Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:17][CH3:18])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].I([O-])(=O)(=O)=[O:20].[Na+].I([O-])(=O)=O.[Na+]>CO.O>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH2:14][S:15]([CH2:16][CH2:17][CH3:18])=[O:20])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCSCc1cc2oc(S(N)(=O)=O)cc2cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: O
Solvent: CO
Product: CCCS(=O)Cc1cc2oc(S(N)(=O)=O)cc2cn1
Yield: 85 %

Procedure:
To a solution of 2-sulfamoyl-6-(propylthiomethyl)furo[3,2-c]pyridine (913 mg, 3.19 mmol) in methanol (23 mL) and water (8 mL) was added sodium metaperiodate (906 mg, 4.24 mmol). This mixture was stirred for 4 hours as sodium iodate precipitated from the solution. This precipitate was filtered off and the methanol was evaporated. Sodium chloride was added to the residual aqueous solution and this was exhaustively extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was triturated with diethyl ether/methylene chloride to give 820 mg of product. This material was crystallized from a large volume of ethyl acetate to give pure product (470 mg, 49% yield), mp: 179°-180.5° C. (dec).
Reaction SMILES: [C:1](=[O:40])([O:9][C:10]1[C:11]([CH3:39])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:14][CH2:13]2)[O:2][CH2:3][CH:4]=[C:5]([CH3:8])[CH2:6][OH:7].ClC1C=CC=C(C(OO)=[O:49])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1](=[O:40])([O:9][C:10]1[C:11]([CH3:39])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:14][CH2:13]2)[O:2][CH2:3][CH:4]1[O:49][C:5]1([CH3:8])[CH2:6][OH:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=CCOC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2)CO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1(C)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 95.3 %

Procedure:
4.1 g (0.0073 mol) of 4-hydroxy-3-methyl-2-butenyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate was dissolved in 80 ml of dichloromethane. To the obtained solution was added 2.6 g (0.012 mol) of m-chloroperbenzoic acid (purity: 80%) in small portions under ice-cooling and stirring. After the completion of the addition, the obtained mixture was further stirred at the same temperature for 1 hour. After filtering off the precipitate thus formed, the filtrate was poured into an aqueous solution of sodium hydrosulfite and extracted with dichloromethane. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane/ethyl acetate). Thus 4.0 g of the title compound was obtained as a colorless viscous liquid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(#N)C.O.C([O-])(=O)C.[K+].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>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>[F:33][C:34]1[N:35]=[CH:36][C:37]([C:2]2[N:12]=[CH:11][C:10]3[O:9][CH2:8][CH2:7][N:6]4[CH:13]=[C:14]([C:16]5[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=5)[N:15]=[C:5]4[C:4]=3[CH:3]=2)=[CH:38][CH:39]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc(F)nc3)ncc1OCC2
Temperature: 25 °C

Procedure:
10-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (85.0 mg, 0.257 mmol) dissolved in Acetonitrile (2 mL, 50 mmol) and Water (2 mL, 100 mmol) with dissolved Potassium acetate (85.5 mg, 0.871 mmol). Degas by bubbling nitrogen for 5 min. 2-Fluoropyridine-5-boronic acid (47.1 mg, 0.334 mmol) was added, then Tetrakis(triphenylphosphine)palladium(0) (4.0E1 mg, 0.035 mmol). The reaction was microwaved at 145 C 35 min, cooled to RT, and extracted with ethyl acetate. Combined organics were concentrated to give fluoro intermediate, 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine, which was dissolved in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol). 10% aqueous HCl (3 mL) was added. The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 306, analyzed by rHPLC. MS: (ESI+)=390.1
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH2:27][CH2:26][CH2:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: C1CNC1
Product: Cc1sc2cc(OCCCCN3CCC3)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Azetidine were converted to yield 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-azetidine, MS: 430 (MH+,1Br).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20](COCCO)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:32]([S:34]SCC)[CH3:33].C([O-])(=O)C.[NH4+]>C1COCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([S:34][CH2:32][CH3:33])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCSSCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
THF (5 mL) was cooled to −78° C. under an argon atmosphere. n-Butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added and the mixture was stirred at −78° C. for 5 min. A mixture of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (0.2 g, 0.54 mmol) in THF (5 mL) was added dropwise, maintaining the temperature below −70° C. The resultant dark red solution was stirred at −78° C. for 30 min and ethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was stirred at −78° C. for 2 h and left to warm to room temperature over 2 h. Water (1 mL) was added and the mixture was poured onto an isolute HM-N SPE cartridge and eluted with ethyl acetate (10 mL). The eluant was evaporated under reduced pressure and the crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.071 g, 53% yield) as a pale yellow oil: m/z 350.14 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 6.21 min. (4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.[F:9][C:10]1[CH:11]=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].ClCCCl.[OH2:24]>>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:19][N:2]1[CH2:6][CH2:5][O:24][CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1F
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A slurry of N-bromosuccinimide (167 g), 3-fluoro-4-nitrotoluene (135 g), 2,2′-azoisobutyronitrile (17.1 g) and 1,2-dichloroethane (1120 g) is stirred at 60° C. for 2 hours and then at 80° C. for 30 min. The reaction mixture is cooled to 23° C. and water (300 ml) is added. The phases are separated and the aqueous is washed with methylene chloride (300 ml). The combined organics are concentrated. Methanol (400 ml) is added and the mixture is cooled to −5° C. Morpholine (218 g) is added slowly while maintaining −5 to 14° C. While maintaining 6 to 14° C., 37% hydrochloric acid (113 ml) is added to adjust the observed pH from 8 to 6. Water (650 ml) and toluene (650 ml) are added and the mixture is warmed to 25° C. The phases are separated and the aqueous is washed with toluene (2×600 ml). To the combined organics is added water (400 ml) followed by 37% hydrochloric acid (53 g). The phases are separated and the organic is washed with water (500 ml). At room temperature, the pH of the combined aqueous is slowly adjusted to pH of 9 with 50% aqueous sodium hydroxide to yield a yellow slurry. The precipitate is collected by filtration, washed with water (200 ml) and is dried in a nitrogen stream to afford a yellow solid (104 g). Physical characteristics: 1H NMR (400 MHz, CDCl3) δ2.47, 3.56, 3.73, 7.27, 7.35, 8.02; 13C NMR (100 MHz, CDCl3) δ53.55, 61.99, 66.83, 118.08, 124.33, 126.01, 148.10, 155.64; MS (EI) m/z 240; Anal. Found: C, 54.84; H, 5.47; N, 11.62.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:22][C:23]([O:25]CC)=[O:24].[CH2:28]1COC[CH2:29]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:28][CH2:29][CH2:22][C:23]([OH:25])=[O:24])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)CCCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added 6-bromoindole (5 g; 25.5 mmol) and THF (50 mL). To this stirred solution, under argon, was added sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran)(51 mL; 51 mmol). The resulting brown solution was stirred at room temperature for 1 h. At this point the mixture was cooled to −5° C., and a solution of ethyl bromoacetate (5.6 mL; 51 mmol) in THF (4 mL) added. The resulting brownish yellow precipitate was warmed to room temperature and further stirred for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and the organic phase successively washed with water (3×50 mL) and brine (100 mL). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo to yield the title compound as a brown oil (crude weight: 7.3 g). 13C NMR (CDCl3): δ 168.3, 137.4, 129.4, 123.2, 122.4, 115.6, 112.2,102.7, 61.7, 47.7, 14.2.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:14][C:13]2=[O:26])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 15.1 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (150 mg, 0.4 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.4 mmol) and N,N-diisopropylethylamine (169 mg, 1.2 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (63 mg, 0.4 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 65 mg, 0.4 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (0.030 g, 14%) as a light yellow sticky liquid: 1H NMR (400 MHz, CDCl3) δ ppm 0.84-1.09 (m, 2H), 1.17 (s, 6H), 1.19-1.35 (m, 3H), 1.53-1.97 (m, 8H), 2.80 (br. s., 1H), 3.82 (s, 3H), 3.97 (s, 2H), 4.09 (d, J=18.0 Hz, 1H), 4.33 (d, J=18.0 Hz, 1H), 4.91 (dd, J=8.8, 6.1 Hz, 1H), 5.04 (s, 1H), 6.66-6.73 (m, 2H), 6.76 (d, J=7.8 Hz, 1H), 6.82 (dd, J=8.3, 1.7 Hz, 1H), 7.28-7.35 (m, 2H), 8.95 (br. s., 1H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])=[N:15][CH:14]=1
Reactant: COC(=O)CN
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 38.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (31 mg. 0.095 mmol), glycine methyl ester hydrochloride (24 mg, 0.20 mmol) and sodium triacetoxyborohydride (61 mg, 0.286 mmol) to afford 15 mg (39%) of the desired product after purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CN1CCC(=O)CC1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Product: CN1CC=C(c2c[nH]c3cc(C(F)(F)F)ccc23)CC1
Yield: 88.5 %

Procedure:
Beginning with 1.00 gm (5.4 mMol) 6-trifluoromethyl-1H-indole and 1.33 mL (11.0 mMol) 1-methyl-4-piperidone, 1.34 gm (89%) of the title compound were recovered as colorless crystals.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C@H:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[C:11](=O)[O-:12])=CC=1)([O-])=O.Cl.CO[C:36](=[O:40])[CH2:37][NH:38][CH3:39].C(N(CC)CC)C.Cl>C1COCC1.O>[ClH:30].[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][C@H:20]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:10]1[C:36](=[O:40])[CH2:37][N:38]([CH3:39])[C:11]1=[O:12]
Reactant: CNCC(=O)OC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)CN(C)C2=O)C1
Reaction time: 8 h

Procedure:
4-Nitrophenyl[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and sarcosine methyl ester hydrochloride and triethylamine were added dropwise with stirring. After stirring for 5 h, the reaction mixture was freed of the solvent, and the residue was admixed with water and 2 N hydrochloric acid and refluxed for 2 h. After standing overnight, the reaction mixture was concentrated and admixed with ethyl acetate, water and saturated potassium carbonate solution. After separation of the phases, the organic phase was washed five times with saturated potassium carbonate solution and twice with saturated sodium chloride solution. Drying over magnesium sulfate and filtration were followed by concentration. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with water/hydrochloric acid and freeze-dried. 60 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([NH:8][NH2:9])=O.[CH3:13][N:14]=[C:15]=[S:16].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:14]([CH3:13])[C:15]([SH:16])=[N:9][N:8]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COc1cc(C(=O)NN)ccn1
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(-c2nnc(S)n2C)ccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
The title compound of example 23.1 (18.35 g, 109.8 mmol) and methyl isothiocyanate (8.83 g, 120 mmol) were stirred together at 60° C. for 30 minutes. Sodium hydroxide (4.83 g, 120 mmol) in water (32 mL) was added to the reaction mixture it was allowed to continue to stir at 60° C. for 12 hours. The reaction mixture was concentrated and diluted with water. It was acidified to pH 4-5 with 3 M HCl. A solid precipitated out which was filtered, washing with portions of water, then dried to afford the product as a beige solid (21.2 g, 87%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8](O)=[O:9])[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][NH:47][C:48](=[O:59])[C@H:49]([NH:57][CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:16]([O:15][C:13](=[O:14])[N:11]([C@@H:7]([C:8](=[O:9])[N:57]([CH3:58])[C@@H:49]([C:48](=[O:59])[NH:47][CH3:46])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:6][C:4]1[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[S:1][CH:5]=1)[CH3:12])([CH3:17])([CH3:19])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1csc2ccccc12)C(=O)O
Reactant: CNC(=O)[C@@H](Cc1ccccc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
(2R)-3-(Benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonyl-methylamino)propionic acid (2.00 g ; 5.96 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.81 g; 5.96 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.26 g ; 6.56 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-phenylpropionamide (1.15 g; 5.96 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (1.02 mL; 5.96 mmol) were added. The reaction mixture was stirred for 48 hours. Methylene chloride (10 mL) was added. The reaction was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate 10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.89 g of ((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl carbamic acid tert-butylester.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].CCOC(C)=O>C1COCC1>[CH3:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To 2-bromo-3-methylpyridine (1.3 mL, 11.7 mmol) in THF (35 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 5.6 mL, 14 mmol). After 30 min, tri-n-butyltin chloride (3.8 mL, 14 mmol) was added. After 1 h at −78° C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (MgSO4). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. for C18H33NSn, 382.2; m/z found 384.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1cccs1
Yield: 43 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 2-thiophenecarbonyl chloride (0.082 mL, 0.77 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)thiophene-2-carboxamide (0.098 g). MS (ESI) m/z 326 ([M+H]+).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:35]1[N:36]([C:40]2[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=2[C:42](O)=[O:43])[N:37]=[CH:38][CH:39]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:42]([C:41]5[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=5[N:36]5[N:37]=[CH:38][CH:39]=[N:35]5)=[O:43])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1ccccc1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H19ClN6O2, 434.89; m/z found 435.1 [M+H]+. 1H NMR (CD3OD): 8.03-7.28 (m, 6H), 7.23-6.88 (m, 3H), 4.72-4.54 (m, 1H), 4.35-3.96 (m, 3H), 3.90-3.35 (m, 3H), 3.13-1.71 (m, 3H).