Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=O.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]#[N:9]
Reactant: Cn1ncc(I)c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: Cn1ncc(I)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A round-bottom flash was charged with Preparation 20, 4-iodo-1-methyl-1H-pyrazole-5-carboxamide (222 g, 886 mmol) and DCM (2.22 L) and the reaction mixture was cooled to 0° C. 2,6-Lutidine (310 mL, 2.66 mol) and trifluoroacetic anhydride (253 mL, 1.77 mol) were added. After reaction was complete, saturated aqueous sodium bicarbonate (800 mL) was added and the layers separated. The aqueous layer was washed with DCM (800 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (800 mL), 1N HCl (800 mL), and brine (800 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was suspended in heptanes (˜2 L) and granulated at 0-5° C. for 30 min. The solid was collected via filtration and dried in a vacuum oven to afford 4-iodo-1-methyl-1H-pyrazole-5-carbonitrile as a colorless solid (196 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:25][CH:26]=2)[C:31]1=[O:35])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2cccn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(-n3cccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1-pyrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-pyrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 15).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][SH:11])=[CH:8][CH:7]=1.CS(O[C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]1)[CH2:27][CH2:26]3)(=O)=O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][S:11][C@@H:19]2[CH2:24][CH2:23][C@H:22]3[C@H:25]4[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]23[CH3:21])[C@:33]2([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]2)[CH2:27][CH2:26]4)=[CH:8][CH:7]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)cc1

Procedure:
To 1.38 gm. of sodium metal dissolved in 120 ml. of ethanol is added 6 ml. of 4-chlorobenzylmercaptan followed by 2.26 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 96 hours. Obtain a residue in a manner similar to that described in Example 1A. Dissolve the residue in a minimum amount of chloroform and pass through a 200 gm. silica gel column. Elute with chloroform following the fractions by TLC. Combine the fractions, reduce, and crystallize the residue from ethyl acetate/hexane to obtain the title compound; m.p. 176°-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
Dissolve 4-(N-tert-butoxycarbonyl-N-ethyl-amino)-benzyl alcohol (1.24 g, 5.52 mmol) in 50 mL acetonitrile. Add to this solution manganese dioxide and stir the mixture for two days at room temperature. Filter the residue through Celite® and concentrate the solvent to give 632 mg of 4-(N-tert-butoxycarbonyl-N-ethyl-amino) benzaldehyde. Yield 52%. 1H-NMR (CDCl3, 300 MHz): 9.95 (s, 1H); 7.83 (d, J=8.7 Hz, 2H); 7.39 (d, J=8.7 Hz, 2H); 3.74 (q, J=7.0 Hz, 2H); 1.45 (s, 9H); 1.18 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][Mg]Br.[NH4+].[Cl-]>C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)=[O:7]
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: Br[Mg]CCC1OCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCC1OCCCO1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-N-methoxy-N-methylbenzamide (0.94 mmol; 173 mg) in anhydrous THF (2 mL), at −78° C. under argon, was added a solution of (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (1.04 mmol; 2.1 mL). The reaction was stirred 16 hours at room temperature. The mixture was cooled to −78° C. and (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (2.00 mmol; 4 mL) was added again. The reaction was stirred overnight at room temperature. The mixture was treated with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo. The title compound was prepared in quantitative yield, used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[C:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[C:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][O:14][S:31]([CH3:30])(=[O:33])=[O:32])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(CCCO)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: -10 °C
Yield: 8.6 %

Procedure:
5-(3-Hydroxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1f (9.20 g, 30 mmol) was dissolved in 150 ml of dichloromethane under stirring, and added with triethylamine (7.0 ml, 50 mmol) to the solution while maintaining the temperature at about −10° C. in an ice-salt bath under an argon atmosphere. Upon completion of the addition, the mixture was added slowly with methanesulfonyl chloride (3.5 ml, 45 mmol). After stirring to mix well, the reaction system was allowed to warm up to room temperature and stirred for 4 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with ice. The reaction mixture was washed successively with dilute hydrochloric acid (0.5 mol/L, 80 ml×2) to remove triethylamine, saturated sodium carbonate solution (80 ml×2) to remove excess hydrochloric acid and saturated brine (80 ml), and concentrated under reduced pressure to obtain the title compound 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (11.4 g, yield 99%) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>CO.C1COCC1>[Br:19][CH2:17][C:16]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:18]
Reactant: [Br-]
Reactant: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Yield: 292.5 %

Procedure:
1-[3-tert-Butyl-5-(2-methoxyethoxy)phenyl]ethanone (O2.043; 1 g) was dissolved in methanol/THF (25 ml/25 ml), admixed with phenyltrimethylammonium tribromide (882 mg) while stirring and stirred at RT overnight. Then 50 ml of 20% citric acid solution were added and the mixture was stirred for 1 h. Subsequently, DCM (200 ml) was added and the mixture was extracted three times with DCM. Then the combined DCM phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30 min). 1.31 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)O
Product: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)Nc1ccc(C(C)C)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 2-methoxy-5-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:22]([OH:24])=O)=O)(C)(C)C.[ClH:25].[C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)#[N:27]>CN(C=O)C>[ClH:25].[ClH:25].[C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9]([C:22]([N:29]3[CH2:30][CH2:31][CH2:32][C@H:28]3[C:26]#[N:27])=[O:24])[CH2:10]2)=[N:15][CH:16]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(C#N)cn2)C[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N[C@H]2CN[C@H](C(=O)N3CCC[C@H]3C#N)C2)nc1

Procedure:
(2S,4R)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-carboxylic acid (title compound of Reference Example 4, 0.73 g) and (S)-2-cyanopyrrolidine hydrochloride (0.29 g) were dissolved in DMF (10 mL), and triethylamine (0.62 mL), HOBT (0.34 g) and EDC hydrochloride (0.42 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl) amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.58 g) as amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O[C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:14]=1[CH:15]=O.C1(P(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[CH3:24][O:23][C:19]1[C:20]([O:21][CH3:22])=[C:13]2[C:14]([CH:15]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9](=[O:11])[O:10]2)=[CH:17][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Reactant: Cc1ccccc1CC(=O)O
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccccc3C)c(=O)oc2c1OC

Procedure:
A mixture of 2-methylphenyl acetic acid (0.60 g), 2-hydroxy-3,4dimethoxy-5-nitro-benzaldehyde (0.91 g), PhPOCl2 (0.60 ml) and triethyl amine (1.7 ml) were reacted in 1,2-dichloroethane as described in example 4. Yield: 0.68 g.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6])#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[NH:38]1[C:1]([C:3]2[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=2[C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]4[C:21]5=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]5[N:19]=[C:18]4[CH2:28][CH3:29])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])=[N:2][N:40]=[N:39]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C#N)c1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2-c2nnn[nH]2)c1
Yield: 59.5 %

Procedure:
To a solution of the product of Example 8, Step B (75 mg, 0.17 mmol) in 5 mL of toluene was added trimethyltin azide (43 mg, 0.21 mmol, 1.2 eq). The mixture was heated at reflux for 18 hours. Toluene was removed in vacuo and the resultant oil was dissolved in 5 mL of THF and treated with 0.5 mL of 2.5N HCl at 0° C. for 5 minutes. The volatiles were removed in vacuo and the resultant oil was flash chromatographed with 20% of 10/1 methanol/NH4OH mixture in chloroform to yield the titled compound (48.2 mg, 60%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([CH3:34])[CH:28]=[C:27]2[NH:35]N>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([CH3:34])[CH:28]=[C:27]2[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(C)nc4ccc(F)cc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=428.2 (M+H)+
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][N:4](CC(O)CO)[C:5]([C:7]1[C:8]([I:19])=[C:9]([OH:18])[C:10]([I:17])=[C:11]([C:14]([NH2:16])=[O:15])[C:12]=1[I:13])=[O:6].Cl>O>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][NH:4][C:5]([C:7]1[C:8]([I:19])=[C:9]([OH:18])[C:10]([I:17])=[C:11]([C:14]([NH2:16])=[O:15])[C:12]=1[I:13])=[O:6]
Reactant: NC(=O)c1c(I)c(O)c(I)c(C(=O)N(CC(O)CO)CC(O)CO)c1I
Agent: Cl
Solvent: O
Product: NC(=O)c1c(I)c(O)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 8 h

Procedure:
N,N-bis(2,3-dihydroxypropyl)-1-hydroxy-2,4,6-triiodobenzene-3,5-dicarboxylic acid diamide (13.1 g, 40 mmol) was dissolved in water (160 mL) and pH was adjusted to 3.9 using aqueous HCl. To this solution, NaICl2 (42.6 g, 50.3%, 40 mmol) was added dropwise during a period of 30 minutes. After standing overnight, the reaction mixture was evaporated. The product was purified by preparative HPLC (RP-18, CH3CN: H2O 15:85, 1% TFA). Yield 22.3 g (79%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.O>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cnc(CCOC2CCCCO2)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cnc(CCO)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-yl}propanamide (118 mg) in THF (10 mL) was added 1 M hydrochloric acid (10 mL) at room temperature, followed by stirring for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the obtained crude product was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (94 mg) as a white amorphous substance.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>>[N+:20]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[C:2]([F:1])([F:13])[F:14])([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccnc2ccccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2c(C(F)(F)F)ccnc12
Yield: 29 %

Procedure:
In a similar fashion using route 11 general procedure 57, 4-trifluoromethyl-quinoline 467 (200 mg, 1.01 mmol) and H2SO4:HNO3 (2:1) gave the title compound (70 mg, 29%) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH3:16])[N:10]=2)[CH:3]=1.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl.C(O)CCC>[CH3:16][NH:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:30][CH:29]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CNc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCCCO
Product: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Yield: 41 %

Procedure:
A solution of N2-(6-chloropyrimidin-4-yl)-N6-methylpyridine-2,6,diamine (0.3 g 1.27 mmol), 4-phenoxy aniline (0.28 g, 1.52 mmol) and conc. HCl (2 drops) in n-butanol (2 mL) was subjected to microwave irradiation (120° C., 1 h). The reaction mixture was cooled, was concentrated under reduced pressure, and the residue was diluted with CH2Cl2 (5 mL). The dichloromethane solution was washed with NaHCO3 (2 mL), water (2 mL), and brine (2 mL), and was dried over Na2SO4. Filtration followed by concentration under reduced pressure gave a residue which was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.2 g, 41%) as a light brown solid.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1.[CH3:17]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:17])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1
Reactant: COc1cc(O)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Thionyl chloride (953 μL, 13.1 mmol) was added dropwise to a solution of 4-hydroxy-2-methoxy-benzoic acid (733 mg, 4.36 mmol) in methanol (30 mL) at 0° C. The mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was dissolved in water (40 mL). The solution was neutralized with saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to dryness to give methyl 4-hydroxy-2-methoxy-benzoate (99%). ESI-MS m/z calc 182.1, found 183.1 (M+1)+. Retention time: 0.73 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=12)CCC>CN(C=O)C>[CH2:22]1[CH2:23][O:24][C:19]2[C:20](=[C:16]([C:2]3[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=3)[S:17][CH:18]=2)[O:21]1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2scc3c2OCCO3)ccc1O
Temperature: 80 °C
Yield: 27 %

Procedure:
The synthesis of this compound is depicted schematically in FIG. 13. A 50 mL schlenk flask was charged with 5-bromosalicylaldehyde (2.408 g, 11.98 mmol) and Cl2Pd(PPh3)2 (0.420 g, 0.599 mmol, 0.05 equiv). To this was added 2-tributylstannyl-3,4-ethylenedioxythiophene (8.784 g, 20.37 mmol, 1.7 equiv) in 25 mL of DMF. The reaction mixture was heated to 80° C. for 18 h, over which time the reaction color changed from light yellow to dark red. The solvent was removed under vacuum and the resulting oil was dissolved in 350 mL of EtOAc and washed with dil. NH4Cl (6×100 mL). The organic layer was filtered through a pad of silica and the solvent was removed to yield a thermally- and light-sensitive yellow-green solid (0.846 g, 3.23 mmol, 27%), mp 132° C., dec. 1H NMR (CDCl3) δ10.98 (s, 1H), 9.94 (s, 1H) 7.92 (d, 1H, J=2.3 Hz), 7.84 (dd, 1H, J=2.4 and 8.7 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.29 (s, 1H), 4.34-4.25 (m, 4H). MS m/z 262 (M+). HRMS (FAB) found m/z 263.0378 (M+H+); calcd for C13H11O4S m/z 263.0378 (M+H+).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH3:16])[C:14]=1[CH3:15])[CH3:7]>CO>[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[C:13]([CH3:16])[C:14]=1[CH3:15])[CH3:7]
Reactant: CCOc1nnc(Cl)c(C)c1C
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c(C)c1C

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.87 g(0.01 mol) of 3-ethoxy-4,5-dimethyl-6-chloropyridazine obtained from Preparation 8. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([OH:21])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:8][CH2:7]2)[O:5]CC1>CC(C)=O>[OH:21][CH:12]([CH:9]1[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(COc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(C(O)COc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2 M hydrochloric acid was added to a solution of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-2-phenoxyethanol (1.25 g, 4.5 mmol) in acetone (30 ml) and the mixture was stirred at room temperature for 48 h. The acetone was removed in vacuo, the pH of the aqueous residue was rendered alkaline with 2 M sodium hydroxide solution and the aqueous residue was extracted with methylene chloride (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][O:9][N:8]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1conc1-c1ccccn1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1conc1-c1ccccn1
Temperature: -10 °C
Yield: 76.1 %

Procedure:
To a solution of 3-pyridin-2-yl-isoxazole-4-carboxylic acid (39.0 g, 200 mmol) in THF (480 mL) at −10° C. was added triethylamine (30.7 mL, 220 mmol) and then a solution of ethylchloroformate (20.0 mL, 210 mmol) in THF (120 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (18.9 g, 500 mmol) in water (200 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature over 2 h and diluted with aqueous sodium hydroxide (2 N, 100 mL) and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1 to 1:2) afforded the title product (26.8 g, 76%) which was obtained as white solid. MS: m/e=177.2 [M]+.