Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[CH:21](O)OCC)=[CH:16][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])C1C=CC=CC=1.[NH2:27][C:28]([CH3:41])([CH3:40])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.[BH4-].[Na+]>>[OH:8][C:9]1[CH:19]=[CH:18][C:17]([CH:20]([OH:26])[CH2:21][NH:27][C:28]([CH3:41])([CH2:29][CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[CH:32]2)[CH3:40])=[CH:16][C:10]=1[NH:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(C)(N)CCn1cnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(CCn1cnc2ccccc21)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
A mixture of 14.4 gm of 2'-benzyloxy-5'-(1-oxo-2-hydroxy-2-ethoxy-ethyl)-methanesulfonanilide, 7 gm of 1-(3-amino-3-methylbutyl)-benzimidazole and 150 ml of alcohol was heated for 3 hours at 50° C. and then admixed in portions with 9.2 gm of sodium borohydride. The resulting solution is kept for 12 hours at room temperature, the alcohol is then removed under reduced pressure on a Rotavapor, and the residue is dissolved with 200 ml of water and 500 ml of ethyl acetate. After decomposition of the sodium borohydride by stirring with concentrated hydrochloric acid and ice cooling, the mixture was made alkaline with aqueous ammonia, and the ethyl acetate phase was separated, dried with sodium sulfate and evaporated on a Rotavapor. The residue was dissolved in 200 ml of alcohol, the solution was acidified with 6.3 gm of oxalic acid, and the precipitated 2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-benzimiazolyl)-2-methyl-2-butylamino]-ethyl]methane sulfonanilide dioxalate (m.p. 185°-187° C.) is extracted. The base (m.p. 65°-70° C.) was liberated from this compound with aqueous ammonia. Catalytic hydrogenation of this compound (m.p. 65°-70° C.) in 250 ml of methanol under standard conditions with palladium charcoal as a catalyst yielded 8 gm of 2'-hydrox-5'-[1-hydroxy-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethyl]-methanesulfonanilide (m.p. 170°-173° C.; 81% of theory) whose formates of the formula ##STR34## had a melting point of 161°-164° C.
Reaction SMILES: Cl.C(OC([N:12]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=2)[CH2:24][CH2:23][NH:22]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[ClH:19].[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=3)[CH2:24][CH2:23][NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(CNc1ccc(Cl)cc1)NCC2

Procedure:
A mixture of 1(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.1 g), conc. hydrochloric acid (51 ml) and acetic acid (51 ml) was refluxed for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in water. The aqueous layer was washed with ethyl acetate, treated with activated charcoal and concentrated to dryness to give crude 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.8 g). The product was converted into its p-toluenesulfonate and then again converted into its hydrochloride by conventional techniques. The salt was recrystallized from water containing a small amount of hydrochloric acid to give pure 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, mp 91° to 93° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[C:21]#[C:22][CH3:23])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH2:17][C@@H:16]2[C:21]#[C:22][CH3:23])=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC#CC1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (155 mg, 0.423 mmol, Example 241, Step 3) and triethylamine (302 μL, 2.17 mmol, Sigma-Aldrich, St. Louis, Mo.) in DCM (3.2 mL) was added benzenesulfonyl chloride (63.5 μL, 0.504 mmol, Sigma-Aldrich, St. Louis, Mo.) drop-wise at 0° C. The solution was stirred for 30 min and then diluted with DCM and washed with water followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol as a mixture of enantiomers.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:2].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([N:7]=[C:13]=[O:15])[C:5]=1[CH3:11])[CH3:2]
Reactant: CCOc1cccc(N)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cccc(N=C=O)c1C
Yield: 249.2 %

Procedure:
At room temperature, to a mixture of 3-ethoxy-2-methylaniline 33.0 g and toluene 400 mL was added triphosgene 25 g, and the resulting mixtures were stirred with heating reflux for four hours. The mixtures were concentrated under reduced pressure to give 1-ethoxy-3-isocyanato-2-methylbenzene 37.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][O:16][C:15]([C:6]1[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid (6.25 g) was dissolved into DMF (50 ml), to which then potassium carbonate (11 g) and methyl iodide (4.9 ml) were added, and was stirred for 2 hours at room temperature. After the insoluble matter was filtered off and the filtrate was concentrated, ethyl acetate (500 ml) was added to the residue, which was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give the intended compound 6.65 g (quantitatively) as yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2([CH3:29])[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:19]=3[O:18][CH2:17]2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+].[OH-].[Li+].CCOC(C)=O>CCCCCCC>[CH3:1][C:2]1[C:3]([C:16]2([CH3:29])[C:20]3[CH:21]=[CH:22][C:23]([C:25]([OH:27])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17]2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C1(C)COc3cc(C(=O)O)ccc31)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2H-1-benzofuran-6-carboxylate (140 mg, 0.36 mmol), sodium hydroxide (0.06 g, 1.54 mmol) and lithium hydroxide (0.06 g, 1.54 mmol) is stirred at room temperature for 24 h. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl ether are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is obtained by recrystallization from a heptane/ethyl ether mixture (3/1). (90 EtOAc, 10 heptane) (Rf: 0.56).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Anisole (6.75 g, 62.4 mmol) was dissolved in dichloromethane (80 ml). The mixture was cooled to −5° C. and aluminum chloride (8.32 g, 62.4 mmol) was added. 4-Chlorobutyryl chloride (8.8 g, 62.4 mmol) was added dropwise to the mixture at −10° C. and stirred at −10° C. for 1 hour. The reaction mixture was poured into iced water (100 ml). After separation, the organic layer was washed with 1N hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml), and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (12.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([Br:25])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.96 g, 3.75 mmol) in dry DMF (10 mL) was added sodium bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide (0.667 g, 3.75 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for about 90 min. The mixture was poured into water (300 mL) and the resulting solid was collected by filtration and washed with water. The solid was dissolved in 10:1 chloroform:methanol (10 mL) and filtered through a pad (0.5 cm) of silica gel using 10:1 chloroform:methanol as eluent. The filtrate was evaporated to leave the title compound as a tan solid, 0.87 g (80%). 1H NMR (d6-DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293 (100), (MH+).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+].O>CS(C)=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(=O)C(C)(C)C)cc1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 1-bromo-3,3-dimethyl-2-butanone (33.3 g, 0.19 mole) in dimethylsulfoxide (330 ml), sodium p-toluenesulfinate (34.9 g, 0.20 mole) was added at 30°-40° C., and reacted with stirring at 60°-70° C. for 18 hours. The reaction mixture was poured into cold H2O (2 liter). The precipitate was filtered, washed with H2O and dried to afford 41.6 g of 1-(p-toluene-sulfonyl)-3,3-dimethyl-2-butanone as white crystals. m.p. 119°-122° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Si]([C:32]([F:35])([F:34])[F:33])(C)(C)C.Cl>C1COCC1>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-methyl-benzaldehyde (1.2 g, 10 mmol) and TMSCF3 (1.8 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1N HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 1.6 g of 1-(4-methylphenyl)-2,2,2-trifluoro-ethanol, yield 86%.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>C(#N)C>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: CCOC(=O)CCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][O:23][C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>C(O)C>[CH2:25]([N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)[CH3:26]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(c1ccccc1)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1c1ccccc1
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (336 mg, 1.01 mmol) in ethanol (3 mL) was added acetaldehyde (62 μL, 1.11 mmol) then sodium cyanoborohydride (89 mg, 1.42 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, partitioned between DCM (50 mL) and 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was further extracted with DCM (2×25 mL). The combined organics were dried with MgSO4 and concentrated in vacuo to give tert-butyl 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (298 mg, 82%). ESI-MS m/z calc. 360.5. Found 361.7 (M+1)+; Retention time: 1.30 minutes (3 min run).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:28]O>CO.O.Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1)=[O:28]
Reactant: OO
Reactant: CSc1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)c1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Example 41 (1-[8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid) (30 mg, 0.07 mmol) is dissolved in methanol (200 μl), and hydrogen peroxide (11.1 μl) is added at room temperature. After 3 hours a further amount of hydrogen peroxide (15 μl) is added and the reaction mixture stirred at 45° C. overnight. The mixture is then cooled to room temperature, diluted with water and acidified with 7 M HCl (1 drop). The reaction mixture is extracted into ethyl acetate, which is washed with water and brine. The organic layer is then dried over magnesium sulfate and concentrated to give the product as an amorphous solid. MS (ES+) 396.1308
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H](O)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NC[C@H](O)C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
Add 2(R,S)-acetylthiomethyl-3-phenylpropionic acid (0.59 g) to (S)-isoserine benzyl ester, hydrochloride (0.578 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.53 g), 1-hydroxybenzotriazole (HOBT) (0.37 g) and N-methylmorpholine (0.80 ml) in dimethylformamide (DMF) (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of silica gel (1 L) using chloroform:methanol 19.5:1 as eluant to give the title compound, a colorless oil, [α]D26 =+12.3° (MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Li+].[Cl-]>O1CCOCC1.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:22])[CH3:21])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.87 g, 6.93 mmol), tributyl(1-ethoxyvinyl)tin (3.00 g, 8.31 mmol), Pd(PPh3)4 (801 mg, 0.693 mmol), and LiCl (734 mg, 17.3 mmol) in 1,4-dioxane (50 ml) was heated to reflux for 7 hours. The mixture was filtered through a pad of Celite with ethyl acetate. The filtrate was washed with water (100 ml) and brine (100 ml), dried over MgSO4, and evaporated in vacuo. To the obtained residue were added 2N HCl (20 ml) and THF (60 ml). The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous NaHCO3 (60 ml) was added and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over MgSO4, and evaporated in vacuo. The resulting residue was chromatographed over slica gel with hexane/ethyl acetate (3:1) to give 1.51 g (94%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:29][CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:30]1[CH2:29][CH2:28][O:27][CH2:32][CH2:31]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: c1nnc(NC2CCOCC2)[nH]1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.3 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 62%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][CH2:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:26][CH:27]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)COc1ccc(C(=O)CNC(=O)c2ccc(C(=N)N)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(N)c1ccc(C(=O)NCC(=O)c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
A mixture of 80 mg of methyl p-(p-amidinobenzamidoacetyl)phenoxyacetate (Example 25), 40 mg of potassium carbonate, 10 ml of ethanol and 4 ml of water was stirred at room temperature under argon for 4 hours. 10 ml of water were then added to the mixture, which was neutralized to pH 6 with 1N HCl. It was concentrated to 10 ml in vacuo and left to stand in a refrigerator overnight. The precipitate which had separated out was filtered off with suction and dried over KOH in vacuo at 50° C. 52 mg of amorphous p-(p-amidinobenzamidoacetyl)phenoxyacetic acid were obtained, IR bands (KBr) at 3354, 3286, 3042, 1647, 1598, 1542, 1485, 1422, 1360, 1232, 1177, 994 and 710 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:15])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([S:17]([CH3:16])(=[O:18])=[O:19])[CH:21]=1
Reactant: CNc1cnccc1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1Cl
Yield: 26 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (prepared according to DE10008042) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Another purification step using preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) gave the desired compound as a colorless foam (26%). MS (ESI): m/z=469.060 [M+H]+.