Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][Cl:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[O:19][CH2:20][Cl:21]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COC(=O)OCCl)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
(R)-Glycerol acetonide (10 g) was dissolved in anhydrous ether (200 ml) and, after adding pyridine (6.6 g) at −10° C., a solution of chloromethyl chloroformate (10.7 g) in anhydrous ether (20 ml) was added dropwise over the period of 10 minutes. After the reaction mixture was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (200 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting to silica gel chromatography (eluent: hexane→ethyl acetate/hexane=1/5→ethyl acetate/hexane=3/5) to obtain chloromethyl [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl carbonate (17 g) as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:57]([O:56][C:54]([CH:51]1[CH2:50][CH2:49][N:48]([C:45]2[CH:46]=[CH:47][C:42]([NH:41][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1)=[O:55])[CH3:58]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Reaction time: 0.5 h
Yield: 291.1 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and ethyl 1-(4-aminophenyl)piperidine-4-carboxylate (63.8 mg, 0.257 mmol, Bionet Research Intermediates) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was continued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester as off-white solid (86.9 mg, 97%). MS (ES+) m/z Calcd: [(M+H)+]: 697. found: 697.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH:14][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(I)c2oc(C3CC3)cc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL), followed by addition of EtSO2Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with DCM (20 mL) and washed with water (20 mL×2) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M+18)+.
Reaction SMILES: [C:1]([S@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:8][C:9]1[N:14]=[C:13]([C:15](=O)[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:10]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][C:9]1[N:14]=[C:13](/[C:15](=[N:7]/[S@@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])/[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:24][CH3:25])[CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(C)=N/[S@](=O)C(C)(C)C)c1F
Yield: 82 %

Procedure:
A mixture of titantetraethoxide (4.26 g, 18.69 mmol), (R)-tert.-butylsulfinamide (1.246 g, 10.28 mmol) and 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (3.45 g, 9.34 mmol, 90% pure) in THF (25 ml) was refluxed under a nitrogen atmosphere for 6 hours. The cold reaction mixture was poured onto icecold brine (200 ml) with gentle stirring. The precipitate was filtered through a pad of hyflo and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude yellow oil (4.55 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 94:6) to give the title compound as a yellow oil. 3.35 g (82% yield).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)=[O:18].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:27]([NH:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]2)[CH2:20]1)=[O:18])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: NCC(=O)C1CN2CCC1CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)C1CN2CCC1CC2
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A suspension of the dihydrochloride salt of (±) 3-(α-aminoacetyl)-1-azabicyclo[2.2.2]octane (D14) (0.8 g; 0.0033 mole) in absolute chloroform (30 ml) was treated with acetyl chloride (0.76 g, 0.01 mole) and pyridine (4.58 g, 0.058 mole) at 0° C. for 1/2 h. The reaction was allowed to warm to room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum, which was chromatographed on neutral alumina in 10% methanol in ethyl acetate. This afforded the title compound as an oil (0.4 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:5].Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[N:23]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[NH:1][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][N:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Clc1ccc2ccncc2n1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2Nc2ccc3ccncc3n2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-amino-N-(4-tert-butyl-phenyl)-benzamide (Step A, 163 mg, 0.61 mmol), 2-chloro-[1,7]naphthyridine (100 mg, 0.61 mmol), Pd2(dba)3 (6.0 mg, 0.006 mmol), 2-dicyclohexyl phosphino-2′-(N-N-dimethyamino)biphenyl (6.0 mg, 0.015 mmol), and LiN(TMS)2 (1 M solution in THF, 2.3 mL) was heated at 80° C. for 12 h in a sealed tube. The mixture was concentrated in vacuo and the crude material was purified with flash chromatography (SiO2, 20% EtOAc/hexane) and crystallization from EtOH to give the desired compound. MS (ES+): 397.0 (M+H)+. Calc'd for C25H24N4O-396.48.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]3[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=3[C:3]=12.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[NH2:28]>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[S:10][C:11]4[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=4[C:3]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 64 %

Procedure:
In analogy to Example 54A, the title compound was synthesized from tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 53A (190 mg, 0.54 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline from Example 6A (127 mg, 0.54 mmol) to yield 215 mg (88% purity, 64% yield), which were used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:32]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19]([F:32])=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of 4.91 g (14.85 mmol) of the product prepared in step 11.1 in 75 mL of dichloromethane are added 2.07 g (14.85 mmol) of triethylamine and then 1.88 mL (22.28 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 2 hours and the solution is diluted with 100 mL of dichloromethane. The organic phase is washed three times with 100 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 4.56 g of the expected product are obtained, and are used directly in the following step. Yield=98%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]([N:16]1[CH2:17][C:18](=[O:19])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])([CH3:15])[CH3:14]
Reactant: CC(C)NCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (6.8 g) as a light pink solid, m.p. 112°-114° C. Anal. Calcd. for. C15H2O N2O S: C, 65.18; H, 7.29; N, 10.13, Found: C, 65.51; H, 7.25; N, 10.32. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a slurry of 6-chloronicotinic acid (5.0 g, 31.73 mmol) in anhydrous toluene (35 ml), was added dropwise with stirring triethylorthoacetate (15.45 g, 95.2 mmol). The mixture was warmed to reflux for two hours, allowed to cool to ambient temperature, and then the resultant solution was washed with saturated NaHCO3 solution (50 ml). The organic phase was dried (MgSO4) and the solvent removed in vacuo to afford the titled compound as a clear, colorless oil (5.43 g, 29.27 mmol, 92.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH3:11])[CH2:5]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1Cc2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-2-methylindole (1.00 g, 6.04 mmol) in acetic acid (7 ml) was added portionwise sodium cyanoborohydride (0.76 g, 12.1 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The resulting solution was diluted with ethyl acetate and washed sequentially with water and with 5 N aq. sodium hydroxide solution. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colourless oil (1.00 g, 100%); MS (ISP): 170.2 ([{37Cl}M+H]+), 168.3 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>C(O)(=O)C>[OH:12][C:13]1[CH:14]=[C:15]([N:16]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride, 3-hydroxyaniline and a glacial acetic acid was heated to obtain N-(3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 199° to 201° C.) and 40.6 g. of the product was dissolved into 600 ml. of glacial acetic acid and 27.2 g. of bromine was added dropwise at 30° to 40° C. and the mixture was stirred at a room temperature for 5 hours to precipitate a crystal. The crystal was separated by a filtration and washed with methanol and recrystallized from benzene-tetrahydrofuran to obtain N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 247°-248° C.; yellow crystal) (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: S=C(Nc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of yellow mercuric oxide (0.62 g, 0.0029 mol), N-[3-(2-,6-dichlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.0 g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.33 g (55%), m.p. 163°-165 ° C.
Reaction SMILES: NC1C=C(F)C=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[F:19][C:17]1[CH:16]=[CH:15][C:14]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:13]([NH:12][C:4]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:5])[CH:18]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: Nc1nccs1
Agent: COc1ccccc1C(=O)c1ccc(F)cc1N
Product: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nccs1
Yield: 68 %

Procedure:
(2-Amino-4-fluoro-phenyl)-(2-methoxy-phenyl)-methanone (784 mg, 32%) was prepared from 2-amino-4-fluoro-benzoic acid (1.55 g, 0.1 mol) following the general procedure S. 1-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-3-thiazol-2-yl-urea (127 mg, 68%) was prepared from (2-amino-4-fluoro-phenyl)-(2-methoxy-phenyl)-methanone (123 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31](C)[C:32](=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
A solution of 3-(4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-phenyl)-propionic acid tert-butyl ester (111 mg, 0.20 mmol) in methanol (5 mL) and THF (5 mL) was treated with 2N NaOH (1.0 mL, 2.0 mmol) and heated at 55° C. for 1 h. The reaction mixture was cooled, concentrated, neutralized with 1N HCl and extracted into EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel radial chromatography (CH2Cl2/methanol 95/5 to 90/10) to the title compound (37 mg, 42%). MS (ES) m/z 451.3 [M+1].
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].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 49.4 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and trimethylacetyl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 2,2-dimethyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]-furan-2-yl]propionamide (0.74 g). Mp 189-190° C.; MS (FAB) m/z 300 ([M+H]+); Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.57; H, 8.38; N, 4.62.
Reaction SMILES: N[C:2](N)=[S:3].BrC[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[OH-].[K+].Cl>C(O)C.O>[SH:3][CH2:2][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
Utilizing the procedure of G. G. Urquhart, J. W. Gates and R. Conner, Org. Syn. Coll. Vol. 3, p. 363, thiourea (6.89 g, 90.5 mmol) was added to a solution of 2-(bromomethyl)naphthalene (20.6 g, 90.5 mmol) in anhydrous ethanol (100 mL) and then heated at reflux. After 17 h, the reaction solution was concentrated to an oil. The oil was dissolved in a solution of potassium hydroxide (11.2 g, 199 mmol) in water (100 mL) and heated at reflux for 2 h. The solution was then cooled to 25° C. and treated with aqueous hydrochloric acid (2.0N). The resulting aqueous mixture was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated to give yellow crystals (14.5 g, 91.9% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][OH:14])[CH:6]=[C:5]2[CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][O:14][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cn([C@@H](c2ccccc2)[C@H](O)CO)c2ccc(F)cc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine(11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313