26]
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1c2ccc(C(C)(C)C)cc2-c2cc(C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
There was washed 1.50 g (11.22 mmol) of potassium hydride having a purity of 30% by weight with each 3 mL of hexane three times in an atmosphere of nitrogen, and 18 mL of THF was added thereto. To the obtained THF slurry of potassium hydride, 2.50 g (8.98 mml) of 3,6-di-tert-butylfluorene was added dropwise at 0° C. using 18 mL of a THF solution thereof. The obtained mixture was stirred for 2 hours at a room temperature, and then 2.92 g (8.98 mmol) of (2-allyloxy-3-tert-butyl-5-methylphenyl)chlorodiethylsilane was added dropwise at −78° C. using 4 mL of a toluene solution thereof. The temperature of the obtained liquid reaction mixture was raised up to a room temperature, and the mixture was stirred for 2 hours. The mixture was added dropwise at 0° C. to a mixture of 18 mL of a 10% aqueous solution of sodium hydrogen carbonate and 18 mL of a 10% aqueous solution of sodium carbonate, and the resultant mixture was extracted with 10 mL of toluene. The obtained extract was dried over sodium sulfate, and dried extract was concentrated under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(3,6-di-tert-butylfluoren-9-yl)diethylsilane.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].C(OCC)(=O)C>CN(C)C=O.O1CCCC1>[CH2:25]([O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCO[C@H]1CCC[C@@H](OCc2cccc(C)c2C(=O)OC)C1
Reaction time: 0.67 h

Procedure:
4.3 g of methyl 2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate are dissolved in 40 ml of dimethylformamide and 1.3 g of sodium hydride (60% strength suspension in paraffin oil) are added. After 40 minutes of stirring, 4 ml of allyl bromide, dissolved in 20 ml of tetrahydrofuran, are added. After 3 hours, 300 ml of ethyl acetate are added and the mixture is washed three times with saturated sodium chloride solution. The combined organic phases are dried over sodium sulfate and the solvents are then removed under reduced pressure. The resulting residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=50:1→5:1. This gives 2.1 g of methyl 2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate as a yellow oil. C19H26O4 (318.42), MS(ESI): 319 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]4[NH:32][C:31]5[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=5[N:29]=4)[CH:22]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOCC>[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:23]1[CH:22]=[C:21]([N:18]2[CH2:19][CH2:20][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:17]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)C2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C(C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
Method G—Step b To a mixture of 4-{1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-pyrrolidine-3-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.21 mmol) in dcm (1 mL), 2M HCl in Et2O (4 mL) was added. The mixture was stirred at room temperature overnight, the precipitate obtained was filtered off, and washed with Et2O. The precipitate was then recovered in saturated NaHCO3 solution (3 mL), extracted with dcm (2×3 mL), solvent removed and the crude filtered through an SCX cartridge, to obtain 0.05 g of the title compound (57%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:11]=2)[CH2:8][CH2:9]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
NaH (330 mg, 8.25 mmol) was added in several batches, to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (1.4 g, 5.42 mmol) in DMF (25 mL) while cooling to 0-5° C. The resulting solution was stirred at room temperature for 0.5 hours, and then benzenesulfonyl chloride (1.5 g, 8.41 mmol) was added dropwise. The reaction was stirred for an additional 4 hours at room temperature, and then filtered. The filter cake was washed with ethanol (3×50 mL) and dried to afford 1.2 g (55%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-indole as a light yellow solid. 1H NMR (DMSO) δ 8.62 (s, 1H), 8.17-8.27 (3H), 8.10 (d, 2H), 7.74 (1H), 7.61 (2H), 6.32 (s, 1H), 3.84 (s, 2H), 3.38 (2H), 2.83-2.87 (5H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([S:32][CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][S:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:35][CH:36]=1
Reactant: NCc1ccc(CSC2CCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CSC4CCCC4)cc3)c2CC1)C(F)(F)F
Yield: 40.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.4 g, 0.94 mmol) with 4-(cyclopentylthiomethyl)-benzylamine (229 mg, 1.03 mmol) in toluene (10 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to obtain 7-chloro-6-[4-(cyclopentylthiomethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 41%). MS (ES+) m/z: 498 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl.C(O)(=O)CCC(O)=O>N1C=CC=CC=1.O>[C:12]([C:11]1[CH:10]=[C:9]([N:8]([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=2)[C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:17]=[CH:16][CH:15]=1)([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=C(O)CCC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 47.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.0 g (0.0088 mole) of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid and 9.0 g (0.090 mole) of succinic anhydride was heated at 150° C. for 15 minutes. The reaction mixture was diluted with pyridine (50 ml) and water, and was poured into cold dilute hydrochloric acid. The resulting precipitate was recrystallized from a mixture of 14 ml of ethanol and 22 ml of water to give a white solid. This solid was heated in 70 ml of water to dissolve any succinic acid, and was collected and heated in 40 ml of ethyl acetate. The ethyl acetate solution was filtered to remove a small amount of insoluble material. The ethyl acetate filtrate was concentrated to 20 ml, and was then diluted with 10 ml of hexane. The resulting precipitate was collected and dried to give 1.85 g of white solid N-(3-carboxyphenyl)-N-(3,5-di-t-butyl-4-hydroxyphenyl)succinamic acid, m.p. 182°-183° C. Analysis: Calculated for C25H31NO6 : % C, 68.0; % H, 7.1; % N, 3.2; Found: % C, 68.2; % H, 7.1; % N, 3.0.