Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:29]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCCC(CNC(=O)OC(C)(C)C)C2)n1
Yield: 83 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl 3-piperidinylmethylcarbamate as in previous examples gave tert-butyl {1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methylcarbamate in 83% yield: mp (CH2Cl2/MeOH) 131-133° C.; 1H NMR (DMSO-d6) δ 7.93 and 7.89 (2d, J=8.6, 8.4 Hz, 1H), 7.68 (t, JHF=53.0 Hz, 1H), 7.46-7.38 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.91 (br, 1H), 4.54-4.41 (m, 2H), 3.97 (s, 3H), 3.79 (br s, 4H), 3.69 (br s, 4H), 3.14-3.05 (m, 1H), 2.94-2.76 (m, 2H), 1.78-1.57 (m, 3H), 1.44-1.24 (m, 2H), 1.39 and 1.32 (2s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H, 6.5; N, 19.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:12])[C:5](/[C:9](=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:14]=2[F:13])/[C:10]#[N:11])=[C:6]([F:8])[CH:7]=1
Reactant: N#CCc1c(F)cc(Cl)cc1F
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1c(F)cc(Cl)cc1F
Yield: 76.2 %

Procedure:
Step B In a manner similar to the method described in Example 1b, (4-chloro-2,6-difluoro-phenyl)-acetonitrile (1.1 g, 6 mmol) was reacted with 2-fluoro-3-chlorobenzaldehyde (1.2 g, 7 mmol), methanolic solution (25 wt %) of sodium methoxide (1.5 mL, 7 mmol) in methanol (40 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white solid (1.5 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20](O)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:19]=1
Reactant: COC(=O)c1ccnc(O)c1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(OCc2c(-c3ccccc3)noc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.5 g, 8.0 mmol) in THF (79 mL) was added 2-hydroxy-isonicotinic acid methyl ester (1.8 g, 12.0 mmol) and triphenylphosphine (2.8 g, 11 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (1.64 mL, 11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Then 2-hydroxy-isonicotinic acid methyl ester (0.2 g, 0.17 mmol) was added and the resulting mixture stirred at room temperature for 1 h and then heated at 60° C. for 1 h. After cooling to room temperature, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (0.99 g, 38%) as a light yellow solid. MS: m/e=325.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([Br:13])=[C:8]([C:14](=[O:16])[NH2:15])[C:7]=1[Br:17].[OH-].[Na+]>O>[C:14]([C:8]1[C:7]([Br:17])=[C:6]([C:11]([Br:12])=[CH:10][C:9]=1[Br:13])[O:5][CH2:4][C:3]([OH:18])=[O:2])(=[O:16])[NH2:15]
Reactant: COC(=O)COc1c(Br)cc(Br)c(C(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(Br)cc(Br)c(OCC(=O)O)c1Br
Temperature: 60 °C

Procedure:
30 g (67 mmol) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid methyl ester is suspended in 300 ml of water, the suspension is heated to 60° C., and the ester is saponified by the dropwise addition of 25 ml of concentrated sodium hydroxide solution. The solution is filtered over active carbon and brought to pH 1 by adding concentrated hydrochloric acid dropwise under ice bath cooling. After several hours of agitation, the thus-formed sediment is vacuum-filtered, washed with water, and dried at 60° C. Yield: 28 g (97% of theory) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid as a white powder, mp 271°-272° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:24])=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])[S:5][C:6]=1Br.[Li]CCCC>C1COCC1>[Br:1][C:2]1[C:3]([CH3:24])=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])[S:5][CH:6]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3C)c(C)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Temperature: 25 °C
Yield: 29.8 %

Procedure:
To a −78° C. solution of 3-(4,5-dibromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 g, 0.47 mmol) and THF (3 mL) is added 1.6 M n-BuLi (0.31 mL, 0.49 mmol). After 20 minutes the solution is quenched with water (1 mL), warmed to ambient temperature, diluted with EtOAc (30 mL), washed with brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-10% EtOAc gradient) furnish the title compound (0.056 g, 0.14 mmol, 31%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.93 (m, 4H), 2.09 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.27-3.36 (m, 1H), 6.68 (s, 1H), 7.44 (s, 1H). LC/MS (m/z): calcd. for C18H22BrN3S (M+H)+: 392.2; found: 392.3.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](Cl)=[N:8][CH:9]=1>>[NH2:2][CH2:1][C:7]1[N:6]=[CH:5][C:4]([Br:3])=[CH:9][N:8]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CN
Product: NCc1ncc(Br)cn1
Temperature: 115 °C
Yield: 93.5 %

Procedure:
Methylamine (2.0 M in methanol, 40 mL, 80 mmol) was added to 5-bromo-2-chloropyrimidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115° C. oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH2Cl2 (200 mL) and washed with 1M NaOH (40 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated yielding an off white solid (5.1 g, 93%). LCMS (m/z): 188.0/190.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[CH:16]1>C(O)(C)C.O.Cl>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([F:1])[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[CH:16]1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(C(F)(F)F)cc(F)c1-n1cnc(C(F)(F)F)cc1=O
Temperature: 100 °C

Procedure:
Reduced iron powder (0.18g) was added to a suspension of 1-(2-fluoro-6-nitro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one (0.6g) in a mixture of isopropanol (6ml) and water (0.6ml). Concentrated hydrochloric acid (1 drop) was added, and the reaction mixture was heated to 100° C. for a period of 5 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite, and the residue washed with ethyl acetate. Evaporation of the filtrate under reduced pressure gave 1-(2-amino-6-fluoro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one as an off-white solid, which was used in Preparation 13 without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[NH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]1)[C:7]=3[CH:6]=[CH:5][CH:4]=2
Reactant: O=S1(=O)Nc2cccc3c(Cl)ccc1c23
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccc(Cl)c3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 90 °C

Procedure:
The experiment is carried out as in Example 18, starting with 6-chloronaphtho[l,8-cd]isothiazole 1,1-dioxide (1.4 g), 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (1.5 g), sodium hydride (0.18 g) in an 80% dispersion in vaseline oil and dimethylformamide (15 cc). The reaction mixture is heated for 1 hour 30 minutes at 90° C., cooled to a temperature of about 20° C. and then concentrated to dryness at 60° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolved in dichloromethane (50 cc) and the solution is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with mixture of dichloromethane and ethyl acetate (95-5 vol) as eluant, then recrystallized from boiling acetonitrile (10 cc). 6-Chloro-2-{3-[4-(4-fluorophenyl)-l-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 is obtained, m.p. 125° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32]([CH2:31][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (452 mg, 13.4 mmol, 60% in mineral oil) in DMF (25 ml) under nitrogen was added dropwise a solution of 6 (3.7 g, 10.35 mmol) in DMF (50 ml) and the mixture was stirred at 60° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of tert-butyl bromoacetate (2.62 g, 13.4 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 3 h. The DMF was removed under high vacuum and the crude product was suspended in water (100 ml) and the mixture was extracted by ethyl acetate (2×100 ml). The combined ethyl acetate phases were washed by water (1×50 ml), brine (1×50 ml), dried over sodium sulphate filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (9/1) to give the title compound 7 (3.5 g, 72%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:31])=[CH:5][C:6]([F:30])=[C:7]([C@:9]23[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10]3)[CH:8]=1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(#N)C>[F:30][C:6]1[CH:5]=[C:4]([F:31])[C:3]([CH2:2][NH:1][CH2:45][C:46]([F:49])([F:48])[F:47])=[CH:8][C:7]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[N:10]2
Reactant: NCc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of N-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (0.598 g, 1.33 mmol) in acetonitrile (13 mL) was treated with triethylamine (0.277 mL, 2.00 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.288 mL, 2.00 mmol). The reaction vial was sealed and the resulting solution was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield a brown solid. The solid was partitioned between water (100 mL) and ethyl acetate (100 mL). The organics were isolated and the aqueous layer was extracted further with ethyl acetate (2×50 mL). The combined organics were then washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as a white solid. Yield: 0.4064 g, 57%. LCMS m/z 532.0 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=8 Hz, 2H), 7.45-7.59 (m, 3H), 7.08 (dd, J=12.3, 9.6 Hz, 1H), 4.50-4.52 (m, 1H), 4.38-4.40 (m, 1H), 4.15 (dd, J=12.1, 2 Hz, 1H), 3.90-3.94 (m, 3H), 3.00 (dd, J=13.4, 4.0 Hz, 1H), 2.77 (dd, J=13.1, 2.9 Hz, 1H), 1.87-1.96 (m, 1H), 1.69-1.72 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C.Br.C(O)(=O)C.CCOCC>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Reactant: BrBr
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(Br)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone from step1 (8.4 g, 0.024 mol) in acetic acid (130 mL), bromine (3.8 g, 0.024 mol) in 25% hydrogen bromide-acetic acid solution (50 mL) was added dropwise at room temperature. After stirring for 4 h at room temperature, concentrated gave the yellow solid. The solid was suspended in ether and collected by filtration, washed with ether to give the title compound (7.5 g, 73%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: Nc1ccc(OCCO)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OCCO)ccc1N
Reaction time: 1 h
Yield: 81.5 %

Procedure:
2-Amino-5-(2-hydroxyethoxy)benzoic acid hydrochloride (0.209 g, 895 μmol; CAS 78299-60-2) was suspended in dichloromethane (10 ml) at r.t under an argon atmosphere. The reaction mixture was diluted with MeOH (3 ml). Then trimethylsilyldiazomethane solution (1.45 ml, 2.9 mmol; 2M in hexane) was added dropwise. The reaction mixture was stirred at r.t for 1 hr. The solvents were evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (154 mg, 82%) as light yellow, waxy solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH:19](I)([CH3:21])[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH:19]([CH3:21])[CH3:20])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.5 ml of tert-butyl diethylphosphonoacetate are dissolved in 20 ml of dimethylformamide, and 820 mg of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0° C. The suspension is stirred at 0° C. for 15 minutes, and 2.4 ml of isopropyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=5:1. This gives 4.2 g of tert-butyl 2-(diethoxyphosphoryl)-3-methylbutyrate as an oil. C13H27O5P (294.33), MS(ESI): 239 (M-C4H8+H+), Rf(n-heptane:ethyl acetate=1:1)=0.34.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
64.6 g (0.25 mol) of 3-trifluoromethyl-4-methylbenzenesulphonyl chloride are taken up in 500 ml of carbon tetrachloride and, after addition of 44.5 g (0.25 mol) of N-bromosuccinimide and 0.4 g of ABN, the mixture is heated under reflux for 24 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography using petroleum ether/toluene (4:1), 50 μm particle size, gives 33.9 g (40% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[NH:7][C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4.[H-].[Na+].I[CH3:35]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[N:7]([CH3:35])[C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4
Reactant: CC(C)(C)OC(=O)c1c(Br)cc(OCc2ccccc2)c2[nH]c3c(c12)C1CCC(C3)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(OCc4ccccc4)c31)C1CCC(C2)N1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of the product of step E (412 mg, 0.85 mmol) in DMF (10 mL) under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 69 mg, 1.70 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h before addition of iodomethane (181 mg, 1.28 mmol). After stirring for an additional 2 h, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 2-bromo-4-benzyloxy-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (420 mg, 99%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.50 (m, 5H), 7.21-7.27 (m, 1H), 6.75 (d, J=1.2 Hz, 1H), 5.05-5.23 (m, 3H), 4.67 (br s, 1H), 3.79 (s, 3H), 3.32 (br s, 1H), 2.42 (d, J=15.9 Hz, 1H), 2.21-2.36 (m, 1H), 2.07-2.21 (m, 1H), 1.85-1.96 (m, 1H), 1.55-1.65 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCBr
Reactant: CN
Solvent: CCO
Product: CNCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of 11-bromoundecanol (25.12 g, 0.10 mol) and methylamine (41% in water, 127 ml, 1.50 mol) in ethanol (50 ml) was heated for 7 h to 70° C. and stirred for a further 16 h at ambient temperature. The solvent was distilled off. After cooling the white solid was dissolved in caustic soda (2N, 200 ml) and diethyl ether (300 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The crude product was recrystallized from diethyl ether. 13.23 g (65.7 mmol, 67% yield) of a while solid (melting point: 58° C.) was obtained.
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: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
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: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:17](Cl)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1nc(N)sc1-c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (3 g) was dissolved in pyridine (30 ml), and then acetyl chloride (2.73 ml) was added dropwise to the solution at 0° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 1.5 hours. Water was added to the solution at 0° C. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.37 g) as a pale brown solid.