Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 58, Step 3, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)=[S:40].O>CC(N(C)C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:40][C:39]([N:41]3[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]3)=[N:38][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[C:20]=2[F:37])[CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
NBS (0.21 g, 1.2 mmol) was added to a stirring solution of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.50 g, 1.13 mmol) in DMA (5.5 ml) at rt. The reaction was allowed to stir for 15 min, then 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (0.55 g, 2.26 mmol) was added and the reaction was allowed to stir for 1 h. LCMS analysis indicated the reaction had progressed sufficiently, the reaction was poured into water and the bright yellow precipitate was collected by filtration. The filter cake was dissolved in DCM, dried over MgSO4, filtered and the filtrate was concentrated onto silica gel. Purification by flash chromatography afforded the title compound of Step B (0.36 g, 45% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.25-7.64 (m, 6H), 6.47 (d, J=5.5 Hz, 1H), 3.53-3.58 (m, 4H), 3.43-3.51 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[SH:24]>>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Yield: 82 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1H-benzo[d]imidazole-2-thiol as the nucleophile to yield 16 as a white solid (82%): MS m/z: 324 (M+H)+. Anal. Calcd. For, C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91. Found: C, 66.78; H, 5.41; N, 12.90; S, 9.72.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]1[CH2:28][OH:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:17][C@@H:16]1[CH:28]=[O:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1CO
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Add triethylamine (1.1 mL, 7.79 mmol) and sulfurtrioxide-pyridine complex (0.63 g, 3.89 mmol) to an ice cold solution of (2R,4R)-4-benzyloxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.95 mmol) in dimethyl sulfoxide (2 mL). Stir 30 minutes, warm to room temperature and stir 30 minutes. Dilute with ethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil (0.59 g, 100%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:12])(=[O:11])[C@@H:8]([CH3:10])[OH:9]>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[C:7]([OH:12])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: C[C@@H](O)C(=O)O
Reactant: C[C@H](O)C(=O)O
Product: CC(=O)C(=O)O
Product: CC(O)C(=O)O

Procedure:
The present inventors found, however, that when the sample is contacted with a mixture of D-LDH and L-LDH, L-lactic acid in the sample is converted to D-lactic acid and D-lactic acid to L-lactic acid and, after a sufficient time, an equilibrium is finally attained between D-lactic acid and L-lactic acid in a ratio of 1:1. When L-lactic acid is .contacted with D-LDH and L-LDH, the amount of L-lactic acid decreases. This phenomenon can be construed as the result of oxidation of lactic acid to pyruvic acid and regeneration of lactic acid from said pyruvic acid and NADH under the catalytic action of D-LDH and L-LDH occurring in the neighborhood.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]#[N:15])[CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[OH2:16].[OH:17]O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:10][C:11]([NH2:12])=[O:17])[CH2:13][C:14]([NH2:15])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(CC#N)CC#N)c1
Reactant: OO
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C(CC(N)=O)CC(N)=O)c1

Procedure:
A sample of 18.7 g of 3-(3-methoxyphenyl)glutaronitrile prepared according to Preparation A, Part 3, is dissolved in 250 ml of acetone. This solution is stirred in an ice-bath and added are 125 ml of water, 40 ml of 30% hydrogen peroxide and 25 ml of 10% sodium carbonate. The mixture is allowed to stand at room temperature over night and is then concentrated to a volume of about 125 ml. The residue is cooled and the resulting crystalline precipitate is collected, washed with water and dried under vacuum to give 17.4 g of 3-(3-methoxyphenyl)glutaramide, mp 161°-162°.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:45]([O-:47])=[O:46])=[C:9]([C:21]2[O:22][C:23]([C:26]3[C:31]([N+:32]([O-:34])=[O:33])=[C:30](OC)[C:29]([N+:37]([O-:39])=[O:38])=[C:28](OC)[C:27]=3[N+:42]([O-:44])=[O:43])=[N:24][N:25]=2)[C:10]([N+:18]([O-:20])=[O:19])=[C:11](OC)[C:12]=1[N+:13]([O-:15])=[O:14]>CO>[OH:2][CH2:1][CH2:3][NH:4][C:28]1[C:27]([N+:42]([O-:44])=[O:43])=[C:26]([C:23]2[O:22][C:21]([C:9]3[C:8]([N+:45]([O-:47])=[O:46])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:4][CH2:3][CH2:1][OH:2])[C:10]=3[N+:18]([O-:20])=[O:19])=[N:25][N:24]=2)[C:31]([N+:32]([O-:34])=[O:33])=[C:30]([NH:4][CH2:3][CH2:1][OH:2])[C:29]=1[N+:37]([O-:39])=[O:38]
Reactant: NCCO
Reactant: COc1c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(OC)c3[N+](=O)[O-])o2)c1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1c(NCCO)c([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c(NCCO)c3[N+](=O)[O-])o2)c([N+](=O)[O-])c1NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.65 g (0.0106 mole) of ethanolamine in 40 ml of methanol was stirred in an ice bath while 1.55 g (0.00253 mole) of 2,5-bis(3,5-dimethoxy-2,4,6-trinitrophenyl)-1,3,4-oxadiazole was added. After 1 hr. at 0° C., the mixture was stirred for 5 hr. at room temperature before the insoluble solid (1.6 g, mp 230° C. dec.) was removed. The product was dissolved in dimethyl sulfoxide and methanol was added to give 1.4 g (76%), mp 237° C., 1H NMR (DMSO-d6 +D2O): 3.12 (m, 8H), 3.63 (m, 8H). Anal. Calcd. for C22H24N12O17 : C, 36.27; H, 3.32; N, 23.07. Found: C, 36.61; H, 3.32; N, 23.13.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 64 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C([Li])CCC.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[O:15])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To stirred solution of 3-[(tert-butyldimethylsilyl)oxy]pyridin-2(1H)-one (1) (4.66 g, 20.7 mmol) in dry THF (150 mL), maintained at −78° C. under a dry nitrogen atmosphere is added n-butyl lithium (1.6 M solution in hexane, 21.0 mmol). After 20 minutes, 4-methylbenzenesulfonyl chloride (3.95 g, 20.7 mmol) is added as a THF solution. The solution is allowed to warm to room temperature over one hour, the water (10 mL) is added and the contents of the reaction vessel is extracted with EtOAc (3×), washed with brine (1×), dried over Na2SO4 and concentrated. The combined organic layers are dried over Na2SO4 and concentrated. The residue is taken up in ethanol (10 mL) and treated with conc. HCl (2 mL). The mixture is allowed to stir for 1 hour and the solvent is removed under reduced pressure to afford the desired compound as a white solid. 1H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 6.14 (t, J=6.9 Hz, 1H), 6.76 (dd, J=7.65 Hz, 1.5 Hz, 1H), 7.18 (dd, J=6.6 Hz, 1.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 2H), 7.98 (d, J=7.9 Hz, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([C:54]23[C:67]4[C:62](=[C:63]([F:69])[CH:64]=[CH:65][C:66]=4[F:68])[O:61][CH2:60][CH:59]2[NH:58][CH2:57][CH2:56][CH2:55]3)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([N:58]1[CH:59]2[C:54]([S:51]([C:48]3[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=3)(=[O:53])=[O:52])([C:67]3[C:62]([O:61][CH2:60]2)=[C:63]([F:69])[CH:64]=[CH:65][C:66]=3[F:68])[CH2:55][CH2:56][CH2:57]1)=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)ccc(F)c12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
BOC-Glycine was dissolved in 150 ml of DMF. 0.5 ml of diisopropylamine was added followed by HATU (2.54 g, 6.68 mmol). The solution was stirred at room temperature for 25 minutes then 4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-1H-9-oxa-1-aza-phenanthrene (541 mg, 1.35 mmol) was added and the reaction was stirred overnight. The reaction was quenched with water and washed with 1:1 mixture of ethyl acetate and hexanes solution. The organic layer was dried over sodium sulfate and concentrated. The product was purified by column using EtOAc/Hex. as the eluent (0/100 to 25/75 in 35 minutes). Yield: 594.6 mg, 79%. 1H NMR (CDCl3 400 MHz) δ 7.57 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.03 (td, J=8.8, 4.4 Hz, 1H), 6.57-6.49 (m, 1H), 5.60-5.55 (m, 1H), 5.35 (bs, 1H), 4.49 (dd, J=11.7, 3.7 Hz, 1H), 4.18 (dd, J=11.7, 5.9 Hz, 1H), 4.00 (s, 1H), 3.90 (d, J=5.1 Hz, 1H), 3.54 (bs, 1H), 2.95-2.80 (m, 1H), 2.65-2.56 (m, 1H), 2.52-2.41 (m, 1H), 2.13-1.98 (m, 1H), 1.51-1.40 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34](=[O:37])(=[O:36])[NH2:35])=[O:26])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:12]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:35][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:36])=[O:37])=[O:26])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(=O)(=O)NC(=O)C=Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
In a stream of nitrogen and at 0° C., 126 mg (0.75 mmol) of cinnamoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.68 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 167 mg (1.36 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting crude crystals were washed with methanol to obtain 370 mg (yield: 95.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.[CH3:23][NH:24][O:25][CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH:6]=[CH:5]2
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
To a DMF (1 ml) solution of 6-bromoquinoline-2-carboxylic acid (4000 mg, 15.9 mmol, US2005165049A1), triethylamine (6.64 ml, 47.6 mmol), N,O-dimethylhydroxyamine hydrochloride (1860 mg, 19.0 mmol) and HBTU (6620 mg, 17.5 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated NaHCO3 aqueous solution and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude residue was applied to a silica gel column chromatography and eluted with hexane/ethyl acetate (4:1) to furnish the title compound (4.29 g, 92% yield) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 3.47 (3H, s), 3.80 (3H, s), 7.68-7.80 (1H, brs), 7.81-7.85 (1H, m), 8.00-8.06 (2H, m), 8.17 (1H, d, J=8.1 Hz). MS (ESI): m/z 295, 297 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].[C:14](O)(=[O:16])[CH3:15]>[Pt]=O>[ClH:1].[C:14]([O:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:16])[CH3:15]
Reactant: CC(O)Cc1ccncc1
Reactant: [H][H]
Reactant: CC(=O)O
Agent: O=[Pt]
Agent: Cl
Product: CC(=O)OC(C)CC1CCNCC1

Procedure:
4-(2-Hydroxypropyl)pyridine hydrochloride (11 g) in glacial acetic acid (110 ml) was hydrogenated at 50°/50 p.s.i. over a platinum oxide catalyst until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ether (100 ml) and the resultant solid was recrystallized from ethyl acetate-isopropyl alcohol (1:1) to give 4-(2-acetoxypropyl)piperidine hydrochloride (1 g) m.p. 188°-191°.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccc(F)cc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(4-fluoro-phenyl)-ethylamine as described in the preparation of Compound 1. (HRMS (M−H) calcd for C21H19F2N2O3: 385.1364. found: 385.1377. 1H NMR (500 MHz, CDCl3) δ: 2.90 (t, 2, J=7), 2.95 (s, 3), 3.71 (t, 2, J=7), 3.95 (s, 2), 4.57 (s, 2), 6.95–7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 33.74, 34.48, 44.70, 49.41, 51.47, 108.82, 115.49, 115.66, 115.71, 115.77, 115.89, 129.22, 129.27, 130.04, 130.10, 131.97, 133.72, 153.60, 160.81, 161.42, 162.76, 163.38, 164.71, 166.21.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.O.[NH2:19][NH2:20]>C(O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[NH:20][N:19]=2)[CH:13]=1
Reactant: O=C(/C=C/c1ccccc1O)c1cccnc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1ccccc1C1CC(c2cccnc2)=NN1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (2E)-3-(2-hydroxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (12.5 g, 55.6 mmol), hydrazine monohydrate (6.00 mL, 123 mmol), and ethanol (160 mL) was allowed to stir at 80° C. overnight. The reaction mixture was filtered over a pad of celite and washed with MeOH and DCM. The resulting filtrate was concentrated to give 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (12.5 g, 94%) as a light grey solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.52-9.67 (bs, 1H), 8.78 (s, 1H), 8.45-8.51 (m, 1H), 7.97 (d, 1H), 7.61 (s, 1H), 7.38 (t, 1H), 7.26 (d, 1H), 7.07 (t, 1H), 6.81 (d, 1H), 6.76 (t, 1H), 5.04 (t, 1H), 3.44 (dd, 1H), and 2.76 (dd, 1H). LCMS: (FA) ES+ 240.2, ES-238.5.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>CO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 12.7 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 6.47 g of 4-chlorothiophenol in methanol to yield a white solid, mp 44°-46° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]2[S:29][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=3)[N:30]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCOCC
Solvent: CCO
Product: COc1cccc(-c2csc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Yield: 100.2 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-bromo-3′-methoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with diethyl ether and little ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(3-methoxy-phenyl)-thiazol-2-yl]-amine as a light green solid. MS ISP (m/e): 393.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.72 (s, 1H), 9.31 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.54-7.51 (m, 4H), 7.35 (t, 1H), 7.28 (d, 1H), 6.90 (d, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:20])([F:19])[C:6]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:12])[O:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C[Si](C#N)(C)C>C(N(CC)CC)C>[F:20][C:5]([F:19])([F:4])[C:6]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:1]#[N:3])[CH:14]=1)([CH3:12])[O:7][Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC#N
Reactant: CC(O[Si](C)(C)C)(c1ccncc1)C(F)(F)F
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC(O[Si](C)(C)C)(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 30 ml of acetonitrile were added 4 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine=N-oxide, 4.45 ml of triethylamine, and 4.75 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.3 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine-2-carbonitrile.