Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:23]#[N:24])(C)C>>[C:2]1([CH:1]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[C:23]#[N:24])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-benzylidene-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2.[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2)#[N:18]
Reactant: CN1CCCC1=O
Reactant: Brc1ccccc1-c1nc2ncccc2o1
Product: N#Cc1ccccc1-c1nc2ncccc2o1
Temperature: 175 °C
Reaction time: 5 h

Procedure:
A mixture of 2.8 g. of 2-(2-bromophenyl)oxazolo[4,5-b]pyridine, 1.6 g. of cuprous cyanide and 15 ml. of N-methylpyrrolidinone was deairated by bubbling nitrogen through the mixture for 5 minutes. It was then heated to 175° C. in an oil-bath and held at that temperature for 5 hours under a nitrogen atmosphere and then allowed to cool to room temperature. The reaction mixture was treated with 75 ml. of 10% ammonium hydroxide and the resulting precipitate was collected. The precipitate was extracted with 100 ml. of boiling methylene chloride and the methylene chloride was evaporated. The residue was recrystallized from methylene chloride to give 2-(2-cyanophenyl)oxazolo[4,5-b]pyridine, m.p. 166°-167° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 71 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-methylbenzenesulfonyl chloride under the conditions used in example 2 giving 71% of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[C:13]([Br:20])[C:12]=2[Br:21])[CH:9]=1)[C:5]#[N:6].[NH3:22].CO>ClCCl>[NH2:22][CH2:18][C:15]1[C:16]([F:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:12]([Br:21])=[C:13]([Br:20])[CH:14]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Br)c1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of 3-chloro-5-{[2,3-dibromo-5-(bromomethyl)-6-fluorophenyl]oxy}benzonitrile (0.185 g, 0.371 mmol) and 7M ammonia in methanol (5 mL, 35.0 mmol) in dichloromethane (5 mL) was stirred at RT overnight. The solvent was evaporated and the residue was purified by chromatography (MeOH:dichloromethane) to give the desired product (37 mg, 19.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.80 (d, 1H), 7.52 (t, 1H), 7.25 (t, 1H), 7.20 (d, 1H), 3.82 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14].[CH2:15]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>COC(O)CC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:16][CH2:17][CH3:18])[C:6]=2[C:13]#[N:14]
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CCCCNCCCC
Agent: CCC(O)OC
Product: CCCCN(CCCC)c1ccc2cc(Cl)cnc2c1C#N
Yield: 82.3 %

Procedure:
22.3 g of 3,7-dichloro-8-cyanoquinoline and 26 g of di-n-butylamine in 300 ml of methoxypropanol were refluxed for 12 hours, the solution was cooled, and the precipitated solid was filtered off under suction and recrystallized from a mixture of naphtha and toluene. 26 g of 3-chloro-8-cyano-7-di-n-butylaminoquinoline of melting point 112° C. were obtained. Yield: 82.5% of theory.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([C:14](OC)=[O:15])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:13]([CH2:14][OH:15])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 50 g of methyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate added toluene (250 ml) and stirred for 15 minutes at 25° C. Cooled the reaction mixture to 0° C. Added 300 ml of DIBAL H (25% solution in toluene) to the reaction mixture slowly in 45 minutes at the same temperature. Stirred the reaction mixture for 1 hr at 0° C. Quenched the reaction mixture with HCl (110 ml) solution at 10° C. and stirred for 15 minutes. Raised the temperature to 25° C. and stirred for 30 minutes. Separated the both aqueous and organic layers. Extracted the aqueous layer with toluene (400 ml). Adjusted the pH of the reaction mixture with 10% sodium bicarbonate solution (200 ml). Washed the organic layer with saturated sodium chloride solution (200 ml). Distilled off the solvent completely to obtain a solid. Added cyclohexane (50 ml) to the solid and distilled it. To the residue added cyclohexane (150 ml) and stir for 30 minutes at 45° C. Cooled the reaction mixture to 25° C. and stirred for 1 hr. at the same temperature. Filtered the cake, washed with cyclohexane (50 ml) and then dried to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30](/[CH:34]=[CH:35]/[C:36]([O:38]CC)=[O:37])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:41].[OH-].[Na+].Cl>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30](/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:41]
Reactant: CCOC(=O)/C=C/c1cccc(-c2c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc3cc(Cl)c(C)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(-c3cccc(/C=C/C(=O)O)c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A solution of ethyl (2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propenoate (200 mg) in a mixture of ethanol (5 ml) and THF (2 ml) was combined with a 1 N aqueous solution of sodium hydroxide (3 ml), and stirred at room temperature for 4 hours. After 1 N hydrochloric acid (10 ml) was added, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated. The resultant crude crystal was recrystallized from THF-ethyl acetate to obtain the title compound as a colorless crystal (137 mg, yield: 70%). Melting point: 191-194° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][C:28]1[O:37][C:36]2[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[NH:33][CH2:32][CH2:31][C:30]=2[N:29]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:33]2[CH2:32][CH2:31][C:30]3[N:29]=[C:28]([CH3:27])[O:37][C:36]=3[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Reactant: Cc1cc(C(=O)O)ccc1CNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid from Example E2h (400 mg, 1.5 mmol) in dichloromethane (20 ml) and triethylamine (to pH9) was treated with WSCD (573 mg, 3.0 mmol) and DMAP (183 mg, 1.5 mmol). The solution was stirred for 30 min at room temperature then 2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E6 (300 mg, 1.5 mmol) was added and the mixture was heated at reflux for 3 days. WSCD (287 mg, 1.5 mmol) was added and the mixture was heated at reflux for another 24h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (62 mg, 9%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[CH:23]=[C:22]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:37])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.CC1C=C(C)C(C)=C(C)C=1C>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:21]=[CH:20][C:19](=[O:37])[N:18]([CH2:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH:23]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCc1cccc(OCc2ccccc2)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCc1cccc(O)c1
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To the mixture of 1-{3-[3-(benzyloxy)phenyl]propyl}-5-(diphenylmethyl)pyridin-2(1H)-one (200 mg) and TFA (3.0 mL) was added 1,2,3,4,5-pentamethylbenzene (305 mg) at ambient temperature. After stirring for 12 hours, the resulting mixture was evaporated in vacuo and 10% K2CO3 aqueous solution was added to the residue. The aqueous solution was extracted with EtOAc The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1-1:2) to give a 5-(diphenylmethyl)-1-[3-(3-hydroxyphenyl) propyl]pyridin-2(1H)-one (147 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>COC(C)(C)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](Oc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg 74844-91-0) (6.1 kg, 24.87 mol), 3-chlorophenol (3.52 kg, 27.39 mol) & triphenylphosphine (7.18 kg, 27.37 mol) in tert-butyl methyl ether (30.5 L) at 0′C. was added diisopropylazodicarboxylate (5.53 kg, 27.35 mol) in tert-butyl methyl ether (15 L) dropwise. The mixture was stirred overnight at 20′C. The reaction was filtered and the liquors washed with 0.5M sodium hydroxide (aq) (2×12.5 L) & water (12.2 L). The tert-butyl methyl ether solvent was replaced with n-heptane (42.7 L) by atmospheric pressure distillation & cooled to crystallise crude product, which was collected by filtration (11.1 kg, 125% contaminated with ca 35% reduced diisopropyl dicarboxylate & triphenylphosphine oxide−corrected yield=86%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1.[CH3:17][NH2:18]>CO.CCOC(C)=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][CH3:17])[N:10]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc(Cl)ccc1C(=O)O
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a steel autoclave was added 2,6-dichloronicotinic acid (tech.) (30 g, 156.2 mmoles), tetrahydrofuran (30 mL) and monomethylamine (68.2 mL. 33 wt % in ethanol, 500 mmol). The reaction vessel was heated at 100° C. for 4 h. The reaction mixture was cooled and the solution transferred from the autoclave to a 500 mL flask and concentrated under vacuum to give a green solid. The solid was dissolved in 300 mL MeOH and 1.2 L EtOAc, poured into a separatory funnel and washed with 1N HCl (2×300 mL) and brine. The organic solution was then concentrated to dryness to yield 6-chloro-2-(methylamino)nicotinic acid (29 g, 96%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH:48]=O)=[CH:44][NH:45]2)=[CH:41][CH:40]=1>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:43]2[C:42]3[C:46](=[CH:47][C:39]([F:38])=[CH:40][CH:41]=3)[NH:45][CH:44]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3cc(F)ccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 36.7 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (50 mg, 0.099 mmol) was condensed with 6-fluoroindole-3-carboxaldehyde (19.4 mg, 0.119 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 yielded 23.5 mg of N-benzyl-2-[8,9-difluoro-4-(6-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.94 (d, 1H), 7.61 (m, 3H), 7.27-7.49 (m, 9H), 6.95 (m, 1H), 6.86 (m, 1H), 6.63 (m, 1H), 4.35-5.0 (m, 5H), 4.20 (m, 1H), 1.23 (m, 6H); MS 647.3 (M+1), 645.3 (M−1).
Reaction SMILES: O[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CO.C(OCC)C>[CH2:13]([NH:23][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCCCN
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 90 %

Procedure:
β-D-galactose (10 g, 1 eq), decylamine (8.7 g, 1 eq), and water (2 g, 3eq) were heated in a reaction flask for 20 min at 80° C. Methanol/ethyl ether (50 v/50 v) was added, the product was filtered, washed with ethyl ether (2×50 ml) and dried, to give a 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1Br.[CH3:17][C:18]1([CH3:33])[CH2:23][CH2:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]1[CH2:22][CH2:23][C:18]([CH3:33])([CH3:17])[CH2:19][CH:20]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2N)CC1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
A solution of 300 mg (0.976 mmol) of 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (as prepared in Example 48, step (a)) in toluene (8 mL) and EtOH (4 mL) was treated with 253 mg (1.07 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3.90 mL (7.81 mmol) of 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 113 mg (0.0976 mmol) of Pd(PPh3)4, and heated to 80° C. for 6 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1-4% MeOH—CH2Cl2 afforded 158 mg (48%) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide as a colorless glassy solid. A suspension of 215 mg (0.704 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) in CH2Cl2 (10 mL) was treated with 60.0 μL (0.704 mmol) of pyridine for 5 min. The mixture was then treated with 51.4 μL (0.704 mmol) of SOCl2 at RT for 30 min. A solution of 158 mg (0.0470 mmol) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide (as prepared earlier in this step) in CH2Cl2 (5 mL) was treated with the acid chloride solution and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 100.0 mg (17%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.95 (br s, 1H), 8.55 (d, 1H, J=8.8 Hz), 7.78 (dd, 1H, J=8.8, 2.4 Hz), 7.78 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 5.92 (s, 2H), 5.84-5.80 (m, 1H), 4.55 (br s, 1H), 3.68-3.62 (m, 2H), 2.32-2.24 (m, 2H), 2.14-2.08 (m, 2H), 1.63-1.56 (m, 2H), 1.23 (s, 9H), 1.11 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C(O)=O.[ClH:46]>O1CCCC1.O.CO.CCOCC>[ClH:46].[O:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:4]([CH3:5])[NH2:1])=[N:13]1
Reactant: CC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(N)c1ccccc1-c1noc2ccccc12
Reaction time: 48 h

Procedure:
To a stirred solution of 0.64 g of 3-[2-(1-azidoethyl)-phenyl]-1,2-benzisoxazole in 10 ml of tetrahydrofuran and 0.1 ml of water was added 0.71 g of triphenyl phosphine. The solution was stirred for 2 days then diluted with 25 ml of water and the solution was extracted with two 50 ml portions of ether and the organic layers were dried over sodium sulfate then evaporated to give a pale yellow gum. This residue was dissolved in a small amount of methanol and 0.37 g of oxalic acid was added and warmed to dissolve. Ether was added and the white solid formed was separed and recrystalised from methanol-ether. To this solid was added 25 ml of a 5% aqueous solution of sodium carbonate and the solution extracted with 50 ml and then 25 ml of methylene chloride. The combined organic layers were washed with 25 ml water, 25 ml of brine then dried over sodium sulfate. Evaporation afforded a colourless oil which was dissolved in methanol and hydrogen chloride in methanol added until the solution was acidic. Evaporation and addition of ether yielded 2-(1,2-benzisoxazol-3-yl)-a-methyl-benzenemethanamine hydrochloride, melting at 229-236° C.
Reaction SMILES: [O-]S([C:5]([F:8])(F)F)(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.[Br:19][C:20]1[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]2[CH:28]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[N:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35](=[O:39])[N:34](C)[CH:33]=3)[C:30](=[O:31])[C:22]=2[CH:21]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Br:19][C:20]1[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]2[CH:28]([C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[N:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35](=[O:39])[N:34]([CH3:33])[C:5]=3[F:8])[C:30](=[O:31])[C:22]=2[CH:21]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1F)C2=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1-Fluoro-2,4,6-trimethyl-pyridinium triflate [107264-00-6] (1.476 mmol) was added to a solution of 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) (0.738 mmol) in 1,2-dichloroethane (12 mL) and then the mixture was heated to 80° C. in the dark. After 12 h, the reaction mixture was cooled to rt, poured into a 2% aqueous solution of sodium sulfite and extracted with EtOAc (2×). The combined organic layers were successively washed with 1M aqueous citric acid, 1M aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a pink foam. ESI-MS: tR=1.16 min, [M]+ 512/514/516 (LC-MS 1); TLC: Rf=0.10 (1.1 EtOAc/heptanes).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)[C:12]([C:26](OCC)=[O:27])=[CH:11][N:10]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)[C:12]([CH2:26][OH:27])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nc(SC)ncc2CO)cc1Cl

Procedure:
To a suspension of lithium aluminium hydride 4.15 g in tetrahydrofuran 150 ml is added a solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 38.32 g in tetrahydrofuran 100 ml at 5–10° C. under ice cooling over a period of 1 hour. After addition the mixture is stirred for a hour without an ice bath. Water 4.15 ml is added under ice cooling thereto, followed by addition of 3N aqueous sodium hydroxide solution 4.15 ml. To the mixture is added water 4.15 ml three times and the mixture is stirred at room temperature for 1 hour. After treating with magnesium sulfate and filtration, the resulting cake-like substances are washed with terahydrofuran. The filtrate is concentrated in vacuo and triturated with ethyl acetate-isopropyl ether. The resulting crystals are filtered and washed well with isopropyl-ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as a pale yellow crystalline powder.