Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=2)[O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[C:34]([O:36]C)=[O:35])=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=2)[O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[S:25][C:21]=3[C:20]=2[C:34]([OH:36])=[O:35])=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
Methyl 6-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazole-7-carboxylate (570 mg, 1.02 mmol) produced in Example 46(iv) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)/methanol (2 mL)/water (2 mL), lithium hydroxide monohydrate (150 mg, 3.66 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate (100 mL)/tetrahydrofuran (100 mL) and washed with water (100 mL). The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (300 mg, 54%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].CO.C([O-])([O-])=O.[Ca+2].[Br-:30].[Br-].[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C([N+](CC)(CC)CC)C1C=CC=CC=1.C([N+](CC)(CC)CC)C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:30][C:11]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: [Br-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Br)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77 %

Procedure:
To a suspension of racemate 1G (323 mg, 1.03 mmol) in mixed solvents of MeOH (3 mL), CH2Cl2 (3 mL) and THF (3 mL) at RT was added CaCO3 (103 mg, 1.03 mmol), followed by benzyltriethylammonium tribromide (445 mg, 1.03 mmol). After addition, the mixture was stirred at RT for 45 min. The resultant precipitate was collected by filtration, washed with 0.2 N aqueous HCl, H2O, then dried to provide the title compound (311 mg, 77%) as a white solid.
Reaction SMILES: C(O[CH:5]([CH2:21][CH2:22][C:23]([C:37]#[N:38])([CH:34]([CH3:36])[CH3:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:6]([N+:18]([O-:20])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=O)C.[BH4-].[Na+]>CC(O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH2:7][CH:6]([N+:18]([O-:20])=[O:19])[CH2:5][CH2:21][CH2:22][C:23]([C:37]#[N:38])([CH:34]([CH3:36])[CH3:35])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(CC(C(CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)OC(C)=O)[N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC

Procedure:
The resulting nitrohexanol acetate of formula 9 is then reduced using a boron-based reducing agent, e.g., sodium borohydride, in a 2° or 3° alkanol at 25°-80° C. for 3-15 hours to produce a nitrohexane derivative of formula 10 (step 8). For example, O-acetyl-1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol (9) is heated with NaBH4 in 2-propanol at reflux for 3-15 hours to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane (10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (64.4 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[I-].[Na+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(OCC)(=O)C>CN(C)C=O>[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1F
Yield: 57.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 101 mg, 0.33 mmol), sodium iodide (53 mg, 0.35 mmol) and 2,4-difluorobenzyl bromide (0.22 mL, 1.68 mmol) in dimethylformamide (0.8 mL) was heated under microwave irradiation at 150° C. for 1 h. Ethyl acetate was added and the solution was washed with 10% aqueous sodium thiosulfate (three times), dried (sodium sulfate), filtered, evaporated, and purified on an RS-4g silica gel column, eluting with 20-100% ethyl acetate/hexanes to give (4R,7S)-1-(2,4-Difluoro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 58%) as a light brown foam. ES(+)-MS (M+H) 431.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH:35][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCCc3ccc(Cl)c(Cl)c3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: [Na].[C:2]1([CH2:8][OH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1>O>[CH3:29][C:25]1[CH:24]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[N:13]=[N:12][C:11]([O:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: [Na]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(OCc4ccccc4)nn3)CC2)c1
Temperature: 180 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a stirred solution of 0.7 parts of sodium in 20 parts of benzenemethanol were added 5.8 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and heated in an oil bath at 180° C. After standing overnight, water was added and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 2,2'-Oxybispropane was added to the residue. The product was filtered off and crystallized from a mixture of 2-propanol and methanol. The product was filtered off and dried, yielding 3.4 parts (47%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-(phenylmethoxy)pyridazine: mp. 159.4° C. (compound 267).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=O)[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:61]3[CH:62]=[N:57][CH:58]=[N:59][CH:60]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]2=3)[CH2:27][CH2:26][O:25]4)[CH2:5]1
Reactant: OB(O)c1cncnc1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: c1ccc(CN2CC3(COc4cc5c(cc43)CCO5)c3c(-c4cncnc4)cccc32)nc1

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bronno-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (16%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH-].[Na+].[Na+].[Cl-].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 105 °C

Procedure:
To a 4-dram vial was added 5-Chloro-2-nitroaniline (0.5 g, 2.90 mmol, 1 equiv.), NaOH (0.229 g, 5.71 mmol, 1.98 equiv.), 4′M NaCl (0.82 mL, aq.), and 1-methylpiperazine (0.643 g, 0.71 mL, 5.79 mmol, 2 equiv.). The mixture was heated on a hot plate to 105° C. for 22 h. De-ionized H2O (6 mL) was added to the mixture, which was cooled to room temperature, and the precipitate collected on a Buchner funnel. The precipitate was then washed with de-ionized H2O (5 mL) and heptane (5 mL). After drying in a vacuum oven (80° C., 30 in. Hg) overnight, the product (0.624 g, 91.1%) was collected. According to HPLC analysis, the sample had a purity of 99.6%.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13](O)[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][C@@H:17](O)[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>[Cl-].[Zn+2].[Cl-]>[C:5]([OH:7])(=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:8]1[C@:12]2([CH3:29])[C:11](=[C:16]3[C@H:15]([CH2:14][CH2:13]2)[C@:20]2([CH3:26])[CH:19]([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Cl-]
Agent: [Zn+2]
Product: C[C@H](CCC(=O)O)[C@H]1CCC2=C3CCC4CCCC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Cholic acid is treated with zinc chloride to afford the corresponding chol-8(14)en-24-oic acid which is subsequently reduced by treatment with lithium aluminum hydride to the corresponding alcohol. Treatment of the alcohol with p-toluenesulfonyl chloride in the presence of 4-dimethylaminopyridine and triethylamine gives the tosylate which is then converted to the 4-chlorophenylseleno derivative by treatment with bis(4-chlorophenyl)diselenide in the presence of sodium borohydride.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.CC1C=CN=C(NC2C=CC=C(C3OC=NC=3)N=2)C=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I:50]C(I)C>C1COCC1>[I:50][C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1
Reactant: CC(I)I
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
Yield: 41 %

Procedure:
The 2-iodooxazole derivative was prepared as for [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine above from (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine with LiHMDS (1M solution in THF) and diiodoethane in anhydrous THF to give the title compound as a yellow solid (41%) after purification by column chromatography on SiO2 eluting with 40% EtOAc in cyclohexane. 1H NMR (300 MHz, DMSO-d6) δ=9.81 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.84-7.51 (m, 4H), 7.23 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.6 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])(=[O:15])=[O:14])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[O:11][CH2:28][CH2:27][N:12]([S:13]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])(=[O:15])=[O:14])[C:6]=2[CH:5]=1)=[O:25]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(C)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Product: COC(=O)c1cc(C)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=514.9 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methyl-benzoic acid methyl ester (example 52, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[CH2:30][CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][CH2:30][C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[F:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCCc1ccccc1F
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCCc2ccccc2F)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 2-fluorophenethylamine (0.531 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.27 g of the product 91. 1H NMR (CDCl3) δ 7.40-6.85 (m, 13 H), 6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H), 3.90-3.60 (m, 2 H), 1.15 (s, 9 H); MS: m/z 460 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(F)c(-c2csc(N)n2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(F)c(-c2csc(NC(=O)c3ccncc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 4-(2-chloro-6-fluoro-4-methoxyphenyl)thiazol-2-ylamine (0.10 g, 0.39 mmol) in CH2Cl2 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2-chloro-6-fluoro-4-methoxyphenyl)thiazol-2-yl)isonicotinamide (13, 60 mg, 0.17 mmol) as white solids in 42% yield: 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 2 H), 7.85 (d, J=4.5 Hz, 2 H), 7.12 (s, 1 H), 6.67 (s, 1 H), 6.45 (m, 1 H), 3.79 (s, 3H). ESI-MS: m/z 364.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(Cl)CCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]12[CH2:7][CH2:6][CH:5]([CH2:4][C:3]1=[O:20])[C:8]([CH3:10])([CH3:9])[O:11]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CC[C@@H](C(C)(C)O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC12CCC(CC1=O)C(C)(C)O2
Temperature: 25 °C

Procedure:
A mixture of 3.08 g. (0.02 mole) α-terpineol and 4.45 g. (0.022 mole) of 85 percent m-chloroperbenzoic acid in 70 ml. of ethylene dichloride is refluxed under nitrogen for 20 hours, then cooled to room temperature and washed with aqueous sodium bisulfite and sodium bicarbonate solutions. The solvent is removed in vacuo and the resulting oil is treated in situ with 2.94 g. (0.0136 mole) pyridinium chlorochromate. The resulting mixture is stirred under nitrogen in 35 ml. of methylene chloride at ambient temperatures for 2.5 hours. After addition of 200 ml. diethyl ether, the mixture is filtered through celite and the solvent evaporated to give, on steam distillation, 1,3,3-trimethyl-2-oxabicyclo [2,2,2]octan-6-one; m.p. 50° to 52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][C:33]#[N:34])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCNCc1ccccc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: COc1ccccc1N(CC(=O)N(CC#N)Cc1ccccc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with benzylamino-acetonitrile
Reaction SMILES: C([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=O)C.[O:28]=[CH:29][C@@H:30]([C@H]([C@H]([C@@H](CO)O)O)O)O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>ClC(Cl)C>[C:25]([O:24][C@@H:23]1[O:4][C@H:5]([CH2:6][O:7][C:29](=[O:28])[CH3:30])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The synthesis of compounds 26-31 are depicted in FIGS. 3A and 3B and are set forth in the examples hereinbelow. In this figure, the synthesis of compounds 26, 27, 28, and 36 parallels that of compounds 17, 18, 19, and 20 as set forth above and illustrated in FIG. 2. In this regard, benzyl 4,6-O-benzylidene-2-O-benzoyl-3-O-chloroacetyl-β-D-thiogalactopyranoside (compound 31) has been produced without the necessity of chromatography. D-Galactose pentaacetate 26 is produced by slurring D-galactose and about an equimolar amount (e.g., about 1.1 equivalents) of sodium acetate (NaOAc) in dichloroethane (DCE), heating to reflux and adding at least 5 equivalents of acetic anhydride (AcOAc) dropwise to the refluxing solution (about 80°-85° C.) and then maintaining the reaction system at this temperature for a sufficient period of time (about 16-32 hours) to result in formation of compound 26. This procedure optimizes the yield of β-D-galactose pentaacetate 26 and controls the exotherm of heretofore known procedures.
Reaction SMILES: [N+]([CH2:4][CH2:5][CH3:6])([O-])=O.[CH:7]1[CH:15]=[CH:14][C:13]2[C:9](=[N:10][O:11][N+:12]=2[O-:16])[CH:8]=1.C(NCC)C>O1CCCC1>[OH:11][N:10]1[C:9]2[CH:8]=[CH:7][CH:15]=[CH:14][C:13]=2[N+:12]([O-:16])=[C:4]1[CH2:5][CH3:6]
Reactant: CCC[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCc1n(O)c2ccccc2[n+]1[O-]
Reaction time: 8 h

Procedure:
To a mixture containing 1-nitropropane (10.7 g., 0.12 moles), benzofuroxan (13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is added dropwise diethylamine (8.7 g., 0.12 moles). The reaction temperature rises almost to reflux on addition of amine. Upon completion, the mixture is allowed to cool and then sit overnight.