Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1

Procedure:
A solution of 15 g of ethyl p-{[2-(2,4-dichlorophenoxy)ethyl]amino}benzoate and 15 g of potassium hydroxide in 200 ml. of 95% ethanol is refluxed for 3 hours. The solution is cooled, diluted with water, acidified with concentrated hydrochloric acid and filtered. The solid is recrystallized from ethanol to give crystals, mp 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=3[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][C:5]=2[N:22]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[C:15]([CH3:17])[N:14]([CH2:23][CH3:24])[C:13](=[O:18])[C:12]=3[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][C:5]=2[N:22]=1
Reactant: Cc1nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c1=O

Procedure:
In analogy to the procedure described in example 2 the 6-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one (example 3) was treated with the ethyl iodide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M+H]+=351.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12]C(F)(F)C(C(F)(F)F)OS(F)(F)F>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][F:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: FC(F)(F)C(OS(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CF)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A solution of 0.77 g (5 mmol) of 4-nitrobenzyl alcohol in 15 ml of methylene chloride was added dropwise over a period of 10 min to a stirred solution of 2.0 g (7.8 mmol) of 2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfur trifluoride in 5 ml of methylene chloride cooled to 10°. The reaction mixture was warmed to room temperature and then evaporated to dryness under reduced pressure. The residue was recrystallized from pentane to give 0.59 g (76%) of 4-nitrobenzyl fluoride as colorless needles: mp 33° to 34°. Recrystallization from pentane raised to melting point to 36° to 37°.
Reaction SMILES: [P:1]([O:18]CC1C=CC=CC=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:26]I>C(Cl)Cl>[P:1]([I:26])(=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1
Solvent: ClCCl
Product: O=P(I)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tribenzyl phosphite (0.708 g, 2.01 mmol) in CH2Cl2 (5 mL) at 0° C. was added I2 (0.49 g, 1.93 mmol). The mixture was stirred at 0° C. for 10 min or until the solution became clear and colorless. The solution was then stirred at room temperature for 10 min and used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1.O>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: BrCCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nc3nn(CCCOC4CCCCO4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30 g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crown ether 18-C-6 (0.01 g, 0.03 mmol) in toluene (10 mL) was heated to 100° C. for 1 h. 2-(3-Bromopropoxy)tetrahydropyran (0.17 g, 0.8 mmol) was, added and stirred at 100° C. for 24 h. It was allowed to cool, water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.22 g of the desired compound (yield: 54%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:23].O>C1COCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])([CH3:23])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(OCC)C(C)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
A solution of diethyl [1-(4-nitrophenyl)ethyl]phosphonate (206 mg, 0.717 mmol) in THF (5 mL) at room temperature under N2, was treated portionwise with NaH (60% in mineral oil, 143 mg, 3.58 mmol). The resulting mixture was stirred for 5 min then iodomethane (0.268 mL, 4.30 mmol) was added dropwise and the mixture stirred for a further 5 h. Water (10 mL) was added slowly followed by EtOAc (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×20 mL). The organic phases were combined, dried (MgSO4), concentrated in vacuo, and the residue purified by chromatography over silica gel eluting with 5% MeOH in dichloromethane to afford 103 mg of desired diethyl [2-(4-nitrophenyl)propan-2-yl]phosphonate (yield: 48%). 1H-NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.2 Hz, 6 H), 1.64 (s, 3 H), 1.69 (s, 3 H), 3.94-4.01 (m, 4 H), 7.78 (dd, J=2.4, 9.2 Hz, 2 H), 8.21 (dd, J=0.8, 8.8 Hz, 2 H). MS (ES+): m/z 302.11 (MH+). HPLC: tR=1.44 min (UPLC TOF, polar).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: Clc1cc(CBr)cc(Br)c1Cl
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(Cl)c(Br)c4)CC3)OC2=O)cc1
Temperature: 55 °C
Yield: 94 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 1-bromo-5-(bromomethyl)-2,3-dichlorobenzene (53.7 mg, 0.168 mmol; from Patent US2007/070805) was added DMF (1.5 mL) and DIPEA (107 μL, 0.612 mmol). The mixture was heated to 55° C. for 2 hours. The mixture was evaporated and the residue was dissolved in saturated aqueous NaHCO3 and then extracted with DCM. The organic layer was evaporated to provide the title compound as a yellow oil (76 mg) that was used without further purification.
Reaction SMILES: BrC1SC([N+]([O-])=O)=C(C(N)=O)C=1.[F:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:28][C:27]([N+:29]([O-])=O)=[C:26]([C:32]([NH2:34])=[O:33])[CH:25]=3)=[CH:20][CH:19]=2)[CH2:17][O:16][CH2:15]1>>[NH2:29][C:27]1[S:28][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:14]3([F:13])[CH2:15][O:16][CH2:17]3)=[CH:19][CH:20]=2)=[CH:25][C:26]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1cc(-c2ccc(C3(F)COC3)cc2)sc1[N+](=O)[O-]
Agent: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2ccc(C3(F)COC3)cc2)sc1N

Procedure:
The title compound was prepared according to the general procedure in Intermediate 10 Step 6 using 5-[4-(3-fluorooxetan-3-yl)phenyl]-2-nitrothiophene-3-carboxamide (272 mg, 0.84 mmol) as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:27])([F:26])[F:28])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Yield: 83 %

Procedure:
Trans-methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.224 g, 0.56 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5 mL, 71.37 mmol) and stirred at room temperature for 1 week. The solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (160 mg, 83%). 1H NMR (600 MHz, dmso) δ 1.48 (ddd, 1H), 1.63-1.81 (m, 3H), 2.51-2.59 (m, 1H), 2.70-2.82 (m, 3H), 2.88-2.95 (m, 1H), 3.07-3.14 (m, 1H), 5.72 (s, 1H), 7.21 (d, 1H), 7.33 (d, 1H), 7.63 (t, 1H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1241
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH:34]=O)[CH:27]=2)[CH:21]=1.CO>COCCOC>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH2:34][C:11]#[N:12])[CH:27]=2)[CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(-c2cccnc2)n2c1CSC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1cc(-c2cccnc2)n2c1CSC2
Temperature: -30 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of tosylmethyl isocyanide (7.5 g) in 1,2-dimethoxyethane (50 cc) is added over 20 minutes at a temperature of about -30° C. to a solution of potassium tert-butylate (8.7 g) in 1,2-dimethoxyethane (140 cc) cooled to a temperature of about -30° C. The solution obtained is cooled to a temperature of about -60° C., and then a solution of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxaldehyde (8 g) in 1,2-dimethoxyethane (70 cc) is added to it over 30 minutes at a temperature of about -60° C. The solution obtained is brought to a temperature of about 0° C. over 1 hour and then kept at this temperature for 1 hour and 20 minutes. Methanol (105 cc) is then added over 15 minutes, at a temperature of between 3 and 7° C. The solution obtained is heated at a temperature of about 72° C. for 1 hour and 15 minutes and is then stirred at a temperature of about 20° C. for 16 hours. Three-quarters of the solvent are evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 40° C. The residue is taken up with a mixture of distilled water (350 cc) and ethyl acetate (250 cc). The organic phase is separated off and the aqueous phase is extracted 3 times with ethyl acetate (750 cc in total). The organic extracts are combined, washed 3 times with distilled water (450 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50° C. A crude product (7.6 g) is thus obtained. This product is chromatographed on a 2.7 cm diameter column containing silica (0.063-0.2 mm; 75 g) by eluting with mixtures of cyclohexane and ethyl acetate and collecting 200-cc fractions. The first 2 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) are rejected. The next 3 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and the following fraction from the elution with pure ethyl acetate, are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. 2-[-5-(3-Pyridyl)-1H,3H-pyrrolo[1,2-c]thiazol-7-yl]acetonitrile (6 g) is thus obtained in the form of light yellow crystals melting at 92° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH:25]O.Cl>O1CCCC1.CO.O.[OH-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:25])[NH2:2]
Reactant: OO
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C4, 800 mg) in tetrahydrofuran (25 mL) and methanol (25 mL), water (2 mL) and 4.0 mol/L aqueous sodium hydroxide (8 mL) were added at room temperature, and the mixture was stirred at 55° C. for 1 hour and 20 minutes. The reaction mixture was cooled to room temperature, and then 35% aqueous hydrogen peroxide (8 mL) was added to the mixture, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture, 3.0 mol/L aqueous hydrochloric acid was added until the reaction mixture was neutralized. The solid matter was taken by filtration, and dried under reduced pressure to obtain 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2, 500 mg) as white solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH3:33][NH:34][CH3:35].O>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6]
Reactant: O=C(NC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Step 2): A solution of 3-chloro-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide (13.5 g, 30 mmol) and 40% dimethylamine (20 ml) in DMF (60 ml) was heated at 130° C. for 15.5 hours in a sealed tube. The mixture was poured into water and extracted with ether. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/hexane) to give 3-dimethylamino-2-nitro-N-(1-diphenylmethyl piperidin-4-yl)benzamide (88.5%): mp 176° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].C([Li])(C)(C)C.CCCCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:26]=[O:27])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)c2[nH]ncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7-Bromo-5-chloro-1H-indazole (0.44 g, 1.90 mmol) and sodium hydride were combined in tetrahydrofuran (5 mL) at 0° C. After 15 min, cooling was removed and the mixture stirred at room temperature for 20 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium in pentane (1.7 M, 2.4 mL, 3.99 mmol) over several minutes. The mixture was allowed to gradually warm to −20° C. over 1 h, re-cooled to −78° C. and treated with dimethylformamide (220 μL, 2.85 mmol). The reaction was warmed to 0° C. over several hours, then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and concentrated to afford 0.3 g (87%) as a white powder. LC/MS (HPLC method 1): tR=1.88 min, 181.02(MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[N:21]=[C:22]=[S:23]>>[CH3:10][C:11]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[N:21]=[C:22]1[S:23][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1
Reactant: NC1(CCl)CCCC1
Reactant: Cc1c(N=C=S)ccc([N+](=O)[O-])c1C
Agent: Cl
Product: Cc1c(N=C2NC3(CCCC3)CS2)ccc([N+](=O)[O-])c1C

Procedure:
2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted into 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in method A2d. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1c to give 2-(2,3-dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2N)c1
Yield: 76.9 %

Procedure:
5% carbon-palladium (3.0 g) was added to an ethanol (100 ml) solution of tert-butyl[2-[3-(3-nitro-2-pyridyloxy)phenyl]ethyl]carbamate (10.1 g, 28 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. Thus was obtained an oil of tert-butyl[2-[3-(3-amino-2-pyridyloxy)phenyl]ethyl]carbamate (7.09 g, 76.9%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
2.5 g (18.4 mmol) of 3-trifluoromethylpyrazole, 2.9 g (18.4 mmol) of 2-chloro-4-fluorobenzonitrile and 2.8 g (20.2 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. After washed with n-hexane, the residue afforded 4.6 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 92.0%) as a white powder, which was used in Reference Example 3 as the starting material.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=1)[C:15]([OH:17])=[O:16]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:24][O:23][C:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:22]
Reactant: c1cocn1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (432 mg, 6.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (2.5 M in hexanes, 2.75 mL, 6.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 18.75 mL, 18.75 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of 3-iodo-5-(methoxycarbonyl)benzoic acid prepared by the method in EXAMPLE SP-281, step 1 (1.8 g, 6 mmol) in anhydrous tetrahydrofuran (10 mL) followed by palladium(0) tetrakis(triphenylphosphine) (291 mg, 0.25 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is cooled, filtered through diatomaceous earth, diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5% methanol/methylene chloride) provides the title compound in pure form. ESI MS m/z 246.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH3:25])C(=O)OC(C)(C)C)=[O:8]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:24][O:23][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]2[NH:9][C:7](=[O:8])[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:22]=2[CH:21]=1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)C(=O)c2sccc2Br)c(C)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1
Yield: 86.5 %

Procedure:
Following Step 3 from General Procedure A, tert-butyl 3-bromothiophene-2-carbonyl(4-methoxy-2-methylphenyl)carbamate (14 g, 33 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (750 mg, 1.5 mmol) to afford the desired product (7.0 g, 85%) as a dark brown solid: ESI MS m/z 250 [C12H8FNO2S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([F:23])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(C#N)c(F)c2)C1=O
Yield: 32.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.693 mmol) was reacted with 4-bromo-2-fluoro-benzonitrile (372 mg, 1.86 mmol), 1,4-dioxane (50 mL), copper iodide (32.2 mg, 0.016 mmol), trans-1,2-diamino cyclohexane (61 mL, 0.5079 mmol) and potassium phosphate (900 mg, 4.23 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 163 mg of 2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (32.5% yield).