Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:25]1([C:2]2[C:7]3[N:8]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C3CC3)c2N(c2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 200 mg), cyclopropylboronic acid (65 mg), potassium phosphate (410 mg), tetrakis-(triphenylphosphine)palladium(0) (66 mg), water (0.1 mL) and toluene (5 mL) was heated at 100° C. under argon atmosphere for 4 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 5-cyclopropyl-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (146 mg) as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
Under Ar protection, 5-bromo-2-chloro-benzoic acid (35 g, 148.6 mmol) was dissolved in toluene (230 ml), followed by addition of DMF (0.5 mL) at room temperature, then the reaction mixture was cooled to 0° C. The reaction mixture was heated to 100° C. after thionyl chloride (44 g, 372 mmol) was dropwise added. After 5 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5-bromo-2-chloro-benzoyl chloride 12n (35.5 g, pale yellow grease), yield: 94.0%.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([C:25]([F:28])([F:27])[F:26])[CH:10]=3)=[N:5][N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:3]1=[O:37].CC(O)=[O:40].OO>O1CCOCC1>[OH:40][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[C:25]([F:28])([F:26])[F:27])[O:8][CH2:7][C:6]1[N:15]2[CH:2]([CH3:1])[C:3](=[O:37])[N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:5]=1
Reactant: CC(=O)O
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(B4OC(C)(C)C(C)(C)O4)cc3N21
Agent: OO
Solvent: C1COCCO1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(O)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.500 g, 0.923 mmol) in dioxane (25 mL) was added AcOH (2.5 mL) and hydrogen peroxide (30%, 5 mL) and the reaction mixture was stirred at ambient temperature overnight. The solution was quenched by the addition of saturated Na2SO3 solution and the volatiles were evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×20 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-20% EtOAc in petroleum ether) to give 6-hydroxy-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.200 g, 50%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.15 (s, 1H), 6.59 (s, 1H), 6.00 (s, 1H), 5.14 (m, 2H), 4.69 (m, 2H), 4.56 (m, 1H), 3.69 (t, J=8.4 Hz, 2H), 1.53 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.04 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:8]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CO>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:21][C:22]#[N:23])[N:8]=1
Reactant: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (0.2 g.), N,N-diethylethylenediamine (0.5 ml.) and methanol (2 ml.) was heated under reflux for 24 hours and then evaporated to dryness. Water was added to the residue, the mixture extracted with ethyl acetate and the ethyl acetate extract dried and evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-diethylaminoethyl]guanidino)propylthio]-pyrimidine (0.08 g.), characterised as the bis hydrogen maleate, m.p. 76°-80° after recrystallisation from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(SC2CC3CCC(C2)N3)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-chlorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane (8.70 g, 20.28 mmol), 48% HBr (17 mL), and acetic acid (68 mL) was heated to 110° C. for 78 h. The reaction was adjusted to pH 11 by addition of 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was filtered through diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated to afford 3-(4-chlorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a yellow oil. The product was kugelrohr distilled (110-130° C., (pot temperature), 1.5 mm Hg) to give 4.1 g (79%) of 3-(4-chlorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a nearly colorless oil which solidified and had: NMR δ7.30 (m, 4 H), 3.54 (br t, J=3.5 Hz, 2 H), 3.32 (sym m, 1 H), 1.97-1.72 (m, 5 H), 1.71-1.52 (m, 4 H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:39][CH2:40][CH3:41])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:38]=1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:39][CH2:40][CH3:41])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N+:21]([O-:6])=[CH:20][C:19]=2[N:38]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCCCN4CCCC4=O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCCN4CCCC4=O)cc3c21
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
3-Chloroperoxybenzoic acid (50% pure, 1.8 g, 5.26 mmol) was added to a solution of 1-[3-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)propyl]-pyrrolidin-2-one (2.9 g, 5.26 mmol) in chloroform (50 mL). After 30 minutes, saturated aqueous sodium carbonate (20 mL) was added to the solution and the resulting mixture was allowed to stir for 1 hour. The layers were separated and the aqueous layer was extracted with chloroform (3×50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-4% methanol in dichloromethane) to yield 1.56 g of 1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one as a tan foam.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](CCl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[CH2:28]([SH:31])[CH2:29][CH3:30].[OH-].[Na+]>>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([S:31][CH2:28][CH2:29][CH3:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CCCS
Agent: [Na+]
Agent: [OH-]
Product: CCCSc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 14, a solution of 8-trifluoromethyl-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was heated with propanethiol and sodium hydroxide to give 8-trifluoromethyl-1-(propylthio)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 1 h

Procedure:
2.42 g (10 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, 2 g (11 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 169 mg (0.75 mmol) of palladium(II) acetate and 393 mg (1.5 mmol) of triphenylphosphine were successively added. Heating was carried out at 60° C. for one hour, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). 1.23 g (35.5%) of 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde, with a melting point of 104°-105° C., was recovered.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(Cc2cccc(OCc3ccc4ccccc4n3)c2)CC1
Yield: 11.5 %

Procedure:
A mixture of 4.7 g (0.015 mol) 2-(3-chloromethylphenoxymethyl) quinoline hydrochloride, 6 g (0.06 mol) N-methylpiperazine in 50 ml acetonitrile was heated over steam bath for a period of 8 hours. Reaction mixture was concentrated to dryness and sluried into water, and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using acetone as eluent. Evaporation of eluent gave solid (0.6 g), m.p. 47°-49° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[CH2:20]([NH:22]CC)C.Cl[Si](C)(C)C.Cl>CN(C)C=O.O>[C:13]([C:12]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]([C:20]#[N:22])=[N:10][CH:11]=1)([OH:15])=[O:14]
Reactant: CCNCC
Reactant: O=C(O)c1c[n+]([O-])ccc1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [C-]#N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)c(C(=O)O)cn1

Procedure:
To a solution of 4-phenylnicotinic acid N-oxide (8.4 g, 0.04 mol), sodium cyanide (6.45 g, 0.13 mol) and diethylamine (26.2 ml, 0.19 mol) in absolute dimethylformamide (200 ml), chlorotrimethylsilane (23.8 ml, 0.19 mol) is added. The reaction mixture is then heated for 26 h at 100°-110°. After cooling, the solution is poured into 200 ml of water and the pH is adjusted to pH 4 by the addition of concentrated HCl. The mixture is extracted with ethyl acetate and the extracts are concentrated. The dark residue is dissolved in 150 ml of ethyl acetate and extracted with a saturated solution of sodium hydrogen carbonate. This latter extract is acidified with concentrated HCl to pH 4 and extracted again with ethyl acetate. The combined ethyl acetate extracts are evaporated to dryness, and the residue is chromatographed in ethyl acetate/methanol (1:1) on Florisil® [magnesium silicate (30-60 mesh, Fluka, Buchs, CH)]to yield 5-carboxy-2-cyano-4-phenyl-pyridine, m.p. 270°-272°, Rf =0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A mixture of 1.35 g of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde and 0.84 g of sodium borohydride in 10 ml of methanol was stirred at room temperature for 30 minutes. Water (10 ml) was added and the mixture was extracted four times with 15 ml of diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated to leave 670 mg of [5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]methanol as a grey paste which was used without further purification. Mass spectrum (ES) m/z 365 [M+H]+, 406 [M+H+CH3CN]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[C:12](=[O:14])[CH3:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(I)ccc1OCCO
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was prepared analogously to Example 7.1e starting from 1-[2-(2-hydroxyethoxy)-5-iodophenyl]ethanone and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.90 g (70% of theoretical); C23H18ClNO3 (M=391.847); calc.: molpeak (M+H)+: 392/394 (Cl); found: molpeak (M+H)+: 392/394 (Cl); Rf value: 0.55 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[C:18]1([NH:24][C:25](=[O:26])[O:14][C:9]2[CH:10]=[C:11]([Cl:13])[CH:12]=[C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(COc1cc(O)cc(Cl)c1)OCC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(COc1cc(Cl)cc(OC(=O)Nc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Diethoxyethoxy)-5-chlorophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-diethoxyethoxy)-5-chlorophenyl] N-phenylcarbamate as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (5.9 g, 32.03 mmol), 2-fluoro-5-trifluoromethyl-benzonitrile (6.07 g, 32.03 mmol) and lithium hydroxide monohydrate (4.03 g, 96.08 mmol) in methyl sulfoxide (DMSO, 60 ml). Heat the resulting mixture to 70° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 400 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Obtained 9.995 g of the title compound (30.73 mmol, 96% yield) as an orange amorphous solid. Product used as is with no further purification: Mass Spectrum (m/e): 326(M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[N:3]1.[CH:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(O)C.C1(=O)CCCCC1>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[N:3]1.[CH:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: Cn1nc(C2CCCCN2)cc1N
Agent: O=COCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O=C1CCCCC1
Product: Cn1nc(C2CCCCN2)c(C2=CCCCC2)c1N
Temperature: 25 °C
Yield: 109.1 %

Procedure:
Under nitrogen atmosphere, to a 250 mL three-neck reaction flask were added the compound of Example 11B (11.7 g, 37 mmol), ethanol (150 mL) and cyclohexanone (15.5 mL, 149 mmol). The mixture reacted overnight at 50° C. to 60° C. After cooled to room temperature, acetic acid was removed by rotary-evaporation to obtain a crude product. The crude product was subject to column chromatography (eluant: petroleum ether:ethyl acetate=2:1) to give 8.0 g of the title compound. Yield: 54.4%. MS (ESI): m/z 395 (M+H)+
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24])([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[CH2:4]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(/C=C/c1ccccc1[N+](=O)[O-])NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (RS)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-nitrophenyl)propenoic acid as a solid; MS (ES+) 302 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.OC[C@@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C@@H:37]5[CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
1,1-Dimethylethyl (3R)-3-[{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl}methyl]pyrrolidine-1-carboxylate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1,1-dimethylethyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate following General Procedure J.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)O)c3)no2)cc1C#N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoate (D58) (523 mg, 1.17 mmol) was dissolved in mixture of ethanol (20 ml) and THF (10 ml) by warming at 50° C. Cooled to RT and added 2N NaOH (1 ml, 2 mmol) and left standing at RT for 30 minutes. Evaporated off the solvent, added water (50 ml) and washed with EtOAc (50 ml). Acidified aqueous layer and extracted product into EtOAc (50 ml). The EtOAc layer was dried (MgSO4) and the solvent evaporated. Triturating with diethyl ether gave the title compound (139 mg) as a beige solid. δH (d6-DMSO, 400 MHz): 1.39 (6H, d), 2.90 (2H, t), 4.66 (2H, t), 4.94-5.03 (1H, m), 7.57 (1H, d), 7.90 (1H, d), 8.07 (1H, dd), 8.28 (1H, d), 8.42 (1H, dd), 8.54 (2H, dd), 12.35 (1H, broad s). MS (ES): C22H19N5O4 requires 417; found (MH+) 418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([NH:23][NH2:24])=[O:22])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=[N:18][CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CS(=O)(=O)c1cncc(C(=O)NN)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cncc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 65 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (50 mg, 0.293 mmol) and 5-(methylsulfonyl)nicotinohydrazide (63.1 mg, 0.293 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (70 mg, 63.0% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.37 (s, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 7.68 (s, 1H), 7.36 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=8.8 Hz), 3.42 (s, 3H), 2.53 (s, 3H). ESI-MS: 368.8 [M+H]+.