Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: CS(=O)(=O)CC(=O)Nc1ccc(O)cc1

Procedure:
This compound was prepared from N-(4-benzyloxy-phenyl)-2-methanesulfonyl-acetamide, using the same method used to prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give the product, 3.45 g (92%) as a colorless solid. MS m/z 230 (MH+). 1H NMR (DMSO-d6) δ 3.18 (s, 3H), 4.22 (s, 2H), 6.72 (d, 2H), 7.36 (d, 2H), 9.35 (br s, 1H) and 10.17 (s, 1H). Anal. calcd for C9H11N4OS: C, 47.15; H, 4.84; N, 6.11. Found: C, 47.04; H, 4.79; N, 6.04.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[S:23][C:24]2[C:25]([N:30]=1)=[N:26][CH:27]=[CH:28][CH:29]=2.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: Clc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (1.5 g, 7.8 mmol) in DMF (78 mL) was added Cs2CO3 (7.6 g, 26 mmol) and 2-chloro-thiazolo[4,5-b]pyridine (1.6 g, 7.8 mmol). The reaction mixture was heated (50° C., 10 h), cooled (rt) and water was added (50 mL). The resulting solid was filtered to provide the title compound as a colorless solid (2.6 g, 100%). MS (ESI): mass calcd. for C16H10N2O4S, 326.0; m/z found, 327.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.6, 1H), 7.84 (d, J=2.4, 1H), 7.64 (d, J=9.0, 1H), 7.54 (d, J=0.9, 1H), 7.47 (dd, J=9.0, 2.5, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.04-3.86 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:35]2([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:37][CH2:36]2)[N:29]=3)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][C:28]4[C:33]([N:34]=3)=[CH:32][CH:31]=[C:30]([C:35]3([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH2:37]3)[N:29]=4)=[CH:24][CH:25]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Temperature: 95 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (162.1 mg, 0.701 mmol) in DMF (4.0 mL) was slowly added to a suspension of sodium hydride (60% w/w in mineral oil) (58 mg, 1.45 mmol) in DMF (4.0 mL), and the resulting mixture was heated at 95° C. for 5 min. 2-(4-Fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (75.3 mg, 0.217 mmol) was then added, and the resulting solution was heated at 95° C. for 18 h. The reaction mixture was subsequently cooled to 25° C. and diluted with EtOAc (5 mL). Excess NaH was quenched with water (5 mL), and the resulting mixture was diluted with 0.1N aq. HCl (40 mL) and extracted with EtOAc. The combined extracts were sequentially washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a yellow solid. MS (ESI) m/z: Calculated: 557.2; Observed: 557.8 (M++1).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.C(OC([N:26]1[CH2:33][CH2:32][CH:31]2[CH:28]([NH:29][CH2:30]2)[CH2:27]1)=O)(C)(C)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]=[C:37]([N:45]([CH3:47])[CH3:46])[N:36]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C@@H:28]12[N:29]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]=[C:37]([N:45]([CH3:47])[CH3:46])[N:36]=3)[CH2:30][C@@H:31]1[CH2:32][CH2:33][NH:26][CH2:27]2
Reactant: CN(C)c1nc(Cl)cc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: Clc1cnc2ccccc2n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and (4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-dimethyl-amine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C13H18F3N5, 301.31. m/z found 302.1 [M+H]+. 1H NMR (CDCl3): 9.04 (s, 1H), 5.98-5.63 (m, 1H), 4.56 (dd, J=4.9, 3.1, 1H), 3.99 (t, J=7.8, 1H), 3.88-3.70 (m, 2H), 3.68-3.37 (m, 2H), 3.33-3.17 (m, 1H), 3.16-3.00 (m, 6H), 2.95-2.74 (m, 1H), 2.33-1.85 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:19]O>>[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([O:17][CH3:19])=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CN(Cc2ccccc2)CCO1
Yield: 80 %

Procedure:
4-Benzylmorpholine-2-carboxylic acid hydrochloride (1.00 g, 3.88 mmol) in a 10 (w/w) % hydrochloric acid/methanol solution (20 mL) was stirred at room temperature for 2 hours. The solvent was evaporated and a saturated aqueous sodium bicarbonate solution was added to the residue to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine and was dried over magnesium sulfate. Evaporation of the solvent gave 730 mg (80%) of the desired compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[F:13][B-:14]([F:17])([F:16])[F:15].[H+].[N:19](OC(C)(C)C)=O>C(O)C>[F:13][B-:14]([F:17])([F:16])[F:15].[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([N+:6]#[N:19])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: CCc1cc(Br)cc(CC)c1N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: CCc1cc(Br)cc(CC)c1[N+]#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
At 0° C., to a stirred solution of commercial 4-bromo-2,6-diethylaniline (10.0 g, 43.9 mmol) in absolute ethanol (219 mL) was added 48% aq. tetrafluoroboric acid (17.2 mL), followed by tert-butyl nitrite (5.7 mL, 48.0 mmol). After 0.5 h, the reaction was poured into ice cold ether (877 mL). The resulting precipitate was washed with cold ether and dried to give 9.39 g (66%) of the title compound. 1H NMR: consistent.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N+:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:2][C:3]#[C:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[N:21]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CC#CCO
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC#CCn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
The 2-(4-hydroxy-but-2-ynyl)-isoindole-1,3-dione (1.29 g, 6.00 mmol), 3-Nitro-1H-pyrazole (prepared in example 3, 655 mg, 5.80 mmol) and triphenylphosphine (1.57 g, 6.00 mmol) were combined and dissolved in tetrahydrofuran (30 mL) and then chilled to 0° C. While stirring, diisopropyl azodicarboxylate (1.77 mL, 9 mmol) was added dropwise. The ice bath was removed and the reaction continued to stir at 25° C. for 1 h. At this point the desired product had precipitated. Collection of the precipitate using in vacuo filtration followed by rinsing with tetrahydrofuran (2×10 mL) then drying in vacuo for 2 h afforded 2-[4-(3-nitro-pyrazol-1-yl)-but-2-ynyl]-isoindole-1,3-dione (1.54 g, 86%) as a white powder: ESI-LRMS m/e calcd for C15H10N4O4 [M+] 310.07. found 311.17 [M+H+], 621.20 [2M+H+].
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)CCC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Reactant: CCC1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-2-trifluoromethanesulfonyloxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.084 g), 4-tributylstannylpyrazole (0.096 g), lithium chloride (0.052 g) and Pd(Ph3P)2Cl2 (0.009 g) in dimethylformamide (1 mL) was heated at 120° C. in a sealed tube 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 5,11-dihydro-11-ethyl-2-(4-pyrazolyl)-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.010 g).
Reaction SMILES: S(=O)(=O)(O)O.O1CCCCC1[O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:16]=[C:17]([O:19]C2CCCCO2)[CH:18]=1>C1COCC1.O>[OH:42][C:40]([CH3:43])([CH3:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]1[CH:29]=[C:28]([CH:27]=[CH:26][C:15]2[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([OH:19])[CH:16]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(O)CCCCCCc1cccc(C=Cc2cc(OC3CCCCO3)cc(OC3CCCCO3)c2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.06 ml of concentrated sulphuric acid with 1.15 g (2.21 mmol) of 8-(3-{2-[3,5-bis(tetrahydropyran-2-yloxy)phenyl]vinyl}phenyl)-2-methyloctan-2-ol in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 40-heptane 60), pinkish crystals (m=331 mg; Y=42%) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:6]1[CH:5]=[C:4]([CH3:18])[C:3]([O:19][CH2:21][C:22]#[N:23])=[C:2]([CH3:1])[CH:7]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: N#CCCl
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC#N

Procedure:
To 2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenol (12.0 g=42 mmol) in 150 ml acetonitrile add chloroacetonitrile (3.8 g=50 mmol) and potassium carbonate (11.5 g=83 mmol). Reflux 6 hours, add more chloroacetonitrile (0.8 g=10 mmol), reflux 1/2 hour, and allow to cool. Filter, concentrate and partition between ether and water. Dry and concentrate the ether. Partition between 1:9 ether-hexane and 1.0 N NaOH. Acidify the aqueous layer with concentrated HCl and extract with ether. Dry and concentrate the combined ether extracts to leave a residue comprising 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetonitrile, together with some of the corresponding acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([CH:25]5[CH2:27][CH2:26]5)[CH2:29][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NC1CCN(C2CC2)CC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C4CC4)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropylpiperidin-4-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (d, J=6.06 Hz, 2H) 0.82 (br. s., 2 H) 1.79 (d, J=10.86 Hz, 2 H) 1.97 (d, J=10.86 Hz, 2 H) 2.43 (s, 4 H) 2.88-3.14 (m, 2 H) 3.35-3.34 (m, 2 H) 4.00 (d, J=6.57 Hz, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.79 (d, J=8.08 Hz, 1 H) 8.16 (s, 1 H) 8.35-8.50 (m, 2 H) 8.66 (d, J=7.07 Hz, 1H) 8.92 (t, J=1.52 Hz, 1 H) 11.41-12.67 (m, 1 H). MS m/z [M+H]+ 443.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:24][N:25]=[C:26]=[S:27].O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@:7]2([C:26](=[S:27])[NH:25][CH3:24])[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: CN=C=S
Reactant: O=[S@@]1CCCC[C@@H]1c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[S@]1=O
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A stirred suspension of (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (50.0 g) in dry tetrahydrofuran (500 ml) is treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (281 ml;1M) at between -5° C. and +5° C. The resulting suspension is stirred for 15 minutes at between -5° C. and +50C. and then it is treated with a solution of methyl isothiocyanate (20.26 g) in dry tetrahydrofuran (63 ml) at between -5° C. and +50C. The mixture is stirred at between -5° C. and +5° C. for 30 minutes and then it is treated with water (500 ml). The aqueous phase is then washed with dichloromethane (2×150 ml), The aqueous solution is then treated with charcoal, filtered, neutralised by treatment with dilute hydrochloric acid (2N) and filtered, to give (1R,2R)-2-(3-pyridyl)-N-methyltetrahydro-2H-thiopyran-2-carbothioamide 1-oxide (50.64 g), in the form of a white powder, m.p. 215°-216° C., enantiomeric excess greater than 99.6%. [NMR (CDCl3):- 1.6(m,1H), 1.7(m,2H),2.2(m, 1H),2.3(m, 1H),2.9(m,1H), 3.0(m,1H),3.1 (d,3H),3.7(m,1H),7.3(m,1H), 8.1 (m,1H),8.3(m,1H),8.5(m,1H),8.7(m,1H)]; specific rotations (sodium D line) -205° (c=1, 28° C., CHCl3); -281° (c=1, 31° C., EtOH).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH2:18]Cl)[CH3:16]>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH2:18][O:17][CH2:15][CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOCCl
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a RBF was added 2-bromo-3-pyridinol (6.0 g, 34.5 mmol) and potassium carbonate (11.91 g, 86 mmol) in Acetone (50 mL). The suspension was stirred at ambient temperature for 30 min and then treated with the drop-wise addition of chloromethyl ethyl ether (3.34 mL, 36.7 mmol) via addition funnel. The mixture was stirred at ambient temperature overnight. The mixture was filtered and the filtrate partitioned between EtOAc and water. The combined organic layers were washed with water, saturated solution of sodium bicarbonate and brine, then dried over Mg2SO4 to afford 7.12 g of desired product as a clear oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])#[N:10]
Reactant: Cc1nn(C)c(N)c1C#N
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: Cc1nn(C)c(NC(=O)c2ccccc2F)c1C#N
Yield: 50 %

Procedure:
5-Amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (10 g, 73.4 mmole) was suspended in pyridine (90 ml) and 2-fluorobenzoyl chloride was added dropwise while cooling reaction mixture on an ice bath. Stirred reaction mixture overnight at room temperature. Removed most of the pyridine and added 100 ml cold water to precipitate the product. Isolated product by filtration, washed with cold water, small amount of cold ethanol and dried under vacuum to obtain 9.15 g product (yield: 50%).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH2:37][CH3:38]>CN(C=O)C.CO>[ClH:1].[CH2:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:38]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCN1CCN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg) in DMF (1 mL) was added sodium hydride (60%, 10 mg). The mixture was stirred for 15 minutes, then iodoethane (11 □L) was added. The mixture was stirred for 90 minutes then diluted with methanol (5 mL) and purified by ion exchange chromatography [SCX-2; MeOH—(1M NH3/MeOH): (100:0) →(0:100)]. The basic washings were concentrated in vacuo and purified by column chromatography [SiO2; cyclohexane-EtOAc-MeOH: (1:1:0)→(0:10:1)] and converted to the hydrochloride salt according to the description given in the general procedure (D6) to give the title compound (49 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:28]([CH3:27])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CN(Cc1ccccc1)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-methyl-1-phenylmethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methylterephthalamide. MS (Q1) 490.1 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH2:11]([S:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O)[CH3:12].CCN=C=NCCCN(C)C.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1ncc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 5-bromo-N2-methylpyridin-2,3-diamine (0.70 g), 2-ethylsulfanylbenzoic acid (0.66 g), WSC (0.80 g), HOBt (23 mg), and pyridine (20 ml) was stirred under reflux at 120° C. for 30 minutes. After the reaction mixture was allowed to stand overnight, the mixture was stirred under reflux at 120° C. for 9.5 hours again. Into the reaction mixture cooled to room temperature, water was poured under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with wafer and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue and acetic anhydride (7 ml) was stirred under reflux at 140° C. for 1 hour. Aqueous sodium hydroxide solution was added to the reaction mixture cooled to room temperature to neutralize, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.60 g of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 42).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:29])=[O:28]>COCCOC.CCO.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]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C:27]([OH:29])=[O:28])[CH:33]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: COCCOC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CCC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3122 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (20 ml) were added 3-carboxyethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:28][C@@H:26]([C:23]4[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=4)[CH3:27])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4cnc(C)nc4)c3C2)nc1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (120 mg, 0.46 mmol) and (R)-1-(2-methylpyrimidin-5-yl)ethanamine (120 mg, 0.87 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (500 μL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-prep HPLC (100×20.2 mm, C18 column; 30-55% CH3CN-water [10 mM Et2NH]) to give a light color solid. LC-MS: 362.4 [M+H]+;