Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=O)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[N+:1]([C:4]1[C:5](/[CH:14]=[N:22]/[S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
Titanium tetra-ethoxide (1.2 ml, 4.95 mmol) was added to a solution of 8-nitro-quinoline-7-carbaldehyde (Intermediate 204) (0.5 g, 2.47 mmol) and 2-methylpropane-2-sulfinamide (660 mg, 5.4 mmol) in THF (20 ml) under a nitrogen atmosphere and the mixture was heated under reflux for 17 h. The solution was cooled to room temperature and poured into rapidly stirring brine (40 ml) and stirred for 30 min. EtOAc (40 ml) was added and the mixture was filtered through Celite and washed with EtOAc (40 ml). The aqueous phase was extracted with EtOAc. The organic phases were dried (MgSO4) and concentrated in vacuo. The solid was purified by column chromatography using heptane/EtOAc (1:1) to give the title compound (577 mg, 76%). The compound could not be detected by HPLCMS therefore structure was confirmed by 1H NMR.
Reaction SMILES: CN(C=O)C.Br[C:7]1[O:11][C:10]([C:12]2[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[N:17]2)=[N:9][CH:8]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45]([CH:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]3)[CH:46]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(N(CC)CC)C.COCCOC.C1COCC1.[Pd](Cl)Cl>[F:30][C:25]1[CH:24]=[C:23]([C:18]2[CH:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][C:14]3[CH:13]=[C:12]([C:10]4[O:11][C:7]([C:42]5[CH:43]=[N:44][N:45]([CH:47]6[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:51][CH2:52]6)[CH:46]=5)=[CH:8][N:9]=4)[CH:33]=[CH:32][CH:31]=3)[N:17]=2)[CH:28]=[C:27]([F:29])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(Br)o2)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)c4)o3)cn2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
21 mg (0.029 mmol) of bistriphenylphosphine)palladium(II) chloride, one drop of triethylamine and 200 μl of DMF are added to a suspension, kept under nitrogen, of 131 mg (0.294 mmol) of 2-[3-(5-bromooxazol-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one, 144 mg (0.382 mmol) of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-piperidine-1-carboxylate and 135 mg (0.382 mmol) of tripotassium phosphate trihydrate in 1.2 ml of 1,2-dimethoxyethane, and the mixture is stirred at 80° C. for 18 hours. The reaction mixture is diluted with THF and filtered off with suction. The filtrate is washed twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol, giving tert-butyl 4-[4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}oxazol-5-yl)pyrazol-1-yl]piperidine-1-carboxylate as yellow-ish crystals; ESI 615.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)CCC1=O.O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)(=O)C>[Cl:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: ClCc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 2-chloro-4-methyl-pyridine (7.28 g, 57.1 mmol), N-Chlorosuccinimide (11.4 g, 85.3 mmol), benzoyl peroxide (276 mg, 1.13 mmol), and acetic acid (200 μL, 3.5 mmol) in acetonitrile (30 mL) was heated at reflux for 2.5 h. The mixture was allowed to cool to room temperature, then poured into water (10 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo at 35° C., yielding the crude product of 4-(chloromethyl)-2-chloropyridine (9.25 g) as an oil. The crude oil was carried on to the hydrolysis step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[CH2:6][CH2:7][CH3:8].[CH3:19]O>>[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([C:14]([O:16][CH3:19])=[O:15])[CH:17]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.5 ml (0.17 mol) of thionyl chloride are added dropwise with ice-cooling to a suspension of 29.25 g (0.15 mol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 200 ml of methanol and the mixture is stirred overnight at room temperature. It is concentrated to dryness and the residue is chromatographed on 450 g of silica gel (230-400 mesh) using dichloromethane→dichloromethane/methanol 10:1. 29.6 g (94%) of colourless crystals m.p.: 106° C. crystallise from dichloromethane, ether and petroleum ether.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 97.9 %

Procedure:
A solution of 4-(diphenylmethoxy)piperidine (5) (1.4 g, 5.2 mmol), methyl acrylate (560 mg, 6.5 mmol) and methanol (9.5 mL) was placed on a preheated orbital shaker at 75° C. for 3 h. The yellow solution was concentrated to yield 1.8 g (98%) of 6b as a yellow oil. The structure was confirmed by 1H NMR. (The propanoate esters 6c and 6e were similarly prepared.)
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19](OC)=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.[C:30]1([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.IC1C=CC(C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]1([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:17]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:37][C:38]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Ic1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Yield: 840.5 %

Procedure:
Xylene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.8 g, 4.4 mmol) and Pd2(dba)3 (1.0 g, 1.1 mmol). The mixture was bubbled with nitrogen for 15 min, then [1,1′:3′,1″-terphenyl]-4′-amine (9.8 g, 40.0 mmol), 4-iodobiphenyl (10.3 g, 36.7 mmol), sodium tert-butoxide (7.0 g, 73.4 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 13 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene. The solvent was removed in vacuo and the residue was purified by flash chromatography using 40-60% toluene/hexane to afford N-([1,1′-biphenyl]-4-yl)-[1,1′:3′,1″-terphenyl]-4′-amine (14.7 g, 92% yield) as a white solid.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:25]([C@H:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:12][C:2](=[O:3])[NH:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@@H](Cc1ccccc1)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)C(c2ccccc2)(c2ccccc2)O1
Reaction time: 5 h
Yield: 97.5 %

Procedure:
Trichloromethyl chloroformate (718 mg, 3.63 mmol) was added to a mixture of (S)-2-amino-1,1,3-triphenyl-1-propanol (6) (1.00 g, 3.30 mmol) and triethylamine (710 mg, 7.02 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 5 h at the same temperature and then poured into a brine solution (150 ml). The aqueous layer was made basic with powdered K2CO3 and organics were extracted into dichloromethane (3×50 ml). The combined organic extracts were dried over MgSO4/K2CO3 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to obtain the title compound (7) (1.06 g, 97%) as a white solid. m.p. 259–261° C. (lit ? ° C.). [α]D25=−241.94° (c, 0.0211 in DMSO), δH (DMSO-d6) 2.18 (1H, dd, 3J=10.8 Hz, 2J=13.8 Hz, CH2—Ph), 2.52 (1H, dd, 3J=3.6 Hz, 2J=13.8 Hz, CH2—Ph), 4.67 (1H, dd, 3J=3.6 Hz, 3J=10.8 Hz, CH—NH2), 6.90–7.60 (15H, m, Ar—H). δC 44.2 (CH2—Ph), 50.5 (CH—NH), 94.1 (C—O), 130.5, 130.9, 131.5, 132.6, 132.8, 133.0, 133.1, 133.3 and 133.4 (o-, m- and p-Ar), 141.1, 143.4 and 146.5 (α-Ar), 163.7 (C═O), ir 3248 (NH2), 1760 and 1725 (C═O). m/e (CI—NH3) 330 (MH+, 5%), 347 (MNH4+, 6%), 196 (100%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([C:51]4[CH2:52][CH2:53][O:54][CH2:55][CH:56]=4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.C1COCC1.Cl.O1CCOCC1>CO>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (4.0 mg, 0.005 mmol) in MeOH (0.3 mL) and THF (0.3 mL) 10% Pd on carbon (2 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.053 mL, 0.21 mmol) and stirred at room temperature for 30 min. then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (1.8 mg, 65%). LCMS calc. for C28H34N9O2 (M+H)+: m/z=528.3. Found: 528.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:13](=O)[C@@H:12]2[CH2:15][CH2:16][CH2:17][N:11]2[C:9](=O)[CH2:8]1.OC1C2C(=CN=CC=2)NC(=O)C=1C1NC2C=C(C)C=CC=2N=1>>[N:11]12[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][NH:7][CH2:8][CH2:9]2
Reactant: O=C1NCC(=O)N2CCC[C@@H]12
Agent: Cc1ccc2nc(-c3c(O)c4ccncc4[nH]c3=O)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Product: C1C[C@H]2CNCCN2C1

Procedure:
(6S)-1,4-diazabicyclo[4.3.0]nonane was synthesized as shown above by LAH (lithium aluminum hydride) reduction of commercially available Cyclo-Gly-Pro, employing the literature procedure set forth in the following reference which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein: de Costa B. R. et al. J. Med. Chem., 1993, 36, 2311. Conversion to the concomitant 3-[6-((1S)-3,6-diazabicyclo[4.3.0]non-3-yl)benzimidazol-2-yl]-4-amino-5-fluorohydroquinolin-2-one was performed according to the procedure in Example 8 (LC/MS m/z 419.1 (MH+), Rt 1.96 minutes).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[C:25](O)(=[O:27])[CH3:26]>C(OC(=O)C)(=O)C>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:25](=[O:27])[CH3:26])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCNc1cc(CNC(C)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 3n-butylamine-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) in acetic acid (10 ml), acetic anhydride (0.4 ml) is added and the mixture is left for 24 hours. Dilution with water (25 ml) precipitates N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide, which is collected by filtration, washed with water and dried in air. After recrystallization from aqueous ethanol it is obtained with a melting point of 190°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@H:26]5[CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:43]#[N:44].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[C:43]([C@@H:28]1[CH2:29][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[CH:19]=2)=[O:22])[CH3:25])[CH2:27]1)#[N:44]
Reactant: [C-]#N
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OS(C)(=O)=O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Temperature: 100 °C

Procedure:
To a solution of methanesulfonic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (crude from step 1, 97 mg, 0.16 mmol) in DMSO (1.5 mL) at room temperature was added potassium cyanide (41 mg, 0.63 mmol) and 18-crown-6 (8 mg, 0.03 mmol). The reaction mixture was heated at 100° C. overnight then cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified via chromatography with 20% to 50% EtOAc/hexanes to isolate 34 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyano-cyclobutyl)-ethyl]-amide as a yellow foam.
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:6]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:8]=[C:9]([CH3:23])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[N:15]3)=[C:11]([CH3:13])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
To a solution of methyl (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinate (753 mg, 1.59 mmol) in tetrahydrofuran (7.97 mL) and methanol (7.97 mL) was added 1 N aq sodium hydroxide (7.97 mL, 7.97 mmol). After 16 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium chloride (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure to provide (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid. 1H NMR (400 MHz, CDCl3, δ): 8.68 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.15 (s, 2H), 6.39 (d, J=9.2 Hz, 1H), 4.28-4.18 (m, 1H), 2.44-2.31 (m, 1H), 2.12-2.05 (m, 1H), 2.01 (s, 6H), 1.78-1.40 (m, 6H), 1.36-1.28 (m, 1H). MS (M+1): 459.5.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].CCOCC>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: COc1ccc(B(O)O)cc1OC
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cc1OC

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.335 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3,4-dimethoxyphenylboronic acid (0.273 g) in ethanol (1 ml). The mixture was heated under reflux for 5 hours, cooled and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, washed with water (2×25 ml), brine (25 ml) and then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (30 g) eluted with dichloromethane: ethanol (99:1). Combination and evaporation of suitable fractions gave the title compound as a pale pink crystalline solid, m.p. 250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH3:21])[C:18]([NH2:20])=[NH:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[CH:26]([CH:28]([CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)[C:29](OC)=O)=[O:27]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH3:21])[C:18]3[NH:20][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:26](=[O:27])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(N(C)CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 200 °C
Yield: 18.6 %

Procedure:
To the solution of N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (78 mg, 0.350 mmol) in NMP (5 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (33 mg, 0.050 mmol, 18.5% yield). LCMS: rt=3.14 min, [M+H+]=545.9
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]3([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[C:40]([O:39][C:38](=[O:44])[NH:37][CH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:31][CH:30]=2)[CH2:35][CH2:34][CH2:33]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Yield: 51 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.9 g, 6.0 mmol) was reacted with tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)methylcarbamate (3.5 g, 9.0 mmol) to afford the desired product (1.5 g, 33%) as a light brown solid: ESI MS m/z 491 [C28H30N2O4S+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 76 %

Procedure:
Following the procedure for Example 517 starting with (R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (0.148 g, 76%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.95 (s, 1H), 7.43-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.57 (m, 12H).