Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:16]([Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20])=[CH2:17]>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][CH2:16][Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=C[Si](OC)(OC)OC
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Solvent: Cc1ccccc1
Product: CO[Si](CCc1ccccc1C(=O)C1(O)CCCCC1)(OC)OC
Yield: 49.4 %

Procedure:
14.4 g (70 mmol) of 1-hydroxy-1-benzoylcyclohexane, 11.75 ml (77 mmol) of vinyltrimethoxysilane and 1.28 g (1.4 mmol) of RuH2 (CO) (PPh3)3 in 100 ml of anhydrous toluene were stirred at reflux for 4.5 hours. Following concentration and chromatography (silica gel, CH2Cl2 /ethyl acetate), 12.2 g (49%) of a yellowish oil were obtained which was found to be pure by 1H-NMR spectroscopy but which was purified further by bulb-tube distillation (200° C., 0.2 mbar). 1H-NMR (CDCl3):1.01 ppm (2H, mc, Et-H2); 1.15-1.28 ppm (1H, m, cyclohexyl-H); 1.57-1.89 ppm (9H, m, cyclohexyl-H); 2.59 ppm (2H, mc, Et-H1); 3.33 ppm (1H, s, OH); 3.35 ppm (9H, s, Si(OCH3)3); 7.17-7.40 ppm (4H, M, Ph-H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:23]=[C:22]([Cl:32])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)=O)=[CH:11][CH:10]=1.Cl.[CH2:34]([O:36][NH2:37])[CH3:35]>N1C=CC=CC=1>[CH2:34]([O:36][N:37]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:25][C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])=[CH:23][C:22]=2[Cl:32])=[CH:10][CH:11]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[CH3:35]
Reactant: O=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1

Procedure:
486 mg of (4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-isoxazol-3-yl-methanone in 25 ml of pyridine are stirred with 184 mg of O-ethylhydroxylamine hydrochloride at 110° C. for 24 hours. The reaction mixture is concentrated and the residue is stirred with tert-butyl methyl ether and 0.5N hydrochloric acid. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:11]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2oc(S)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A 100 mg portion of 5-methyl-2-mercaptobenzoxazole was suspended in 20 ml of anhydrous toluene, and the suspension was mixed with 150 mg of phosphorus pentachloride and heated under reflux for 1 hour. The reaction solution was cooled in an ice bath and, with stirring, 500 mg of piperazine was added thereto. After 30 minutes of stirring, the ice bath was removed to carry out 1 hour of stirring at room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution, and then the water layer was washed with ethyl acetate and concentrated under a reduced pressure. Thereafter, the thus obtained mixture was purified by an LH-20 gel column chromatography (chloroform:methanol=1:1) to obtain the title compound (40 mg) in white color.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3]1.C([O:30][C:31](=O)[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])C>>[Cl:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:31]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:30])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CCOC(=O)NS(C)(=O)=O
Product: CS(=O)(=O)NC(=O)N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 8.1 %

Procedure:
N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 31) (0.15 g) and (methylsulfonyl)-carbamic acid ethyl ester (0.065 g) were heated with a single mode microwave in a sealed 10 mL vial for 30 minutes at 130° C. The residue was purified on a Varian® NH2 cartridge washed with methanol (50 mL) and eluted with acetic acid:methanol (10:90) to afford the title product (0.016 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.C([Mg]Cl)(C)C>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH:15]([CH3:19])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 50.2 mmol) and THF (100 mL, 1000 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2.0M isopropylmagnesium chloride in THF (30.1 mL, 60.2 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then saturated aqueous NH4Cl (100 mL) was added dropwise to quench the reaction. The THF was removed under vacuum and the resulting mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with saturated aqueous NaCl (1×100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (300 g SiO2, 12 g crude, 50-60% diethyl ether in hexanes) to yield the following as clear oils:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])[CH3:31])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36][C:37](=O)C>>[CH:30]1([N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:18]4[CH:19]=[C:20]5[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=4)[NH:14][CH:13]=[C:12]5[CH:9]4[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]4)[CH:22]=3)[CH2:26]2)[CH2:31][CH2:37][CH2:36][CH2:32]1
Reactant: CC(C)=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C4CCCC4)C5)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting cyclopentanone (17 mg, 0.198 mmol) for 2-propanone to afford 4.8 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:9]=[C:8]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:22][OH:23]>>[OH:23][N:22]=[C:4]([C:3]1[C:2]([CH3:1])=[N:9][C:8]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[CH:7][CH:6]=1)[NH2:5]
Reactant: NO
Reactant: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Product: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 2-methyl-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.63 g, 2.1 mmol) that was obtained in Example 24 (24c) and a 40% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane (1:9) to afford the title compound (0.61 g) in a yield of 86% as a white crystalline solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:29]3[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)CC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (72 mg, 0.19 mmol), 4-methylpiperidine (0.2 mL, 168 mg, 1.69 mmol) and DMAP (69 mg, 0.61 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 38 mg (45% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.90 (d, J=5.86 Hz, 3 H), 1.16-1.34 (m, 3 H), 1.49-1.64 (m, 4 H), 1.67 (s, 9 H), 1.67-1.73 (m, 2 H), 2.23-2.32 (m, 2 H), 2.33-2.44 (m, 1 H), 3.31-3.40 (m, 2 H), 3.73-3.82 (m, 2 H), 3.91-3.98 (m, 2 H), 4.52 (d, J=7.42 Hz, 2 H), 7.84 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.20 Hz, 1 H), 8.08 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=434.0; Anal. Calcd for C23H35N3O3S+1.10 TFA+0.40 CH3OH (571.86): C, 53.77; H, 6.65; N, 7.35. Found: C, 53.76; H, 6.69; N, 7.33.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[CH2:5][CH2:6][S:7]2.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:6][S:7]2
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(Cl)c2c1SCCC2=O
Product: COC(=O)c1ccc(Cl)c2c1SCC(=CN(C)C)C2=O
Yield: 97 %

Procedure:
30 g (0.078 mol) of methyl 5-chloro-4-oxothiochromane-8-carboxylate in 300 ml of N,N-dimethylformamide dimethyl acetal were heated under reflux for 6 hours. Volatile components were then distilled off, the residue was taken up in methylene chloride and the organic phase was washed with water. Drying and removal of the solvent gave 35.3 g (97%) of methyl 5-chloro-3-(N,N-dimethylaminomethylidene)-4-oxothiochromane-8-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CNc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: CNc1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1
Yield: 44 %

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(methylamino)isonicotinic acid. (Yield: 44%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ 1.45 (br m, 2H), 1.68 (br m, 1H), 1.91 (br m, 1H), 2.15 (br m, 1H), 2.77 (d, J=7.6 Hz, 3H), 3.02 (br m, 1H), 1.97 (br m, 1H), 2.13 (br m, 2H), 2.80 (br m, 2H), 3.19 (br m, 1H), 3.30-4.09 (br m, 4H), 6.34 (br m, 1H), 6.38 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.74 (m, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.73 (br s, 2H), 8.01 (m, 1H), 10.70 (br s, 1H). MS 445 (MH+).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=3[CH3:21])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:26])(=O)=O>>[Cl:26][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=2[CH3:21])[S:10]1(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Product: Cc1ccc(C)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 51 %

Procedure:
The 0.07 g sample of material obtained in the early fractions from the chromatographic separation described above in Preparation 16A consisting predominantly of 2-phenylthiomethyl-4,7-dimethylsaccharin was reacted with 0.05 ml of sulfuryl chloride in MDC and the product recrystallized from cyclohexane-ethyl acetate to give 20 mg (51%) of 2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:23])=[CH:16][CH:15]=1.[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:23])=[CH:18][CH:19]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: COCCOc1ccc(C(=O)O)cc1
Reactant: O=C(/C=C/c1ccc(O)cc1)OCCCCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OCCCCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.7 %

Procedure:
3 g (15 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added to a solution of 3.1 g (15 mmol) of 6-chlorohexyl(2E)-3-(4-hydroxyphenyl)prop-2-enoate, 0.186 g (1.5 mmol) of 4-dimethylaminopyridine in 70 mL of dichloromethane at 0° C. To this mixture, 5.1 g (15 mmol) of 4-(2-methoxyethoxy)benzoic acid in 40 mL of dichloromethane are added at 10° C. The solution is allowed to stir at room temperature for 22 hours. The reaction mixture is then partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using cyclohexane: ethylacetate 4:1 yielded 5.3 g (73%) of pure 4-{(1E)-3-[(6-chlorohexyl)oxy]-3-oxoprop-1-enyl}phenyl 4-(2-methoxyethoxy)benzoate as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([CH2:26][N:27]4C(=O)C5C(=CC=CC=5)C4=O)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].NN>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(CN4C(=O)c5ccccc5C4=O)cccc23)CC1
Agent: NN
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(CN)cccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sulfonamide mixtures 54 (3.11 g, 5.97 mmol) in methanol (30 mL) was added hydrazine (3.4 mL). The resulting solution was stirred at 25° C. for 2 hr. The mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous layer was re-extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by preparative TLC to provide 4-(5-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 55 as a white solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Si:9]([O:26][CH2:27][C@@H:28]([N:32]1[C@H:37]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C@@H:36]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:35][C@@:34]([C:53](=[CH2:58])[C:54]([O:56][CH3:57])=[O:55])([CH3:52])[C:33]1=[O:59])[CH:29]1[CH2:31][CH2:30]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[Si:9]([O:26][CH2:27][C@@H:28]([N:32]1[C@H:37]([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[C@@H:36]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:35][C@@:34]([C:53]2([C:54]([O:56][CH3:57])=[O:55])[CH2:2][CH2:58]2)([CH3:52])[C:33]1=[O:59])[CH:29]1[CH2:30][CH2:31]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(C(=O)OC)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C3CC3)C2=O)CC1
Reaction time: 0.25 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (39 mg, 0.18 mmol) in DMSO (0.71 mL) was added a suspension of 60% sodium hydride in mineral oil (7.1 mg, 0.18 mmol). After being stirred 15 min, a solution of methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate (66 mg, 0.089 mmol; Example 270, Step B) in DMSO (0.71 mL) was added and the mixture was stirred at rt for 3 h. The reaction was quenched (ice cold sat. NH4Cl), extracted (2×EtOAc), and washed (brine×3). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10% and 20% EtOAc/Hex) provided the title compound as a colorless film.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1S(C1C=CC(C)=CC=1)(=O)=O)([CH3:3])[CH3:2].[OH-:26].[Na+].Cl>CO.O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[OH:26])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)C)c(O)cc1C(F)(F)F
Yield: 80.4 %

Procedure:
A solution of 1-Isopropyl-5-methoxy-2-(toluene-4-sulfonyl)-4-trifluoromethyl-benzene (0.40 g, 1.03 mmol) and NaOH (0.5 g, 12.5 mmol) in MeOH (5 ml) and H2O (5 ml) was heated at 90° C. for 2 hrs. The cooled reaction mixture was acidified with 3N HCl and extracted into methylene chloride. The combined extracts was dried with Na2SO4, filtered and concentrated to give desired 2-Isopropyl-4-methoxy-5-trifluoromethyl-phenol (0.194 g, 81%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Cl)cc1Br
Product: Clc1cc(Br)c2nccn2n1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3-amine (6.0 g, 28.8 mmol) was added 2-chloroacetaldehyde (22.60 g, 144 mmol) (50% water solution). The reaction mixture was heated to 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with CH2Cl2. Then, saturated NaHCO3 was added slowly until bubbling ceased. The layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was washed with water and brine, dried over Na2SO4. The crude product was purified by BIOTAGE® (10-40% EtOAc/CH2Cl2, 2.1 L) to give 4.1 g (61%) product as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1H, s), 7.84 (1H, s), 7.39 (1H, s); 13C NMR (101 MHz, CDCl3) δ ppm 145.92 (1 C, s), 136.93 (1 C, s), 134.77 (1 C, s), 124.20 (1 C, s), 121.22 (1 C, s), 118.81 (1 C, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH:14]([CH3:18])[C:15](Cl)=[O:16].Cl>ClCCCl>[Cl:13][CH:14]([CH3:18])[C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: Fc1cccc(F)c1
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into the solution of 1,3-Difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 mol eqnt.) at 25-30° C. and stirred for 30 minutes. The reaction mixture was then cooled to 0° C. and (±)2-chloropropionyl chloride (1.1 molar equivalent), diluted in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 20° C. After the addition was over, reaction mixture was stirred at room temperature for 5-7 hours. For workup, reaction mixture was diluted with DCE and poured into chilled aq. hydrochloric acid solution (5%). The mixture was extracted with DCE and the combined organic layer was washed with 5% aq. sodium bicarbonate solution and water. The solvent was evaporated off under reduced pressure to afford an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[CH:30])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCN(CC)CC.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>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[C:30][C:17]1[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 29.2 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N (60 mL) was added Cul (63 mg, 0.3 mmol) and Pd(PPh3)4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was complete. The mixture was extracted with EtOAc and washed by water. The crude product was purified on a silica gel column eluting with 20–40% EtOAc in hexanes to provide (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-prop-2-ynyl)-carbamic acid tert-butyl ester (2.2 g, 29% yield).
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH3:18])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8][CH2:7]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:18][C@:6]1([CH2:5][OH:4])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8][CH2:7]1
Reactant: CC(=O)OC[C@]1(C)CCn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Yield: 96.3 %

Procedure:
Hydrolysis of (S)-acetate 161 (426 mg, 1.67 mmol) with K2CO3 in MeOH/water as in Example 2EEE above, followed by chromatography of the product on silica gel, eluting with 0-1% MeOH/CH2Cl2 (forerun), and then with 1-2.5% MeOH/CH2Cl2, gave [(7S)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (162) (343 mg, 96%) as a pale yellow solid that was used directly in the next step; 1H NMR [(CD3)2SO] δ 8.03 (s, 1H), 5.22 (br t, J=5.7 Hz, 1H), 4.13 (dt, J=13.0, 6.0 Hz, 1H), 4.05 (ddd, J=12.9, 8.1, 5.6 Hz, 1H), 3.54 (dd, J=11.6, 5.4 Hz, 1H), 3.48 (dd, J=11.6, 5.7 Hz, 1H), 2.21 (ddd, J=14.4, 8.1, 5.9 Hz, 1H), 2.00 (dt, J=14.4, 5.8 Hz, 1H), 1.32 (s, 3H); [α]D27 18.0° (c 1.00, DMF).