Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 106229.7 %

Procedure:
A solution of 27 grams (0.125 mmoles) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (0.31 moles of N,N-dimethylformamide dimethyl acetal in 120 ml of DMF was heated at 80° C. for 2 hours. After cooling, the reaction was poured onto water and extracted with ethylacetate. Then was dried over sodium sulfate and evaporated to give 36 grams of the titled compound as a purple solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO>[CH3:18][O:19][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)cnn2)c1
Agent: [Na+]
Solvent: CO
Product: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 74 %

Procedure:
5-Chloro-3-[3-(trifluoromethyl)phenyl]pyridazine (4 g, 0.015 mole, Compound No. 5) and NaOMe in MeOH (16.71 g of a 25% by weight solution, 0.077 mole) were stirred at RT under N2 in MeOH (100 mL) for 4 h. The mixture was then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude solid was recrystallized from ethyl acetate/cyclohexane to give 5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (2.92 g, 74% yield, Compound No. 8) as a brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[N:9]1[C:14]2[NH:15][C:16]3[CH:36]=[CH:35][CH:34]=[CH:33][C:17]=3[N:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][C:23]=3[C:29]([F:32])([F:31])[F:30])=[O:21])[CH2:19][C:13]=2[CH:12]=[CH:11][CH:10]=1>CCCCCC>[CH3:3][C:4]1[CH:8]=[CH:7][N:6]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([N:18]3[C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[NH:15][C:14]4[N:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH2:19]3)=[O:21])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[N:5]=1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium hydride (60% suspension in oil, 0.83 g, 20.8 mmol) was washed once with hexane, dried under nitrogen and resuspended in dry dimethylformamide (60 mL). 3-methyl pyrazole (0.90 mL, 11.2 mmol) was added in one portion. After the gas evolution subsided the stirring was continued at room temperature. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethylphenyl)-methanone of Step B (3.6 g, 9.3 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane provided 3.3 g of the desired product as a foam which crystallized by sonication from ethanol-hexane, m.p. 212-214° C. Further elution with 30% ethyl acetate in hexane yielded the more polar 5-methylpyrazole regioisomer of Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH2:14]C([O-])=O)=[O:10])=[CH:4][CH:3]=1.CC(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:23])[C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)NC(C)(C(=O)CC(=O)[O-])C(C)C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Temperature: 60 °C
Yield: 89.7 %

Procedure:
In a reactor were placed 57.5 g (0.156 mole) of 4-[2-(4-chlorophenyl)propanoylamino]-4,5-dimethyl-3-oxohexanoate, 156 ml of 2-propanol, 62.4 ml of water and 15.6 ml of concentrated sulfuric acid. The mixture was refluxed for 7 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled to 60° C. 446 ml of water was added for further cooling. The mixture was neutralized with a 23% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration to obtain 41.5 g (0.14 mole) of 2-(4-chlorophenyl)-N-[1-methyl-1-(methylethyl)-2-oxopropyl]propanamide (yield=90%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19]O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19][F:37])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCO)ccc(C#N)c1Cl
Solvent: ClCCl
Product: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(2-hydroxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (30 mg, 0.066 mmol) in DCM (3 mL) at 0° C. was added DAST (0.008 mL, 0.066 mmol) and stirred for 1 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was used in the next step without any purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[CH2:22]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 70 %

Procedure:
Combine (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (150 mg, 0.526 mmol) dissolved in dimethylformamide (˜2 mL) and add 0.13 M solution of 4-benzylpiperidine in ethanol (˜4 mL) and heat for 10 hours at 85° C. Concentrate and purify the reaction mixture by flash (silica) chromatography on a Water's Sep-Pak 5 g silica cartridge using a graded solvent mixture of dichloromethane to 10% methanol in dichloromethane to give the title compound (169.9 mg, 70% Yield). Purity by LC/MS=99%, [M+H]+=461.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Reactant: NCCCN1CCOCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCCN4CCOCC4)ccc3Cl)ccn2)n1
Yield: 45.6 %

Procedure:
Following procedure of Example 83, 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.100 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol), (DMF (3 mL), ethyl carbonochloridate (0.02641 mL, 0.2762 mmol) and 4-(3-aminopropyl)morpholine (0.07242 g, 0.5022 mmol) were reacted to afford 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(3-morpholinopropyl)benzamide hydrochloride (0.030 g, 20.50% yield) as off white solid. 1H NMR (DMSO) δ 11.20 (bs, 1H), 10.37 (bs, 1H), 8.83 (t, 1H), 8.23 (d, 1H), 7.87 (dd, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 6.58 (m, 2H), 6.55 (d, 1H), 3.94 (d, 2H), 3.72 (t, 2H), 3.40 (d, 2H), 3.32 (q, 2H), 3.12 (m, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 1.93 (m, 2H); Mass spectrum (esi) m/z=488 (100) (M+H—HCl).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]([NH:14][NH2:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NN
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: CCO
Solvent: O
Product: NNc1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a suspension of 2,3-dichloroquinoxaline (33.5 g; 0.168 mole) in 500 ml ethanol, hydrazine hydrate (18.5 g; 0.37 mole) was added and the reaction mixture was stirred vigorously at room temperature for 16 hours. The thick slurry was filtered, washed with ethanol to give 23.7 g of 2-chloro-3-hydrazinoquinoxaline having a mp of 181°-182° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH:21]1[O:23][CH2:22]1>>[OH:23][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4][CH3:5])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCC1CO1
Product: CCCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CCC)cc2)cc1

Procedure:
Bis-phenol A, that is 2,2-di(p-hydroxy-phenyl-)propane, was reacted in known manner with an excess of pentene - 1,2-oxide. The product, the mixture of diastereisomers, 2,2-bis-(p-(β-hydroxy-pentoxy-)phenyl)propane was obtained as a yellow-brown, semisolid mass, which was obtained as a colorless substance by distillation b.p.:192°-210° C/O .005 mm. The OH-equivalent was 207.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl([O-])=[O:13].[Na+].O.O.P([O-])([O-])(O)=O.[Na+].[Na+].Cl>C(O)(C)(C)C.O>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[F:1])[C:10]([OH:13])=[O:11])#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1cc(C(=O)O)ccc1F
Yield: 90 %

Procedure:
To a stirred solution of 15.0 g (97.6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol were added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture was stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value was readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution was extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases were dried (sodium sulphate) and concentrated. The residue was purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous solution and subsequent filtering. The solid crude product 2a was obtained in 90% yield (14.5 g, 87.8 mmol) and was used for the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])([O-:23])=[O:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:37][NH:36][C:34]([C:32]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:21]([O-:23])=[O:22])[CH:33]=3)=[O:35])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 82.9 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (1.149 mmol, 312.9 mg) synthesized in Synthetic Example 3, methyl 2-nitro-4-hydrazinocarbonylbenzoate (1.149 mmol, 274.8 mg) synthesized in Reference Synthetic Example 40 and p-tosylic acid monohydride (30 mol %, 59.4 mg) were dissolved in isopropyl alcohol (30 mL) and stirred under heating with reflux for 6 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a yellow solid (470 mg, yield 83%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][N:10]=1)([F:4])[CH3:3].[H][H]>CO.[Pt]=O>[F:1][C:2]([CH:5]1[NH:10][CH2:9][CH2:8][NH:7][CH2:6]1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cnccn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(F)(F)C1CNCCN1

Procedure:
A 4.3 g portion of 3-(1,1-difluoroethyl)pyrazine in 25 ml of methanol was reduced with 50 psi hydrogen and 750 mg of platinum oxide at 20° C. for 5 hours. The resulting oil was purified by chromatography, giving about 700 mg of 3-(1,1-difluoroethyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 205° C.; 1H NMR (400 MHz, DMSO-d6) δ2.37 (s, 3 H), 3.99 (s, 2 H), 6.69 (s, 1 H), 7.26 (m, 7 H), 7.68 (m, 2 H), 11.83 (bs, 1 H).
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1>C(#N)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:14]=2)[CH:13]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1ncc(Br)cn1
Solvent: CC#N
Product: O=Cc1cnc2ncc(Br)cn12
Yield: 40 %

Procedure:
Bromomalonaldehyde (500 mg, 2.90 mmol) was added to a solution of 5-bromopyrimidin-2-amine (526 mg, 3.49 mmol) in acetonitrile. The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 2% methanol in chloroform gradient to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): δ 9.98(s, 1H), 9.75-9.76 (d, 1H, J=2.4 Hz), 8.97-8.98 (d, 1H, 2.4 Hz), 8.70 (s, 1H); MS (m/z): 226 (M+1)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[N:28]=[C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)[CH:26]=[CH:25][N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Clc1nccc(-c2cccs2)n1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4cccs4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for C25H22N4OS2, 458.60; m/z found, 459.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[NH:10][C:9]=1[C:19]([NH:21][CH3:22])=[O:20])=[O:4].ClCCl.B(Br)(Br)Br>CO>[F:23][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:19]([NH:21][CH3:22])=[O:20])=[O:4]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(=O)C(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-methoxy-N-methyl-1H-indole-2-carboxamide (2.52 g) and dichloromethane (50.0 mL) was added boron tribromide (1.0 M dichloromethane solution, 23.3 mL) under ice-cooling, followed by slowly warming to room temperature, and then stirring at room temperature overnight. The reaction mixture was cooled to −15° C. and methanol (5.00 mL) was added thereto, followed by warming to room temperature. The reaction mixture was concentrated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 5:1) to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (2.37 g) as a yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH:23]([NH2:25])[CH3:24]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:25][CH:23]([CH3:24])[CH2:22][O:21][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: COCC(C)N
Product: COCC(C)NCc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of example 15 and 2-methoxy-1-methyl-ethylamine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6]([OH:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 95.8 %

Procedure:
5-Trifluoromethyl-2(1H)-pyridone (10.0 g) and sodium acetate (5.25 g, 64 mmol) in acetic acid (100 ml) was treated with bromine (3.3 ml, 63 mmol) and heated at 80° C. for 2 hrs, before being cooled and concentrated. The residue was basified with sodium hydrogen carbonate solution (250 ml) and extracted with ethyl acetate (2×250 ml). The extracts were dried (MgSO4) and concentrated to give the product as a tan solid (14.22 g, 96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Temperature: 25 °C
Yield: 102.3 %

Procedure:
To a stirred solution of (2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) was added BH3.DMS (0.63 ml, 6.3 mmol) at 0° C. The mixture was raised to room temperature immediately and then heated at 50° C. for 1.5 h. After cooling to room temperature, the mixture was quenched by the addition of water at 0° C. and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (50/1)], to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (1.10 g, 100%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.45 (m, 1H), 3.58–4.80 (m, 4H), 5.01 (br, 1H), 7.04–7.99 (m, 7H).
Reaction SMILES: C([C:4]1[O:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[O:12][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc2cccnc2c1-c1ccc(F)cc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Fc1ccc(-c2coc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A mixture of 2-carboxy-3-(4-fluorophenyl)-furo[3,2-b]pyridine (1.8 g, 7 mmol), copper metal (0.56 g, 8.81 mmol) in quinoline (10 ml) was heated at reflux. After 45 min., the reaction was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid and acetic acid. The product was filtered and dissolved in ether. The ether layer was dried over sodium sulfate and concentrated in vacua. Purification by flash chromatography using ethyl acetate-hexanes (1:9) as the eluant gave 3-(4-fluorophenyl)-furo[3,2-b]pyridine as a solid (0.85 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[NH:7][CH2:6][CH2:5]2.[C:15](Cl)(=O)C>CO>[CH3:15][O:13][C:12]([CH:8]1[C:9]2[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1)=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1NCCc2cc(O)ccc21
Solvent: CO
Product: COC(=O)C1NCCc2cc(O)ccc21
Temperature: 25 °C
Yield: 75 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-hydroxy-1-isoquinolinecarboxylic acid (5.0 g, 25.9 mmol, prepared according to W. K. Anderson, H. L. McPherson, J. S. New and A. C. Rick, Journal of Medicinal Chemistry, Vol. 27, p. 1321, 1984) in methanol (150 mL) was treated with acetyl chloride (3 mL) (reaction mixture became homogenous) and heated under reflux for 24 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and water. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo to yield the title compound (4.0 g, 75%) as a colorless solid, mp 214-216° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([S:16]Cl)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:18][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(SCl)cc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. To the stirred solution there was added dropwise p-toluenesulfenyl chloride (2.92 g., 20 mmoles), with the temperature maintained below 30° C. by occasional cooling with an ice-water bath. The reaction was stirred for 60 minutes at room temperature. The reaction mixture was concentrated in vacuo to an oil. The residue was taken up in a mixture of isopropyl alcohol and hexane, a small amount of gum removed by filtration and the filtrate reevaporated in vacuo to an oil (5.0 g.). The latter was chromatographed on 150 g. of silica gel, with 100 ml. fractions of the benzene eluant collected. Fractions 10 to 19 were combined to yield the desired product (1.41 g.) contaminated with an impurity showing a mass spectral peak at 281. The latter was removed by recrystallization from methylene chloride/hexane to yield purified methyl 5-(4-methylphenylthio)pyrrole-3-carboxylate (1.14 g., m.p. 118°-121° C., m/e 247).