Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][P:5]([CH:11]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([CH2:21][O:22]C(=O)C)[O:12]1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2]>CO.C[O-].[Na+]>[CH:1]([O:4][P:5]([CH:11]1[CH:15]2[CH:14]([O:18][C:17]([CH3:19])([CH3:20])[O:16]2)[CH:13]([CH2:21][OH:22])[O:12]1)(=[O:6])[O:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: CC(=O)OCC1OC(P(=O)(OC(C)C)OC(C)C)C2OC(C)(C)OC12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OP(=O)(OC(C)C)C1OC(CO)C2OC(C)(C)OC21
Yield: 99.1 %

Procedure:
Acetic acid 6-(diisopropoxy-phosphoryl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester (467 mg, 1.22 mmol) in dry methanol (10 mL) and methanolic sodium methoxide (0.1M, 1 mL) was stirred at RT for 0.5 h. Dowex acidic resin was added until neutral pH was attained, the reaction mixture filtered and concentrated to give (6-Hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-phosphonic acid diisopropyl ester as a colorless syrup (409 mg, 99%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([CH3:16])[C:9]=2[F:15])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 0.36 g (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was dissolved in 5 ml of 6N hydrochloric acid and 5 ml of glacial acetic acid and stirred for five hours at room temperature. The solution was concentrated to a solid which was suspended in water, made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.8). The solids were filtered and washed with water to give 0.32 g of white solid, mp 218°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:22][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]2)[CH:51]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:22][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:63][CH:60]5[CH2:59][CH2:58][N:57]([CH2:56][C:52]6[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=6)[CH2:62][CH2:61]5)=[O:21])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Reactant: NC1CCN(Cc2cccnc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2cccnc2)CC1)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (24, 50 mg, 0.16 mmol) in DMF (2.0 mL), HATU (75 mg, 0.2 mmol), 1-(pyridin-3-ylmethyl)piperidin-4-amine dihydrochloride (48 mg, 0.16 mmol) and triethylamine (150 μL, 110 mg, 1.1 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (10 mL) to give a precipitate, filtered and dried under vacuum overnight. Trituration with ethyl ether provided 2-(4-fluorophenyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 36) as a pale yellow solid (57 mg, 73%). 1H NMR (DMSO-d6, 300 MHZ) 11.08 (s, 1H), 8.49 (d, J=1.4 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.70 (dt, J=7.7, 1.8 Hz, 1H), 7.56 (dd, J=8.4, 1.5 Hz, 1H), 7.35 (dd, J=7.7, 4.7 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.06 (d, J=5.0 Hz, 2H), 7.05 (d, J=3.3 Hz, 2H), 4.37 (s, 2H), 3.87-3.72 (m, 1H), 3.63 (t, J=5.2 Hz, 2H), 3.52 (s, 2H), 2.92-2.78 (m, 4H), 2.12-2.00 (m, 2H), 1.80 (d, J=10.5 Hz, 2H), 1.61 (qd, J=11.7, 3.0 Hz, 2H) ppm; MS (ES) 484 (M+H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH:24](I)([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:25][CH2:24][CH3:26])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)I
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 49.6 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and isopropyl iodide (10.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylethyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (11.2 mg).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH:10]([OH:14])[CH2:11][CH2:12]Br.Cl>O>[CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: OC(CBr)CCBr
Agent: Cl
Solvent: O
Product: OC1CCN(C2CCCCC2)C1

Procedure:
To 99 g. of cyclohexylamine at reflux temperature is added 115.5 g. of 1,4-dibromo-2-butanol at a rate which maintains reflux without external heating. The temperature of the reaction mixture is maintained at 130°-140° C. in an oil bath for two hours after addition is complete. Water (100 ml.) is added and this mixture is then acidified with concentrated hydrochloric acid, cooled and extracted with ether. The aqueous layer is made alkaline with 50% aqueous sodium hydroxide solution, saturated with solid potassium carbonate and extracted three times with chloroform. The combined chloroform extracts are dried over potassium carbonate, concentrated and the residue distilled in vacuo to give N-cyclohexyl-3-pyrrolidinol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:21][C:22]1[C:23](=[O:32])[N:24]([CH3:31])[CH:25]=[CH:26][C:27]=1[C:28](Cl)=[O:29].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:28]([C:27]3[CH:26]=[CH:25][N:24]([CH3:31])[C:23](=[O:32])[C:22]=3[OH:21])=[O:29])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C(=O)Cl)ccn(C)c1=O
Reactant: N[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(C(=O)N[C@@H]2CC[C@H](c3ccc(Cl)c(Cl)c3)c3ccccc32)c(O)c1=O
Reaction time: 2 h

Procedure:
To a solution of cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (10 mg, 0.034 mmol) (Intermediate 16) and 3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 12A) (6.90 mg, 0.034 mmol) in DCM (1 mL) was added Et3N (0.014 mL, 0.10 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was quenched with H2O and DCM. The DCM portion was dried over Na2SO4, filtered and the solvent removed under reduced pressure to give Example 8A which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=O)[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH3:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>>[CH3:28][C:26]([C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]=2[N+:14]([O-:16])=[O:15])=[CH:33][CH:34]=1)([CH3:25])[CH3:27]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)CN1CC([N+](=O)[O-])=C(Cc2ccc(C(C)(C)C)cc2)C=C1C
Yield: 72.9 %

Procedure:
This compound is prepared from 5 g (13.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 4.54 g (20 mmol) of 4-(1,1-dimethylethyl)phenylmethyl bromide according to the method described in 1.5. 3.5 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:33])[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH3:24])=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=1)[CH2:38][N:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[N:40]1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:33])[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:20]([CH3:24])=[C:21]([NH:23][C:44]([C:42]2[CH:41]=[N:40][N:39]([CH2:38][C:37]3[CH:47]=[CH:48][CH:49]=[C:35]([F:34])[CH:36]=3)[CH:43]=2)=[O:45])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnn(Cc2cccc(F)c2)c1
Reactant: Cc1c(N)cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n1COCC[Si](C)(C)C
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Product: Cc1c(NC(=O)c2cnn(Cc3cccc(F)c3)c2)cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n1COCC[Si](C)(C)C

Procedure:
The title compound was prepared according to the experimental used in Example 20, Step 4 with intermediate (7d), 2-[5-amino-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydropyridin-3-yl]indole-1-carboxylic acid tert-butyl ester, and 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, which was synthesised according to the protocol described for intermediate (6e) in Example 21. The resultant crude product was purified by flash chromatography on SiO2 with hexane—50% ethyl acetate/hexane (gradient) to afford the title compound as a yellow oil, 80 mg, 70%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][CH3:5].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:6][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOCc1ccc(C(=O)O)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution of propanol (0.6 g) in DMF (8 ml). After gas evolution ceased, methyl 4-bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 194.23 (C11H14O3); MS (ESI): 195 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
5-Fluoro-2-methylbenzenesulfonyl chloride (35.1 g, 168.5 mmol) in diethyl ether (50 mL) was added drop-wise to a suspension of piperazine (28.8 g, 337.0 mmol) in diethyl ether (500 mL) and triethylamine (47 mL, 337.0 mmol). The white suspension was stirred at room temp for 1.5 h. The mixture was washed with saturated aqueous sodium carbonate. The organic phase was washed with water and brine and dried (Na2SO4). Concentration gave a white solid that was triturated with diethyl ether to give the title compound as a white solid (30.95 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ: 7.57 (1H, dd, J=8.6, 2.7 Hz), 7.25 (1H, dd, J=8.4, 5.1 Hz), 7.12 (1H, td, J=8.1, 2.8 Hz), 3.13-3.10 (4H, m), 2.98-2.85 (4H, m), 2.55 (3H, s), 1.69 (1H, bs). LCMS (M+H) calcd for C11H16FN2O2S: 259.09; found: 259.18.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N(C)C2CCCCC2)CCCCC1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[O:39]1[CH:40]=[CH:41][CH2:42][CH2:43][CH:44]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: C1=COCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 105 °C

Procedure:
A 25 mL reseable vial was charged with bis(tri-tert-butylphosphine) palladium (0) (83 mg, 0.163 mmol) and N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (650 mg, 1.632 mmol). The vial was sealed and placed under an atmosphere of nitrogen. After addition of dioxane (5.38 ml), N-cyclohexyl-N-methylcyclohexanamine (1.072 ml, 4.90 mmol) and 3,4-dihydro-2H-pyran (549 mg, 6.53 mmol) were added and the mixture was heated to 105° C. Following complete consumption of the starting material, the reaction mixture was cooled to room temperature and transferred to a 100 mL round bottom flask, and the solvent was removed under reduced pressure. Following purification by silica gel chromatography the desired product was obtained as a racemic mixture. MS (ESI, pos. ion) m/z: 402.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[CH3:34][O:36][C:37](=[O:40])[CH2:38][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(CCNC(=O)c3cc4ccccc4cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CCNC(=O)c1cc2ccccc2cc1O
Reaction time: 12 h
Yield: 24 %

Procedure:
To a solution of the 3-Hydroxy-naphthalene-2-carboxylic acid [2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (18 mg, 0.039 mmol) was in DMF were added ethylbromoacetate (0.039 mmol) and Cs2CO3 (0.039 mmol, 13 mg). The reaction mixture was for 12 hr and the reaction mixture was diluted with ethylacetate and washed with water. The organic layer was separated, dried and the crude obtained after removal of the solvent was purified on a silicagel column to afford the desired product 5 mg, and 5 mg of bis ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O.C(O)C.N>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Nc1n[nH]c2ccc([N+](=O)[O-])cc12)c1ccccc1
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1
Yield: 74.6 %

Procedure:
N-(5-Amino-1H-indazol-3-yl)benzamide can be obtained as described in Example 4 from 0.6 g of N-(5-nitro-1H-indazol-3-yl)benzamide, 21 ml of ethanol, 4.2 g of ferrous sulfate, 6.6 ml of water and 5.1 ml of 32% aqueous ammonia. 0.4 g of N-(5-amino-1H-indazol-3-yl)benzamide is thus obtained in the form of a yellow powder melting at 116° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[OH:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[OH:6]
Reactant: COc1cc([C@H](O)CN=[N+]=[N-])cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc([C@H](O)CN)cc(OC)c1OC
Yield: 95 %

Procedure:
A mixture of Example 23D (253 mg; 1.0 mmol) and 10% Pd/C (50 mg) in ethanol (7 mL) was stirred for 18 hours under hydrogen (balloon), filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was redissolved in ethanol, filtered again through diatomaceous earth, and concentrated to provide 216 mg (95%) of the desired product as an off-white solid which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19]/[CH:20]=[CH:21]/[C:22]#[N:23])[CH:16]=[C:15]([Cl:24])[C:14]=2[Cl:25])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH:16]=[C:15]([Cl:24])[C:14]=2[Cl:25])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C/C=C/C#N)cc(Cl)c1Cl)C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc(CCCC#N)cc(Cl)c1Cl)C1CC1
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl({2,3-dichloro-5-[(2E)-3-cyano-2-propen-1-yl]phenyl}methyl)carbamate (1 eq.) from the previous step in EtOAc (0.04 M) was added palladium (10% w/w over activated carbon, 0.1 eq). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1.5 h. The reaction was quenched with dichloromethane and filtered through a bed of celite. The insolubles were washed further with EtOAc. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](I)[N:20]=1>O1CCCC1.CN(C)C=O.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>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:21]2[CH:22]=[N:23][CH:24]=[C:19]([I:18])[N:20]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cncc(I)n1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 15.3 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid benzylamide (800 mg, 2.57 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (10 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min. at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2,6-diiodopyrazine (680 mg, 2.1 mmol, 0.8 equiv), Pd(PPh3)4 (236 mg, 0.2 mmol, 7 mol %) in tetrahydrofuran (5 mL) and dimethyl formamide (0.2 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 160° C. for 16 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 40:60, v/v] to afford 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (140 mg, 13%). MS (M+H)+=436, Rt=1.51 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-methylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.C(N(CC)CC)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[CH2:13]([NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(C(=O)OC(C)(C)C)n1cccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNn1cccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 113.3 %

Procedure:
A mixture of butyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.435 g), triethylamine (2.06 mL) and TMSOTf (1.79 mL) in DCM was stirred at rt for 15 min. The mixture was then diluted with DCM, washed with water, saturated sodium chloride solution and then dried over sodium sulfate, filtered, concentrated to give the desired product as oil (943 mg). 1H NMR (CDCl3, δ in ppm): 6.74 (m, 2H), 6.04 (m, 2H), 4.9 (very broad, 1H), 3.11 (t, 2H, J=7.1 Hz), 1.44-1.22 (m, 4H), 0.92 (t, 2H, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[CH2:31]([Zn+])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 3): tR=0.94 min; Mass spectrum (ESI+): m/z=505 [M+Na]+.