Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].CO>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])=[C:6]([N+:21]([O-:23])=[O:22])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccn1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1c(-c2ncccn2)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 5400.6 %

Procedure:
To a 5° C. suspension of N-(4-bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide (32.6 grams, 97.5 mmoles) in TFA (400 mL) was added 90% nitric acid (70 mL, 1.46 mmoles) over a 30 minute period. The mixture was then allowed to warm to room temperature and stir for a total of 2 hours. The crude reaction (now homogenous) was poured into ice producing a pasty mass. The mixture was diluted to 2 L total volume with water, treated with 500 mL of methanol, and vigorously stirred for 12 hours. The resulting solids were filtered, washed with copious amounts of water, then vacuum dried at 50° C. to afford the title compound (29.9 grams, 81% yield) as a tan powder.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[CH3:23])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:34](OC(C)C)([O:39]C(C)C)[O:35]C(C)C.[OH-].[Na+]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:34]([OH:39])[OH:35])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[C@H:11]([CH3:23])[CH2:12]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Yield: 73.4 %

Procedure:
To a 150-mL round-bottomed flask was added (3R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (3.0 g, 9.28 mmol), and tetrahydrofuran (100 mL, 9.28 mmol). The solution was stirred at −78° C. and treated dropwise via syringe with butyllithium solution, 2.5 m in hexanes (4.08 mL, 10.20 mmol) (Aldrich). The solution was stirred at −78° C. for 1 hr and treated in one portion with triisopropyl borate (2.55 mL, 11.13 mmol) (Aldrich). The mixture was stirred at −78° C. for 1 hour. NaOH (1.0N (30 mL) was added and the solution was stirred at room temperature for 30 minutes. The aqueous layer was separated and the organic layer was extracted with additional NaOH (1.0N, 30 mL). The combined aqueous layer was carefully acidified with 5N HCl (12 mL) to a final pH of about 4 to 5. The reaction mixture was extracted with EtOAc (3×100 mL) and the organic extract was dried over sodium sulfate, filtered and concentrated under a vacuum to give 5-(1-((R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (2.5 g, 6.81 mmol, 73.4% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Benzyloxy-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H28O6 [M−H]−: 435.
Reaction SMILES: [H-].[K+].[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][OH:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22]I>O1CCCC1>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][O:21][CH3:22])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1Cc2ccccc2N(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
2.3 g of a potassium hydride suspension (20% in oil) are added to a solution of 2.6 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline in 30 ml of tetrahydrofuran at 0° C., while stirring, and 1.9 ml of methyliodide are then added. After 1 h, the reaction mixture is concentrated and the residue is purified over 160 g of silica gel with a 20:1 mixture of hexane and ethyl acetate. 1-Benzyl-3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinoline is obtained as a yellow solid: Rf (20:1 mixture of hexane and ethyl acetate)=0.32. A solution of 2.9 g of the product thus obtained in 30 ml of tetrahydrofuran is hydrogenated in the presence of 0.6 g of palladium-on-charcoal under the customary conditions. Purification of the crude product over 80 g of silica gel with methylene chloride as the eluting agent gives 3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinoline: Rf (methylene chloride)=0.32; Rf (A)=0.56.
Reaction SMILES: O1CCCC1.C(CC[N:10]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]1[S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)#N.Cl.O>C(OCC)(=O)C>[N+:15]([C:14]1[N:10]=[C:11]([S:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[NH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: N#CCCn1c([N+](=O)[O-])cnc1Sc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Sc2nc([N+](=O)[O-])c[nH]2)cc1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To tetrahydrofuran (1 ml) solution of 1-(2-cyanoethyl)-5-nitro-2-(4-nitrophenylthio)imidazole (36 mg) was added 1,8-diazabicyclo[5.4.0]undecene-7 (0.02 ml) at a room temperature, and stirred at the same temperature for 5 hours. To the reaction mixture were added 1N hydrochloric acid (0.2 ml), water and ethyl acetate, then the organic layer was taken by liquid separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate=4/1), there was obtained 4-nitro-2-(4-nitrophenylthio)imidazole (27 mg, yield 91%) as pale yellow powder product.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[S:19]([NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)(=[O:21])=[O:20])[CH2:13][CH2:12]1)(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)CCCC.C(Cl)(=O)C1C=CC=CC=1>>[C:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:19]([NH:22][C:23](=[O:38])[C:24]2[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=2)(=[O:21])=[O:20])[CH2:13][CH2:12]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(COC(=O)c2ccccc2)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCCC(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CCCCC(=O)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Following procedure to make (5), valeryl chloride was substituted for benzoyl chloride to give the title compound after purification. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.14 (s, 1H), 7.36 (d, 2H), 7.25 (t, 2H), 7.17 (t, 1H), 4.38 (s, 2H), 3.70 (d, 2H), 3.30 (water), 2.917 (d, 2H), 2.48 (DMSO), 2.22 (t, 2H), 1.62 (m, 2H), 1.52 (m, 2H), 1.45 (m, 2H), 1.37 (m, 1H), 1.26 (m, 1H), 1.22 (m, 2H), 0.82 (t, 3H), 0.63 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH:10]2C(=O)O[C:13](C)([CH3:17])[O:12][C:11]2=[O:19])=[C:4]([F:32])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19])=[C:6]([F:8])[CH:7]=1
Reactant: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1c(F)cc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12

Procedure:
11 mg (166 μmol) of copper powder were added to a solution of 1.60 g (3.33 mmol) of the compound from Example 96A in 6 ml of pyridine and 1.3 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified firstly by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.15 g (81% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[ClH:10].Cl.[O:12]([CH2:16][CH:17]1[CH2:22][NH:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1)[N+:13]([O-:15])=[O:14].P(C#N)(OCC)(OCC)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1.CN(C)C1C=CN=CC=1.C(N(CC)CC)C.CN(C)C=O>[ClH:10].[O:12]([CH2:16][CH:17]1[CH2:22][NH:21][CH:20]([CH2:23][NH:24][C:7]([C@@H:5]2[CH2:4][S:3][C:2](=[O:1])[NH:6]2)=[O:9])[CH2:19][CH2:18]1)[N+:13]([O-:15])=[O:14]
Reactant: NCC1CCC(CO[N+](=O)[O-])CN1
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](C(=O)NCC2CCC(CO[N+](=O)[O-])CN2)CS1
Yield: 8.4 %

Procedure:
In 40 ml of dry tetrahydrofuran and 20 ml of dry dimethylformamide were suspended 224 mg of (4R)-2-oxo-4-thiazolidinecarboxylic acid and 350 mg of 5-nitroxymethyl-2-piperidylmethylamine dihydrochloride, and 0.94 ml of triethylamine and 0.188 ml of diethyl cyanophosphate were added thereto with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were added 0.463 ml of di-t-butyl dicarbonate and a catalytic amount of 4-dimethylaminopyridine, and the resulting mixture was stirred at room temperature for 1 hour. Further, 2.0 ml of di-t-butyl dicarbonate was added thereto and the mixture was stirred at 30° C. for 1.5 hours. The insolubles were filtered and the solvent was distilled off under reduced pressure. The residue was purified by using silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=2/3-1/6) and the fraction having an Rf of 0.14 by thin layer chromatography (developing solvent: cyclohexane/ethyl acetate=1/2) was collected by separation. The thus obtained foam was dissolved in 5.0 ml of 4N hydrochloric acid-dioxane and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 20 ml of ether, and the crystal was collected by filtration to obtain 40 mg of the desired compound as a pale yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#Cc1ccc(F)cc1
Product: CSc1ccc(NC(=N)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-fluorobenzonitrile (2.176 g, 17.98 mmol) and 4-methylthioaniline (2.5 g, 17.98 mmol) by following the procedure described in preparation 1, (2.06 g, 44.1%, purity 98.8% by HPLC), mp 121-124° C. 1H-NMR (CDCl3):δ 2.48 (s, 3H), 4.82 (bs, 2H, D2O exchangeable), 6.91-6.93 (d, 2H), 7.1-7.14 (m, 2H), 7.26-7.30 (m, 2H), 7.86 (bs, 2H). MS m/z:261.1(M+)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1c[nH]cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cn(-c2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (1.59 mmol) of methyl 1H-imidazole-4-carboxylate, 496 mg (3.17 mmol) of 2-chloro-phenylboronic acid, 100 mg of 3 Å molecular sieve and 432 mg (2.28 mmol) of copper(II) acetate were initially charged in 2 ml of dichloromethane, and 256 μl (3.17 mmol) of pyridine were added. The mixture was stirred at RT for 20 h. For work-up, the mixture was filtered through a little kieselguhr, the filter residue was rinsed with about 15 ml of ethyl acetate and the combined filtrates were washed with 5 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1→1:1→1:3). This gave 55 mg (13% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C(O)(=O)C.[CH3:36][O:37][C:38](=[O:41])[CH:39]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH:25][C@H:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COC(=O)C=O
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](N)C4)c23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)CN[C@H]1CCC[C@H](Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dissolve 132 mg (0.318 mmol) of −(+/−)-cis/trans-N-[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]-cyclohexane-1,3-diamine (Example 36A) in 1.5 ml of dichloromethane and add 18.7 μl of acetic acid at RT. Add 28 mg (0.318 mmol) of oxoacetic acid methyl ester and, after 5 min, 101 mg (0.478 mmol) of sodium triacetoxyborohydride. Stir the mixture at RT for 2 h and then dilute with water and dichloromethane. Wash the organic phase with saturated sodium carbonate solution, dry over sodium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient) and separate the cis/trans isomers:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27]Cl)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)=[O:25])=[CH:29][CH:30]=1
Reactant: O=C(OCCl)c1ccc(F)cc1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.29 g of chloromethyl 4-fluorobenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 4-fluorobenzoate (present compound (38)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[O:18]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:28]1[CH:29]=[CH:30][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccc(Oc4ccccc4)cc3)ccc2oc1=O

Procedure:
4-Hydroxy-2-oxo-6-(4-phenoxy-phenyl)-2H-chromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester and 4-phenoxyphenylboronic acid under conditions analogous to example 3-a. MS ESI(+) m/e: 389 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([O:21]C)=O)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[NH3:25]>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([NH2:25])=[O:21])[CH:8]=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Solvent: CO
Product: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Methyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (360 mg, 1.12 mmol) was suspended in 7N ammonia in methanol (12 mL, 84.0 mmol) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (317 mg, 1.03 mmol, 92%) as a yellow powder. MS (EI/CI) m/z: 306.0 [M+H]. This material was used directly in the next step without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl-].[NH4+].Cl.C[N:19](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:19])=[O:9])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1-n1cccn1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1-n1cccn1

Procedure:
A solution of 2-pyrazol-1-yl-benzoic acid (50 mg, 0.26 mmol), ammonium chloride (28 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol), 1-hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) and diisopropylethylamine (0.17 ml, 1.0 mmol) in N,N-dimethylformamide (0.75 ml) was stirred at room temperature for 5 h. Water was added and the reaction mixture was extracted with ethyl acetate. Drying and solvent evaporation gave 2-pyrazol-1-yl-benzamide; 1H NMR (CD3OD, 400 MHz) δ7.92 (d, 1H, J=2.4 Hz), 7.70-7.48 (m, 5H), 6.49 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]4[O:26][C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])=[CH:23][CH:24]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)o2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)o2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 6 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)furan-2-yl)benzoic acid as described in example 8 step 6 (20 mg, yield 6%). 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.49 (t, J=6.2 Hz, 1H), 8.30-8.29 (t, J=1.6 Hz, 1H), 8.09-8.06 (dt, J=8.1 Hz, 1.2 Hz, 1H), 8.01-7.98 (m, 4H), 7.94-7.92 (dt, J=8.1 Hz, 1.2 Hz, 1H), 7.66-7.62 (t, J=7.8 Hz, 1H), 7.51-7.50 (d, J=4.0 Hz, 1H), 7.35-7.31 (t, J=9.0 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O4: 500.14. found: 499.4 (M−H)−.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (900 mg, 5 mmol) in dichloromethane (25 mL) is added 4-fluorobenzoyl chloride (730 μL, 6.1 mmol) followed by DIPEA (2.0 mL, 11 mmol). After 1 day, the mixture is concentrated and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3×40 mL). The combined organic layers are washed with brine (3×25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is passed through a pad of silica gel using dichloromethane-heptane (1:1) to load the sample and then eluting with dichloromethane to afford N-(3-chloro-pyrazin-2-ylmethyl)-4-fluoro-benzamide as an oil which partially solidified.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[CH:7]=[C:8]3[C:15]4[N:16]=[N:17][NH:18][C:19](=[O:20])[C:14]=4[S:13][C:9]3=[N:10][C:11]=2[CH:12]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[CH:7]=[C:8]3[C:15]4[N:16]=[N:17][N:18]([CH3:23])[C:19](=[O:20])[C:14]=4[S:13][C:9]3=[N:10][C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2cc3c(nc2cc1OC)sc1c(=O)[nH]nnc13
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc2cc3c(nc2cc1OC)sc1c(=O)n(C)nnc13
Reaction time: 3 h

Procedure:
To a mixture of 8.8 g of 8,9-dimethoxy-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one and 12 g of potassium carbonate in 50 ml of dimethylformamide at 75° C. is added 6 ml of methyl iodide. Stirring at this temperature is continued for 3 hours. The mixture is then diluted with water and the precipitate which forms is separated by filtration to give 8,9-dimethoxy-3-methyl-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one.