Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@]1(C)O
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1R,4S)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (38.7 mg, 0.084 mmol, 34% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.90 (s, 1H), 8.57-8.54 (s, 1H), 8.34 (s, 1H), 4.92 (t, J=12.0 Hz, 1H), 4.81-4.78 (m, 2H), 4.34-4.28 (m, 1H), 2.04-1.95 (m, 3H), 1.92-1.68 (m, 6H), 1.47-1.45 (m, 3H), 1.09-1.01 (m, 6H). MS (ESI) m/z 462.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:21]2[CH:22]=[C:23]3[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]3[C:25](=[O:27])[N:26]=2)=[CH:10][C:11]=1[F:12]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccc(F)c(F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:18])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:19]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COCC(=O)C(=NNc1ccccc1)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccccc2)cc(OC)c1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of methyl 4-methoxy-3-oxo-2-(phenylhydrazono)butanoate (25.03 g) in dimethylformamide dimethylacetal (120 mL) was stirred at 90° C. for 1 hr. The mixture was allowed to cool to room temperature, and stirred for 1 hr. The precipitate was collected by filtration, washed successively with diethyl ether and hexane, and dried to give the title compound (24.7 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)[NH:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C2NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 5.2 grams (g) (10.6 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-propoxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide in 50 ml of tetrahydrofuran (THF) that had been cooled under a nitrogen atmosphere to -75° C. was added 28 ml of 1.0M diisobutylaluminum hydride (DIBAL-H) in THF. The reaction mixture was warmed to 20° C. and stirred for 5 hours. An additional 6 ml of the 1.0M DIBAL-H solution was added. After stirring at 20° C. overnight, the mixture was cooled to 0° C. and carefully quenched with 10 ml of methanol, a solid forms. Into this mixture was poured a mixture of 20 g of water and 10 ml of 12M aqueous hydrochloric acid. After the solid dissolved, the mixture was concentrated in vacuo and partitioned between diethyl ether and water. The organic layer was washed with dilute aqueous sodium hydroxide and brine and then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica gel using diethyl ether and hexanes to give the expected compound, an oil. NMR (200 MHz, CDCl3) 1.1 t 3H, 1.8 sextet 2H, 2.6 s 3H, 3.6 s 3H, 4.0 t 2H, 4.1-4.6 m 3H, 5.5 bd 1H, 6.9 d 2H, 7.1 m 5H, 7.5 d 2H, 8.5 s 1H. Peaks exibit satellites due to hindered rotation.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:37]3[C:38]4[CH:39]=[C:40]5[C:27]6([CH2:30][O:31][C:32]5=[CH:33][C:34]=4[CH2:35][CH2:36]3)[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]6)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(-c2ccc(C3=NCCO3)cc2C)cc1
Product: Cc1cc(C2=NCCO2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Yield: 35 %

Procedure:
This was prepared from methyl 4'-(4,5-dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylate (D114) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine (D8) following the procedure of Example 12. This gave the title compound (35%) as a light yellow solid.
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][NH:16][NH2:17])=[CH:13][CH:12]=1>C(O)C>[NH2:8][C:7]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][C:11]([Br:10])=[CH:12][CH:13]=2)[C:5](=[O:4])[CH:6]=1
Reactant: CCOC(=O)CC#N
Reactant: NNCc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)cc2)[nH]1
Temperature: 60 °C

Procedure:
9.2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of p-bromobenzylhydrazine in 50 ml of ethanol is then added at room temperature. The mixture is warmed to 60°C for 2 hours, the substance which was precipitated is filtered off and the filtrate is evaporated. The residue is taken up with water, the mixture is shaken with ether and the aqueous phase is acidified with dilute acetic acid. The crude product is purified by twice recrystallising it from alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:15])[NH:13][N:14]=[C:4]2[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:13]1[C:12](=[O:15])[N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[N:14]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Solvent: CC(=O)O
Product: CC(=O)n1nc2c(=O)n(C)c3ncccc3n2c1=O

Procedure:
A mixture of 1.8 g. of 5-methyl-pyrido(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione in 25 ml. of acetic anhydride and 50 ml. of acetic acid was stirred and refluxed for 5 hours.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (22 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(#N)C>[NH2:14][CH2:13][CH2:12][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: NCCN
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 77.5 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A mixture of 2-amino-6-chloro-3-nitropyridine (0.52 M) in acetonitrile (70 ml), and ethylene diamine (40 ml) were stirred overnight (ca. 20 h) at 75-80° C. under argon. The ethylene diamine was removed under reduced pressure. The residual solution was basified with 1M sodium hydroxide solution (50 ml). The aqueous solution was saturated with sodium chloride and extracted with a solution of 95% ethyl acetate and 5% methanol (3×150 ml) and with a solution of 95% acetonitrile and 5% methanol (3×150 ml). The organic extracts were combined and extracted with a saturated sodium chloride solution (2×75 ml). The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow solid was triturated with ether (2×25 ml) and dried overnight in vacuo resulting in 2-(2-aminoethyl)amino-6-amino-5-nitropyridine in 99% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]([F:28])([CH3:27])[CH3:26])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]([F:28])([CH3:26])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:34])=[CH:15][C:14]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2cnc3cccnc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c[n+]([O-])c3cccnc3c21
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-[2-(Benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.89 g, 5.0 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (1.50 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 50 mL of 2% Na2CO3 solution and the layers were separated. The aqueous portion was extracted with an additional 25 mL of CH2Cl2. The combined organic layers were washed successively with 2% Na2CO3, H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.97 g of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([O:21]C)=[O:20].O.O[Li].O.Cl>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccc(Oc2cccnc2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(Oc2cccnc2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(3-pyridyloxy)phenylacetate (0.45 g, 1.3 mmol) from Step 2 above in THF (4 mL) and water (1 mL) was added LiOH.H2O (0.065 g, 1.5 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-20% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoro-ethoxy)-4-(3-pyridyloxy)-phenylacetic acid as a gum (HPLC retention time=5.4 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.[H-].[Na+]>COCCOC>[Cl:12][C:13]1[N:14]=[N:15][C:16]([CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[CH:17][CH:18]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ccc(Cl)nn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
The 1-(2,4-difluorophenyl)ethanone (Apollo, 1.00 g, 6.40 mmol) and 3,6-dichloropyridazine (0.95 g, 6.4 mmol) in DME (10 mL) were treated with NaH (0.512 g, 12.8 mmol, 60% dispersion in oil) then warmed at about 50° C. in an oil bath. The mixture was stirred for about 4 h then sodium hydride (0.26 g, 6.4 mmol, 60% dispersion in oil) and 3,6-dichloropyridazine (0.48 g, 3.2 mmol) were added. The reaction was heated for about 0.5 h and then quenched with acetic acid and water. The mixture was extracted with EtOAc then purified by flash chromatography on silica with EtOAc as an eluent to give the title compound (0.98 g, 57%): LC/MS (Table 1, Method a) Rt=2.34 min; MS m/z: 269.1 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cl)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][N:12]2[CH2:17][CH:16]([CH3:18])[NH:15][CH2:14][CH:13]2[CH3:19])=[CH:9][CH:8]=1.[OH-].[K+].CS(C)=O>O>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:2][CH2:3][CH2:4][Cl:5])[CH2:14][CH:13]2[CH3:19])=[CH:9][CH:8]=1
Reactant: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1CCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
22.0 g g of 1-bromo-3-chloropropane were added to a mixture of 33.0 g of 4-chlorobenzyl-2,5-dimethylpiperazine, 25.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide. After stirring the solution for 3 hours at room temperature, water was added, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated to give 25.8 g (58% of theory) of 1-(4-chlorobenzyl)-2,5-dimethyl-4-(3-chloropropyl)piperazine as an oil, suitable for use in the next reaction.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)([O-:25])=[O:24].[H-].[Na+].O>CN(C=O)C>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:18]([CH2:19][CH2:20][C@:3]23[CH3:4])[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (1.07 g, 3.5 mmole) and p-nitrofluorobenzene (2.0 ml, 14 mmole) in DMF (15 ml) under N2 was added 95% NaH (180 mg, 7 mmole) in two portions during 10 mins. The mixture was stirred for 3 hours at room temperature and poured onto ice (50 g) and water (50 ml). The mixture was extracted with CH2Cl2 (30 ml×2). The organic layer was washed with brine and dried (Na2SO4). Removal of solvent gave the crude product which was purified via a flash silica gel column eluting with 1:1 ethyl acetate-CH2Cl2 to give the desired title product. Mp. 183°-184° C. (recrystallized from CH2Cl2 -hexane).
Reaction SMILES: [C:1](OCC)(=S)C(N)=O.[CH:9]([C:12]1[N:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:15][CH:16]=1)([CH3:11])[CH3:10]>>[CH2:20]([O:19][C:17]([C:14]1[S:15][CH:16]=[C:12]([CH:9]2[CH2:11][CH2:1][CH2:10]2)[N:13]=1)=[O:18])[CH3:21]
Reactant: CCOC(=S)C(N)=O
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Product: CCOC(=O)c1nc(C2CCC2)cs1
Yield: 64 %

Procedure:
Compound V2 (yellow oil) was synthesized from compound U2 (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) in 64% yield, following the procedure as described for compound 36.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -50 °C
Yield: 0 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (2.028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran under stirring, and added with 1.3 ml of pyridine to the solution at room temperature. The reaction system was cooled down to about −50° C. in a dry ice-ethanol bath. A solution of methoxy-acetyl chloride (1.35 g, 12.5 mmol) in tetrahydrofuran (20 ml) was added dropwise to the above reaction system. Upon completion of the addition, the ice-ethanol bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water (10 mL×3) and recrystallized with methanol to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a (1.18 mg, yield 40.6%) as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=2[CH2:21][CH3:22])=[C:4]([F:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:21]([C:8]1[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([NH:1][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:3][C:4]=1[F:25])[CH3:22]
Reactant: CCc1c(Oc2ccc(N)cc2F)ccnc1NC(=O)OC(C)(C)C
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1c(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccnc1NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate (20 mg, 0.058 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (232 μL, 0.070 mmol) in THF in the same manner as Step D of Example 33. MS(ESI+): m/z 527.31 (M+H)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.103 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.046 g, 11%). MS (ISP) 426.0 [(M+H)+]; mp 275° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[C:25](=[O:27])=[O:26]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[C:18]([CH:19]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1OC(F)(F)F
Temperature: -100 °C
Reaction time: 2 h

Procedure:
A 1.6 M solution of butyllithium in hexanes (26.5 mmol, 16.5 mL) was added to a 0° C. solution of diisopropylamine (2.65 g, 26.5 mmol) in tetrahydrofuran (50 mL). The solution was cooled to −100° C., and 1-chloro-4-(trifluoromethoxy)benzene (Matrix) (5.0 g, 26.5 mmol) was added. After 2 h at −100° C., the mixture was poured onto an excess of freshly crushed dry ice. After evaporation of the volatiles, the residue was dissolved in a 1 M aqueous solution (50 mL) of sodium hydroxide, washed with diethyl ether (2×15 mL), and acidified to pH 1 by the addition of concentrated hydrochloric acid (7 mL). The aqueous layers were extracted with diethyl ether (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54 (dd, J=8.8, 1.0 Hz, 1H) 7.78 (dd, J=8.8, 2.7 Hz, 1H) 7.92 (d, J=2.7 Hz, 1H).