Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[C:13](=[O:35])[N:14]([CH3:34])[CH:15]=[C:16]([C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)[CH:17]=1>>[CH2:23]([N:22]1[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[N:19]=[C:18]1[C:16]1[CH:17]=[C:12]([NH:11][CH:8]=[O:10])[C:13](=[O:35])[N:14]([CH3:34])[CH:15]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1cc(-c2nc3ccccc3n2Cc2ccccc2)cc(N)c1=O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: Cn1cc(-c2nc3ccccc3n2Cc2ccccc2)cc(NC=O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Acetic anhydride (0.050 ml; 0.518 mmol) is added to formic acid (1.000 ml; 25.974 mmol), the mixture is stirred at 50° C. for 1 h. The reaction is then cooled to RT and 3-amino-5-(1-benzyl-1H-benzoimidazol-2-yl)-1-methyl-1H-pyridin-2-one V-2 (97.000 mg; 0.294 mmol) is added in one portion. The reaction is stirred at RT for 16 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in water/dcm (20 ml) and extracted 3 times with DCM (10 ml). The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 88%; 93 mg; 0.259 mmol).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 2.5 g of 3-aminoanisole and 1.5 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 3 hours, the mixture is poured onto water and extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated and the residue is crystallised from ether/hexane. Methyl N-(3-methoxyphenyl)-oxamate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)NS(=O)(=O)C2CC2)cn1
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[6-methoxypyridin-3-yl]-1-[1-(pyridin-3-yl)indazol-5-yl]oxypropan-2-amine (45 mg, 120 μmol) in dichloromethane (4.5 mL) was added triethylamine (40 μl), followed by cyclopropane sulfonic acid chloride (25 mg, 180 μmol) and DMAP (1.5 mg, 12 μmol). The stirring was continued for 20 hours at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane, then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 4 mg as a racemic mixture of two diastereomeres (7%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([O:13]CC)=[O:12])=[C:6]([C:16]([O:18]CC)=[O:17])[N:5]=2.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([OH:13])=[O:12])=[C:6]([C:16]([OH:18])=[O:17])[N:5]=2
Reactant: CCOC(=O)c1cc2nc(C)oc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cc(C(=O)O)c(C(=O)O)nc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of diethyl 2-methyloxazolo[5,4-b]pyridine-5,6-dicarboxylate (5.42 g, 0.0195 mol) dissolved in absolute methanol (160 mL) is added a 10% aqueous sodium hydroxide solution (36.1 mL, 0.0974 mol). A white precipitate slowly forms. The reaction is stirred at room temperature for one hour, diluted with water (20 mL) to dissolve the precipitate, and concentrated in vacuo. The residue is dissolved in water and acidified to pH 2-3 with concentrated HCl. The resulting white precipitate is collected by filtration, washed with water, and air dried to give 2-methyloxazolo[5,4-b]pyridine-5,6-dicarboxylic acid in 61% yield, melting point 235°-236° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B. MS 511 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.30 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 56(f)] was N-alkylated using 0.60 g of benzyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25](O)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([CH:24]1[CH2:28][CH2:29][CH2:30][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:26])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCCN(C(=O)OC(C)(C)C)C1)CC2
Yield: 71.2 %

Procedure:
A conventional amidation reaction was carried out using a dichloromethane solution (40 ml) of 2.53 g of (±)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 3.0 g of N-(tert-butyloxycarbonyl)nipecotic acid, 3.0 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.89 g of 1-hydroxybenztriazole to give 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Deprotection of 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was further carried out using 10 ml of an ethyl acetate solution containing 4N hydrochloric acid to give 2.30 g of (±)-6,7-dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C:14]2[N:23]3[N:24]=[C:25]([NH2:27])[N:26]=[C:22]3[C:21]3[CH:20]=[CH:19][C:18]([F:28])=[CH:17][C:16]=3[N:15]=2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:14]([CH2:13][C:12]3[CH:29]=[CH:30][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)=[N:15][C:16]3[CH:17]=[C:18]([F:28])[CH:19]=[CH:20][C:21]=32)[N:24]=1
Reactant: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1O
Temperature: 70 °C
Yield: 98.2 %

Procedure:
To a solution of 5-(4-benzyloxy-3-methoxy-benzyl)-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.04 g, 0.09 mmol) in MeOH (5 mL), prepared as described in example 34, were added 1,4-cyclohexadiene (0.1 mL, 1.40 mmol) and 10% Pd/C (0.02 g, 50% w/w). The reaction was heated at 70° C. for 1 h, then filtered through Celite® washing with MeOH and THF and evaporated, to afford the title compound (0.03 g, 97% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]3[C:12](=[C:13]([C:15]([NH2:17])=[O:16])[CH:14]=2)[CH2:11][CH2:10][CH2:9]3)[CH:2]=1.[Cl:18]N1C(=O)CCC1=O>>[Cl:18][C:14]1[C:13]([C:15]([NH2:17])=[O:16])=[C:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)c1cc(-c2cccnc2)n2c1CCC2
Product: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCC2

Procedure:
6-Chloro-5-(3-pyridyl)-2,3-dihydropyrolizine-7-carboxamide is prepared as described in Example 45, from 0.45 g of 5-(3-pyridyl)-2,3-dihydropyrrolizine-7-carboxamide and 0.29 g of N-chlorosuccinimide. 0.27 g of expected product are thus obtained in the form of cream powder which melts at 215° C.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].FC(F)(F)C(O)=O>CCOCC>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Yield: 78 %

Procedure:
9.13 g. (26 mmoles) of Z-Asn-Gly-OtBu are dissolved in 90 ml. of trifluoroacetic acid, and after 0.5 hours of standing 450 ml. of dry ether are added to the solution. The separated white precipitate is filtered off, washed with ether and crystallized from 35 ml. of water. 6.56 g. (78 %) of Z-Asn-Gly-OH are obtained. M.p.: 170°-172° C, Rf4 = 0.45.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:49])([F:48])[C:33]([F:47])([F:46])[O:34][C:35]([F:45])([F:44])[C:36]([F:43])([F:42])[O:37][C:38]([F:41])([F:40])[F:39])([F:30])[F:29])=CC=2)=NC=1)CCCCCCC.[CH2:50]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH2:50]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:48])([F:49])[C:33]([F:46])([F:47])[O:34][C:35]([F:44])([F:45])[C:36]([F:42])([F:43])[O:37][C:38]([F:40])([F:41])[F:39])([F:30])[F:29])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Product: CCCCCCCOc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)1-bromobutane (6.1 g, 15.0 mmol, Example 25) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol). The resulting crude product was further purified by recrysallization from ethanol and subsequent Kugelrohr distillation (b.p. 200-210° C. at 0.3 torr; yield of 5.2 g).
Reaction SMILES: [CH:1]([CH:4]=[CH:5][N:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH:14]1[CH:18]=[N:17][C-:16]=[N:15]1.[Na+]>O1CCCC1>[CH:1]([CH:4]=[CH:5][N:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)C=CN(C(=O)Cl)C(C)(C)C
Reactant: [c-]1nc[nH]n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C=CN(C(=O)n1cncn1)C(C)(C)C
Temperature: 65 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
21 g (0.103 mole) of N-(2-isopropylvinyl)-N-tert.-butylcarbamyl chloride are added dropwise to a suspension of 10.5 g (0.115 mole) of sodium 1,2,4-triazolide in 100 ml of dry tetrahydrofuran at 20° C. The mixture is stirred for 6 hours at 65° C., after which it is cooled to 20° C., the resulting precipitate is filtered off under suction, the filtrate is evaporated down and the oil which remains is distilled under reduced pressure. 13.6 g of 1-(N-(2-isopropylvinyl)-N-tert.-butylcarbamoyl)-1,2,4-triazole are obtained as a colorless liquid of boiling point 95°-97° C./0.15 mbar and nD 1.4815 (Compound No. 2)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[OH:26].C(Cl)CCl>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:20]([OH:26])[CH:21]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc(Br)cc2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (0.5 g, 2.055 mmol) in acetonitrile (6 mL) was added 2-amino-5-bromophenol (0.421 g, 2.24 mmol), followed by EDC (0.508 g, 2.65 mmol). The mixture was stirred at rt overnight. It was quenched with NH4Cl (aq, sat, 5 mL). The organic layer was separated; the aqueous layer was back extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to afford Compound 29A as a light yellow oil (412 mg, 47% yield). 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.65 (s, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.03-6.91 (m, 2H), 2.83-2.66 (m, 2H), 2.36 (d, J=7.1 Hz, 2H), 2.10 (m, 2H), 1.76 (d, J=12.6 Hz, 2H), 1.46 (s, 9H), 1.23-1.13 (m, 2H). LCMS (m/z)=414 (M+H)+.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([N+:24]([O-:26])=[O:25])=[C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1>O.C(O)C>[CH2:17]([O:16][C:14]([C:13]1[C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[N:9][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([N+:24]([O-:26])=[O:25])[C:12]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)O)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 59.9 %

Procedure:
A solution of 0.28 g of sodium sulfite in 7 ml of water was added to a solution of 0.70 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine in 7 ml of ethanol, and the mixture was heated under reflux for minutes. After the reaction mixture was concentrated, the concentrate was acidified with 1N HCl, followed by extraction with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After concentration to dryness under reduced pressure, the residue was recrystallized from chloroform/ether, to give 0.47 g of white crystals.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C1(C)C=CC=CC=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of aminomethylcyclopropane (61.3 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 8:2) to yield the title compound (30 mg, 36%) as a light yellow solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.C([Li])CCCCC.CCCCCC.[Cl:23][CH2:24][C:25]([CH2:27][Cl:28])=[O:26]>C(OCC)C>[Cl:23][CH2:24][C:25]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1)([OH:26])[CH2:27][Cl:28]
Reactant: O=C(CCl)CCl
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [Li]CCCCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(CCl)(CCl)c1cc(F)cc(Cl)c1

Procedure:
Preparation according to Preparation 1: 1-bromo-3-chloro-5-fluorobenzene (5 g, 23.9 mmol), dry diethyl ether (100 mL), n-hexyllithium in hexane (2.3 M, 10.4 ml, 23.9 mmol) and 1,3-dichloroacetone (3.03 g, 23.9 mol). Yield: 4.49 g (73%). MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 209 (65), 207 (bp), 211 (11), 143 (28).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (1.50 g, 3.91 mmol), 1-bromoundecane (1.31 ml, 5.87 mmol) and potassium carbonate (811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.80 g (yield: 85.7%)
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]([F:8])([F:9])[C:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)C(F)(F)Cl
Reaction time: 2 h

Procedure:
A solution of 20 g of ethyl chlorodifluoroacetate in 150 ml ether was treated with one equivalent of benzyl magnesium chloride in 63 ml THF at -40° C. under nitrogen. After 2 hours, the reaction was poured into aqueous NH4Cl and extracted with ether. Evaporation and distillation (0.1 mm Hg) of the residue gave 24.8 g of an oil which was used directly.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:16](O)[CH2:17][CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCO
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenyl acetic acid (9.12 g, 0.06 mol), n-propanol (40 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours, then evaporated in vacuo. The residue was extracted with ethyl acetate (200 mL), washed with 10% Na2CO3, then water dried (MgSO4), and evaporated in vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A solution of n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 mol) in epichlorohydrin (50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol for 2 hours. After the excess epichlorohydrin was removed, the residue was refluxed with isopropylamine (20 mL, 0.23 mol in n-propanol (50 mL), for 4 hours, then was evaporated in vacuo. The residue was crystallized from n-hexane to yield 3.8 g (41%) of n-propyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, melting at 61°-62° C. and having the structural formula: ##STR29##
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12](=[O:20])[C:13]([N+:18]#[C-:19])=[CH:14]N(C)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]([C:13]1[N:18]=[CH:19][N:5]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:14]=1)=[O:20]
Reactant: NCc1ccccc1F
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(Cc2ccccc2F)cn1
Temperature: 25 °C

Procedure:
8 g of o-fluorobenzylamine and 6.6 g of 2-isocyano-3-dimethylaminoacrylic acid methyl ester are dissolved in 66 ml of xylene and heated under reflux for 3 hours while stirring. After cooling to room temperature, the whole is diluted with ethyl acetate and extracted by shaking twice with 50 ml of 2N hydrochloric acid each time and then with water. The aqueous phases are washed twice with 50 ml of ethyl acetate each time. All the aqueous phases are combined, rendered alkaline with concentrated ammonia and then extracted by shaking three times with 100 ml of dichloromethane each time. The extracts are combined, washed twice with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is dissolved in ethyl acetate, filtered over silica gel, concentrated and caused to crystallise by the addition of diethyl ether. 1-(o-fluorobenzyl)-imidazole-4-carboxylic acid methyl ester having a melting point of 87°-89° is obtained.