Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3I)=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH2:38]([NH2:40])[CH3:39]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[NH:40][CH2:38][CH3:39])=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Reactant: CCN
Product: CCNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Yield: 76.9 %

Procedure:
Using the procedure of Example 7, 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(2-acetylamino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-amide (90 mg, 0.145 mmol) and a methanolic solution of ethylamine (10 mL) were combined to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (60 mg, 76.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1 H), 10.58 (s, 1 H), 10.49 (m, 1 H), 8.47 (dd, J=12.9, 7.2 Hz, 1 H), 8.18 (d, J=5.8 Hz, 1 H), 7.70 (d, J=7.9 Hz, 1 H), 7.65 (m, 1 H), 7.52 (dd, J=11.2, 7.4 Hz, 1 H), 7.47 (m, 2 H), 7.34 (m, 2 H), 6.70 (dd, J=5.8, 2.5 Hz, 1 H), 6.28 (d, J=7.9 Hz, 1 H), 3.42 (m, 2 H), 2.03 (s, 3 H), 1.24 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 538.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Product: O=C(O)c1cc(NCCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 50.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 3-(4-nitrophenyl)propyl bromide (950 mg, 3.92 mmole), 520 mg (50% yield) of 5-[3-(4-nitrophenyl)-n-propyl]aminosalicylic acid was obtained as a pale yellow solid.: mp 229-231° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])=[CH:5][CH:6](Br)[CH3:7].C(N(CC)CC)C.[CH3:18][N:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])=[CH:5][CH:6]([S:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]([CH3:27])[CH3:18])=[CH:21][CH:22]=1)[CH3:7]
Reactant: COC(=O)C(C)=CC(C)Br
Reactant: CN(C)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C(C)=CC(C)Sc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 4-bromo-2-methylpent-2-enoic acid methyl ester (0.414 g, 2.0 mmol) in dry benzene (4 mL) under an atmosphere of argon was added a solution of triethylamine (0.28 mL, 2.0 mmol) and 4-dimethylamino-benzenethiol (0.306 g, 2.0 mmol) in dry benzene (2 mL). The mixture was stirred at 20° C. for 2 hours (TLC monitoring). The solvent was then removed under reduced pressure to give a yellow oil that was purified by column chromatography (20:79:1 diethyl ether:60-80° C. petroleum ether:triethylamine) to give the title compound (0.53 g, 95%) as a colourless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: C1=COCCC1
Reactant: O=C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C1CCC(OC2CCCCO2)CC1
Reaction time: 2.5 h

Procedure:
A solution comprising 10 g. of 4-hydroxycyclohexanone, 10 g. of dihydropyran and 0.5 g. of p-toluenesulfonic acid in 100 ml. of ether is allowed to stand at room temperature for about 2.5 hours. The solution is then washed with saturated aqueous sodium bicarbonate solution and brine, 50 ml. of dry benzene added and the solution then evaporated to dryness to give 4-[(tetrahydropyran-2-yl)oxy]cyclohexanone as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH:36]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[CH3:7])[CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2cc(-c3cc4ccccc4o3)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 2.8 mL of methylene chloride and 0.36 mL of triethylamine containing 50 mg of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzofuran-2-yl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (659 mg) in dimethyl sulfoxide (10 ml) was added sodium azide (487 mg), and the mixture was stirred at 90° C. for 8 hours. The mixture was diluted with water (20 ml), and the precipitate was filtered and washed with water to give 4-azido-8-(2,6-dichlorobenzoylamino)quinoline (560 mg) as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CN1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-G2, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and tert-butyl 2-bromoacetate were converted to provide tert-butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate as a clear, glassy solid (55 mg, 69%): 1H NMR (500 MHz, DMSO-d6) δ 12.94 (br s, 0.25H), 12.71 (br s, 0.75H), 7.37-7.33 (m, 1H), 7.50-7.49 (m, 1H), 4.86-4.84 (m, 1H), 4.68-4.66 (m, 1H), 3.67-3.63 (m, 2H), 3.34-3.30 (m, 2H, partially merged with H2O peak), 3.14-3.13 (m, 2H), 2.59-2.58 (m, 3H), 2.59-2.50 (m, 2H, partially merged with DMSO peak), 1.76-1.70 (m, 4H), 1.43 (s, 9H); ESI MS m/z 529 [M+H]+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:22])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C@H:8]([CH2:10][C:11](=[O:13])[OH:12])[NH2:9].[CH:23](N[C@@H]1C(=O)OC(=O)C1)=[O:24].N[C@H](C(O)=O)CC1C=CC=CC=1>O.CO>[CH:23]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:10][C:11](=[O:13])[OH:12])=[O:24]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: Cl
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
This invention relates to a preparation process of α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. More specifically, this invention provides a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required. Further, this invention provides another process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water containing methanol in an amount of 6 moles or less per mol of the L-phenylalanine at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OCC)C=C.[C:17]([O:21][C:22](=[O:50])[NH:23][CH:24]([CH3:49])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](=[O:48])[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][C:42]1C=CC=CC=1)=[O:26])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:50])[NH:23][CH:24]([CH3:49])[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](=[O:48])[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][CH3:42])=[O:26])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) carbamic acid allyl ester 74 following the method used in the synthesis of 75 to give the title compound as a pale yellow solid (660 mg, 73% yield). 1H-NMR (500 MHz, CD3OD) δ 1.14-1.36 (m, 6H), 1.42 (s, 9H), 1.75-2.29 (m, 4H), 2.48 (dd, 0.5H), 2.58 (dd, 0.5H), 2.72-2.85 (m, 0.5H), 2.99 (dd, 0.5H), 3.43-3.91 (m, 4H), 4.07-4.52 (m 2.5H), 4.53-4.72 (m, 0.5H), 5.37 (s, 0.5H), 5.57 (d, 0.5H). Analytical HPLC (mixture of 2 diastereomers) 7.92, 8.14 min. LC-MS (ES+) m/e=414.3 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH3:28])=[CH:23][CH:22]=1)=O)(C)(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH:29]1([N:27]([C:24]2[CH:25]=[CH:26][C:21]([C@H:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:22][CH:23]=2)[CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN(c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1)C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1ccc([C@H]2CNCCN2)cc1)C1CCCCC1
Reaction time: 0.67 h
Yield: 8 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazine in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL). After stirring for 40 min, the white precipitate was collected, which included impurities. The mixture was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazine (59 mg 8% in 2 steps) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH2:16][CH:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][N:13]=2)=[C:10]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([C:12]2[CH2:16][CH:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][N:13]=2)=[C:10]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(Cc3ccccc3)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC(Cc2ccccc2)C1
Reaction time: 16 h
Yield: 86.3 %

Procedure:
1.02 g (2.5 mmol) of methyl 2-chloro-3-(5-benzylisoxazolin-3-yl)-4-methylsulfonylbenzoate are dissolved in 20 ml of methanol and combined with 0.15 g (3.7 mmol) of sodium hydroxide—dissolved in 10 ml of water—at room temperature. After 16 hours, the methanol is removed by distillation, the residue is diluted with water and, after acidifying to pH 2, the mixture is extracted with dichloromethane. After concentrating in a rotary evaporator, 0.85 g (87% of theory) of 2-chloro-3-(5-benzylisoxazolin-3-yl)4-methylsulfonylbenzoic acid is obtained as a yellowish resin.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH:19]([CH3:21])[CH3:20])[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH:19]([CH3:20])[CH3:21])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1sc(Br)nc1C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C(C)C
Yield: 65.8 %

Procedure:
A solution of 3-tert-butoxycarbonylaminoazetidine (136 mg, 0.79 mmol), ethyl 2-bromo-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (23b) (200 mg, 0.72 mmol) and diisopropylethylamine (0.25 mL, 1.44 mmol) in DMF (8 mL) was stirred at 90° C. for 11 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with 10% saline and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1) to obtain 175 mg of the title compound as a white solid (66%).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:20][CH:19]=1)[CH2:12][OH:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2ccc(CO)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of methyl 4-(4-ehtylbenzyl)-3-hydroxy-benzoate (1.3 g) in N,N-dimethylformamide (15 mL) were added potassium carbonate (0.79 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (10 mL). The resulting solution was added to a suspension of lithium aluminium hydride (0.57 g) in diethyl ether (50 mL) at 0° C., and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to 0° C., water (0.60 mL), 15% aqueous sodium hydroxide solution (0.60 mL) and water (1.8 mL) were successively added to the reaction mixture, and the mixture was stirred for 5 minutes. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (1.3 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[C:45]([F:51])[N:44]=1)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:50])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[C:45]([F:51])[N:44]=1)[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (9, 40 g, 97.0 mmol) in 400 mL of tetrahydrofuran under nitrogen at −20° C., isopropylmagnesium chloride (54.8 mL, 2 M in tetrahydrofuran, 110 mmol) was added and the reaction allowed to warm to 0° C. over 30 minutes. The reaction was cooled to −40° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (83, 15.81 g, 43.9 mmol) in tetrahydrofuran was added. The reaction was allowed to warm to 0° C. over an hour, then quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (136, 21 g, 32.4 mmol, 73.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:40]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:40][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: COc1nccnc1NS(=O)(=O)c1cccc(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1nccnc1NS(=O)(=O)c1cccc(F)c1Cl
Yield: 29 %

Procedure:
Prepared as for Example 130, 3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 131a) (0.283 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.092 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]1([CH2:15]Br)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:15][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1ccccc1S
Reactant: BrCC1CCCCC1
Product: Oc1ccccc1SCC1CCCCC1
Yield: 87 %

Procedure:
This compound was prepared in 87% yield from 2-mercaptophenol and cyclohexylmethyl bromide according to the procedure for 1p in Example VIII. Colorless oil; 1H NMR (CDCl3): 0.91-0.99, 1.10-1.24 (m, 3H), 1.39-1.47 (m, 1H), 1.62-1.67 (m, 2H), 1.85-1.87 (m, 2H), 6.74 (s, 1H), 6.85 (dt, J=1.35 Hz, J=7.70 Hz, 1H), 6.97 (dd, J=1.35 Hz, J=8.25 Hz, 1H), 7.24 (dt, J=1.65 Hz, J=7.42 Hz), 7.45 (dd, J=1.65 Hz, J=7.70 Hz); 13C NMR (CDCl3): δ 26.09, 26.45, 32.70, 37.86, 44.71, 114.83, 120.20, 120.85, 130.92, 135.86, 156.88; HRMS (FAB): 222.10784 calcd for C13H18OS [M]+. found 222.1064 (−6.5 ppm, −1.4 mmu).
Reaction SMILES: CC[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)[CH2:4][CH3:5].[C:16](N)(=O)CCCC>>[CH2:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH2:4][CH2:5][CH3:16]
Reactant: CCCCC(N)=O
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Product: CCCCc1nc(C(=O)O)cs1

Procedure:
Prepared by the method of Carboxylic Acid 3, from step b using pentanamide (10 g) in place of 2-ethylbutanamide in step b. Yield 4.6 g.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]O)[CH3:2].C(=O)(O)[O-].[Na+].[NH3:15]>[Ni]>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:15])[CH3:2]
Reactant: N
Reactant: CCCCC(CC)CO
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCC(CC)CN
Reaction time: 8 h

Procedure:
The procedure described in Example 1 is followed. 650 parts of 2-ethyl-hexan-1-ol, 300 parts of a reduced nickel catalyst which contains 60% of nickel on kieselguhr and 7 parts of sodium bicarbonate are heated to 140° C. and at this temperature ammonia gas is passed into the well-stirred suspension at the rate at which it is converted. The reaction ends after 8 hours. The mixture is worked up by distillation and gives 96% of theory of di-2-ethylhexylamine, 1% of theory of 2-ethylhexylamine and 0.3% of theory of tri-2-ethylhexylamine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.C1C(=O)N([Br:24])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:24][C:5]1[S:1][C:2]([C:6]2([OH:16])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (15.0 g, 62.2 mmol) in DMF (75 mL) was added NBS (6.9 g, 55 mmol) and the solution warmed to 45° C. for 8 hours. The solution was treated with Na2SO3 (3.9 g, 31 mmol) in H2O (150 mL) and the resulting slurry was filtered and washed with water (70 mL) to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol as a white solid (16.8 g, 52.5 mmol).