Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:13][C:9]=2[C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)=[CH:22][CH:23]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cl
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ncc[nH]2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 116.2 %

Procedure:
To a solution of 5-(1-allyl-1H-imidazol-2-yl)-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (99.0 mg, 0.252 mmol) and tetrakis(triphenylphosphine)palladium (14.6 mg, 0.0126 mmol) in DCM (3.38 mL) was added acetic acid (0.623 mL, 11.0 mmol) and phenylsilane (0.158 mL, 1.28 mmol) and the mixture was stirred for 2 h at 40° C. The reaction mixture was evaporated to remove volatiles and DCM (10 mL) added. To this solution was added saturated sodium bicarbonate (4 mL) and the resulting mixture was stirred for 30 min. The mixture was extracted with DCM (3×10 mL) and the combined DCM layers were washed with brine. The organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→10/90) to give 57 mg of the title compound as a yellow solid (64% yield). The HCl salt was made as follows. To a mixture of the free base (57 mg, 0.162 mmol) in ethanol (5 mL) was added 1.0 M HCl in ether (0.178 mL, 0.178 mmol) and the mixture was stirred for 2 hours then concentrated in vacuo. The residue was taken up in a minimum of methanol, and acetonitrile was added to give a precipitate. Ether was added and the precipitate was filtered, washed with ether and dried to give the title compound as an orange solid. LC/MS (FA) ES+ 353. 1H NMR (400 MHz, d6-DMSO) δ: 8.78-8.74 (m, 2H), 7.96-7.91 (m, 2H), 7.48-7.43 (m, 2H), 7.34-7.28 (m, 4H), 4.51 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46](OC)[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2(O)[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.S(Cl)([Cl:60])=O.N1C=CC=CC=1.[C:68](=[O:71])([O-])O.[Na+]>ClCCl>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([Cl:60])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([OH:50])[CH:46]([O:71][CH3:68])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: O=C([O-])O
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=S(Cl)Cl
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(Cl)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of FR-900506 (500 mg) in dry dichloromethane (25 ml) was added dropwise over 1 minute to a stirred, cool (0° C.) solution of thionyl chloride (0.45 ml) and pyridine (1.11 ml) in dry dichloromethane (20 ml) under nitrogen. After 20 minutes, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was stirred at room temperature for 20 minutes. The organic extract was then separated and washed with dilute aqueous hydrochloric acid (1M, 20 ml), water (20 ml) and brine (10 ml) before being dried (MgSO4), filtered and evaporated in vacuo to give the sub-title compound as an an oil (512 mg).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[Cl:16].C[N:18](C)[CH:19]=[O:20]>CO>[CH3:1][O:2][C:19](=[O:20])[NH:18][CH2:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[Cl:16]
Reactant: CN(C)C=O
Reactant: Clc1ccc(I)cc1CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)NCc1cc(I)ccc1Cl
Temperature: 110 °C

Procedure:
To a mixture of potassium carbonate (4.30 g, 53.3 mmol) in N,N-dimethylformamide (47 mL) and methanol (5 mL) at 50° C. was added a solution of 2-(bromomethyl)-1-chloro-4-iodobenzene (i.e. the product of Step A) (5.20 g, 15.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated at 110° C. for 1 h and then cooled to room temperature. The reaction mixture was partitioned between diethyl ether (200 mL) and water (200 mL), the organic layer was separated, washed with water (3×50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow oil (4.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[C:29]([NH:33][NH2:34])([CH3:32])([CH3:31])[CH3:30]>C(O)(=O)C>[C:29]([N:33]1[C:14]2[CH2:15][CH:16]3[N:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:12]([CH2:19][CH2:18][CH2:17]3)[C:13]=2[CH:21]=[N:34]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a suspension of the enol-ketone (9-[(4-chlorophenyl)sulfonyl]-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one, 34 mg, 0.10 mmol), sodium acetate (41 mg, 0.5 mmol) and glacial acetic acid (0.8 mL) in a vial was added the tert-butylhydrazine hydrochloride (31 mg, 0.25 mmol) with good stirring. The vial was capped and the reaction mixture was stirred evenly and heated to 100° C. Upon complete consumption of the enol-ketone (2-18 h, LC-MS), the reaction mixture was evaporated under a stream of nitrogen while being warmed in a 90° C. bath. The brown residue was dissolved with dichloromethane and water. The organic phase was washed with 5% NaHSO4 (3×), 5% NaHCO3 (2×), and brine (2×), dried (Na2SO4), applied to a silica gel column and eluted (0-10% EtOAc in dichloromethane) to yield the product upon evaporation. MS (ES) m/e 306.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O1CCCCC1[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([NH:26][NH2:27])[CH:23]=[CH:22][N:21]=1>CO.Cl>[NH2:6][C:5]1[N:26]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]([O:19][CH2:18][CH2:17][OH:16])[CH:25]=2)[N:27]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccnc(OCCOC2CCCCO2)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2ccnc(OCCO)c2)n1

Procedure:
4,4-Dimethyl-3-oxopentanenitrile (293 mg, 2.34 mmol) and Intermediate 67b (593 mg, 2.34 mmol) were suspended in MeOH (10 mL) and a few drops of concentrated HCl added and the reaction heated to reflux for 72 h. The reaction was cooled, concentrated in vacuo and partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4 and subjected to FCC, eluting with 10-50% EtOAc/cyclohexane to afford the title compound after crystallisation (139 mg, 21%). LCMS (Method 3) Rt 2.77 min, m/z 277.3 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>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:11]1([S:17][C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: Sc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(Sc2cnc3[nH]ccc3c2)cc1
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 5-bromo-7-azaindole (1)(0.5 g, 2.54 mmol; preparation disclosed in WO2004/078757), benzenethiol (274 μL, 2.66 mmol), sodium t-butoxide (488 mg, 5.07 mmol) and Pd(PPh3)4 (235 mg, 0.20 mmol) in EtOH (25 mL) was heated at reflux for 19 h. More benzenethiol (274 μL, 2.66 mmol), sodium t-butoxide (488 mg, 5.07 mmol) and Pd(PPh3)4 (235 mg, 0.20 mmol) were added and reflux continued for a further 24 h. The reaction mixture was filtered, concentrated, and the residue was extracted with CH2Cl2:hexane=1:1 (v/v). The extract was concentrated and purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 2 as a white solid (142 mg, 25%); 1H NMR (400 MHz, CDCl3) δ 6.53 (dd, J=3.5, 2.0 Hz, 1H), 7.10-7.30 (m, 5H), 7.41 (dd, J=5.9, 2.5 Hz, 1H), 8.16 (dd, J=2.0, 0.6 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 10.00-10.20 (bs, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCC4)cc3)c2cc1OC
Yield: 79.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclobutylmethanol (22 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 67%).
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[CH3:13][O:14][C:15](=[O:24])[C:16]([CH:19](OC)OC)=[CH:17]O.O>CN(C=O)C>[CH3:13][O:14][C:15]([C:16]1[CH:17]=[N:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][CH:19]=1)=[O:24]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 100° C. under N2 for 1 hour. The reaction is cooled to room temperature and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, D. J. Fairfax, S. A. Eisenbeis, Synthesis, 2002, 720-722.)
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([O:8]C)=O.[S:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[CH:22]1.[CH3:33][O:34][C:35]1[N:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=O.C(O)(=O)C>O1CCOCC1>[CH3:20][C:2]([CH3:1])([CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:3]([C:4]1[CH:37]([C:36]2[C:35]([O:34][CH3:33])=[N:42][CH:41]=[CH:40][CH:39]=2)[N:30]([C:29]2[CH:31]=[CH:32][C:26]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)=[CH:27][CH:28]=2)[C:6](=[O:8])[C:5]=1[OH:10])=[O:11]
Reactant: COc1ncccc1C=O
Reactant: COC(=O)C(=O)CC(=O)C(C)(C)COC1CCCCO1
Reactant: Nc1ccc(-c2ccsc2)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ncccc1C1C(C(=O)C(C)(C)COC2CCCCO2)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 54.7 %

Procedure:
A mixture of methyl 5,5-dimethyl-2,4-dioxo-6-(tetrahydro-2H-pyrane-2-yloxy)hexanoate (0.29 mg, 1.0 mmol), 4-(3-thienyl)aniline (0.18 g, 1.0 mmol), 2-methoxynicotinaldehyde (0.14 g, 1.0 mmol), acetic acid (0.043 mL, 0.75 mmol) and dioxane (2 ml) was heated at reflux overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform) to give 4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxy-3-pyridyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.30 g, yield: 55%) as pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>O1CCOCC1.C(OCC)(=O)C>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[CH:16]=[CH:17][N:18]=[C:3]1[C:2]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:11]2
Reactant: NCCCO
Reactant: FC(F)(F)c1ccc2c(c1)nc(Cl)c1nccn12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
To a solution of 4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline (2.00 g; 7.36 mmol; 1 eq) in anhydrous dioxane (250 mL), 3-aminopropanol (6.2 mL; 81.0 mmol; 11 eq) is added, under argon atmosphere. Complete conversion was achieved after 17 hours of stirring under reflux. The initially cloudy yellow solution turns first orange and then becomes translucid. The reaction mixture is cooled to room temperature and diluted in ethyl acetate (500 mL). The organic phase is washed three times with a solution of saturated sodium hydrogenocarbonate (3×330 mL). The organic phases are combined, dried over sodium sulfate and concentrated under vacuum to provide pure title compound (1.94 g; 6.25 mmol; 85%) as a grey powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2nc3ccccc3s2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4s3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)benzothiazole (10.0 moles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (10.0 moles, 2.4 g) were reacted according to procedure C to yield of the title compound, 1.5 g, 30%. Mass Spec (FD) 495. Calculated for C21H13ClF3N3S3 : C, 50.85 H, 2.64 N, 8.47. Found: C, 51.02; H, 2.71; N, 8.31.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(Cl)cc3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester, Example 13d for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-chlorophenyl)-piperazine hydrochloride for 1-(3-chlorophenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:17])=[O:16])[CH:3]=1.[ClH:18]>C(O)C.[Pd]>[ClH:18].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:16])=[O:17])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 4 h
Yield: 100 %

Procedure:
4-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile (1.37 g, 5.4 mmol) was dissolved in ethanol (120 mL). To this was added 1N HCl (20 mL) and a catalytic amount of 10% Pd—C. The mixture was shaken under hydrogen at 55 psi for 4 h then filtered through Celite® and concentrated to give the title compound as white solid (1.58 g, 100% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38 (1H, dd, J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2.7 Hz), 7.26 (2H, dd, J=21.4, 13.7 Hz), 3.93-3.84 (1H, m), 3.50-3.41 (3H, m), 2.40-2.31 (2H, m), 2.04-1.96 (2H, m). LCMS [M+H]+ calcd for C11H16N2O6FS: 259.087; found: 259.24.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: Fc1cccc(CNc2nc(-c3cc(F)ncc3Cl)ccc2F)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3ccc(F)c(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
5′-chloro-2′,5-difluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (0.022 g, 0.063 mmol) was dissolved in anhydrous DMSO (0.93 mL) and charged to a microwave vial, and then treated with trans-cyclohexane-1,4-diamine (0.072 g, 0.629 mmol). The reaction mixture then was heated at 100° C. for 18 hr. The material was purified by preparative reverse-phase HPLC to yield 0.0151 g (44%) of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine as the TFA salt. LCMS (m/z): 444.2 (MH+), retention time=0.7 min.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][NH2:73])[CH:67]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([NH:73][CH2:72][C:68]4[CH:67]=[N:66][CH:71]=[CH:70][CH:69]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.11 g, 0.30 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added 1-hydroxybenzotriazole (HOBt) (0.08 g, 0.60 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.19 g, 0.60 mmol), N,N-diisopropylethylamine (0.23 g, 1.80 mmol) and pyridin-3-ylmethanamine (0.05 g, 0.45 mmol). The resulting mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was diluted in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-8% methanol in dichloromethane to afford the title compound as a colorless solid (0.09 g, 70%): mp 67-70° C. (hexanes/diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.57 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.40-7.34 (m, 3H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.1, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.1, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ161.5 (d, 1JC-F=244 Hz), 161.8, 157.2, 154.9, 151.2, 148.8, 148.0, 135.1, 135.1, 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 123.5, 117.6, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 40.4, 18.4, 17.1; MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: O[Li].O.[O:4]=[C:5]1[C:14]2[C:9](=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:8][C:7]([C:19]2[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6]1.O>O.C1COCC1.CO>[O:4]=[C:5]1[C:14]2[C:9](=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:8][C:7]([C:19]2[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6]1
Reactant: COC(=O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.9 %

Procedure:
LiOH.H2O (28 mg, 0.64 mmol) was added to a solution of methyl 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromene-8-carboxylate 40 (120 mg, 0.32 mmol) in H2O/THF/MeOH (5 mL, 1:2:2). The reaction mixture was stirred at ambient temperature for 12 h, poured into H2O and the pH adjusted to 3. The mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to give 41 (120 mg) which was with no further purification.