Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=1[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:26][C:27]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=3[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.39 g (0.0028 mole) of anhydrous potassium carbonate, and 0.92 g (0.0038 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate in 20 mL of N,N-dimethylformamide was heated at 90° C. for approximately 17 hours. At the end of this period the mixture was poured over ice, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an orange oil as a residue. This oil was placed on a silica gel column and eluted first with methylene chloride and then with methylene chloride/ethyl acetate (97.5/2.5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 0.82 g of 2-[2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate was recovered as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.30 (s, 3H); 2.44 (s, 3H); 3.76 (s, 3H); 4.84 (q, 1H, JHH =8.0 Hz); 5.16 (dd, 2H, JHH =10.0 Hz); 6.56 (s, 1H); 6.78-7.32 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: Cc1cccc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: Cc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N

Procedure:
Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.6 Hz, 1H), 7.52-7.68 (m, 5H), 8.02-8.08 (m, 2H), 11.32 (s, 1H), 11.46 (s, 1H). MS 280 (MH+).
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)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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:22]1[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
A mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV (1.0 g, 4.0 mmol), ethyl piperazine-1-carboxylate (1.2 ml, 8 mmol) and potassium carbonate in DMF (5 ml) was heated at 120° C. for 18 h. After cooling the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (3×30 ml). The combined extract was washed with water, brine, dried (MgSO4) and concentrated and the resulting product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as off-white solid (400 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:13][C:14](O)=[O:15]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: Cc1ccc(-c2nc(CC(=O)O)c(C)o2)s1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(CCO)c(C)o2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
BH3-THF complex (15 mL of a 1.0 M solution in THF) was added dropwise via addition funnel over 50 min to a solution of [5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acid (1.5 g, 6.33 mmol) in THF (10 mL). The reaction mixture was stirred at ambient temperature for 3 h, and then quenched with MeOH (4 mL). After heating at 50° C. for 2 h, the reaction mixture was cooled to ambient temperature, and then partitioned between CH2Cl2 and 1N NaOH. The organic phase was washed with brine (1×50 mL), dried over MgSO4 and concentrated to obtain a colorless oil (1.4 g, 99%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=3.6 Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.89 (q, J=5.6 Hz, 2H), 3.04 (t, J=5.9 Hz, 1H), 2.68 (t, J=5.6 Hz, 2H), 2.51 (s, 3H), 2.30 (s, 3H); MS (EI+) 224.04 (M+H); 246.06 (M+H+Na).
Reaction SMILES: [C:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([O:20]C)=[O:19])=[C:10]([CH2:22][NH2:23])[CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=[O:19])=[C:10]([CH2:22][NH2:23])[CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1c(CN)cc(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(CN)c(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
The compound obtained in Example 25-1 (266.6 mg) was dissolved in THF (2.7 ml) and methanol (2.7 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (2.7 ml), the mixture was stirred for 5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water and 1 mol/l aqueous solution of hydrochloric acid was added to produce a precipitate. The precipitate was collected by filtration and dried to obtain the title compound (233.5 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1

Procedure:
The colourless oil, (E)-ethyl 3-(4′-tert-butyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 4-tert-butylphenylboronic acid by a procedure analogous to that described in example 52a
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH2:16][C:17](=O)[CH3:18])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[C:25]4[C:24](=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=4)[NH:28][C:17]=3[CH3:18])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cccc(SCC(C)=O)c2)CC1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)C1(c2cccc(Sc3c(C)[nH]c4cc(Cl)ccc34)c2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 1-[3-(2-oxo-propylsulfanyl)-phenyl]-cyclopropanecarboxylic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31].[CH3:32][Si:33]([CH3:36])([CH3:35])Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][Si:33]([CH3:36])([CH3:35])[CH3:32])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 107.7 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 2g (1.31 g, 2.84 mmol) was dissolved in 15 mL pyridine, followed by addition of 4-dimethylamino pyridine (70 mg, 0.57 mmol) and trimethyl-chloro-silane (514 mg, 3.4 mmol). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The resulting residue was dissolved in 150 mL ethyl acetate and washed with pyridine (50 mL×2), water (30 mL) and saturated sodium chloride solution (30 mL) in turn. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-6-(trimethylsilyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63 g, pale yellow solid), yield: 100%.
Reaction SMILES: C[O:2][CH2:3][CH:4]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[CH2:9][CH2:10][N:11]([CH:20]([C:24]([OH:26])=[O:25])[CH2:21][O:22]C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:5]([OH:7])=[O:6].C[Si](I)(C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[OH:22][CH2:21][CH:20]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH2:10][CH2:9][N:8]([CH:4]([C:5]([OH:7])=[O:6])[CH2:3][OH:2])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[C:24]([OH:26])=[O:25]
Reactant: COCC(C(=O)O)N(CCN(Cc1ccccc1O)C(COC)C(=O)O)Cc1ccccc1O
Agent: C[Si](C)(C)I
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(O)C(CO)N(CCN(Cc1ccccc1O)C(CO)C(=O)O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.7 g N,N'-bis-(2-methoxy-1-carboxy-1-ethyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylenediamine (Example 17), 16 g trimethyl silyl iodide (0.08 mol), 6.32 g pyridine (0.08 mol) in 10 ml of chloroform is stirred at room temperature overnight, under nitrogen. The reaction mixture is filtered and the solvent evaporated in vacuo. The residue is poured in water giving a solid that after purification by chromatography furnishes N,N'-bis-(2-hydroxy-1-carboxy-1-ethyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: NCc1ccncc1
Product: CC1(C)CN(CC(=O)NCc2ccncc2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 53 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 4-(aminomethyl)pyridine. The product was isolated as hydrochloride salt in 53% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([Br:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([Br:11])=[CH:9][N:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)ncc1Br

Procedure:
A solution of 2,5-dibromoisonicotinic acid (1-1, 5 g, 17.80 mmol) and sulfuric acid (1.23 mL, 23.1 mmol) in ethanol (100 mL) was heated to reflux overnight. After reducing the volume of ethanol by rotary evaporation to approximately ¼ of it's original volume, the crude reaction mixture was partitioned between 2M sodium carbonate solution and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. This solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product (1-2) as a dark oil. ESI+MS [M]+C8H7Br2NO2=308.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>O1CCOCC1.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>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19])=[CH2:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)(-)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][O:31][CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)CC1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 3, tert-butyl 4-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)piperidine-1-carboxylate was reacted with 4-morpholinophenylboronic acid to provide the title compound at 70% yield. 1H NMR (CDCl3, 400 MHz) 8.03 (s, 1H), 7.35 (d, 2H), 6.89 (d, 2H), 5.17 (sb, 1H), 4.16-4.03 (m, 6H), 3.83 (m, 4H), 3.15 (m, 4H), 2.66 (m, 2H), 1.91-1.44 (m, 11H), 1.41 (s, 9H), 0.95 (d, 3H); MS (ESI) m/z: Calc: 565.4 (M+). Found. 566.3 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(N2CCC(O)CC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with piperidin-4-ol (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide. MS (Q1) 451.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([N:35](CC3C=CC(OC)=CC=3OC)[C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1.O1CCOCC1>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)nccc2c1
Temperature: 100 °C
Yield: 22.4 %

Procedure:
A pressure vessel was charged with (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (56.5 mg, 0.252 mmol), potassium carbonate (145 mg, 1.048 mmol), 1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.210 mmol), tetrakis(triphenylphosphine)palladium(0) (24.23 mg, 0.021 mmol), dioxane (1398 μl) and water (699 μl). The reaction vessel was swept with nitrogen, sealed with a cap and then heated in a microwave at 100° C. for 30 minutes. The mixture was cooled to room temperature. The organic layer was separated by pipet and then purified by reverse phase HPLC (Column: Gemini 150×30 mm, 5 μm, Phenomenex, Torrance, Calif., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing pure product were dried under a vacuum to provide 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (22 mg, 0.047 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.57 (br. s., 1H) 3.63-3.80 (m, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.79 (d, J=7.90 Hz, 1H) 7.86-7.96 (m, 1H) 8.12 (s, 1H) 8.25 (d, J=5.61 Hz, 1H) 8.47 (s, 1H) 8.65 (d, J=1.49 Hz, 1H) 8.77 (d, J=5.73 Hz, 1H); m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:31].FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:31]
Reactant: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1F
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
3-(6-Fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine was dissolved in trifluoroacetic acid (5 mL) and methylene chloride (5 mL). To the solution was added trifluoromethanesulfonic acid (104.2 uL, 1.18 mmol) and triethylsilane (18.1 uL, 1.18 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 274 as an off-white solid (7.8 mg, 11%). 1H NMR (400 MHz, DMSO) δ 9.29-9.21 (m, 2H), 8.81 (s, 1H), 8.62 (dd, J=4.7, 1.4 Hz, 1H), 8.42 (dt, J=8.0, 1.9 Hz, 1H), 8.06 (dd, J=7.6, 1.6 Hz, 1H), 8.01-7.95 (m, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 2.34 (s, 3H); ESI MS m/z=306.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([NH:25]CC2C=CC=CC=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([NH:25][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of 1-bromo-4-fluoro-3-nitrobenzene (0.125 mol, 26.0 g) in ethyl acetate (300 mL) add (3S,4S)-3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.113 mol, 23.0 g) and triethylamine (0.339 mol, 35.0 g), reflux for 14 h, cool to room temperature, and wash with water and brine. Dry over anhydrous sodium sulfate, evaporate the solvent, and purify by flash column chromatography to give the title compound as a yellow solid (43.0 g, 90%). APCI MS m/z 403 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[N:5]=[CH:6][C:7]=1[NH:8][CH3:9].[OH-].[Na+].[H][H]>C(O)C.[Pd]>[CH3:9][NH:8][C:7]1[CH:6]=[N:5][N:4]([CH:10]2[CH2:15][C:14]([CH3:16])([CH3:17])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:3](=[O:20])[CH:2]=1
Reactant: CNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1

Procedure:
4-Chloro-5-methylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one (0.15 g, 0.5 mmoles) was dissolved in ethanol (20 mL) and 1M sodium hydroxide (1 ml) was added. 10% Palladium on charcoal (40 mg) was added and the reaction mixture was stirred overnight under a balloon of hydrogen. Filtered off the catalyst and evaporated to a low bulk. Partitioned between water and ethyl acetate, separated and dried over magnesium sulphate. Evaporated to give the required product as a buff solid. (0.125 g, 94%). 1H NMR (300 MHz CDCl3) 7.32 (d, 1H, J=3 Hz), 5.7 (d, 1H, J=3 Hz), 5.3 (m, 1H), 4.2 (brs, 1H), 2.85 (d, 3H, J=5 Hz), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1>O1CCCC1.Cl>[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1
Reactant: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal (2.8 g, 0.01 mol) in 200 ml (1:1) tetrahydrofuran-hydrochloric acid (1N) was allowed to stir at room temperature for 16 hours. The mixture was concentrated to half volume. The aqueous was extracted with ethyl acetate. The organic extracts were washed with brine, dried (anhydrous sodium sulfate), and filtered. The crude product was purified by flash chromatography (40% ethyl acetate in hexane) to afford 2.1 g (91%) of product as yellow solid: mp 112-114° C.