Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:13][CH:14]=[CH2:15])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:22]([O:12][CH2:11][C@H:9]1[O:10][C@H:2]([O:1][CH2:13][CH:14]=[CH2:15])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: O
Product: C=CCO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of allyl α-D-glucopyranoside (1) (prepared according to R. E. Wing, J. N. BeMiller, Carbohydr. Res. 1969, 10, 441) (12.5 g, 56.8 mmol) and triphenylmethyl chloride (20.0 g, 71.7 mmol) in dry pyridine (120 ml) was stirred at r.t. for 12 h, and at 60° for 1 h. After the addition of triphenylmethyl chloride (12.0 g, 43.0 mmol), the solution was stirred at 60° until all starting material has disappeared (3-4 h). H2O (120 ml) was added to the still warm solution. Extraction with EtOAc, extraction of the combined org. layers with 1M aq. H2SO4 and brine, evaporation of the organic layer and FC (400 g SiO2, toluene/actone 2:1→toluene/acetone 1:1) gave 23.3 g (90%) of 2. Grey glassy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of 6.0 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 50 ml DMF were added 3.3 g piperazine-1-carboxylic acid cyclobutyl ester, 9.1 ml N-ethylmorpholine and 5.9 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 11.1 g.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cccnc2[nH]1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (from MolBridge, 1.0 g, 6.2 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 g, 8.0 mmol) and triethylamine (4.3 mL, 31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (0.78 g, 8.0 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-65% EtOAc/hexane) to give the desired product (1.0 g, 79%). LCMS calculated for C10H12N3O2(M+H)+: m/z=206.1. Found: 206.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH3:41])[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](O)=[O:35])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[NH:31][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:41])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)cc1
Yield: 60.8 %

Procedure:
Preparation of example 122 from the title compound of Example 7 (100 mg, 0.362 mmol), 2-(toluene-4-sulfonylamino)-benzoic acid (158 mg, 0.542 mmol), triethylamine (0.201 mL, 1.446 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (206 mg, 0.542 mmol) in N,N-dimethylformamide (4.0 mL) was carried out analogously to Example 11. When the reaction was judged complete, N,N-dimethylformamide was evaporated and methanol was added. The mixture was filtered and the solids collected and washed with methanol, dichloromethane and diethyl ether. After drying under vacuum, the title compound (121 mg, 0.220 mmol) was obtained as a yellow powder in 61% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:29])=[O:28]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CCCCC[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitropentane (0.091 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.049 g (32%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.10 (dd, J=4.4, 10.0 Hz, 1H), 2.61 (m, 4H), 1.63 (m, 6H), 1.35 (m, 6H) 0.92 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.5, 128.6, 128.5, 126.0, 94.5, 39.5, 35.9, 31.3, 29.6, 28.7, 28.1, 23.3, 22.2, 13.9 ppm; IR νmax (cm−1) 3027, 2931, 2859, 1731, 1559, 1454, 1363, 1030, 748, 700; HRMS (FAB) calcd for C17H25NO3 (MNa+) 314.1727, found 314.1722.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]=[C:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH3:24]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 100 °C
Yield: 96.7 %

Procedure:
118-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (750 mg, 2.12 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (712 mg, 4.24 mmol) Cs2CO3 (1.72 g, 5.29 mmol) and Pd(PPh3)4 (122 mg, 0.11 mmol) in dioxane/H2O (9:1, mL) was heated to 100° C. for 2 h in a microwave reactor. The mixture was then concentrated in vacuo and the residue purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) to give the title compound (550 mg). UPLC-MS: MS 269.2 (M+H+); UPLC rt 0.83 min.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:42].[Ca+2].[OH-:44]>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=2)(=[O:44])=[O:42])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCCO)cc2)ccc(C(C)=O)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCO)cc2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
The compound of Example 46. Step B (330 mg, 0.767 mmoles) was dissolved in chloroform and cooled to 0°. m-Chloroperbenzoic acid (328 mg, 1.57 mmoles) was added and the reaction stirred for one hour. Calcium hydroxide (195 mg) was added and the reaction stirred for 90 minutes at room temperature. The mixture was filtered and the filtrate evaporated to dryness. The residue crystallized from ethyl acetatehexane to yield the title compound; m.p. 99°-100°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[C:10]([CH:15]=[CH2:16])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([CH2:15][CH3:16])=[N:9][CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cnc1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 5,6-divinyl-nicotinic acid tert-butyl ester (890 mg, 3.8 mmol) in THF (20 mL) containing some methanol, Pd/C (100 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 3 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by FC (SiO2, EA-heptane) to give 5,6-diethyl-nicotinic acid tert-butyl ester (860 mg) as an oil; LC-MS: tR=0.79 min, [M+1]+=236.14.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([Br:16])[CH:13]=[CH:14][CH:15]=1.[CH:17](=[O:19])[CH3:18]>C1COCC1>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH:17]([OH:19])[CH3:18]
Reactant: Clc1cccc(Br)c1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (6 mL, 12 mmol) in THF (10 mL) was added 3-chlorobromobenzene (1.91 g, 9.98 mmol) in THF (5 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of acetaldehyde (0.66 g, 15 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.64 (d, J=6.8 Hz, 3H), 2.98 (d, J=10.4 Hz, 1H, —OH), 5.58 (m, 1H), 7.04 (t, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 1.2 Hz, 1H), 7.49 (dd, J=8.1, 1.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]=[N+:13]=[N-:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 4-chlorobenzenesulfonyl chloride (5.28 g) in tetrahydrofuran (25 mL) was added a solution of sodium azide (1.79 g) in water (12.5 mL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-chlorobenzenesulfonyl azide (4.27 g, yield: 78%) as a colorless liquid.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]2([CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]2([CH2:26][N:27]([C:2]3[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=3)[CH2:28][CH2:29][CH2:30]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Reactant: c1ccc(CN2CCCC3(CCCNC3)C2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Temperature: 90 °C
Yield: 30.1 %

Procedure:
A suspension of 4-iodo-2-methyl-6-nitroaniline (1.39 g, 5 mmol), 2-benzyl-2,8-diaza-spiro[5.5]undecane (1.22 g, 5 mmol), CuI (190.5 mg, 1.0 mmol), ethylene glycol (931 mg, 15 mmol) and K3PO4 (3.2 g, 15 mmol) in isopropanol (40 mL) was sealed and heated at 90° C. for 19 h. After cooled down to room temperature, the reaction mixture was concentrated. The residue was purified by chromatography (99:1 CH2Cl2/MeOH) to afford the title compound (593 mg, 30%). 1H NMR (CDCl3) δ 1.24 (m, 2H), 1.48-1.68 (6H), 2.01-2.24 (m, 2H), 2.24 (s, 3H), 2.57 (m, 2H), 2.73 (d, J=12 Hz, 1H), 2.82 (m, 1H), 3.03 (m, 1H), 3.14 (d, J=12 Hz, 1H), 3.47 (d, J=9 Hz, 2H), 5.30 (br s, 2H NH), 7.11 (s, 1H), 7.19-7.33 (5H), 7.44 (s, 1H). ESI-MS m/z 395 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>IC1C=CC(C)=CC=1.[Cu]>[CH3:18][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(I)c1
Reactant: Cc1ccccc1
Agent: [Cu]
Agent: Cc1ccc(I)cc1
Product: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29 %

Procedure:
To a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g) was added copper powder (31.8 g) gradually at 180°-190° C. The mixture was then stirred for 6 hours at 200°-210° C. The reaction mixture was cooled to room temperature, to which was added toluene. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (6.61 g, 29%).
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:22][C:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=2[CH:15]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:22][C:21]3[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=3[CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCC3)cc2C1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a toluene solution (30 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) was added potassium carbonate (26.5 mmol) and pyrrolidine (6.36 mmol) and the resulting reaction mixture was refluxed for 16 h. It was cooled to 25° C., diluted with ethyl acetate and the organic layer was successively washed with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (5% methanol in dichloromethane). Yield: 35%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: ClCCCOc1ccc(I)cc1
Reactant: C1CCNCC1
Product: Ic1ccc(OCCCN2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
1-[(3-chloropropyl)oxy]-4-iodobenzene (10 g, 33.7 mmol) and piperidine (2.87 g, 67.4 mmol) were mixed, and stirred at 85° C. for 4 hours. After cooled to room temperature, this was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline, and the organic layer was dried with sodium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=50/50 to chloroform/methanol=10/1) to obtain the entitled compound (8.39 g, 72%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[S:20][C:5]2[N:6]=[C:7]([NH:18][NH2:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]1[S:20][C:5]2[N:6]3[C:23]([CH2:22][Cl:21])=[N:19][N:18]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NNC1=Nc2sc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: ClCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 7-chloro-5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are introduced, with cooling at 15° C., into 15 ml of glacial acetic acid and a solution of 0.25 g of chloroacetyl chloride in 5 ml of glacial acetic acid is slowly added dropwise thereto. The mixture is then stirred for a further 2 hours, treated with 0.3 g of sodium acetate and stirred for 1 hour. The solution is poured on to ice-water, neutralized and shaken out with methylene chloride. After evaporation of the solvent, the residue is refluxed with 30 ml of absolute xylene for 1 hour. After evaporation of solvent, the residue is recrystallized from ethyl acetate containing active carbon to yield 2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 101°-103° C.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH2:28])[CH:20]=1)[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH:28][C:5](=[O:7])/[CH:4]=[CH:3]/[C:2]([F:1])([F:9])[CH3:8])[CH:20]=1)[CH3:17]
Reactant: CCOc1ccnc(NCCN)c1
Reactant: CC(F)(F)/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccnc(NCCNC(=O)/C=C/C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-ethoxy-2-pyridyl)ethane-1,2-diamine (27 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 18.7 mg of a residue that was purified again by preparative HPLC (gradient of water containing 0.1% trifluoroacetic acid and 10% to 100% acetonitrile). The product obtained was converted to the free base by dissolving in DCM, washing with 1N NaOH solution, water and evaporation to dryness under reduced pressure to yield 13.2 mg of a solid (0.044 mmol, 29%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Mg].[CH3:17][CH:18]([CH3:36])[CH2:19][CH2:20][Si@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH:32](Br)[CH2:31][CH2:30]2)[CH2:23][CH2:22]1>[Cu]Cl.C1COCC1>[CH3:17][CH:18]([CH3:36])[CH2:19][CH2:20][Si@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=4)=[CH:4][CH:3]=3)[CH2:33][CH2:34]2)[CH2:25][CH2:26]1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1F
Reactant: CC(C)CC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
26.9 g (0.1 mol) of 4-bromo-3',4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of copper (I) chloride and 85.9 g (0.1 mol) of 4-(2-(trans-4-(3-methylbutyl)-4-silacyclohexyl)ethyl)cyclohexyl bromide. After a conventional after treatment, 4-(trans-4-(2-(trans-4-(3-methylbutyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 34.2 g (yield 73.0%) of the trans isomer.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH3:35])=[C:22]=[O:23]>CO>[CH3:35][C:25]1[N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:28][C:24]=1[NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9]
Reactant: Cc1nc(-c2ccccc2)sc1N=C=O
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (21 mg, 0.13 mmol) and diisopropylethylamine (68 uL, 0.39 mmol) in MeOH (2 mL) was added 5-isocyanato-4-methyl-2-phenylthiazole (57 mg, 0.26 mmol) and the reaction stirred for 18 hrs. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a yellow powder (6 mg, 12%). 1H NMR (400 MHz, CD3OD) δ 7.85-7.82 (m, 2H), 7.47-7.41 (m, 3H), 4.73-4.71 (m, 1H), 3.82-3.57 (m, 2H), 3.26 (s, 9H), 2.79-2.75 (m, 2H), 2.37 (s, 3H); MS ESI 377.1 [M+H]+, calcd for [C18H24N4O3S+H]+ 377.47.