Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl[CH2:27]Cl>CO.S(=O)(=O)(O)O>[CH3:27][O:24][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([C:14]2[CH:15]=[CH:16][C:11](/[CH:10]=[CH:9]/[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[CH2:18]1)=[O:25]
Reactant: ClCCl
Reactant: COc1ccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2ccc(/C=C/c3ccc(OC)cc3)cc2)C1
Temperature: 40 °C

Procedure:
A solution of 700 mg (2.1 mmol) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid in 7 ml of dichloromethane and 0.7 ml of methanol is treated with 1drop of sulfuric acid and heated at 40° C. for 20 hours. For the working-up, the solvent is evaporated, thereafter, the residue is treated with water and ethyl acetate. The organic layer is separated, dried over magnesium sulfate, and evaporated under reduced pressure. After crystallization from ether of the crude ester, 584 mg (80% of theory) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methyl ester are obtained as a light brown solid; MS: m/e=352 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(I)c(C(=O)Cl)c1
Temperature: 100 °C

Procedure:
To a solution of 5-methyl-2-iodobenzoic acid (3.0 g, 11.4 mmol) in toluene (150 mL), SOCl2 (8.35 mL, 114 mmol) was added and the mixture was heated at 100° C. for 3 hours. The solvent was concentrated in vacuum and the residue was co-evaporated from toluene twice to give the title compound as a grey solid. Yield (3.2 g, 100%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:9][NH:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22](COCC2C=CC=CC=2)[N:21]=[C:20]3[CH3:35])[N:12]=1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[ClH:44].[CH3:35][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:13]3[N:12]=[C:11]([NH:10][CH2:9][C@@H:8]([NH2:7])[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:16]=[N:15][CH:14]=3)[CH:18]=2)[NH:22][N:21]=1
Reactant: Cc1nn(COCc2ccccc2)c2ccc(-c3cncc(NCC(Cc4ccccc4)NC(=O)OC(C)(C)C)n3)cc12
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2ccc(-c3cncc(NC[C@@H](N)Cc4ccccc4)n3)cc12
Temperature: 50 °C

Procedure:
The compound from step D (0.53 g, 0.92 mmol) was mixed with ethyl alcohol (8 mL) and 2N HCl (8 mL) and heated at 90° C. for 2 h, 50° C. overnight. The mixture was evaporated to dryness and purified by reversed phase HPLC eluting with a gradient of 10% to 60% of acetonitrile/water with 0.1% TFA. The desired fractions were evaporated to dryness and treated with 2N HCl/ethanol to give the HCl salt. The salt was dried in high vacuum at 78° C. overnight to give the title compound (0.18 g, 45%). LCMS (+APCI) 359 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:28][C:13]1[C:14]2[C@:19]([CH3:20])([CH2:18][CH2:17][C:16](=[O:27])[CH:15]=2)[C@@H:21]2[C@H:11]([C@H:10]3[C@:24]([CH3:25])([CH2:23][C@@H:22]2[OH:26])[C@@H:7]([C:6](=[O:30])[CH2:5][OH:4])[C@H:8]([CH3:29])[CH2:9]3)[CH:12]=1
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO

Procedure:
A solution of 2.95 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-4,6-pregnadiene-3,20-dione in 80 ml. of methanol is combined with 800 mg. of potassium carbonate and stirred for 5 minutes at room temperature under argon. After adding 5 ml. of acetic acid and 5 ml. of water, the reaction solution is completely evaporated under vacuum. The residue is chromatographed on silica gel. With 42-50% acetone-hexane and after recrystallization from acetone-diisopropyl ether, 1.55 g. of 6-chloro-11β,21-dihydroxy-16α-methyl-4,6-pregnadiene-3,20-dione is obtained, m.p. 229° [α]D25 =+175° (methanol). UV: ε285 =19,850 (methanol).
Reaction SMILES: [C:1](N=NC(Cl)(C)C)(C)(C)[CH3:2].[K].C(OO)(C)(C)C.[C:18]([N:22]=[N:23][C:24]([O:27][O:28][C:29]([CH3:32])(C)C)([CH3:26])[CH3:25])([CH3:21])([CH3:20])[CH3:19].C(N=NC(O)(C)C)(C)(C)C>>[C:18]([N:22]=[N:23][C:24]([O:27][O:28][CH2:29][CH2:32][CH2:1][CH3:2])([CH3:25])[CH3:26])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Reactant: CC(C)(C)N=NC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)N=NC(C)(C)O
Agent: CC(C)(C)OO
Agent: [K]
Product: CCCCOOC(C)(C)N=NC(C)(C)C

Procedure:
Crude 2-t-butylazo-2-butylperoxypropane was prepared by reacting 2-t-butylazo-2-chloropropane with an aqueous solution of the potassium salt of t-butyl hydroperoxide according to the method described in MacLeay, Lange and Sheppard application Ser. No. 426,411 filed Dec. 19, 1973, (which is incorporated herein by reference). The resultant product contained approximately 75% 2-t-butylazo -2-t-butylperoxypropane and 25% 2-t-butylazo-2-hydroxy-propane (which has been marketed as "LUCEL 3").
Reaction SMILES: C1(C(=O)C)CC1.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[S:22]([NH:25]/[N:26]=[C:27](/[CH:29]([CH3:31])[CH3:30])\[CH3:28])(=[O:24])=[O:23])([CH3:9])[CH3:8]>>[CH:29]1(/[C:27](=[N:26]/[NH:25][S:22]([C:11]2[C:12]([CH:19]([CH3:20])[CH3:21])=[CH:13][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:10]=2[CH:7]([CH3:8])[CH3:9])(=[O:24])=[O:23])/[CH3:28])[CH2:31][CH2:30]1
Reactant: C/C(=N\NS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)C(C)C
Agent: CC(=O)C1CC1
Product: C/C(=N\NS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)C1CC1

Procedure:
The title compound was prepared from 2,4,6-triisopropylbenzenesulfonyl hydrazide (Aldrich, 20 g, 67.01 mmol) and 1-cyclopropylethanone (Aldrich, 6.28 mL, 67.01 mmol) following the procedure described for Intermediate 33. The desired product was obtained as a white solid (15 g, 61%).
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][CH:31]3[CH2:32][CH2:33][CH2:34][O:30]3)[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC2CCCO2)C12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (150 mg, 0.37 mmol) in dichloromethane (3 ml) under argon atmosphere was added 2,3-dihydro-furan (56 μl, 52 mg, 0.74 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (2 mg). The reaction mixture was stirred at room temperature for 4 hours, diluted with dichloromethane, washed twice with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1). Yield: 114 mg of carbonic acid ethyl ester 8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.9) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCN(C)CC2)c(Cl)cc1N
Solvent: CC#N
Solvent: ClCCCl
Product: CN1CCN(c2cc3c(cc2Cl)nc(Nc2cc(CNC(=O)C4(C(F)(F)F)CC4)ccc2Cl)n3C)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (176 mg, 0.5 mmol), 5-chloro-2-methylamino-4-(4-methyl-piperazin-1-yl)-aniline (134 mg, 0.5 mmol) and EDC (93 μL, 0.5 mmol) in MeCN (5 mL) in analogy to example 1 step (g).
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH2:10]([C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:10]([C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([CH:25]3[O:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][O:7]3)=[CH:27][CH:28]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CO)CO
Reactant: CCCCc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1ccc(C(=O)Oc2ccc(C3OCC(CCCC)CO3)cc2)cc1
Yield: 67.7 %

Procedure:
A mixture of 2-n-butylpropane-1,3-diol (6.6 g, 0.05 m) and p-(4'-n-butylbenzoyloxy)benzaldehyde (14.2 g, 0.05 m), benzene (100 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(5-n-butyl-1,3-dioxan-2-yl)phenyl p-n-butylbenzoate (13.4 g 67%) CN 79.2°-80.2° C., NL 160° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH:12]([CH3:14])[CH3:13])[C:7]=1[C:8]([F:11])([F:10])[F:9].[C-:15]#[N:16].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.CCOC(C)=O>[CH:12]([N:6]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:3]([CH2:2][C:15]#[N:16])[CH:4]=[N:5]1)([CH3:14])[CH3:13]
Reactant: CC(C)n1ncc(CCl)c1C(F)(F)F
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncc(CC#N)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 104 %

Procedure:
Tetrabutyl ammonium bromide (7.95 gm, 24.7 mmol) was added to 4-(chloromethyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole (7 g, 31 mmol) in dioxane (75 mL) and water (75 mL) and the mixture was stirred for 10 minutes. Potassium cyanide (7.42 g, 114 mmol) was added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc (100 mL) then the organic phase was washed with water (100 mL), brine (100 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo and purified by silica gel column chromatography eluting with hexane:EtOAc 90:10 to afford the title compound as a white solid (100%, 7.00 g).
Reaction SMILES: N1(C[N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)CCCC1.C([Li])CCC.[CH3:17][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32](N(OC)C)=[O:33])[N:22]=1)([CH3:20])[CH3:19]>O1CCCC1.C1CCCCC1>[CH3:20][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32]([C:11]2[CH:10]=[CH:9][NH:8][N:7]=2)=[O:33])[N:22]=1)([CH3:17])[CH3:19]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: c1cnn(CN2CCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)c1nc(C(=O)c2cc[nH]n2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1-(1-pyrrolidinomethyl)pyrazole (0.64 g, 4.2 mmol) (See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q; J. Org. Chem 1988, 53, 5688) in tetrahydrofuran (10 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.20 mmol) in cyclohexane. The resulting mixture is stirred 1 hour at -78° C. and warmed to ~0° C. After stirring 0.5 hours at 0° C., this mixture is cannula transferred to a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide in tetrahydrofuran (10 mL) at ~0° C. This reaction mixture is warmed to room temperature and stirred 16 hours. After quenching with aqueous saturated ammonium chloride solution, the mixture is extracted with ethyl acetate and the combined extracts washed with brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/hexane) followed by recrystallization from isopropanol and water to give 0.22 g (43%) of title compound as a mixture of tautomers, mp 156°-161° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].N([O-])=O.[Na+]>CO>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Brc1coc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1oc2ccccc2c1Br
Reaction time: 0.25 h

Procedure:
A 5.0 g. sample of powdered 3-bromobenzofuran on a glass dish is placed next to a container of nitric acid. Sodium nitrite is added periodically to the nitric acid, and the entire experiment is covered with a bell jar. After about 15 minutes the powder becomes an oil. After 12 hours the product is dissolved in hot methanol and slowly crystallized by cooling. Recrystallization from methanol provides yellow crystals of 3-bromo-2-nitrobenzofuran, m.p. 130°-132° C. (lit. 132° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][C:10]=2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 80 °C
Reaction time: 30 h
Yield: 72.8 %

Procedure:
A solution of Example A4 (1 g, 3.76 mmol) in EtOH (37.6 mL) was treated with tin(II) chloride dihydrate (4.25 g, 18.82 mmol) and stirred at 80° C. for 30 h. The mixture was cooled to RT, treated slowly with satd. NaHCO3 (5 mL), stirred for several minutes and filtered through diatomaceous earth. The filtrate was dried over Na2SO4 and concentrated to dryness to afford crude 5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-amine (645 mg, 73%) as an orange solid which was used without further purification. MS (ESI) m/z: 236.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH:16](O)=[O:17]>>[CH:16]([NH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[C:12]=1[CH3:13])=[O:17]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Reactant: O=CO
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(C)O2
Yield: 93.3 %

Procedure:
5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (1.00 g, 4.87 mmol) was dissolved in formic acid (20 ml) and the solution was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol, 97:3) to obtain the desired compound (1.06 g, yield: 93.3%). A part of it was recrystallized from dichloromethan-isopropyl ether to obtain white prisms, m.p. 177°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[C:10]=1[N+:21]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[C:10]=1[NH2:21]
Reactant: CCCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Yield: 95.6 %

Procedure:
[4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methyl-butyl)-amine (0.25 g, 0.71 mmol) and Na2S2O4 (1.00 g, 5.72 mmol) were treated substantially as described in Part E of Example 9 to yield 0.22 g (96%) of crude 4-(2,4-dichloro-phenyl)-N2-(1-methyl-butyl)-pyridine-2,3-diamine: MS (AP) m/z 324.3 [(M+H)+, 76].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.[F:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=S)=[O:31])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1.C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30](/[N:32]=[C:33]2/[N:12]([C@H:13]3[CH2:14][CH2:15][C@@H:16]([C:19](=[O:20])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:18]3)[C:3]3[CH:4]=[C:5]([S:8]([CH3:11])(=[O:9])=[O:10])[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:31])=[CH:35][CH:36]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2N)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(S(C)(=O)=O)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of cis-4-(5-Amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (0.069 g, 0.195 mmol) in THF (0.5 mL) was cooled to 0° C. and 4-fluorobenzoyl isothiocyanate (0.053 g, 0.292 mmol) was added as a THF solution. The mixture was stirred at 0° C. for 30 minutes and then was warmed to 20° C. and stirred for 1 hour. To the mixture was added DIPEA (0.051 mL, 0.292 mmol) and EDC (0.056 g, 0.292 mmol), and the reaction was heated at 60° C. for 1 hour. The reaction mixture was diluted with DCM and then washed with water and brine. The organic layer was concentrated under vacuum. The sample was purified by flash chromatography, eluting with 0-70% 90/10/1 DCM/MeOH/NH4OH:DCM to afford impure product as a light yellow solid. The impure material was further purified by preparative TLC, eluting with 90/10/1 DCM/MeOH/NH4OH:DCM to afford (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as a pale yellow solid (0.046 g, 47.1% yield). MS, m/z (C24H28FN5O4S); Calcd, 501.58. found 502.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C.CO.S(=O)(=O)(O)[OH:21]>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=[O:21])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C)=O)cc1OC

Procedure:
(3,4-Dimethoxyphenyl)-2-nitropropene (11) (200 g, 0.90 mol), palladium 10%/charcoal (10.0 g, either fresh or recycled), methanol (750 ml), water (220 ml) and sulfuric acid (96%, 28 ml) are charged to a steel autoclave thermostatted at 15° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@@H:13]3[C@@H:11]([CH2:12]3)[C@H:10]2[CH2:15][OH:16])=[O:8])[N:6]=1.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][O:16][CH2:15][C@H:10]2[N:9]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2CO)c(-c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2COCc2ccc(F)cc2)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of {(1R,2S,5S)-3-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hex-2-yl}methanol (0.025 g, 0.080 mmol) in THF (0.50 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.008 g, 0.206 mmol) followed by 4-fluorobenzylbromide (0.039 g, 0.206 mmol) and the system was stirred at 0° C. for 3 h. The mixture was then quenched with ice, extracted with EtOAc, purified using reverse phase conditions (5%→85% 0.1% TFA in water: 0.1% TFA in acetonitrile) followed by free basing with saturated sodium carbonate to afford the title compound as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.36-7.33 (m, 4H), 7.08-7.02 (m, 3H), 4.64 (m, 1H), 4.52 (m, 1H), 4.43 (m, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.14 (m, 1H), 2.71 (s, 3H), 1.84 (m, 1H), 1.60 (m, 1H), 1.43 (m, 1H), 0.560 (m, 1H). HRMS [M+H] C24H23F1N2O2S1 calc'd 423.1537, found 423.1542.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([Cl:36])[C:23]=1[CH:24]=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]4[N:19]=[C:24]([C:23]5[C:22]([Cl:21])=[CH:29][C:28]([N:30]6[CH2:31][CH2:32][O:33][CH2:34][CH2:35]6)=[CH:27][C:26]=5[Cl:36])[NH:20][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cc(N6CCOCC6)cc5Cl)[nH]c4c3)o2)cc1
Reaction time: 18 h

Procedure:
To a 50 ml rbf was added 0.2250 g (0.785 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine, 0.2041 g (0.785 mmol) of 2,6-Dichloro-4-morpholin-4-yl-benzaldehyde, and 5 mL of DMSO. To this dark brown solution was added 0.0190 g (0.118 mmol) of FeCl3. It was allowed to stir open to air for 18 h. The crude was then extracted with EtOAc, and the combined extracts were washed with water, brine and dried with Na2SO4. The volatiles were removed in vacuo and the concentrate was purified on silica gel (ACN/DCM, 1:9 to 10:0) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (d, J=5.05 Hz, 4H) 3.71-3.77 (m, 4H) 7.17 (s, 2H) 7.70-7.75 (m, 2H) 7.90 (d, J=8.72 Hz, 1H) 7.99-8.07 (m, 1H) 8.19 (d, J=8.21 Hz, 2H) 8.27 (br. s., 1H) 8.47 (s, 1H) 13.17 (d, J=8.97 Hz, 1H). MS (m/z) 528.0 M (+1), tR=1.41, Meth 10
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([NH:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnc(-n2ncc(-c3ccc(C#N)cc3)c2O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid (200 mg, 0.625 mmol), HATU (356.25 mg, 0.938 mmol) and triethylamine (315.63 mg, 3.125 mmol) and stirred at room temperature for 0.5 h. Then methanamine (108.75 mg, 1.25 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the title compound as a light yellow solid (88.38 mg, 42.46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (brs, 1H), 8.49-8.48 (m, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.11 (m, 2H), 7.77 (d, J=8.0 Hz, 2H), 2.79 (d, J=4.4 Hz, 3H), 2.48 (s, 3H). MS m/Z [M+H]+ 334.1.