Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH3:45])=[C:34]([NH2:46])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH3:45])=[C:34]([NH:46][C:7](=[O:9])[CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: O=C(O)Cc1ccco1
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(N)c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 1.26 g of 2-furyl-acetic acid in 15 ml of dry DMF 1.50 g of HOAT, 2.11 g of EDC and 8 ml of DIPEA were added at 0° C. After 30 min 1.31 g of 3-Amino-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester were added, and the reaction was stirred at rt for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 1.85 g (100%) of 3-(2-Furan-2-yl-acetylamino)-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [OH2:1].[OH-].[K+].OO.[C:6]([N:10]1[C:14]([NH2:15])=[C:13]([C:16]#[N:17])[C:12]([CH3:18])=[N:11]1)([CH3:9])([CH3:8])[CH3:7]>C(O)C>[C:6]([N:10]1[C:14]([NH2:15])=[C:13]([C:16]([NH2:17])=[O:1])[C:12]([CH3:18])=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1nn(C(C)(C)C)c(N)c1C#N
Reactant: O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c(N)c1C(N)=O
Reaction time: 4 h
Yield: 94 %

Procedure:
To a mixture of water (200 mL), ethanol (120 mL) and KOH (37 g, 0.56 mol) at 0° C. was added 30% H2O2 (89.1 g, 0.786 mol), followed by 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (20.0 g, 0.112 mol). The reaction mixture was stirred for 4 hours and the product was collected by filtration, washed with water and dried to afford 20.64 g (94%) of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide, as white needles, m.p. 195°-196° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (0.5 g, 1.83 mmol) and commercially available 3-bromo-benzene-boronic acid (0.48 g, 2.39 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.11 g, 15%). MS (ISP) 395.0 [(M+H)+]; mp 102.5° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:51]([NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:52])[CH2:39][CH2:38]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 39% yield. LCMS for C29H29ClN7O (M+H)+: m/z=526.1. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 9.35 (br s, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.49-7.46 (m, 2H), 7.25-7.21 (m, 2H), 7.13-7.04 (m, 3H), 6.95-6.83 (m, 3H), 3.61 (br s, 4H), 2.99 (s, 4H), 2.84 (br s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][NH:25][C:26](C3C=CC=CC=3)([C:33]3C=CC=CC=3)[C:27]3C=CC=CC=3)=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:46]>CO.CC(C)=O>[ClH:46].[ClH:46].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][N:25]=[C:26]([CH3:27])[CH3:33])=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCC(O)COc2ccc(NNC(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(NN=C(C)C)nn2)cc1OC

Procedure:
A solution of 3-[3-[[2-(3.4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-6-(2-triphenylmethylhydrazino)pyridazine (330 g) and 37% hydrochloric acid (0.12 liter) in methanol (0.5 liter) and acetone (0.5 liter) was heated at reflux for 3 hours, then the solvent was evaporated under vacuum. The residue was diluted with n-butanol (100 ml). evaporated to dryness and triturated with acetone (1 liter) to afford 235 g of crude product which was dissolved in hot methanol (0.65 liter). The solution was filtered and dilured, while hot, with acetone (1.6 liter).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[C:34](Cl)(=[O:50])[O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2>O1CCOCC1.O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:34]([N:16]3[CH2:17][C@H:13]([O:12][C:3]4[C:2]([Br:1])=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:14][C@H:15]3[C:18]([OH:20])=[O:19])=[O:50])[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg, 0.687 mmol) in 1,4-dioxane (3 mL) and water (12 mL) was added potassium carbonate (380 mg, 2.75 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (178 mg, 0.687 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water, 0.1% TFA buffer) to afford the product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid (250 mg, 65% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.90-7.75 (m, 2H), 7.73-7.63 (m, 2H), 7.58-7.49 (m, 2H), 7.49-7.39 (m, 2H), 7.37-7.31 (m, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.20-7.14 (m, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.04 (td, J=7.4, 1.0 Hz, 1H), 4.68-4.56 (m, 2H), 4.51 (t, J=8.3 Hz, 1H), 4.44-4.33 (m, 2H), 4.27-4.16 (m, 2H), 3.99-3.92 (m, 1H), 3.81-3.73 (m, 1H), 3.73-3.64 (m, 1H). ESI-MS(+) m/z=337 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH2:11][C:12]1[C:13]([CH3:18])=[N:14][O:15][C:16]=1[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])[CH:8]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(Cl)cnc1=O
Temperature: 90 °C
Yield: 32.6 %

Procedure:
A mixture of 5-chloropyrimidin-2-one hydrochloride (0.668 g), 4-chloromethyl-3,5-dimethylisoxazole (0.874 g), anhydrous sodium carbonate (1.272 g) and benzyltrimethylammonium chloride (15 mg) in dimethylformamide (20 ml) was stirred and heated at 90° C. After 2.25 h the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (100 ml, 2×50 ml). The combined extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to an orange crystalline solid (0.811 g). The solid was subjected to preparative layer chromatography (p.l.c.) on silica developing with chloroform-ethyl acetate (1:1) (two runs). The major band was eluted with chloroform-ethanol (1:1) (three times) to give a cream crystalline solid (0.313 g) which was recrystallised from ethanol to give the title pyrimidone (0.189 g) m.p. 218°-219° C. (Kofler), λmax (EtOH) 225 nm (ε 9,300), 310 nm (ε 2,200) inflection at 245 nm (ε 4,300) νmax (CHBr3) 1677 cm-1 (C=O), (Nujol) 1668 cm-1 (C=O).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](S(C)(=O)=O)=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.O>O1CCCC1>[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13]([C:1]#[N:2])=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1
Reactant: [C-]#N
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C#N)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
An aqueous solution (2 ml) of sodium cyanide (338 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (758 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OCC)(OCC)(OCC)[CH3:26]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:25]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: CCOCC
Product: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 160 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the resulting solution was heated at reflux (160° C.) overnight. The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate formed. Diethyl ether was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 6.81 g of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:17]([CH3:18])[CH2:16][N:15]([C:19]2[C:28]([F:29])=[CH:27][C:26]3[C:30](=[O:36])[C:31]([C:33]([OH:35])=[O:34])=[CH:32][N:24]4[C:25]=3[C:20]=2[CH2:21][CH2:22][N:23]4[CH3:37])[CH2:14]1)=[O:11])=O)(C)(C)C.C(O)C.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:17]([CH3:18])[CH2:16][N:15]([C:19]2[C:28]([F:29])=[CH:27][C:26]3[C:30](=[O:36])[C:31]([C:33]([OH:35])=[O:34])=[CH:32][N:24]4[C:25]=3[C:20]=2[CH2:21][CH2:22][N:23]4[CH3:37])[CH2:14]1)=[O:11]
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
750 mg (1.5 mmol) of the compound (84) obtained in Example 10 (1) was added to 10 ml of dioxane and 10 ml of ethanol, and then 2.5 ml of 4N hydrochloric acid solution in dioxane was added to the solution. The solution was stirred at room temperature for 1 hour, and the solvent was removed by distillation. The powder was filtered off and washed successively with ethanol and ether to obtain 324 mg of the subject compound (88) in a 49% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].B(OC(C)C)(OC(C)C)OC(C)C.C([N-]C(C)C)(C)C.[Li+].Br[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:6]2[N:2]([CH3:1])[C:3]([C:7]#[N:8])=[CH:4][CH:5]=2)=[CH:32][CH:33]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Cn1cccc1C#N
Agent: [Pd]
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Solvent: COCCOC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred solution of 1-methyl-2-cyanopyrrole (1.6 g, 15 mmol) and triisopropyl borate (7.0 mL, 30 mmol) in THF (45 mL) at 0° C. was added lithiumdiisopropylamide (LDA—2.0 M in heptane/THF/ethylbenzene, 13.3 mL, 26.6 mmol) in a dropwise fashion over 45 minutes. The resulting solution was stirred at 0° C. for 1 hour. To the solution was added 1-(4-bromophenyl)-ethanone (1.0 g, 5 mmol) dissolved in glyme (45 mL), sodium carbonate (1.59 g, 15 mmol) dissolved in water (9 mL), and tetrakis(triphenylphosphine) palladium (0) (0.28 g, 0.25 mmol). The resulting solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and partitioned between a saturated ammonium chloride solution (50 mL) and ethyl acetate (80 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a yellow solid (0.62 g, 55%). MS (ES) m/z 225.1; HRMS: calcd for C14H12N2O+H+, 225.1022; found (ESI, [M+H]+), 225.1039.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]3[C:23]([C:37]([F:40])([F:39])[F:38])=[N:24][N:25]([C:26]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=4[C:28](Cl)=[O:29])[C:19]=3[C:18]2=[O:41])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH3:42]>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]3[C:23]([C:37]([F:40])([F:39])[F:38])=[N:24][N:25]([C:26]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=4[C:28]([NH2:42])=[O:29])[C:19]=3[C:18]2=[O:41])=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-c4ccccc4S(C)(=O)=O)cc2)CC3)c(C(=O)Cl)c1
Reactant: N
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-c4ccccc4S(C)(=O)=O)cc2)CC3)c(C(N)=O)c1

Procedure:
Part C: 2-[6-(2′-Methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride (0.10 mmol) was dissolved in dry dichloromethane (1 mL) under a nitrogen atmosphere, and a stream of ammonia gas was introduced for 30 sec. The solvent was evaporated, and the residue was purified by reverse phase HPLC to give the title compound as a colorless solid. MS (ES+) 607.1 (M+Na)+(100%); 1H NMR (DMSO-d6) δ 8.08 (d, 1H, J=6.6 Hz), 7.79-7.34 (m, 10H), 7.16 (d, 1H, J=2.9 Hz), 7.09 (dd, 1H, J=8.5, 2.6), 4.11 (t, 2H, J=6.4 Hz), 3.84 (s, 3H), 3.11 (t, 2H, J=6.4), 2.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9](Br)=[CH:8]2)=[O:4].[C:24]1([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCC(CC)Cn1c(=O)c(Br)cc2c(O)c(C(=O)OC)ncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Temperature: 120 °C
Yield: 56.6 %

Procedure:
A mixture of 3-bromo-1-(2-ethyl-butyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (500 mg, 1.3 mmol), PhSnBu3 (0.51 mL, 1.6 mmol), and PdCl2(PPh3)2 (183 mg, 0.26 mmol) in DMF (25 mL) was heated at 120° C. under nitrogen atmosphere for 3 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (3-35% EtOAc/hexanes+1% AcOH) to give 280 mg of the title compound as a yellow solid. MS: (+) m/z 381.34 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]([O:10][C:11]2[N:16]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:14]([N+:27]([O-])=O)=[CH:13][N:12]=2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CCOC(C)=O.CCO.[Pd]>[NH2:27][C:14]1[C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[N:16][C:11]([O:10][C:7]2[N:6]=[C:5]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:4]([NH2:1])=[CH:9][N:8]=2)=[N:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ncc([N+](=O)[O-])c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnc(Oc2ncc(N)c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Temperature: 25 °C

Procedure:
The crude nitronaphthyl-pyrimidinyl ether from above (459 mg, 1.42 mmol, 1 equiv.) was taken up in 35 mL EtOAc and 35 mL EtOH. Ammonium formate was added (537 mg, 8.52 mmol, 6 equiv.) as well as 400 mg of 10% palladium-on-carbon. The reaction mixture was heated to a gentle reflux for one h, cooled back to room temperature, filtered through diatomaceous earth and the volatiles were removed in vacuo. The crude product was purified by chromatography on SiO2, eluting with 20-40% EtOAc in hexanes. The desired aminonaphthyl-pyrimidinyl ether was isolated as a yellow foam (176 mg, 0.6 mmol, 42% for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1.FC(F)(F)C(O)=[O:33].[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:25][CH2:26][CH:27]([OH:33])[CH2:29][OH:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC(O)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg) was dissolved in dichloromethane (2 ml) to prepare a solution. Trifluoroacetic acid (2 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 4 hr. The reaction solution was made alkaline by the addition of 1 N sodium hydroxide, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, yield 29%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[Cl:17][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([N+:26]([O-:28])=[O:27])[C:19]([F:18])=[CH:20][C:21]=2[O:29][CH3:30])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 79 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 1.4 g, 5.28 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.032 g, 5.55 mmol) and p-toluenesulfonic acid monohydrate (1.105 g, 5.81 mmol) was heated at 125° C. in 2-pentanol (40 mL) for 18 h. The mixture was then cooled and a solid was collected by filtration. The solid was washed with CH3OH and diethyl ether, and was then dried on the filter to give the title compound (1.73 g, 79%) as a yellow powder; 1H NMR: 3.98 (3H, s), 7.16 (1H, td), 7.33-7.48 (2H, m), 8.49 (1H, d), 8.53 (1H, d), 8.66 (1H, d), 8.86 (1H, d), 8.90 (1H, s), 8.96 (1H, s).