Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.CS[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:22]=[CH:21]2)=[N:18][CH:19]=1.[O-:31][S:32]([O-:35])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:2][S:32]([C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:22]=[CH:21]2)=[N:18][CH:19]=1)(=[O:35])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-n2cncc2-c2ccccc2)nc1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2cncc2-c2ccccc2)nc1

Procedure:
M-chloroperoxybenzoic acid (230 g) and 5-(methylthio)-2-(5-phenyl-1H-imidazol-1-yl)pyridine (118 g) were dissolved in 3 L dichloromethane, and stirred to react for 2 hours at 0° C. After the reaction was complete, 1000 mL saturated Na2S2O3 solution was added. The mixture was extracted with dichloromethane, the organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography to obtain the target compound (50 g). 1H-NMR (300 MHz, CDCl3): δ 3.14 (3H, s), 6.90 (1H, d), 7.24 (3H, m), 7.39 (3H, m), 8.06 (1H, dd), 8.30 (1H, s), 9.05 (1H, d); LC-MS m/z: 300 [M++1], purity (HPLC)>95%.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].I[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](I)=[CH:18][C:17]=1[CH3:24].ClCCl.O>CS(C)=O.[Cu]>[F:2][C:1]([F:3])([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:1]([F:3])([F:2])[C:4]([F:5])([F:6])[C:7]([F:8])([F:9])[C:10]([F:13])([F:12])[F:11])=[CH:18][C:17]=1[CH3:24])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Cc1cc(I)c(C)cc1I
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C)cc1C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
A solution of C4F9I (0.96 mL, 5.6 mmol) was added dropwise over 10 min to a stirred mixture of 2,5-diiodo-ρ-xylene (0.5 g, 1.4 mmol), copper powder (1.4 g, 22.4 mmol) in DMSO (10 mL) at 130° C. The reaction mixture was subsequently stirred for a further 24 h at this temperature. After cooling to room temperature, it was poured into a beaker containing dichloromethane (30 mL) and water (30 mL). After filtering, the organic layer was separated, washed with water (3×30 mL) and dried over MgSO4. The residue was purified by column chromatography (hexane as eluant) to give the product 8 as a white solid (553 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(Br)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.80 g), tetrahydrofuran (3 mL) and methanol-(3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.63 g, 83%) of 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=1)#[CH:26].C1(C(O)(C#C)C)C=CC=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[C:25][C:27]4[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc[n+]([O-])c1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: C#CC(C)(O)c1ccccc1
Product: O=C(NC1CC1)c1cn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of PREPARATIVE EXAMPLE 4, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 of PREPARATIVE EXAMPLE 3 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, and 3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, the N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](O)=[O:10])=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([Cl:16])=[O:10])=[O:6]
Reactant: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 25 parts of N-[(2,2,2-trichloroethoxy)carbonyl]glycine in 250 parts by volume of toluene is added dropwise with stirring 20 parts of thionyl chloride. The resultant reaction mixture is heated on a steam bath for about 2 hours, then the solvent and excess of thionyl chloride are removed by distillation to afford {[(2,2,2-trichloroethoxy)carbonyl]amino} acetyl chloride represented by the following formula
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([F:23])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Reactant: F[B-](F)(F)F
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(F)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and α-methylthio-4-fluoroacetophenone (6.5 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-fluorophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (9 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCCCBr
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCO)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 38.5 %

Procedure:
Ex-39A: A solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-13C, 500 mg, 2.13 mmol) in DMF (20 mL) was treated with potassium carbonate (589 mg, 4.26 mmol) followed by the addition of 3-bromo-propan-1-ol (356 mg, 2.56 mmol). The reaction mixture was heated to 80° C. for 2 h followed by another addition of potassium carbonate (294 mg, 2.13 mmol) and 3-bromo-propan-1-ol (296 mg, 2.13 mmol). The reaction mixture was stirred for an additional 45 minutes, quenched with water (15 mL), and extracted with ethyl acetate (2×25 ml). The organic phase was washed with brine, dried over sodium sulfate, and concentrated to a beige oil. The oil was purified by column chromatography (elution: 30, 50, and 80% ethyl acetate in hexane) to yield 240 mg (38%) of 2-(3-hydroxypropoxy)-4-methoxy-5-thiophen-2-ylbenzaldehyde as an off-white solid. 1H-NMR (300 MHz, CDCl3) 10.21 (s, 1H), 8.02 (s, 1H), 7.41 (br d, 1H, J=3.9 Hz), 7.28 (d, 1H, J=5.10 Hz), 7.06 (dd, 1H, J=3.0, 5.7 Hz), 6.48 (s, 1H), 4.24 (t, 2H, J=7.0 Hz), 3.92 (s, 3H), 3.88 (br s, 2H), 2.11 (q, 2H, J=7.0 Hz).
Reaction SMILES: O1C2C=CC=CC=2C[C:3](=[O:11])N1.[C:12]([C:16]1[CH:44]=[CH:43][C:19]([C:20]([NH:22][C:23]2[CH:38]=[C:37](C(OC)=O)[CH:36]=[CH:35][C:24]=2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)=[O:26])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C1C[O:48][CH2:47]C1>>[C:12]([C:16]1[CH:44]=[CH:43][C:19]([C:20]([NH:22][C:23]2[CH:38]=[CH:37][C:36]([C:47]([O:11][CH3:3])=[O:48])=[CH:35][C:24]=2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)=[O:26])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1Cc2ccccc2ON1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Into 25 mL THF was dissolved 0.174 g (0.5 mmol) of the above benzoxazinone intermediate. The solution was cooled in an ice bath and placed under nitrogen atmosphere. To the mixture was added 1.5 mL (0.6 mmol) of a 0.4 M solution of the magnesium salt of 2-amino-5-chloropyridine (See Prep. D, Example 278). After 30 min, an additional 1.5 mL (0.6 mmol) of the magnesium salt was added. Stirring was continued for 15 min, and the reaction mixture was quenched with 100 mL cold dilute HCl. The mixture was extracted with 100 mL EtOAc, and the organic layer was washed with 100 mL cold dilute HCl, dried (MgSO4), and concentrated under vacuum. The crude product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 91 mg (39%) of title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13](Cl)(=[O:17])C(Cl)=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>ClCCl>[CH:19]1([NH:22][C:13]([NH:6][C:4]([C:3]2[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[C:8]([F:12])[CH:7]=2)=[O:5])=[O:17])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Solvent: ClCCl
Product: O=C(NC(=O)c1cc(F)c(Cl)nc1Cl)NC1CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of 5.8 g (27.8 mmol) of 2,6-dichloro-5-fluoronicotinamide (Chem. Pharm. Bull., 1987; 35:2280) in 60 mL of dichloromethane is treated dropwise with 5.1 g (40 mmol) of oxalyl chloride, and the reaction mixture is heated at reflux for 18 hours. The solvent is removed in vacuo, and the residue is dissolved in 50 mL of dichloromethane, which is also removed in vacuo. The residue is dissolved in 50 mL of dichloromethane, cooled to −20° C. and treated dropwise with 2.28 g (40 mmol) of cyclopropylamine. The reaction mixture is stirred at −20° to −10° C. for ½ hour, then allowed to come to room temperature over 2 hours. The solvent is removed in vacuo and the residue is triturated with 25 mL of dichloromethane, which is also removed in vacuo to give 8.0 g of the title compound, mp 171–173° C.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].O.[CH3:18]O>[Cl-].C([N+](CC)(CC)CC)C>[CH3:18][O:1][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CO
Reactant: [OH-]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
45 g of sodium hydroxide and 10 g of tetraethylammonium chloride in 200 g of methanol are initially introduced, 112.5 g of 2-chloro-5-nitro-benzotrifluoride are added dropwise at 25° to 30° C. and the mixture is then stirred at 30° C. for a further 5 hours. The mixture is then poured into 250 ml of water and extracted with methylene chloride. After evaporating off the solvent, the compound is recrystallised from isopropanol. 67 g of 2-methoxy-5-nitro-benzotrifluoride with a melting point of 70° to 74° C. are obtained.
Reaction SMILES: I[CH2:2][C:3]1([CH3:32])[CH2:7][C:6]2[C:8]([CH3:31])=[C:9]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:5]=2[O:4]1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]2[C:5]3[O:4][C:3]([CH3:32])([CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:7][C:6]=3[C:8]([CH3:31])=[C:9]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:10]=2[CH3:22])=[CH:18][CH:17]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(CI)O2
Reactant: C1CCNC1
Solvent: O
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(CN1CCCC1)O2
Yield: 95 %

Procedure:
A mixture of N-(2-(iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (102 mg, 0.19 mmol) obtained in Example 336 and pyrrolidine (1.5 mL) was reacted using a microwave reactor (110° C., hold time 20 min, 250 W). Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 86 mg (yield: 95%) of the title compound. Melting point: 143-144° C. (THF-hexane).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].O.[NH2:33][NH2:34]>C(O)C>[F:28][C:27]([F:29])([F:30])[C:23]1[CH:22]=[C:21]([CH2:20][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]5[NH:33][N:34]=[C:8]([NH2:9])[C:7]=45)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])[CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cncc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added hydrazine monohydrate (0.266 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed 80% product and 20% SM. Additional hydrazine monohydrate (0.266 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and it was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was then transferred into a 40 mL vial with MeCN, water was added and the solution was freeze-dried to afford 4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (20 mg, 25.3% yield) as a white solid. LC/MS (ES) m/z=438.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.74 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.44 (s, 1H), 7.33 (d, J=8.34 Hz, 1H), 4.61 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.26-3.30 (m, 2H).
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:4])[CH3:2]
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (4 ml) is heated under reflux for about 1.5 hours. The reaction mixture is then concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride and methylene chloride (10 ml) is added slowly a solution of ethyl 2-hydroxyiminopropionate (320 mg, 2 eq.) and methylene chloride (5 ml) containing triethylamine (0.2 ml, 1.2 eq.). The resulting mixture is stirred at RT for 2 hours. The reaction is then worked up in methylene chloride, washed, dried and evaporated to dryness to give an oily product. The oily product is purified by preparative thin layer chromatography (prep. TLC) in silica gel (50% ethyl acetate/hexane) to yield ethyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>CCOC(C)=O>[ClH:22].[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the ester from step (b) above (8.6 g) and saturated solution of hydrogen chloride in EtOAc (100 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was washed with EtOAc, and dried in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 192 (M+1).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7](N1C=CN=C1)(N1C=CN=C1)=[S:8].[CH2:19]([CH:21]1[CH2:25][NH:24][N:23]=[CH:22]1)[CH3:20]>C(#N)C>[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][C:7]([N:23]1[CH2:22][CH:21]([CH2:19][CH3:20])[CH:25]=[N:24]1)=[S:8]
Reactant: CCC1C=NNC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: CC#N
Product: CCC1C=NN(C(=S)NCC(F)(F)F)C1
Reaction time: 8 h
Yield: 1.2 %

Procedure:
A solution of 3.2 mL (1 mol equiv.) 2,2,2-trifluoro-ethylamine in 60 mL acetonitrile was added to a stirred solution of 7.4 g (2.1 mol equiv.) 1,1′-thiocarbonyldiimidazole in 100 mL acetonitrile at room temperature. The reaction mixture was stirred overnight, and 1.96 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) was added to the reaction mixture. After 1 hour volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (Et2O:PA=1:3) to afford 2.85 g (60%) 4-ethyl-4,5-dihydro-pyrazole-1-carbothioic acid (2,2,2-trifluoro-ethyl)-amide. 1H NMR (400 MHz, CDCl3) δ 1.01 (t, J=7.5 Hz, 3H), 1.50-1.74 (m, 2H), 3.13-3.23 (m, 1H), 3.86 (dd, J=11.6, 7.1 Hz, 1H), 4.27 (t, J=11.6 Hz, 1H), 4.44 (m, 2H) 6.99 (d, J=1.5 Hz, 1H), 7.32-7.40 (br.s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[NH:6]2.[OH-].[K+].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]2[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2c(Cl)cc(Cl)cc2n1CCN1CCOCC1

Procedure:
To a solution of 4,6-dichloro-2-methylindole (75 mg, 0.37 mmol) in 0.5 mL DMSO was added pulverized KOH (95 mg, 1.69 mmol), then 2-chloroethylmorpholine HCl (140 mg, 0.75 mmol) and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 91 mg (0.29 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.42-2.55 (m, 4H), 2.44 (s, 3H), 2.60 (t, J=7.0 Hz, 2H), 3.65-3.79 (m, 4H), 4.08 (t, J=7.0 Hz, 2H), 6.31 (s, 1H), 7.09 (s, 1H), 7.16 (s, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.84, 41.59, 54.10, 57.79, 66.91, 98.99, 107.84, 119.47, 125.23, 125.51, 126.17, 137.22, 138.20. MS m/z 313.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:13]=[C:11]([CH3:12])[N:1]=2)[CH:4]=1.[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:11]([N:13]([CH3:15])[CH3:14])[CH3:12])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=Nc1ccc(Br)cn1)N(C)C
Product: Cc1nc2ccc(Br)cn2n1
Temperature: 130 °C

Procedure:
To a stirred solution of 2-amino-5-bromopyridine (1.73 g, 10 mmol) in N,N-dimethylformamide (20 mL) was added dimethylacetamide dimethylacetal (3.99 g, 30 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to afford the desired product N′-(5-bromo-pyridin-2-yl)-N,N-dimethyl-acetamidine as a brown oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[CH:8]([CH2:13][CH:14]=[O:15])CCCC.S(=O)(O)[O-].[Na+].[C-:21]#[N:22].[Na+]>O>[CH:3]12[CH2:1][CH:2]1[CH2:6][CH2:5][CH:4]2[CH2:8][CH2:13][CH:14]([C:21]#[N:22])[OH:15]
Reactant: CCCCC(C)CC=O
Reactant: CCCCCC
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: N#CC(O)CCC1CCC2CC12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.01 Mole of exobicyclo[3.1.0]hex-2-yl acetaldehyde and 0.01 mole of sodium bisulfite are stirred in 20 ml. of water at room temperature until all of the aldehyde is dissolved. 0.02 Mole of sodium cyanide in 5 ml. of water is then added and the mixture stirred for 30 minutes at room temperature. The solution is then extracted three times with ethyl acetate and the combined ethyl acetate extract dried over anhydrous magnesium sulfate, filtered and then evaporated under vacuum to remove the solvent, yielding 1-(bicyclo[3.1.0]hex-2-yl)-3-cyano-3-hydroxypropane.