Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]=[CH:23][C:22]=4[O:31]CC4C=CC=CC=4)[C:16](=[O:39])[CH2:15]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:42])#[N:2].[BH4-].[Na+].CCOC(C)=O>C1COCC1.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>[C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]=[CH:23][C:22]=4[OH:31])[C:16](=[O:39])[CH2:15]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:42])#[N:2]
Reactant: C=CCOc1ccc(OCc2ccccc2)c(CN2CCN(Cc3cncn3Cc3ccc(C#N)c(F)c3)CC2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1ccc(O)c(CN2CCN(Cc3cncn3Cc3ccc(C#N)c(F)c3)CC2=O)c1

Procedure:
To a solution of the product of Step G (800 mg, 1.38 mmol) in 20 mL of THF at room temperature was added Pd(PPh3)4 (203 mg, 0.176 mmol), followed by sodium borohydride (86.2 mg, 2.28 mmol). The reaction was stirred for several hours, then poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was taken up in methanol, filtered, and the solids were dried in vacuo to afford the titled product as an off-white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH3:13][S:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH:22]=2)[NH:17][C:16]1=[O:29].[O:30]1[C:34]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)=[CH:33][N:32]=[CH:31]1.[CH2:45]([O:47][CH:48]=[C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[O:62][CH:61]=[N:60][CH:59]=3)[CH:56]=2)[NH:51][C:50]1=[O:63])[CH3:46].[CH3:64][N:65]([CH3:76])[S:66]([C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=1)(=[O:68])=[O:67]>>[CH3:13][S:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH:22]=2)[NH:17][C:16]1=[O:29].[O:30]1[C:34]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)=[CH:33][N:32]=[CH:31]1.[CH2:45]([O:47][CH:48]=[C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[O:62][CH:61]=[N:60][CH:59]=3)[CH:56]=2)[NH:51][C:50]1=[O:63])[CH3:46].[CH3:64][N:65]([CH3:76])[S:66]([C:69]1[CH:74]=[CH:73][C:72]([NH:75][CH:20]=[C:21]2[C:11]3[C:9](=[CH:8][CH:7]=[C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[CH:12]=3)[NH:10][C:24]2=[O:28])=[CH:71][CH:70]=1)(=[O:67])=[O:68]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: CSC1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: O=C1Cc2cc(-c3cnco3)ccc2N1
Product: CN(C)S(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1

Procedure:
3-Methylsulfanyl-5-oxazol-5-yl-1,3-dihydro-indol-2-one was prepared from 4-oxazol-5-yl-aniline according to Procedure D: 1H NMR (DMSO-d6): δ10.7 (s, 1H), 8.3 (s, 1H), 7.5 (s, 3H), 6.9 (d, 1H), 4.5 (s, 1H), 2.0 (s, 3H); APCI−M m/z 247 (M+H)+. 5-Oxazol-5-yl-1,3-dihydro-indol-2-one was prepared from 3-methylsulfanyl-5-oxazol-5-yl-1,3-dihydro-indol-2-one according to Procedure D: 1H NMR (DMSO-d6): δ10.5 (s, 1H), 8.3 (s, 1H), 7.5 (m, 3H), 6,8 (d, 1H), 3.5 (s, 2H); APCI−MS m/z 201 (M+H)+. 3-Ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one was prepared from 5-oxazol-5-yl-1,3-dihydro-indol-2-one according to Procedure I: 1H NMR (DMSO-d6): δ10.43 (s, 1H), 8.37 (s, 1H), 7.76 (s, 1H), 7.51 (m, 2H), 6.90, (d, 1H), 4.43 (q, 2H), 1.4 (t, 3H): APCI−MS m/z 255 (M−H)+. The title compound was prepared in 36% yield from 3-ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and N,N-dimethyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ10.9 (d, 1H), 10.8 (s, 1H), 8.8 (d, 1H), 8.4 (s, 1H), 8.0 (s, 1H), 7.7 (br d, 4H), 7.5 (m, 2H), 7.0 (d, 1H), 2.6 (s, 6H); APCI−MS m/z 409 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[C:29]([Cl:31])[C:14]([CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[C:17]2=[O:28])=[C:13]([Cl:32])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:34]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([Cl:32])[C:14]([CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C@H:21]3[CH2:22][CH2:23][C@H:24]([O:27][CH3:34])[CH2:25][CH2:26]3)[C:17]2=[O:28])=[C:29]([Cl:31])[CH:30]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Suspend sodium hydride (0.45 g, 11.15 mmol) in 10 ml of dry dimethylformamide at 0° C. After stirring for 10 minutes, add the solution of (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (2.50 g, 5.58 mmol) in 5 ml of dry dimethylformamide. Stir the resulting mixture for 15 minutes at 0° C. Add iodomethane (1.40 ml, 22.32 mmol) and allow the mixture to warm to room temperature. Stir the reaction at room temperature for an additional 12 hours then quench with water and filter the white precipitate. Dry under vacuum to recover 2.59 g of the title compound: MS (m/z): 462 (M+).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:20])[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:12][C:6]2=[CH:5][N:4]=1.ClN1C(=O)CCC1=O.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>CN1CCCC1=O.O>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:3]2[N:8]=[C:7]3[NH:9][C:10](=[O:20])[N:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])[CH2:12][C:6]3=[CH:5][N:4]=2)[CH2:31][CH2:32]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CSc1ncc2c(n1)NC(=O)N(c1ccccc1C)C2
Agent: O=C1CCC(=O)N1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccccc1N1Cc2cnc(N[C@H]3CC[C@H](O)CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sulfide 10.2 (2 g) in 4 mL 1-methyl-2-pyrrolidinone was combined with N-chlorosuccinimide (1.03 g) in 4 mL 1-methyl-2-pyrrolidinone and 0.125 g water, and the mixture was stirred for 1.5 hours at 25° C. To this solution was added trans-4-aminocyclohexanol (2.65 g). The mixture was heated to 60° C. for 48 hours, cooled to 20-25° C. and treated with 10 mL water. This mixture was cooled to 5° C. and stirred for 2 hours. The solid was collected by filtration, washed with water, hexanes and dried in vacuo. The solid was purified by flash column chromatography using 95/5-90/10 dichloromethane/methanol as eluant to give 614 mg of 7-(trans-4-hydroxycyclohexylamino)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. The resulting solid was converted to the hydrochloride salt by the action of ethereal hydrochloric acid/ethyl acetate on the free base.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[CH:10]1([C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+]>C(O)CCC>[Cl:24][C:22]1[CH:23]=[C:18]2[C:19](=[CH:20][CH:21]=1)[N:25]([S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28])[CH:2]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[C:16]2([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[OH:17]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)C2CCCCC2)cc1
Reactant: CCCCOC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2C1(O)C1CCCCC1

Procedure:
This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][C:26]2[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=2)=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[NH:30][N:29]=[C:28]([NH:31][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH:27]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cc2cc(N)n[nH]2)cc1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(NC=C3C(=O)Nc4ccccc43)n[nH]2)cc1

Procedure:
The named compound is prepared by substituting 5-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.041 gms.) is reacted with 0.078 gms. of 5-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (1.0 mL).
Reaction SMILES: [C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1.O>C1COCC1>[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43][O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:41][CH:40]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O[C@@H]1CCCC[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C(N[C@H]2CCCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Cis-2-triphenylmethylaminocyclohexanol (1.52 g; 4.25 mmol) is added to a solution of sodium hydride (256 mg; 60%; 6.4 mmol) in 20 ml dry THF and refluxed overnight. The solution is cooled, 4-(benzoxazol-2-yl)benzyl bromide (1.3 g; 4.5 mmol) is added in one portion and refluxed for 5 hrs. This is then poured into water and extracted with 2×100 ml CH2Cl2, dried (Na2SO4), concentrated to dryness and flash chromatographed using 4:1 8:1; hexane:EtOAc to obtain Cis-1-[4-(benzoxazol-2-yl)benzyloxy]-2-triphenylmethylaminocyclohexane which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-].[Na+:28]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Temperature: 2 °C
Reaction time: 2 h

Procedure:
A 100 ml round bottomed flask equipped with a magnetic stir bar was charged with acetone (50 ml). Pantoprazole (10 g, 25.7 mmol) was then added to the flask. After the pantoprazole had completely dissolved, the solution was cooled to about 2° C. Forty seven percent sodium hydroxide (aq.) equivalent to 2.4 grams of solid sodium hydroxide (60.0 mmol) was slowly added to the cooled solution. A precipitate began to form immediately. The mixture was stirred for another two hours while the flask was allowed to warm to room temperature. The precipitate was filtered and washed with acetone (20 ml) and dried at 40° C. under vacuum to yield pantoprazole sodium Form 11 (6.9 g, 65%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)#[N:2].CN(C=O)C.S(Cl)([Cl:20])=O>>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:20])=[O:9])=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCc1ccc(C(=O)Cl)cc1

Procedure:
A solution of 4-cyanomethylbenzoic acid (10.0 g, 62.2 mmol) in thionyl chloride (65 mL) containing DMF (1 mL) was refluxed for three hours, cooled, concentrated, dissolved in hot EtOAc, treated with activated charcoal, filtered through Celite, and concentrated to yield 4-cyanomethylbenzoyl chloride. 4-Cyanomethylbenzoyl chloride was converted to the title compound following the procedure described in step A of Example 82 with the following modifications: 1) 1-(4-cyanomethylphenyl)-2-phenylethanone was chromatographed on silica gel using 2:3 EtOAc/hexane; 2) purification of N-[1-(4-cyanomethylphenyl)-2-phenylethyl]formamide entailed treatment with activated charcoal in EtOAc followed by recrystallization from EtOAc/hexane; and 3) the title compound was chromatographed on silica gel eluting with 10% acetone/EtOAc.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>CC#N>[CH3:33][O:34][CH2:35][CH2:36][NH:37][C:19]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=1)=[O:20]
Reactant: COCCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: COCCNC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (170 mg, 384 μmol, example 88) in MeCN (0.2 mL) was added 2-methoxyethylamine (36.7 μL, 423 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, 2-methoxy-ethylamine (0.02 mL) was added and the mixture was subjected to a microwave irradiation at 180° C. for an additional 15 min. Then, the solvent was removed and the residue was dissolved in a solution of DMSO and MeOH (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (2.0 mL). The solution was washed through PL-HCO3 MP resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 379 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.CCN=C=NCCCN(C)C.Cl.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][S:31]([NH:34][C:13](=[O:14])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:7]([C@@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[CH:8][CH:9]=1)(=[O:33])=[O:32]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
(R)-[4-(3-Oxo-cyclopentyl)-phenoxy]-acetic acid (preparation 31) (2.5 mmol, 585 mg) was dissolved in DCM (30 mL) and cooled to 0° C. on an icebath. EDCI.HCl (3.75 mmol, 720 mg), methanesulfonamide (2.75 mmol, 261 mg) and DMAP (3.75 mmol, 458 mg) was added and the reaction mixture left an additional 15 min on the ice bath. The ice bath was then removed and the reaction was allowed to warm to r.t. over night. Quenched with citric acid (10% aq.) and extracted with DCM, then dried over Na2SO4 and concentrated in vacuo to yield the title compound (745 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 8.84 (bs, 1H), 7.25-7.19 (m, 2H), 6.95-6.85 (m, 3H), 4.58 (s, 2H), 3.58-3.08 (m, 5H), 2.78-2.58 (m, 1H), 2.58-2.15 (m, 5H), 2.15-1.78 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:20])[C:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:11]([Cl:19])[CH:10]=1)([CH3:8])[CH3:7])=[N+]=[N-]>CCO.Cl.O=[Pt]=O>[ClH:19].[NH2:1][CH2:4][C:5](=[O:20])[C:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:11]([Cl:19])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C(=O)CN)c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 189.2 %

Procedure:
A pressure bottle was charged with a solution of 4-(4-azido-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (8 g, 25.2 mmol) in EtOH (100 mL), conc HCl (20 mL) and PtO2 (114 mg, 0.5 mmol, 0.02 eq) and then was purged with hydrogen (2×45 psi). The bottle was pressurized with hydrogen (45 psi) and agitated 2 h. The reaction mixture was filtered through Celite™ and the filtrate was evaporated. The residue was triturated with Et2O, filtered and dried to afford 4-(4-amino-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide hydrochloride (7.8 g, 94% yield) as yellow solid. 1H NMR (400 MHz, DMSO) δ 8.22 (br s, 3H), 7.91 (d, J=8.4 Hz, 1H), 7.60 (s, 2H), 7.50 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 3.92 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH:21]=[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23])C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24](/[C:22](/[CH3:23])=[CH:21]/[CH2:20][OH:19])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\CO)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A 1M solution of DIBAL-H in toluene (40 ml, 40 mmol) was added dropwise at −70° C. over 20 min. to a stirred solution of 3-biphenyl-4-yl-but-2-enoic acid ethyl ester (2.66 g, 10.0 mmol) in dry THF (100 ml) and the mixture stirred for 30 min. Methanol (2 ml) was added, followed by saturated aqueous Rochelle's salt (100 ml), and the resulting mixture extracted with ethyl acetate (200 ml), separated and the organic phase washed with brine, dried (Na2SO4), evaporated and dried in vacuo yielding (E)-3-biphenyl-4-yl-but-2-en-1-ol as colorless crystals: 1.94 g (86%)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(C1C=CC(C(C)C#N)=CC=1)C(C)C.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1)[CH:24]([CH3:26])[CH3:25].N>>[CH3:37][C@H:33]([C:34]([OH:36])=[O:35])[C:30]1[CH:31]=[CH:32][C:27]([CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:28][CH:29]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CC(C)Cc1ccc(C(C)C#N)cc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 32 °C
Reaction time: 24 h

Procedure:
One ml of the reaction solution containing 100 μmol of potassium phosphate buffer solution (pH 8.0), 4.77 μmol of 2-(4'-isobutylphenyl)propionitrile and 0.02 unit of nitrilase was thoroughly shaken at 32° C. to carry out the reaction. The amounts of 2-(4'-isobutylphenyl)-propionitrile, 2-(4'-isobutylphenyl)propionic acid and ammonia for each reaction time were determined. The results are shown in the Figure. The optical purity of the formed S-(+)-2-(4'-isobutylphenyl)propionic acid was 98% for 6 hours, 96% for 24 hours and 95% for 40 hours.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH2:10][CH2:11][CH3:12].[OH-].[K+]>>[CH2:1]([NH:8]/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC=O
Reactant: NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC/C=C/NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To benzylamine (5.46 mL, 50 mmol), at 0° C., was added butyraldehyde (4.51 mL, 50 mmol). The mixture was warmed to room temperature and KOH (1.5 g) was added. The mix was stirred at room temperature for 15 minutes, the water was removed and 0.5 g of KOH was added. The mixture was stirred at room temperature overnight and filtered to remove the KOH to yield 6 g (74%) of 62a.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:17][C:13]1[CH:12]=[C:11]([NH:18][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(N)c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cccc(N)c2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.0 mmol) and benzene-1,3-diamine (324 mg, 3.0 mmol) in isopropanol (18 mL) was added triethylamine (2.8 mL). The reaction mixture was stirred at 80° C. overnight. Then the mixture was evaporated under reduced pressure to afford 219a (480 mg, 81%) as a white solid. MS-ESI: [M+H]+ 295.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH3:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([CH3:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1cc(Cl)c(B(O)O)cc1C
Product: COc1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1C
Yield: 39 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (924 mg, 3.49 mmol) and 2-chloro-5-methyl-4-methoxyphenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (770 mg, 3.84 mmol) were treated substantially as described in Part A of Example 19a to give 514 mg (39%) of 2-benzyloxy-4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.47–7.44 (m, 2H), 7.40–7.30 (m, 3H), 7.00 (s, 1H), 6.94 (d, J=5.4 Hz, 1 H), 6.90 (s, 1 H), 5.55 (s, 2 H), 3.84 (s, 3 H), 2.17 (s, 3 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CCO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)c1
Yield: 69.9 %

Procedure:
A mixture of N-[5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]acetamide (Step 1.3) (2 g, 7 mmol), a 6N aqueous solution of HCl (10 mL) and EtOH (50 mL) is stirred for 2 h at 85° C., allowed to cool, quenched by addition of a saturated solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 1.21 g of the title compound as a yellow solid: ESI-MS: 248.1 [M+H]+; TLC: Rf=0.36 (DCM/MeOH, 9:1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
In a reaction flask 5 mg of palladium on charcoal were added to 50 mg of 4-isopropylbenzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester from example 59(0.12 mmol) in dry ethyl acetate (5 ml). The atmosphere was then charged with hydrogen gas and the reaction mixture was stirred at room temperature for 1 hour. Thereby, 4-isopropyl-benzenesulfonic acid 6-(4-propyl-piperazin-1-yl)-pyridin-3-yl ester were obtained in 58% yield. The compound was converted into its hydrochloride salt by addition of HCl in ether.