Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]CO>C1(C)C=CC=CC=1.CCO.CCO.CCO.CCO.[Ti]>[Cl:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:17][O:16][C:14](=[O:15])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:29][CH:28]=1)[C:10]([O:12][CH2:13][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Cl:30])=[O:11]
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: OCCCCCCCl
Agent: [Ti]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(OCCCCCCCl)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCCCCCCl
Yield: 69.4 %

Procedure:
26.1 g (0.065 mol) dimethyl bis(4-nitrobenzyl)malonate, 84 g (0.61 mol) 6-chlorohexanol, 23.0 g (0.10 mol) tetraethyl orthotitanate were suspended in 50 ml toluene. The reaction mixture was subsequently allowed to react for 72 h at refluxing temperature. The reaction mixture was partitioned between water and ethyl acetate; the organic phase was washed repeatedly with water, dried over magnesium sulphate, filtered and concentrated by rotary evaporation. The product was precipitated with 200 ml cyclohexane, collected by filtration and washed with hexane to yield 27.6 g of bis[6-chlorohexyl]2,2 bis(4-nitrobenzyl)malonate as beige powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCOCCO
Solvent: CCN(CC)CC
Product: OCCOCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(2-aminoethoxy)ethanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCCC(Nc2cc(I)cc(Cl)n2)C1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of Example 260a (0.320 g, 0.910 mmol) in DMF (6 mL) were added triethylamine (0.165 mL, 1.183 mmol) and cyclopropanesulfonyl chloride (0.102 mL, 1.001 mmol). The reaction mixture was stirred at room temperature overnight, quenched with brine and NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/EtOAc (7:3 to 1:1) to give 0.092 g of the title compound.
Reaction SMILES: B1C2CCCC1CCC2.C1COCC1.[CH3:15][C:16]([OH:20])([CH:18]=[CH2:19])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:47]1[CH:48]=[C:49]2[C:71](=[CH:72][CH:73]=1)[C:57]1[NH:58][C:59]([C:61]3[C:68]([C:69]#[N:70])=[CH:67][CH:66]=[CH:65][C:62]=3[C:63]#[N:64])=[N:60][C:56]=1[C:55]1[CH:54]=[CH:53][C:52]([Cl:74])=[CH:51][C:50]2=1>[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[Cl:74][C:52]1[CH:51]=[C:50]2[C:55](=[CH:54][CH:53]=1)[C:56]1[NH:60][C:59]([C:61]3[C:68]([C:69]#[N:70])=[CH:67][CH:66]=[CH:65][C:62]=3[C:63]#[N:64])=[N:58][C:57]=1[C:71]1[CH:72]=[CH:73][C:47]([CH2:19][CH2:18][C:16]([OH:20])([CH3:17])[CH3:15])=[CH:48][C:49]2=1
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3cc(Br)ccc3c2[nH]1
Reactant: C=CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9-BBN in THF (24 ml, 12 mmol, 0.5 M) was added 2-methyl-3-buten-2-ol (345 mg, 4.0 mmol) and the resulting solution was stirred under N2 at rt for overnight. In a second flask charged with PdCl2(dppf) (324 mg, 0.40 mmol), Cs2CO3 (2.4 g, 8.0 mmol) and Ph3As (124 mg, 0.4 mmol) was added 2-(6-bromo-9-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Example 36, DMF (24 ml) and H2O (0.88 ml) and the mixture was stirred under N2 for 5 minutes. The hydroboration mixture was then transferred to the second flask and the resulting reaction suspension was stirred at rt under N2 for 5 days. After being treated with brine, the aqueous phase was extracted with EtOAc and the combined organic solution washed with water and brine, dried over MgSO4. After removing the drying agent by filtration, the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (50% EtOAc/Hexane) to yield 600 mg of 2-[9-chloro-6-(3-hydroxy-3-methylbutyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile as a yellow solid. 1H NMR (400 MHz, Acetone): δ 13.10 (s br, 1H); 8.94 (s, 1H); 8.77 (s, 1H); 8.70-8.60 (m br, 2H); 8.39 (d, 2H); 8.03 (t, 1H); 7.75 (dd, 1H); 7.69 (dd, 1H); 4.92 (s, 1H); 3.05 (m, 2H); 1.95 (m, 2H); 1.33 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH3:13][N:14]=[C:15]=[S:16]>C(#N)C>[CH3:13][NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1
Reactant: N#CCCCCn1ncc(N)n1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)Nc1cnn(CCCCC#N)n1

Procedure:
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in acetonitrile (5 ml.) and methylisothiocyanate (0.73 g.) was stirred for 18 hours at ambient temperature and then heated under reflux for 6 hours. The solvent was evaporated and the residue was triturated with ether/EtOH to give 5-[4-(3-methylthioureido)-1,2,3-triazol-2-yl]valeronitrile as a white solid.
Reaction SMILES: Cl[C:2]([O:4][N:5]=[C:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[OH:23].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[O:23][C:2]([O:4][N:5]=[C:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)C(C#N)=NOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=NOC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of ethyl 2-chlorocarbonyloxyimino-2-cyanoacetate (0.05 mol) prepared as in Example 11 (1), a solution of 2,4,5-trichlorophenol (9.9 g) and pyridine (3.9 g) in benzene (50 ml) is dropwise added under cooling with icewater. The resulting mixture is stirred for 1 hour and allowed to stand over night. The reaction mixture is washed with water, dried and concentrated. The residue is admixed with petroleum ether and filtered to collect crystals, which is dried and recrystallized from a benzene-petroleum ether mixture to give ethyl 2-(2,4,5-trichlorophenyl)oxycarbonyloxyimino-2-cyanoacetate (12.0 g). M.P. 101 to 103°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:22])[CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][O:22][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([Cl:14])[N:3]=2)[CH:17]=[N:16]1
Reactant: OCCc1cn[nH]c1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(OCCc3cn[nH]c3)c2c1=O
Temperature: 80 °C

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (115.0 mg, 0.50 mmol), 2-(1H-pyrazol-4-yl)ethanol (112.1 mg, 1.00 mmol) and K2CO3 (138.2 mg, 1.00 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. overnight, cooled down, quenched with H2O (25 mL) and extracted with EtOAc (3×12.5 mL). The combined organic layer was evaporated under reduced pressure and purified by reverse phase HPLC to afford 5-(2-(1H-pyrazol-4-yl)ethoxy)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 87 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.33 g).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:28]Cl)[N:19]([CH2:20][C:21]3([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1>CN(C=O)C>[C:1]([O:4][CH2:28][C:18]1[N:19]([CH2:20][C:21]2([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:6])[C:16]=2[N:17]=1)(=[O:3])[CH3:2]
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCCCC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium acetate (0.28 g, 2.89 mmol) was added to a solution of 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (0.83 g, 2.41 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure to provide crude [4-amino-1-(1-hydroxycyclohexylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:11][C:10]2[C:12]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:12]1[C:10]2[O:11][C@@H:5]([CH2:4][NH2:1])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.6 %

Procedure:
To a solution of (2R)-2-azidomethyl-9-(2,6-dichloro-phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepine (0.24 g, 0.689 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.69 g, 2.068 mmol) and the reaction mixture stirred at room temperature for 20 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 179 mg (80%) of {[(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (3 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.55 mL, 0.55 mmol) was added followed by hexane (4 mL). The resulting white precipitate was filtered to afford 182 mg (73%) of {[(2R)-9-(2.6-dichlorophenyl)-2,3.4,5-tetrahydro-1-benzoxepin-2-yl]methyl}amine hydrochloride as a white solid. MS (ESI) m/z 322 ([M+H]+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[C:11]([C:12](O)([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[Na+].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O>[CH3:5][C:6]1[C:11]([C:12]([CH3:14])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1ncccc1C(C)(C)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(C)(C)c1ccccc1
Yield: 75 %

Procedure:
To a mixture of AlCl3 (2.173 g, 16.3 mmol) in benzene (20 mL) was added a solution of 2-(2-methyl-pyridin-3-yl)-propan-2-ol (0.455 g, 3.00 mmol) in benzene (10 mL) and the resultant mixture was stirred at room temperature overnight. The mixture was poured onto ice (200 mL), diluted with EtOAc (200 mL), and neutralized with 10 N NaOH (4 mL). The phases were separated and the organic phase was washed with brine (3×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2-MeOH) provided 0.479 g (75%) of 2-methyl-3-(1-methyl-1-phenyl-ethyl)-pyridine as a colorless oil. 1H NMR (CDCl3) δ 1.68 (s, 6H), 2.01 (s, 3H), 7.11-7.20 (m, 4H), 7.24-7.30 (m, 2H), 7.86 (dd, 1H, J=8.1, 1.5 Hz), 8.39 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1F.[CH:10]1([CH:13]([OH:25])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1.[H-].[Na+].O>CS(C)=O>[CH:10]1([CH:13]([O:25][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:12][CH2:11]1
Reactant: Fc1cc(Cl)ccc1Cl
Reactant: CN(CCC(O)C1CC1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCC(Oc1cc(Cl)ccc1Cl)C1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
1,4-Dichloro-2-fluorobenzene (165 mg, 1.00 mmol) and (3-cyclopropyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester (230 mg, 1.00 mmol) were dissolved in dimethylsulfoxide (10 ml) under nitrogen at room temperature. To the resulting solution was added sodium hydride (60% in oil) (80 mg, 2.00 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted with diethyl ether three times. The combined organic fractions were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 175 mg (47%) of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([S:16][C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC.CN(C=O)C>CCOCC>[CH3:25][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([S:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH:15]=[C:7]([O:6][C:5]2[CH:23]=[CH:24][C:2]([I:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Cn1ccnc1Sc1cc(Oc2ccc(I)cc2)cc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(I)cc2)cc(Sc2nccn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid (1.4 g, 3.1 mmol), K2CO3 (856 mg, 6.2 mmol), iodomethane (0.29 mL, 4.65 mmol) and 16 mL of DMF were stirred for 2 h at rt. Then the mixture was diluted with ether and washed with water, brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 from CH2Cl2 and subjected to MPLC on a 40 g column of SiO2 eluting with % EtOAc in hexanes (time): 33% (10 min), 35-50% (20 min ramp) which provided 1.32 g (91%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.79 (s, 3H), 6.91 (d, 21-1, J=8 Hz), 6.96 (dd, 1H, J=2, 1 Hz), 7.14 (d, 1H, J=1 Hz), 7.23 (dd, 1H, J=2, 1 Hz), 7.32 (t, 1H, J=1 Hz), 7.51 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 467.4 [C18H15IN2O3S+H]+.
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]([F:17])([F:16])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+]>O>[F:16][C:9]([F:17])([O:8][C:7]1[C:2]([OH:19])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(=O)(O)O
Reactant: Nc1ncccc1OC(F)(F)C(F)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ncccc1OC(F)(F)C(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
2.6 g (10 mmol) of 2-amino-3-(1,1,2,3,3,3-hexafluoro-1propyloxy)pyridine were diazotized at 0° C. in 35 ml of 2N sulfuric acid using 0.76 g (11 mmol) of sodium nitrite in 5 ml of water. The reaction mixture was stirred for 30 minutes and the product was extracted using ethyl acetate. The organic phase was washed until neutral, dried using MgSO4 and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[CH:5]=1)=[O:3].[BH4-].[Na+].O.[Cl-].[NH4+]>CO>[I:10][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(I)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(O)c1cccc(I)c1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
To a cold (ice water) solution of 3-iodoacetophenone (2.59 gm; 10.5 mmol) in methanol (10 mL) is added sodium borohydride (395 mg; 10.4 mmol) is stirred for thirty minutes. Water (10 mL) is added to the solution and stirred 15 minutes. Saturated ammonium chloride (40 mL) is added and the solution is extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed to give 2.26 grams of 1-(3-iodophenyl)-ethanol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].C(=O)([O-])O.[Na+:28]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O-:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].[Na+:28]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=O

Procedure:
100 Mg. of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid are dissolved in 3 ml. of 0.1 N-sodium hydrogen carbonate solution. The solution is made up to 10 ml. with water and sterilized.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:6](O)=[O:7].[N:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[S:31][C:30]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:6]([NH:38][C:30]1[S:31][C:32]2[C:37]([N:29]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:7]
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: Nc1nc2cccnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccnc2s1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 119 %

Procedure:
The compound of example A78 was obtained by similar method described in example A75 using (2,4-Difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid (Preparation 2) (0.1 g, 0.27 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.042 g, 0.33 mmol), HOBt (0.044 g, 0.33 mmol), and EDCI (0.062 g, 0.33 mmol), N-methyl morpholine (0.034 g, 0.33 mmom) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.CC(O)=O>CCO.[Pd]>[F:20][C:17]([F:18])([F:19])[CH:15]([CH3:16])[CH2:14][C:11]1([OH:21])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(CC1(O)CCNCC1)C(F)(F)F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate (100 mg, 0.32 mmol) in EtOH (5 mL) was added 10% Pd/C (20 mg) and a drop of AcOH. The mixture was stirred at 40° C. for 16 hrs under H2 atmosphere. The reaction mixture was filtered through a celite pad; the filtrate was concentrated to get the title compound which was used directly for the next step without purification. LC-MS: m/z 212.2 (M+H)+
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:12]=[N:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:9]4[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)[CH:10]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CC1(C)OB(c2cncc(CN3CCOCC3)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCOCC5)c4)cc23)CC1
Yield: 43 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).