Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].[CH3:21]N(C)C=O.[OH-].[K+].COS(OC)(=O)=O>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[O:6][CH3:21]
Reactant: CN(C)C=O
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (1.09 g, 0.004 mole) were added dried dimethylformamide (6 ml) and potassium hydroxide (0.29 g, 0.0044 mole) and the mixture was stirred at room temperature for 15 minutes. Then, dried toluene (6 ml) was added to the mixture, to this was further added dropwise dimethylsulfate (0.61 g, 0.0044 mole) under ice cooling. After completion of the addition, the mixture was stirred at room temperature for 2 hours. Then, ether (100 ml) was added, followed by washing with water three times. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-phenoxyphenylacetic acid methyl ester (1.20 g, yield: 80.6%) as colorless crystals (melting point: 109°-110° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].CO>C(OCC)(=O)C>[NH2:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:13][CH2:12][CH2:10][OH:11])[CH:3]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N)cc(NCCO)n1
Temperature: 250 °C
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-2-methylpyrimidin-4-ylamine (717 mg, 5.0 mmol) and ethanolamine (0.602 mL, 10.0 mmol) were heated at 250° C. in a microwave for 30 seconds. After cooling, the residue was dissolved in ethyl acetate, containing a small amount of methanol and was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid (334 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.45 (br s, 1H), 5.98 (br s, 2H), 5.25 (s, 1H), 3.47 (t, J=6.0 Hz, 2H), 3.23-3.14 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#N.[OH-:19].[K+].[CH2:21]([OH:23])C.Cl>O>[OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)\[C:4]([O:23][CH3:21])=[O:19]
Reactant: CCO
Reactant: [OH-]
Reactant: N#CC(=NO)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)/C(=N\O)c1cccc(Oc2ccccc2)c1
Yield: 33 %

Procedure:
A mixture of 2-hydroxyimino-2-(3-phenoxyphenyl)acetonitrile (3.00 g), potassium hydroxide (3.40 g), ethanol (15 ml) and water (15 ml) was heated under reflux for 24 hours. The reaction mixture was acidified with 1 N HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The reaction mixture was dissolved in methanol (30 ml), admixed with concentrated sulfuric acid (a catalytic amount), and then heated under reflux for 24 hours. The reaction mixture was combined with aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl Z-2-hydroxyimino-2-(3-phenoxyphenyl)acetate (1.14 g, yield 33%) as an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:15])=[C:7]([CH:14]=1)[CH2:8][NH:9][C:10](=[O:13])[O:11][CH3:12].[C-:16]#[N:17].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Cl:15][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:16]#[N:17])=[CH:14][C:7]=1[CH2:8][NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: COC(=O)NCc1cc(CBr)ccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NCc1cc(CC#N)ccc1Cl
Reaction time: 1 h
Yield: 69.3 %

Procedure:
2.3 g of the methyl N-(5-bromomethyl-2-chlorobenzyl)carbamate obtained in Reference Example 3 was dissolved in 20 ml of N,N-dimethylformamide, and 0.43 g of sodium cyanide was added thereto at 0° C. Stirring was carried out at 0° C. for 1 hour, and stirring was carried out further for 4 hours at room temperature, then water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic solvent was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 1.3 g of methyl N-(2-chloro-5-cyanomethylbenzyl)carbamate as white crystals.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH:26]=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1.O>[C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][OH:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Crude 2-(1-trityl-1H-imidazol-2-yl)acetaldehyde (2.025 g (5.75 mmol) was dissolved in MeOH/THF (1:1, 40 ml) and NaBH4 (0.435 g, 11.5 mmol) was added portionwise to the above mixture. The mixture was stirred for 18 hours, diluted with 100 ml of water and extracted with 2×DCM. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated in vacuum. Weight of the residue 1.915 g (94%). 1H NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 9H), 7.12 (dd, J=6.7, 2.7, 6H), 6.93 (d, J=1.0, 1H), 6.74 (d, J=1.0, 1H), 5.04 (br, 1H), 3.46 (t, J=5.4, 2H), 2.00 (t, J=5.4, 2H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:10]1[N:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][N:19]([C@@H:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:18]2=[O:34])[CH:13]=[CH:12][CH:11]=1)(=O)[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([C:10]1[N:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][N:19]([C@@H:22]([C:30]([CH3:33])([CH3:31])[CH3:32])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:18]2=[O:34])[CH:13]=[CH:12][CH:11]=1)([CH3:1])=[CH2:8]
Reactant: CC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of methyltriphenylphosphonium bromide (0.33 g, 0.923 mmol) in THF (2.5 mL) was treated with a solution of potassium tert-butoxide in THF (0.89 mL, 1 M) dropwise, stirred for 1 hour at 25° C., treated with a solution of the product from Example 117A (0.116 g, 0.298 mmol) in THF (2 mL), stirred at 25° C. for 16 hours, quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 15%-25% ethyl acetate in hexane to give the title compound (0.040 g, 35% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[N:75]1([CH2:80][CH2:81][CH2:82][NH2:83])[CH:79]=[CH:78][N:77]=[CH:76]1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[NH:83][CH2:82][CH2:81][CH2:80][N:75]2[CH:79]=[CH:78][N:77]=[CH:76]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: NCCCn1ccnc1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(NCCCn4ccnc4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was 3-imidazol-1-yl-propylamine. Yield: 31 mg.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:24][CH:25]([CH2:28][CH3:29])[CH2:26][OH:27]>CCCCCC>[Si:1]([O:27][CH2:26][CH:25]([CH3:24])[CH2:28][CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 46.27 grams (0.168 mole, 1.01 equivalents) of t-butyldiphenylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 2-Methyl-1-butanol, 14.69 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was twelve minutes. A fine white precipitate formed almost immediately. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After seven hours, both starting materials were still present. Therefore, the reaction mixture was heated to 60° C. with a heating mantle, controlled by the THERM-O-WATCH®. The reaction mixture was stirred overnight at 60° C. The sample after 23.5 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was allowed to cool to room temperature, then it was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:10](=[O:27])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:35][C:36](=O)[CH2:37][CH2:38][C:39](=O)[CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:10](=[O:27])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([N:26]5[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]5[CH3:35])(=[O:24])=[O:25])[CH:18]=4)[C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1S(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1

Procedure:
A mixture of 3-[6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzene sulfonamide (prepared as described in example 6, 10.00 g, 17.95 mmol), hexane-2,5-dione (6.14 g, 53.9 mmol), and p-toluenesulfonic acid monohydrate (1.000 g, 5.257 mmol) in dry toluene (250 mL) is heated to reflux in a Dean-Stark apparatus for 18 h. The reaction mixture is concentrated and the residue obtained is stirred in ethyl acetate and filtered. About 7.1 g of starting material is recovered. Concentration of the filtrate afforded the crude product. It is then purified by column chromatography (silica gel, 60-120 mesh) to afford the 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-[3-(2,5-dimethyl-pyrrole-1-sulfonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C(#N)C>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=4)[CH3:28])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: C[C@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1CN(c1ccc(Cl)cn1)CC2)c1ccc(C(F)(F)F)nc1
Yield: 55.6 %

Procedure:
4-Bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (25 mg, 0.077 mmol), (S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (73.0 mg, 0.384 mmol), N,N-diisopropylethylamine (40.1 μL, 0.230 mmol), and acetonitrile (1.0 mL) were added to a 0.5 to 2 mL microwave vial. The mixture was reacted in the microwave reactor for 2.5 hrs at 200° C. The resulting mixture was treated with CH2Cl2 and washed with 1 M NaH2PO4, dried (Na2SO4), and evaporated. The residue was purified by silica gel column to obtain a light yellow solid (18.6 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9](Cl)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2].[SH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2]
Reactant: CNc1cc(Cl)c(N)cc1[N+](=O)[O-]
Reactant: Oc1ccc(S)cc1
Product: CNc1cc(Sc2ccc(O)cc2)c(N)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
11.5 g (0.057 mol) of 2-nitro-4-amino-5-chloro-N-(methyl)aniline and 11.9 g (0.085 mol) of 4-mercaptophenol were used as the starting materials to give brown-orange crystals (11.3 g) recrystallized from 96° ethanol and melting at 206° C., whose elemental analysis calculated for C13H13N3O3S was:
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]=[C:10]3[C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH:32]3[CH2:34][CH2:33]3)[N:27]=2)=[N:5][N:6]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1.C(Cl)Cl>[CH:32]1([C:28]2[N:27]=[C:26]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]5[O:3][C:2]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:6][N:5]=5)[CH:8]=4)[N:12]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:11]=3)[CH:31]=[N:30][CH:29]=2)[CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(Br)o4)ccc32)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(N5CCCC5)o4)ccc32)cc1
Yield: 66.2 %

Procedure:
A brown-orange solution of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (35.0 mg, 0.065 mmol) and pyrrolidine (16.2 μL, 0.195 mmol) in NMP (1.0 mL) was heated in a sealed microwave process vial under argon at 120° C. for 18 h. The mixture was then diluted with DCM (5 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(pyrrolidin-1-yl)-1,3,4-oxadiazole (22.7 mg, 0.043 mmol, 66%) as a yellow oil: MS (ESI, pos. ion) m/z: 527.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(C)=O.CCCCCCC>C1(C)C=CC=CC=1>[F:15][C:7]1([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]2[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][CH3:24])[C:17]([F:18])=[CH:16][C:5]=2[O:6]1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NC(=O)OCC)cc21
Yield: 40.6 %

Procedure:
A mixture of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (2.0 g, 7.8 mmol) and ethyl chloroformate (1.14 g, 10.5 mmol) in dry toluene was heated to reflux for 2 hours. The mixture was evaporated to dryness to obtain a brown solid. Column chromatography (silica, EtOAc: heptane, 1:3) gave the product (1.04 g), which was used without further purification in the next step 1.8a.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CSCCC1N=CNC=1)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)([O-:23])=[O:22]
Reactant: NCCSCCc1c[nH]cn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1

Procedure:
4-[2-(2-Aminoethylthio)ethyl]imidazole (from the dihydrobromide (4.0 g)) isreacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure ofExample 8(i) and the resultant 1-nitro-2-methylthio-2-[2-(2-(4-imidazolyl)ethylthio)ethylamino]ethylene is treated with methylamine according to the procedure of Example 8(ii) toyield the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]=O)[C:8]([OH:21])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:21])=[C:7]([CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2cccc(C(F)(F)F)c2)c1O

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 27, Step 2 5-(tert-butyl)-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine HPLC/MS Rt=6.64 min, m/z 380.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1OC
Yield: 86.3 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (10.9781 mmol, 2.0 g) in CH2Cl2 (20 mL) with a drop of DMF, was added oxalyl chloride (10.9781 mmol, 957.702:l) dropwise at RT After 2 hrs the reaction mixture was concentrated in vacuo to afford 2,3-dimethoxybenzoyl chloride (1.9 g, 90%): 1H NMR (CDCl3, 300 MHz, ppm): 7.52 (m, 1H), 7.12 (d, 2H), 3.89 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N:13]=[O:14]
Reactant: CCCn1c(=O)cc(N)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-amino-3-propyl-1,3-dihydropyrimidine-2,4-dione (5.6 g) in a mixture of 50% acetic acid/water (160 ml) at 70° C. was added sodium nitrite (4.5 g) in portions over a period of 15 minutes. The mixture was stirred at 70° C. for 45 minutes, then the reaction mixture concentrated to a low volume under reduced pressure. The solid was filtered off, and washed with water, to provide 6-amino-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (11).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][N:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[N+:25]([O-])=O)[C:12](=O)[CH2:11][CH:10]1[C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>O.[Ni]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]2[C:12](=[N:25][C:16]3[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:23]=[CH:24][C:15]=32)[CH2:11][C@@H:10]1[C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(N2CC(NC(=O)OC(C)(C)C)C(c3cc(F)c(F)cc3F)CC2=O)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added 15 mL of THF, and 2 mL of a slurry of Raney 2800 nickel in water. The mixture was then stirred under hydrogen (1 atm) for 1 h, filtered trough a pad of Celite and the filter cake washed with 50 mL of methanol and 25 mL of methylene chloride. The solution was concentrated in vacuo, the product dissolved in 15 mL of a 13:1 solution mixture of toluene/acetic acid and the mixture heated to reflux for 2 h. After cooling to ambient temperature, the mixture was concentrated in vacuo and the product purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 80% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 476.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[C:6]=1[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:23](OC(=O)C)(=O)C.[NH2:30][CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34]>C(OC(OCC)OCC)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[C:6]=1[C:7]([C:8](=[CH:23][NH:30][CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14]
Reactant: CCOC(=O)CC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Reactant: CCCC(N)CCC
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCCC(CCC)NC=C(C(=O)OCC)C(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To 1.20 g (3.3 mmol) of ethyl 3-[4-bromo-1-(2,4-dimethylphenyl)-1H-imidazol-5-yl]-3-oxopropanoate in 1.5 mL of triethylorthoformate was added 0.68 mL (7.2 mmol) of acetic anhydride. The solution was heated to 120° C. for 90 min, cooled to room temperature and concentrated in vacuo. The crude ethoxymethylene oxobutanoate was then dissolved in 35 mL of ethanol, cooled to 0° C., treated with 0.59 mL (3.9 mmol) of 4-aminoheptane and stirred at 0° C. for 1 h. The reaction mixture was concentrated in vacuo to a thick golden oil. The crude oil was purified by flash chromatography eluting with a 25-33% ethyl acetate/hexanes gradient mixture to give 0.62 g of the title compound as a white semisolid. Dirty fractions were combined, concentrated and purified to give an additional 0.20 g of the title compound. The overall yield of the title compound was 0.82 g (36%) which was found to be 70% pure by LCMS analysis. This material was used without further purification in the next step.