Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:19])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:19])=[CH:6][CH:5]=1
Reactant: Cc1cc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2ccccc2n1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred suspension of the above nitro compound ( 300 mg, 1.2 mmol) in EtOH (25 mL) and EtOAc (5 mL) was added solid ammonium formate (750 mg, 11.9 mmol) followed by 10% Pd—C (50 mg). The mixture was stirred for 2 h at room temperature, and then filtered through a short pad of diatomaceous earth and washed with EtOH/EtOAc. The filtrate was concentrated to give 1-(4-aminophenyl)-2-methylindol (0.22 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-]#N.[Na+].[CH3:23][N:24](C=O)C>C(OCC)(=O)C.O>[OH:19][C@@H:16]1[CH2:15][CH2:14][C@H:13]([CH2:12][C:23]#[N:24])[CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](O)CC2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC[C@H]1CC[C@@H](O)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (cis-4-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate (6.9 g, 24 mmol) (first fraction from last step), sodium cyanide (1.43 g, 29.1 mmol) and DMF (86 mL) was stirred at 80° C. for 1 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate once. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified with flash chromatography (eluting with a gradient of 0-50% ethyl acetate in hexanes) to give the desired product (2.5 g, 74%). 1H NMR (300 MHz, CDCl3) δ 3.58 (m, 1H), 2.27 (d, J=6.3 Hz, 2H), 2.02 (m, 2H), 1.88 (m, 2H), 1.78-1.45 (m, 2H), 1.42-1.07 (m, 4H) ppm.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[C:17]1([N:23]2[CH:27]=[N:26][C:25]([C:28](O)=[O:29])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:28]([C:25]4[N:26]=[CH:27][N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=4)=[O:29])[CH2:12]3)[C:6]=12
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3cnnc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a suspension of the above (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (90 mg, 0.32 mmol), 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (58 mg, 0.30 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 23 mg of the title compound (20% yield) as white solid. 1H NMR (400 MHz, d6-DMSO) δ 2.10-2.38 (two sets of m, 2 H), 3.50-4.60 (br, 4 H), 4.65 (m, 1 H), 7.29 (d, J=4.4 Hz, 1 H), 7.46 (t, J=7.3 Hz, 1 H), 7.59 (t, J=7.3 Hz, 2 H), 7.75 (d, J=4.7 Hz, 1 H), 7.90 (d, J=8.0 Hz, 2 H), 9.00 (d, J=7.0H, 1 H), 9.20 (s, 1 H), 9.40 (s, 1 H). MS: (ES) m/z calculated for C18H17N9O [M+H]+ 376.2, found 376.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11](OC)=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:18][NH2:19].O>C(O)C>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11]([NH:18][NH2:19])=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(=O)NN)s1
Yield: 89 %

Procedure:
Methyl 5-(diethylcarbamoyl)thiophene-2-carboxylate (247 mg, 1.02 mmol) in ethanol (9 mL) was stirred with hydrazine monohydrate (495 mg, 10.2 mol) at 90° C. for 6 hours. After addition of water, the reaction solution was extracted with ethyl acetate and chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 89%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[OH-].[NH4+:14]>CO.[Ni]>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([NH2:14])[CH3:2])=[CH:5][C:6]=2[CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: [NH4+]
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)CCO2
Yield: 70 %

Procedure:
A mixture of 5-acetyl-2,3-dihydrobenzo[b]furan, oxime, (Preparation 3, 2.7 g, 16 mmole) in methanol (50 mL), ammonium hydroxide (5 mL) and Raney nickel (3 mL) was hydrogenated on a Parr hydrogenator (H2, 50 psi) for 2 days. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using methanol (100%) to give the title compound (1.74 g, 70%) as a brown oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].C([N:15]1[CH2:19][CH2:18][C@H:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16]1)C1C=CC=CC=1.CO.O>CCCCCCC>[CH2:5]([O:4][C:2]([N:15]1[CH2:19][CH2:18][CH:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16]1)=[O:3])[CH:6]=[CH2:7]
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: C=CCOC(=O)Cl
Solvent: O
Solvent: CO
Solvent: CCCCCCC
Product: C=CCOC(=O)N1CCC(OS(C)(=O)=O)C1
Reaction time: 0.75 h

Procedure:
6.4 ml of allyl chloroformate were added dropwise to 10.2 g of methanesulphonic acid (S)-1-benzyl-pyrrolidin-3-yl ester in 880 ml of n-heptane at room temperature within 10 minutes under argon and with slight cooling. The two-phase mixture was stirred vigorously for 2 hours 45 minutes and subsequently treated with 40 ml of methanol/water (1:1). The aqueous methanolic phase was separated, extracted with 40 ml of heptane and thereafter the methanol was distilled off on a rotary evaporator. The aqueous phase was extracted twice with 30 ml of ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered and the filtrate was concentrated. 8.23 g of beige oil were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[O:6])[CH2:4]Cl.[CH2:8]([PH:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:1][N:2]([CH3:7])[C:3]([CH2:4][P:16](=[O:25])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:6]
Reactant: CCCCCCCC[PH](=O)CCCCCCCC
Reactant: CN(C)C(=O)CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCP(=O)(CCCCCCCC)CC(=O)N(C)C
Yield: 82.1 %

Procedure:
Into a 500 ml, three-necked, round-bottom flask equipped with a thermowell, a mechanical stirrer, a condenser and a septum, was placed a solution of 13.4 g (0.11 mole) of N,N-dimethylchloroacetamide, 27.4 g (0.10 mole) of di(n-octyl)phosphine oxide, and 1.0 g of Adogen 464 in 150 ml of methylene chloride along with 100 ml of 50% sodium hydroxide solution. The solution was stirred at 300 rpm under a gentle reflux until GLC analysis of removed aliquots (2 hours) indicated the consumption of the starting materials. The aqueous layer was extracted with 50 ml of pentane and the combined organic layers were washed with three 50 ml portions of water followed by one 50 ml portion of saturated sodium chloride solution. After drying over anhydrous potassium carbonate, and filtering, the filtrate was evaporated in vacuo (80° C.; 2mm Hg) to yield 29.5 g of an amber oil which was 77% pure by GLC. Upon cooling, the oil crystallized. Recrystallization from pentane afforded a colorless hygroscopic solid which was chromatographically pure, Mp 38.5-40.5. Analytical data obtained for this product is summarized in Table I.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C.C(OCC)(=O)C.CO>O1CCOCC1>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
600 ml of a methanolic solution containing 10% w/v hydrogen chloride were added to a solution of 140 g of (2S,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl] -1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine dissolved in 150 ml of dioxane, and the resulting mixture was stirred at 50° C. for 1 hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 1500 ml of ethyl acetate, after which it was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The mixture was then washed with 300 ml of water and with 300 ml of an aqueous solution of sodium chloride, after which it was freed from the solvent by distillation under reduced pressure. The residue thus obtained was subjected to column chromatography through silica gel using mixtures of ethyl acetate and methanol ranging from 30:1 to 20:1 by volume as the eluent. Those fractions containing the desired compound were collected and concentrated to afford 96.44 g of the title compound as a colorless powder.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[CH:9]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([N:22]1[CH2:27][CH2:26][N:25]([CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)[CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1cscn1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(Cc3cscn3)CC2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
A mixture of 4-chloromethylthiazole monohydrochloride (1.7 g), 1-benzhydrylpiperazine (3.21 g) and potassium carbonate (5.3 g) in N,N-dimethylformamide (40 ml) was stirred at 65° C. for 2 hours. After concentration of the reaction mixture, the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was chromatographed on silica gel (120 g) using a mixture of chloroform and methanol (50:1 by volume) as an eluent. The eluates containing the desired compound were collected and evaporated to dryness under reduced pressure to give crystals, which were recrystallized from chloroform to obtain white crystals (1.2 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[N:21][CH:20]=[CH:19]4)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[S:26]([N:29]=CN(C)C)(=[O:28])=[O:27].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[N:21][CH:20]=[CH:19]4)[CH2:13][CH2:14]2)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27]
Reactant: CN(C)C=NS(=O)(=O)c1cc(CN2CCC(Oc3ccc4cnccc4c3)CC2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc(CN2CCC(Oc3ccc4cnccc4c3)CC2)ccc1Cl
Temperature: 60 °C

Procedure:
133 mg (0.27 mmol) of 2-Chloro-N-dimethylaminomethylene-5-[4-(isoquinolin-6-yloxy)-piperidin-1-ylmethyl]-benzenesulfonamide (169) were dissolved in ethanol. After adding 50 ml of 2N NaOH, the solution was heated to 60° C. for 6 h. After cooling to room temperature, the mixture was neutralized by addition of aqueous HCl and the solvent was removed i. vac. The residue was stirred with ethanol, the inorganic salts were filtered off and the filtrate was evaporated. Rt=0.78 min (Method #2), Detected mass: 432.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20 g, 0.09 mol) in MeOH (400 mL) was added Ni (2 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a pad of Celite and the filtrate was evaporated under vacuum to give crude product, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=10:1) to give methyl 1-(4-aminophenyl)cyclopropanecarboxylate (11.38 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.1 Hz, 2 H), 6.86 (d, J=7.8 Hz, 2 H), 4.31 (br, 2 H), 3.61 (s, 3H), 1.55-1.50 (m, 2 H), 1.30-1.12 (m, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2[nH]1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2[nH]1
Yield: 58.9 %

Procedure:
The procedure of Method A was followed in that -indolesulfonamide (10.2 mmol) was reacted with 4-chlorophenylisocyanate (10.2 mmol) to obtain 2.1 g of title product as a solid. The 2-indolesulfonamide was prepared by procedures well known in the art. See, e.g., European Patent Application 070698 (published Jan. 26, 1983). 1H NMR (CD3SOCD3): δ12.14 (s, 1 H), 10.82 (bs, 1 H), 9.07 (s, 1 H), 7.73 (d, J =8 Hz, 1 H), 7.56 (d, J =8 Hz, 1 H), 7.43 (d, J =9 Hz, 2 H), 7.34 (d, J =9 Hz, 2 H), 7.32 (m, H), 7.19 (m, 1 H), 7.15 (dd, J =6, 8 Hz, 1 H).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:28]1[CH2:31][CH:30]([C:32]([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([CH:41]3[CH2:44][CH2:43][CH2:42]3)[CH2:36][CH2:35]2)=[O:33])[CH2:29]1>ClCCl.CN(C=O)C>[CH:41]1([N:37]2[CH2:38][CH2:39][CH2:40][N:34]([C:32]([CH:30]3[CH2:29][N:28]([C:10]([C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)=[CH:14][CH:13]=4)=[O:12])[CH2:31]3)=[O:33])[CH2:35][CH2:36]2)[CH2:44][CH2:43][CH2:42]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 4.3 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)benzoic acid (150 mg, 0.80 mmol) in dichloromethane (10 mL) cooled to 0° C. was added oxalyl chloride (1 mL). DMF (2 drops) was added and the mixture was stirred for 45 min at 0° C. and volatiles were then removed at reduced pressure. The residue was diluted with dichloromethane (20 mL), cooled to 0° C. and triethylamine (201 mg, 2.0 mmol) was added followed by 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (187 mg, 0.79 mmol). The resulting mixture was stirred at RT for 16 h before being diluted with more dichloromethane (50 mL) and quenched by addition of water (50 mL). The organic layer was then washed with saturated aqueous NaHCO3 (50 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (using a gradient of eluents; 97:3 to 95:5 DCM/2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (14 mg, 4% yield) as pale yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=NOCCBr)C1(C)OCCO1

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer)(218.9 g), ethylene glycol (156 ml), and benzene (400 ml) was refluxed in the presence of p-toluenesulfonic acid monohydrate under an azeotropic dehydration condition for 3 days. The mixture was poured into a mixture of ethyl acetate and saturated aqueous solution of sodium bicarbonate under ice-cooling. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a residue. The resiue was distilled at 2 mmHg at 144° to 149° C. to give ethyl 2-(2-bromoethoxyimino)3,3-ethylenedioxybutyrate (syn isomer)(333.3 g) as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH3:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 8.9 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 5.0 g of 1-(2-chlorophenyl)ethanol, 11.2 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 9.8 g of di-tert-butyl azodicarboxylate in 260 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: CN(CN(C)C)C.C(Cl)(=O)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[N:15]=1.C[N:31]([CH2:33][C:34]1C2C(=CC=C(OC3N=C(OC)C=CN=3)C=2)NC=1)C.[C-]#N.[K+].CI>C(Cl)Cl.CN(C=O)C>[C:33]([CH2:34][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([O:20][C:16]3[N:15]=[C:14]([O:13][CH3:12])[CH:19]=[CH:18][N:17]=3)[CH:22]=2)[NH:26][CH:25]=1)#[N:31]
Reactant: COc1ccnc(Oc2ccc3[nH]cc(CN(C)C)c3c2)n1
Reactant: COc1ccnc(Oc2ccc3[nH]ccc3c2)n1
Agent: CN(C)CN(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccnc(Oc2ccc3[nH]cc(CC#N)c3c2)n1

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (1.18 g, 1.58 mL, 11.5 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.90 g, 0.81 mL, 11.5 mmol) followed by a solution of 5-(4-methoxypyrimidin-2-yloxy)indole (2.0 g, 8.2 mmol) in CH2Cl2 (100 mL), gave after work-up: 3-(N,N-dimethylaminomethyl)-5-(4-methoxypyrimidin-2-yloxy)indole as a white solid. This was treated with finely ground potassium cyanide (1.75 g, 26.8 mmol) and methyl iodide (3.80 g, 1.65 mL, 26.8 mmol) in DMF (130 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4-methoxypyrimidin-2-yloxy)indole was obtained as a white solid, 2.20 g (96%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(F)c2)cc1
Yield: 29.6 %

Procedure:
The title compound (85 mg, 30%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (275 mg, 0.818 mmol, prepared in example 1), 3-fluorobenzeneboronic acid (140 mg, 1.001 mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.033 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water), and 1,2-dimethoxyethane (5.5 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 270 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]