Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][C@@H:11](O)[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:27])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C@@H:11]1[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1.[F:27][C@@H:11]1[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CC1c1cccc(F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1c1cccc(F)c1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4) (2.7 g, 9.6 mmol) in DCM (25 mL) in a plastic bottle at −78° C. was added DAST (2.5 mL, 19.2 mmol). The mixture was stirred at −78° C. for 2 hours and then was warmed slowly to room temperature overnight. The mixture was added drop wise to aqueous NaHCO3 at 0° C. and was extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The two diasteromers were separated by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (2R,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-5A) (first eluting compound) and (2S,4S)-tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-5B). 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J=6.0, 6.0 Hz, 1 H), 6.92 (bd, J=8.0 Hz, 1 H), 6.88-6.82 (m, 2 H), 5.20 (bd, J=52.0 Hz, 1 H), 4.80 (bs, 1 H), 4.02 (dd, J=13.6, 22.8 Hz, 1 H), 3.65 (dd, J=12.8, 38.4 Hz, 1 H), 2.67-2.56 (m, 1 H), 1.89 (dt, J=11.2, 42 Hz, 1 H), 1.09 (s, 6 H). MS m/z 284.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:27]1([O:32][C:33](=[O:47])[C@@H:34]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:37][CH2:36][CH2:35][C@@H:34]([C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:47])[NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reactant: Oc1ccc(Br)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCOc1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 4-bromophenol (261 mg, 1.510 mmol) in acetonitrile (2 ml) under nitrogen, was added BEMP (397 μl, 1.373 mmol). The mixture was stirred at 50° C. for 30 minutes before being cooled to room temperature and (S)-5-bromo-2-tert-butoxycarbonylamino-pentanoic acid cyclopentyl ester (500 mg, 1.373 mmol) added as a solution in acetonitrile (2 ml). The reaction was heated at 50° C. for a further 1 hour and then the mixture was analysed by LCMS. The reaction was poured onto 2M Na2CO3 (100 ml) and extracted with EtOAc (2×100 ml). The combined organic layers were washed with 2M Na2CO3 (3×100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to afford a colourless oil. MP-carbonate (1.0 g) was added to a solution of the crude product in dichloromethane (3.4 ml) and the solution was left overnight at room temperature. LCMS indicated complete removal of 4-bromophenol and so the reaction was filtered to remove the MP-carbonate and the resin was washed with DCM (2×50 ml). The filtrate was concentrated to afford the crude product which was purified by column chromatography eluting with 5% EtOAc in iso-hexane. Yield of title compound=435 mg, 0.953 mmol, 69.4% yield. m/z 456 and 458 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]([F:32])([F:31])[CH2:8][O:9][C:10]1[C:11]([OH:30])=[CH:12][C:13]2[C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][C@@:21]1([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]1[OH:28].Cl.[NH2:34][OH:35]>CO.O>[F:6][C:7]([F:32])([F:31])[CH2:8][O:9][C:10]1[C:11]([OH:30])=[CH:12][C:13]2[C:14](=[N:34][OH:35])[CH2:15][C@@H:16]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][C@@:21]1([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]1[OH:28]
Reactant: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(O)cc4C(=O)C[C@H]3[C@@H]1CC[C@@H]2O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(O)cc4C(=NO)C[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 90 °C
Reaction time: 6 h
Yield: 62.6 %

Procedure:
Sodium acetate (2.86 g, 35 mmol) was added to a stirred solution of 6-oxo derivative (9) (0.45 g, 1.2 mmol) in methanol (55 mL). Hydroxylamine hydrochloride salt (2.2 g, 32 mmol) in water (3 mL) was then added at room temperature. The resulting mixture was stirred at 90° C. for 6 h. Then solvent was removed under reduced pressure, the resulting residue was diluted with water (60 mL), and product was extracted into ethyl acetate (3×120 mL). The combined organic layer was washed with water (70 mL), brine (70 mL), and dried over anhydrous sodium sulfate. The organic layer on evaporation under reduced pressure provided the crude product, which on crystallization from ethyl acetate-hexane mixture gave oxime (12) (0.3 g, 65%): mp 187-191° C.; IR (KBr) 3330, 2960-2860, 1500, 880, 750 cm-1 ; 1H NMR (CDCl3 +DMSO-d6 +D2O) δ 0.77 (s, 3 H), 1.10-2.38 (m, 11 H), 2.67 (s, 2 H), 3.05-3.27 (m, 2 H), 3.72 (t, J=8.5 Hz, 1 H), 4.50 (q, J=8.5 Hz, 2 H), 6.88 (s, 1 H), 7.57 (s, 1 H) 10.20 (s, 1 H). Anal. (C20H24NF3O4) C, H.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9]O.CN(C)C=O.[OH-].[Na+].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][Cl:20]
Reactant: OCc1c(F)cccc1Br
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(Br)c1CCl

Procedure:
After dissolving (2-bromo-6-fluorophenyl)methanol (CAS 261723-33-5) (4.07 g) in toluene (50 ml), thionyl chloride (2.21 ml) was added dropwise while stirring on ice. N,N-Dimethylformamide (0.1 ml) was then added and the mixture was stirred for 6 hours. The reaction mixture was diluted with water, a 1N aqueous solution of sodium hydroxide was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.45 g).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:11][CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1.ClCCl>C(N(CC)CC)C>[Cl:11][CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCN)c12
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)NC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Cyclohexyl isocyanate (0.285 mL, 2.20 mmol) was added to a flask containing 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butan-1-amine hydrochloride (680 mg, 1.98 mmol), triethylamine (0.311 mL, 2.2 mmol), and dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours and additional triethylamine and cyclohexyl isocyanate (1.1 equivalents each) were added. The reaction mixture was stirred overnight at room temperature, then was partitioned between dichloromethane (50 mL) and 2:1 water/saturated aqueous sodium carbonate (30 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with 0.5 M aqueous sodium hydroxide (2×30 mL), and concentrated under reduced pressure. The resulting white solid was triturated with ethyl acetate, isolated by filtration, and washed with ethyl acetate and water to provide 777 mg of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-N′-cyclohexylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]2[CH:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]=2[CH:10]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)cc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(Cl)cc3c2ccn3COCC[Si](C)(C)C)cc1
Yield: 0.1 %

Procedure:
6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-amine (880 mg, 2.52 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (572 mg, 2.77 mmol) according to the method described in Preparation 15b to give 1.48 mg (97% yield) of the title compound. Purity 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([CH:12]([C:19]3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C@H:27]([OH:29])[CH3:28].C([O:32]CC)C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([CH2:12][C:19]([NH:25][CH2:26][C@H:27]([OH:29])[CH3:28])=[O:32])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: CCOCC
Reactant: C[C@@H](O)CN
Solvent: Cc1ccccc1
Product: C[C@@H](O)CNC(=O)CN1CC(c2ccc(Cl)cc2)C1

Procedure:
This compound was prepared from compound (6) and (R)-1-amino-2-propanol using the procedure outlined in Example 4, m.p. 92-93° C. (diethyl ether-toluene). Found: C, 58.97; H, 6.38; N, 9.96. C13H17CIN2O2.0.2PhCH3, requires C, 60.23; H, 6.48; N, 9.76%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:16][CH2:15][N:23]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccccc1
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
A mixture of 4-nitrophthalic anhydride (18 g, 93.3 mmol) and phenethylamine (11.5 g, 95 mmol) in toluene (250 mL) was heated to reflux using a Dean-Stark trap to remove water. After 2.5 h, the mixture was concentrated to solid residue, which was triturated and filtered to give the titled compound (24.5 g, 89%): mp 142-3° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:82])[C@H:71]([CH2:73][CH2:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[NH2:72].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:72][C@@H:71]([CH2:73][CH2:74][C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[C:70]([O:69][CH3:68])=[O:82])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.1 mmol), HATU (500 mg, 1.32 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (334 mg, 1.32 mmol). The mixture was stirred for another 10 minutes and poured into 200 ml of water. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% MeOH/CHCl3 to give (S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as off-white solid. Yield: 380 mg, 52%.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>O1CCCC1>[N:5]1[CH:4]=[CH:3][C:2]([C:1]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:9])=[CH:7][CH:6]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1ccncc1
Solvent: C1CCOC1
Product: O=C(c1ccncc1)N1CCc2ccccc2C1
Reaction time: 0.5 h

Procedure:
50 g (406 mmol) of isonicotinic acid are dissolved under an argon atmosphere in 1000 ml of tetrahydrofuran and 25 g of N,N'-carbonyldiimidazole are added while stirring, the mixture is stirred for half an hour, a further 25 g of N,N'carbonyldiimidazole are added, the mixture is stirred for a further half hour and 15 g of N,N'-carbonyldiimidazole are added. Stirring is continued for 1 h 30 min, 51.39 g (385.8 mmol) of 1,2,3,4-tetrahydroisoquinoline dissolved in a few milliliters of tetrahydrofuran are introduced slowly into the mixture, which has become clear, and the mixture is stirred overnight at room temperature. The solvent is then evaporated off, the oily residue taken up with approximately 700 ml of dichloromethane, and the solution obtained washed twice with saturated sodium bicarbonate solution and thereafter twice with water and dried over magnesium sulphate. 87.48 g of an orange-coloured oil, which solidifies slowly in the cold, are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C>O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Phenylproylamine (10 ml, 70.0 mmol) was added at 0° C. dropwise to formic acid (80 ml). Acetic acid anhydride (30 ml) was added dropwise to the reaction mixture. After the addition the reaction mixture was warmed to room temperature. It was stirred for 2.5 h. It was cooled to 0° C. Water (30 ml) was added dropwise. The reaction mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The organic phase was washed with saturated sodium chloride solution (2×150 ml) and with saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo to furnish 5.82 g of N-(3-phenylpropyl)formamide, which was used without further purification.
Reaction SMILES: [CH:1]([C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)=[CH:2][CH2:3][CH3:4].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCC=Cc1cccc(C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1cccc(C)n1
Yield: 92.5 %

Procedure:
The picoline from Step 1 (970 mg) was hydrogenated for 50 minutes at 20 psi of hydrogen in EtOAc (30 mL) using 5% Pd/C (90 mg) as catalyst. Filtration and concentration in vacuo gave 910 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9]([NH:16][CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCC(C(=O)O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(C(=O)NC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
2-(4-Fluorophenyl)pent-4-enoic acid (Bioorg. Med. Chem. Lett. 2000, 1893; 4.20 g, 21.6 mmol) was dissolved in CH2Cl2 (75 mL) and to the resultant solution was added TBTU (7.29 g, 22.7 mmol). The mixture was stirred at RT for 15 min and then methylamine (11.9 mL of 2M THF solution, 23.8 mmol) and DIPEA (11.2 g, 86.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, subsequently diluted with CH2Cl2 (50 mL) and then washed several times with water. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (heptane-ethyl acetate, 1:1). There was obtained 3.5 g (78%) of 2-(4-fluorophenyl)-N-methylpent-4-enamide as an oil, which shortly after crystallized. 1H NMR (400 MHz, CDCl3): 2.5 (qn, 1H), 2.7 (d, 3H), 2.9 (qn, 1H), 3.4 (t, 1H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.0-6.2 (b, 1H), 7.0 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]4[CH:30]=[CH:31][C:32]5[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=5[CH:39]=4)=[O:28])[CH2:22][CH2:21]3)=[N:14]2)=[CH:9][CH:8]=1.CO>ClCCl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]4[CH:30]=[CH:31][C:32]5[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=5[CH:39]=4)=[O:28])[CH2:22][CH2:21]3)=[N:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M boron tribromide in dichloromethane (2.93 mL, 2.93 mmol, 8.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (190 mg, 0.37 mmol, 1.0 eq) in dichloromethane (2.5 mL). The reaction mixture is stirred at 0° C. for 30 minutes and then at 40° C. for 24 hours. The reaction mixture is cooled down to 0° C. before the addition of methanol (1 mL). Solvents are evaporated and the crude is taken in water (10 mL), the pH is adjusted to 10 by the addition of 1N sodium hydroxide aqueous solution and the resulting aqueous layer is extracted with dichloromethane (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (28 mg, 30% yield).
Reaction SMILES: Br[CH2:2][CH2:3]/[CH:4]=[C:5](\[CH3:15])/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:15]/[C:5](/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4]\[CH2:3][CH2:2][C:16]#[N:17]
Reactant: CCCCCCCCC/C(C)=C/CCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCC/C(C)=C/CCC#N
Temperature: 70 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
A mixture of the (E)-1-bromo-4-methyl-3-tridecene (3) (38.0 g, 138 mmols) and KCN (11.5 g, 176 mmols) in DMF (100 ml) and water (30 ml) was stirred for 24 hours at 70° C. Then, the mixture was poured into ice water (1 L) and extracted with ether (500 ml). The ether solution was washed with water, dried (MgSO4), and concentrated in a vacuum. The residue was subjected to silica gel chromatography, and eluted with n-hexane-ether (100:1) to obtain 30.0 g (98%) of (E)-5-methyl-4-tetradecenenitrile (4) as oily matter.
Reaction SMILES: C(N[C:6](=[O:8])O)(C)(C)C.COC[NH:12][S:13]([CH:16]1[CH2:18][CH2:17]1)(=[O:15])=[O:14].[C:19](O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:19][O:8][CH2:6][C:16]1([S:13]([NH2:12])(=[O:14])=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)NC(=O)O
Reactant: COCNS(=O)(=O)C1CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(S(N)(=O)=O)CC1

Procedure:
Step 15IIe) A solution of 1-methoxy-methylcyclopropylsulfonylamine tert-butylcarbamate (1.14 g, 4.30 mmol) was dissolved in a solution of 50% TFA/CH2Cl2 (30 mL) and was stirred stirred at rt for 16 h. The solvent was removed in vacuo and the residue chromatographed over 80 g of SiO2 (eluting with 0% to 60% EtOAC/Hexanes to afford Example 15, 1-methoxymethylcyclopropylsulfonamide, as a white solid (0.55 g, 77% overall over two steps): 1H NMR (CDCl3) δ 0.95 (m, 2H), 1.44 (m, 2H), 3.36 (s, 3H), 3.65 (s, 2H), 4.85 (s, 2H); 13C NMR (CDCl3) δ 11.17, 40.87, 59.23, 74.80; LRMS m/z 183 (M++NH4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+].CO>CC(=O)CC.C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:9][CH2:10][OH:11])[CH:3]=1
Reactant: OCCCl
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Solvent: ClCCl
Product: OCCOc1cccnc1
Yield: 23.5 %

Procedure:
This compound was prepared according to the procedure in Preparation 19. Thus, reacting 14 g (0.15 mole) of 3-hydroxypyridine with 27 ml (0.4 mole) of 2-chlorethanol and 85 g of potassium carbonate in 150 ml of 2-butanone at reflux temperature gave 4.9 g of the title compound after column chromatography (5% methanol in methylene chloride on silica gel).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)(C)C.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O1C[CH2:31][CH2:30][CH2:29]1>>[C:23]([NH:27][S:10]([C:8]1[CH:9]=[CH:4][C:5]([CH:30]([CH3:31])[CH3:29])=[CH:6][C:7]=1[CH2:14][CH2:15][NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])(=[O:11])=[O:12])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(CCNC(=O)C(F)(F)F)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Reactant: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)NC(C)(C)C)c(CCNC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.463 g of 5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonyl chloride in 30 mL of tetrahydrofuran was added 0.500 mL of tert-butylamine. The mixture was sealed and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30 mL of water and 10 mL of 1 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.481 g of N-[2-(2-tert-butylsulfamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamide.