Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:33][C:31]1[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Reactant: Cn1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)ccc2C#N)cn1
Yield: 32.1 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (150 mg, 0.380 mmol), 1-methyl-1H-pyrazol-4-amine dihydrochloride (80 mg, 0.470 mmol), sodium phenoxide trihydrate (300 mg, 1.76 mmol), xantphos (30 mg, 0.051 mmol) and Pd2(dba)3 (30 mg, 0.032 mmol) in dioxane (3 mL) was degassed with Ar, then was heated at 170 C for 30 min by microwave. It was concentrated in vacuo. The residue was purified by HPLC to give tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-pyrazol-4-ylamino)phenylamino)cyclohexylcarbamate (50 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CCN(CC)CC.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][CH:37]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)[C:38]1[CH:43]=[CH:42][C:41]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[CH:40][CH:39]=1>CN1C(=O)CCC1.O.C(OCC)(=O)C>[OH:1][C:2]1[C:7]([C:8]([NH:36][CH:37]([C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)[C:38]2[CH:39]=[CH:40][C:41]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[CH:42][CH:43]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccc(OC)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(OC)cc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (580 mg, 2.6 mmol) in NMP (2 ml) was added Et3N (540 mg, 5.2 mmol). The mixture was aged for 15 min at room temperature. To the mixture was added CDI (480 mg, 2.86 mmol) and the resulting mixture was heated to 70° C. for 1 h. To the hot homogeneous solution was then added in one portion diethyl 4-(amino(4-methoxyphenyl)methyl)phenylphosphonate, 1-1-d, (940 mg, 2.6 mmol). Heating was continued for 30 min at 70° C. The reaction mixture was then cooled to room temperature and diluted with water (12 ml) and ethyl acetate (5 ml). The resulting aqueous layer was slowly neutralized to pH=7. The neutralized aqueous layer was then extracted with ethyl acetate. The organic layer was concentrated under vacuum and the residue was purified on silica gel column with the eluent of dichloromethane/methanol=50/1 and subsequently prep-HPLC to provide the product as a white solid, 1-1-1, (260 mg, 18%). 1H NMR (CD3OD, 300 MHz,): δ 8.60 (m, 2H), 8.40 (m, 1H), 7.90 (m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.40 (m, 2H), 7.20 (m, 2H), 6.84 (m, 2H), 6.24 (s, 1H), 3.99 (m, 4H), 3.68 (s, 3H), 1.08 (t, 6H, J=6 Hz).
Reaction SMILES: [C:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>C(O)C>[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:3][NH:2][C:1]([O:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: NNC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: O=C(NN=Cc1ccncc1)OC(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
To 24.11 gm (0.1 mole) of benzhydryl carbazate in 200 ml of warm absolute ethanol is added 10.66 gm (0.1 mole) of 4-pyridinecarboxaldehyde in 75 ml of absolute ethanol. The mixture is refluxed 7 hr and cooled. The solvent is removed in vacuo. Recrystallization from ethanol/Skellysolve B yields 26.03 gm (78.5%) of the title compound having a melting point of 159°-160° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: N#Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4-chlorobenzonitrile (136 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 159 mg (89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Preparation No. 9 (300 mg,), K2CO3 (485.1 mg), and CH3I (0.11 mL) in 4 mL anhydrous DMF is heated at 90° C. for 3 h. The reaction is cooled to room temperature and diluted with H2O to dissolve any salts and precipitate the product. The crude product is adsorbed onto silica and chromatographed eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 154.2 mg (49%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C(O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[C:3]([O:5][CH2:6][CH3:7])[C:2](=[O:1])[CH2:8][CH2:9][CH3:10])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: CCCC(=O)C(=O)OCC
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: CCCC(=O)C(=NNc1ccc([N+](=O)[O-])cc1)OCC
Reaction time: 0.5 h

Procedure:
To a solution of the ester (D28) (0.53 g, 3.6 mM) in ethanol (20 ml) was added 4-nitrophenylhydrazine (0.56 g, 3.6 mM) and the suspension stirred for 0.5 h. Concentrated hydrochloric acid (2 ml) was added to give a brown solution. After stirring for 0.5 h the solution was cooled in ice and the precipitated title compound filtered off (0.72 g; 69%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][OH:34])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OCCN1CCNCC1
Agent: OC1CCNC1
Product: OCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-(2′-hydroxyethyl)piperazine. A yellow solid 137 was obtained (0.034 g, 67%). 1H-NMR (CDCl3, 400 MHz) δ 2.65-3.20 (br m, 4H), 3.24 (br m, 2H), 3.42-3.54 (m, 2H), 4.06 (br m, 2H), 4.05-4.18 (br m, 2H), 4.28-4.34 (m, 4H), 6.88 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.02-7.06 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=5.9 Hz, 1H); MS (APCI) m/z 518 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: CCCCN=C=O
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCNC(=O)n1cnc2c(-c3ccco3)nc(N)nc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.050 g, 0.25 mmol) and DMAP (5 mg, 0.03 mmol) in anhydrous DMF (1 μL) was treated with n-butylisocyanate (0.029 g, 0.30 mmol), shaken at 65° C. for 1 h, poured onto ice-cold water (10 mL), cooled at 0° C. for 15 min and the resulting precipitate filtered and dried in vacuo over P2O5 to give the title compound (74 mg, 100%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:42][CH2:43][CH2:44][NH2:45])=[CH:37][CH:36]=1.C(OCC)C>CN(C=O)C>[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:46]2[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=2)[CH2:42][CH2:43][CH2:44][NH:45][C:5]([C@@H:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])=[O:7])=[CH:37][CH:36]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
(S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.940 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.490 mL, 2.81 mmol) and solid O-benzotriazol-1-yl-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.280 g, 0.940 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 35 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a solid. Recrystallization from ether afforded 0.18 g (34%) of the pure titled compound as a white solid; mp 138-141° C. APCI-MS m/z 563.4 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Na].O.C(O)(=O)C.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml of diethylcarbonate, kept under stirring and at room temperature, are added portionwise 0.232 g of sodium. The reaction mixture is refluxed for 2 hours 30 minutes, then it is concentrated in order to eliminate the not reacted diethylcarbonate and it is added with 20 ml of cold water. The resulting mixture is acidified with acetic acid until weak acidity is reached, then it is extracted three times with diethyl ether. The pooled organic extracts are dried over sodium sulfate and the solvent is evaporated off, to give, after recrystallization from diethyl ether (19 ml), 1.015 g of the product as a white solid.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[C@H:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[N:22]=[C:23]4[N:31]=[C:30]5[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]5)[N:24]4[CH:32]=2)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[OH-].[Na+:46].C(OCC)(=O)C>C1COCC1.C(#N)C.[Zn]>[Na+:46].[N:22]1[C:21](/[CH:20]=[C:15]2\[CH:16]3[N:13]([C:14]\2=[O:37])[C:12]([C:10]([O-:11])=[O:9])=[CH:18][S:17]3)=[CH:32][N:24]2[N:25]3[C:30]([CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:31][C:23]=12
Reactant: CC(=O)OC(c1cn2c(n1)nc1n2CCCC1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C([O-])C1=CSC2/C(=C\c3cn4c(n3)nc3n4CCCC3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
(5R,6RS)-6-{(RS)-Acetoxy-[4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a] indene-2-yl]-methyl}-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (643.6 mg) was dissolved in THF (9 mL) and acetonitrile (4.2 mL). Freshly activated Zn dust (2.57 g) and 0.5 M phosphate buffer (pH 6.4, 13.2 mL) were added to the reaction mixture. The reaction vessel was covered with foil to exclude light. The mixture was vigorously stirred for 2 h at room temperature. The mixture was cooled to 3° C., and 1 N NaOH aqueous solution was added to adjust pH to 7.5. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water. The aqueous layer was concentrated to 20 mL under high vacuum at 35° C. The concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 2.5-10% acetonitrile-water. The combined fractions was concentrated under high vacuum at 35° C. and lyophilized to give the title compound as a yellow amorphous solid (68 mg, 18%, pH 7.4). Mp 175° C. (dec); 1H-NMR (400 MHz, D2O) δ 1.85-2.03 (m, 4H), 2.85-2.99 (m, 2H), 4.07-4.14 (m, 2H), 6.34 (s, 1H), 6.74 (s, 1H), 6.76 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][N:9]([CH3:11])[N:8]=[C:7]1[CH:12]([F:14])[F:13])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[F:14][CH:12]([F:13])[C:7]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:10][N:9]([CH3:11])[N:8]=1
Reactant: CCOC(=O)C1CN(C)N=C1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CC(C(=O)O)C(C(F)F)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Difluoromethyl-1-methyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (0.15 g, 0.7 mmol) was dissolved in 2 ml of dioxan. 1.5 ml of a 1 N aqueous sodium hydroxide solution (1.5 mmol) were added and the reaction mixture was stirred for 2 h at room temperature. Subsequently the mixture was acidified with concentrated hydrochloric acid (pH 2). The dioxan was removed in vacuo, the residue was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering 0.1 g of 3-difluoromethyl-1-methyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid, which could be directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[CH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C=Cc2ccc(OC)cc2)nc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCc2ccc(OC)cc2)nc1

Procedure:
The starting material was prepared by hydrogenating for 4 hours at ordinary pressure and room temperature methyl 6-p-methoxystyrylnicotinate (25 g.) in tetrahydrofuran (300 ml.) in the presence of Raney nickel (10 g.). After filtration and removal of the solvent in vacuo, the residue was crystallised from hexane (500 ml., with active carbon) to give methyl 6-p-methoxyphenethylnicotinate, m.p. 82° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCC(c2ccccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 28.9 %

Procedure:
(2R,3R)-2-(2,4-Difluorophenyl-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 2-(4-piperidyl)pyridine (4.3 g, 26.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (4.25 g, 26.5 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.37 g of the intended substance (yield 28.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(CC)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1C(F)(F)F
Reaction time: 16 h
Yield: 46.3 %

Procedure:
According to general procedure B, 4-bromo-N,N-diethyl-2 (trifluoromethyl)benzenesulfonamide (201 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzenesulfonamide (100 mg, 46%) was provided after purification. MS (ESI) m/z 385. HPLC purity 100.0% at 210-370 nm, 11.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [S:1](=[C:4]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[CH2:5][CH2:6][CH3:7])(=[O:3])=[O:2].[CH3:14]I>>[CH3:14][N:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:4](=[S:1](=[O:3])=[O:2])[CH2:5][CH2:6][CH3:7])[CH2:13]1
Reactant: CI
Reactant: CCCC(c1cnccn1)=S(=O)=O
Product: CCCC(C1=NC=CN(C)C1)=S(=O)=O

Procedure:
3.6 g of 2-(1-sulfonylbutyl)pyrazine (1100) was added to a solution of 10 ml methyl iodide/25 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 3.2 g of product (1200) which was recrystallized from propanol/water, m.p. 293°-5° (dec). UV H2O max: 206 (3.87), 283 (3.90). 1H NMR: 9.41, D, T (H6); 9.11, S (H2); 8.94, D (H5); 4.63-4.58, M (CHSO3-); 4.52, S (NCH3); 2.31, M (CH2CHSO3-); 1.27, M (CH2CH3); 0.89, T (CH3).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([C:14]#[N:15])[CH:3]=1.FC1C(C#N)=CC2SC(SC)=NC=2C=1>>[F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([CH2:14][NH2:15])[CH:3]=1
Reactant: CSc1nc2c(F)cc(C#N)c(F)c2s1
Agent: CSc1nc2cc(F)c(C#N)cc2s1
Product: CSc1nc2c(F)cc(CN)c(F)c2s1

Procedure:
(4,7-Difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine was synthesized as a clear oil (646 mg, 64%) using a procedure analogous to that described in Step 3 of Example 154, substituting 4,7-difluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile from the previous step for 5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile used in Example 154. LCMS (ESI) m/z 247 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.Cl.[CH2:13]([O:15][CH2:16][C:17]1[N:18]=[C:19]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:14].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(O)C>[CH2:13]([O:15][CH2:16][C:17]1[N:18]=[C:19]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[CH2:30][CH2:29]2)[O:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:14]
Reactant: COc1ccc(CCCl)cc1
Reactant: CCOCc1nc(C2CCNCC2)oc1-c1ccccc1
Agent: Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOCc1nc(C2CCN(CCc3ccc(OC)cc3)CC2)oc1-c1ccccc1
Temperature: 150 °C
Yield: 86.5 %

Procedure:
1-(2-chloroethyl)-4-methoxybenzene (486 mg, 2.8 mmol), 4-(4-ethoxymethyl-5-phenyl-oxazol-2-yl)-piperidine hydrochloride (1 g, 2.2 mmol), prepared as in Intermediate 4, K2CO3 (393 mg, 2.85 mmol) and Nal (427 mg, 2.85 mmol) in ethanol are mixed together in a sealed tube and heated to 150° C. overnight. The mixture is cooled, filtered and concentrated. The crude material is purified by column chromatography (SiO2, 10% methanol: methylene chloride), followed by another column (SiO2, 15% methanol: ethyl acetate) to afford an oil which is triturated from 70% hexane; ether, 800 mg of the title compound is obtained.