Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:28]O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reactant: OO
Product: CC(C)(C)c1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-tert. butylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1]CN(CC)CC.[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15](=[S:19])[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=1.CI>CS(C)=O>[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15]([S:19][CH3:1])=[N:14][CH:13]=[N:12][C:11]=2[CH:10]=1
Reactant: Nc1cc2nc[nH]c(=S)c2cn1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CS(C)=O
Product: CSc1ncnc2cc(N)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
NEt3 (6 mL, 43 mmol) is added to a solution of 7-amino-4-thiono-3H-pyrido[4,3-d]pyrimidine (0.77 g, 4.3 mmol) in DMSO (7 mL) stirred under N2 at 25° C. After the two phases have been stirred for 20 min, MeI (0.26 mL, 4.2 mmol) is added. After 2 h, the reaction mixture is poured onto stirring ice-water. Solid forms instantly. After further cooling at 0° C., the solid is collected by suction filtration and dried in a vacuum oven to give 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.564 g, 68%). 1H NMR (DMSO) δ 8.98 (1H, s), 8.71 (1H, s), 6.94 (2H, brs), 6.49 (1H, s) 2.63 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C:6]=2[CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.7 g) in pyridine (50 ml) is added with stirring methanesulfonyl chloride (0.71 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with successively with diluted hydrochloric acid and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.8 g) as colorless amorphous.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+]>ClCCl>[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of t-butyl trans-4-hydroxycyclohexyl-carbamate (1.00 g) and pyridine (773 mg) in dichloromethane (40 ml) under ice-cooling was added a solution of 4-methylbenzoylchloride (754 mg) in dichloromethane (10 ml) over 10 minutes. The mixture was stirred overnight at room temperature, and then saturated aqueous ammonium chloride was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.30 g of t-butyl trans-[4-(4-methylphenylcarbonyloxy)cyclohexyl]-carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[N:13]=[C:14]([CH2:35][CH2:36][CH3:37])[N:15]2[C:20]=1[C:19](N1C=NC=N1)=[N:18][C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])=[N:16]2>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:19]2[C:20]3=[C:12]([CH3:11])[N:13]=[C:14]([CH2:35][CH2:36][CH3:37])[N:15]3[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH3:34])[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCCc1nc(C)c2c(-n3cncn3)nc(-c3ccccc3OCC)nn12
Solvent: CCN(CC)CC
Product: CCCc1nc(C)c2c(NCCc3cccc(Cl)c3)nc(-c3ccccc3OCC)nn12

Procedure:
In a parallel synthetic run, 18.7 mg (0.12 mmol) of 2-(3-chlorophenyl)ethylamine are introduced into a reaction vessel and treated with 1,2-dichloroethane solutions of Example 39A and triethylamine. The amount added is 29.1 mg (0.08 mmol; solution: 0.08 mol/l) of Example 39A and 8.10 mg (0.08 mmol; solution: 0.08 mol/l) of triethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc23)CC1
Yield: 58.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 18.0 mg (0.09 mMol) 4-(methanesulfonyl)benzoic acid, 7.2 mg of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:8].C(=O)(O)[O-].[Na+]>C(O)C>[NH:8]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C#N
Reactant: Cn1cccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=N)c1cccn1C

Procedure:
A stream of dry halogen chloride is passed as a moderate rate through a solution of 12.5 g of N-methylpyrrole and 16.8 g of ethyl cyanoformate in 125 mls of ethanol-free chloroform at 22° C. for 31/2 hours. The reaction mixture is added dropwise with stirring to a 1.5 liter solution of 5% sodium bicarbonate. The chloroform layer is separated, dried over Na2SO4 and evaporated in vacuo at room temperature to give a brown oil (ethyl α-imino-1-methylpyrrole-2-acetate).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.34 g, 95%) was prepared as a white solid from 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (Example 146, Step 4, 0.20 g, 0.80 mmol), 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (0.33 g, 1.12 mmol), K2CO3 (0.23 g, 1.60 mmol) in DMF (7 mL) in a manner similar to Example 139, Step 3. The reaction mixture was cooled to ambient temperature, and poured into water (50 mL). The precipitate was collected and washed with water, air dried to give 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (bs, 1H), 8.14 (d, 2H, J=7.5 Hz), 8.01 (d, 2H, J=7.3 Hz), 7.80-7.70 (m, 1H), 7.34 (bs, 1H), 4.18 (bs, 2H), 3.91 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 2.85-2.65 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.40-1.20 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([C:25]2[C:26]([CH3:31])=[N:27][O:28][C:29]=2[CH3:30])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:31][C:26]1[C:25]([C:18]2[C:17]3[CH2:32][N:33]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[C:34](=[O:35])[C:16]=3[C:15]([OH:14])=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(C)c1-c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 279 dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and purified by prep-HPLC to remove Ph3PO. The crude mixture was diluted with EtOAC and extracted with 1N HCl. The aqueous phase containing product 280 was re-purified by HPLC to afford 5-(3,5-dimethyl-isoxazol4-yl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 280, (0.4 mg) as a TFA salt solid: 1H NMR (CD3OD) δ 9.0 (d, 1H), 8.1 (d, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.4 (dd, 1H), 7.1 (t, 2H), 4.8 (s, 2H), 4.2(s, 2H), 2.0 (s, s, 2×3H); MS: 404 (M+1). HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH3CN; gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ, C18 (2), 150 mm×21.1 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[F:16][C:17]1[CH:18]=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1n[nH]c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 18.3 %

Procedure:
3-Fluoro-N-(3-methylsulfonylamino-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 0.1 g of 5-amino-3-methylsulfonylamino-1H-indazole, 5 ml of pyridine and 83 mg of 3-fluorobenzenesulfonyl chloride. 30 mg of 3-fluoro-N-(3-methylsulfonylamino-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a beige solid melting at 230° C. (analysis C14H13FN4O4S2.0.57H2O % calculated C, 43.75; H, 3.41; F, 4.94; N, 14.57; O, 16.65; S, 16.68. % found C, 43.75; H, 2.86; N, 14.77; S, 15.93).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C1C=CC=CC=1>O1CCCC1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[I:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1I
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)c1ccccc1I

Procedure:
In accordance with the procedure of Example 3, 12.1 g of cyclohexylamine was reacted with 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran. There was obtained by recrystallization from benzene 5.7 g of fine white crystals of N-cyclohexyl-o-iodobenzamide, m.p. 148°-149°, Rf 0.74.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][CH:13]([CH3:16])[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:14][CH:13]([CH3:16])[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 2-methyl-1-propanamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21][C:22](=[O:30])[CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=O)=[C:4]([F:31])[CH:3]=1.C(O)(=O)C.[O-:36][C:37]#[N:38].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:21]2[C:22](=[O:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[NH:38][C:37]2=[O:36])=[CH:6][C:7]=1[O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide and 2 ml of acetic acid, 0.33 g of potassium cyanate was added, and the mixture was stirred at 50° C. for 1 hour, then, at 110° C. for 1.5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=[O:27])[C:17]#[N:18].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C@:36]([OH:51])([C@H:43]([S:45][CH:46]([CH2:49]O)[CH2:47][OH:48])[CH3:44])[CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1>ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C@H:26]2[O:48][CH2:47][C@H:46]([S:45][C@H:43]([CH3:44])[C@:36]([C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])([OH:51])[CH2:37][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH2:49][O:27]2)=[C:14]([F:13])[CH:15]=1)#[N:18]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
791 mg (4.16 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 760 mg (3.77 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]-benzonitrile [obtained as described in Example 1(ii) above] and 1.36 g (3.77 mmol) of (2R,3 R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2 -hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 13 ml of dichloromethane. The resulting mixture was concentrated using a rotary evaporator. 13 ml of dichloromethane and 13 g of 4A molecular sieves were added to the resulting residue and the mixture was then stirred at ambient temperature overnight. At the end of this time, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The molecular sieves were removed by filtration and the filtrate was partitioned between ethyl acetate and water. The organic layer was dried and concentrated under reduced pressure. The resulting oil residue was purified by chromatography on a silica gel (20 a) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to afford 1.42 g (yield 69%) of the title compound as an amorphous solid. The spectral data were identical to those of the title compound of Example 1.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)(Cl)Cl>[CH3:18][S:17][C:11]1[CH:16]=[CH:15][C:14]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a cold (0° C.) solution of phenylacetyl chloride (92.8 g, 0.6 mol) in CHCl3 (1.2 L) was added AICl3 (80 g, 0.6 mol) in portions. Thioanisole (62.1 g, 0.5 mol) was then added dropwise. The resulting mixture was stirred at r.t. for 1.5 h. The mixture was poured into 4 L of ice and water and extracted with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was slurried in 300 mL of 20% EtOAc/hexane, filtered and washed with hexane to give 78 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:34][C@H:31]2[CH2:32][CH2:33][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: N[C@H]1CCOC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N[C@H]2CCOC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), (S)-tetrahydrofuran-3-ylamine hydrochloride (68.2 mg, 552 μmol), diisopropylethylamine (193 μl, 1.1 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording (S)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N4-(tetrahydrofuran-3-yl)-1H-pyrazole-4,5-dicarboxamide (118 mg, 99.1%) as a white solid. mp.: >250° C. MS: m/z=432.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[CH3:15][O:16]C(Cl)Cl.Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH:15]([C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])=[O:16]
Reactant: COC(=O)CCc1ccc(OC)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OC)c(C=O)c1
Temperature: -20 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
Methyl 3-(4-methoxyphenyl)propanoate (500 mg, 2.56 mmol) was dissolved in 30 mL of anhydrous dichloromethane. TiCl4 (2.1 mL, 19 mmol) and MeOCHCl2 (0.81 mL, 9.0 mmol) were added subsequently at −20° C. under Argon. The reaction mixture was stirred at −20° C. for 6 hours. Then the reaction mixture was slowly poured into a diluted hydrochloric acid solution. The dichloromethane layer was separated and washed with water followed by brine then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Then the crude residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10) to obtain methyl 3-(3-formyl-4-methoxyphenyl)propanoate (ss-2) as a colorless oil (429 mg, 75% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)(=[O:33])=[O:34]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h
Yield: 5.5 %

Procedure:
To stirred suspension of 4-(4-chlorophenyl)piperazine dihydrochloride (3.0 g) in dichloromethane (100 ml) at 0° C. was added triethylamine (4.6 ml). After 15 mins, a solution of 2-chlorosulfonylbenzoic acid methyl ester (2.90 g) in dichloromethane (30 ml) was added. Stirring was continued overnight with the temperature rising to RT. The reaction mixture was diluted with dichloromethane (100 ml) and then washed with 10% aqueous citric acid (3×50 ml), saturated aqueous sodium hydrogen carbonate solution (3×50 ml), water (3×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (0.24 g, 48%) as an off-white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[O:6][N:5]=1)([CH3:3])[CH3:2].O.NN>C(O)C>[CH:1]([C:4]1[N:8]=[C:7]([CH2:9][NH2:10])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1noc(CN)n1

Procedure:
To a vigorously stirred suspension of compound 2-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]-1H-isoindole-1,3(2H)-dione (79 g, 0.29 mol) in ethanol (500 mL), hydrazine hydrate (16 g, 0.32 mol) was added. After the precipitate was completely dissolved, the reaction mixture was heated to reflux for 4 h. The precipitate was removed by filtration. The mother liquor was evaporated. The residue was dissolved in ether (200 mL). The precipitate was removed by filtration. The filtrate was evaporated. The residue was redistilled under high vacuum collecting the fraction boiling at 62-65° C./0.02 mmHg to yield the title compound.