Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-4-nitrobenzene (1.0 g, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (512 mg, 3.6 mmol), and triethylamine (560 μL, 4.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with EtOH (2×15 mL) and diethyl ether (3×25 mL), and dried in vacuo, affording the title compound (1.0 g, 90% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 4.53 (s, 2H), 6.00 (s (br), 1H), 7.78 (d, 1H, J=8.8 Hz), 8.15 (dd, 1H, J=2.9 Hz, 8.8 Hz), 8.59 (d, 1H, J=2.7 Hz); M+ 312.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[N:4][N:3]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:10]1[N:9]=[N:8][C:7]([C:5]2[S:6][C:2]([Br:1])=[N:3][N:4]=2)=[N:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1nnc(-c2nnn[nH]2)s1
Product: CC(C)(C)OC(=O)Cn1nnc(-c2nnc(Br)s2)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 5 from 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole and tert-butyl bromoacetate. The isolated title compound was contaminated with ˜20% of tert-butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate. 1HNMR (CDCl3 300 MHz): δ 5.43 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:33](=[O:36])(=[O:35])[NH2:34])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:33](=[O:36])(=[O:35])[NH2:34])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(O)cc1

Procedure:
A suspension of 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid (0.5 g) in water (5 ml) was adjusted to a pH of 11 by addition of 1N sodium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressue after addition of Pd-on-carbon powder catalyst (0.025 g catalyst containing 10% of Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and from the filtrate the 3-benzylamino-4-(4-hydroxyphenoxy)-5-sulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid until a pH of 2. After isolation by filtration and recrystallization from aqueous ethanol, the compound was obtained with a melting point of 276°-277° C (decomp.).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(Cl)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(Cl)cc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(Cl)ccc3n21
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (200 mg) was dissolved in 1,4-dioxane (3 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added to give a light red solution. Refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butyramide (165 mg) as light yellowish solid.
Reaction SMILES: ClC(Cl)(Cl)F.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:12]F.[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[Na+]>C(#N)C>[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[F:12][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: FF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Solvent: CC#N
Product: F[n+]1ccccc1
Temperature: -40 °C

Procedure:
To a 50 ml trichlorofluoromethane solution containing 1.0 g (12.6 m moles) of pyridine a mixed gas of fluorine and nitrogen in a volumetric ratio of 1:9 was introduced at a rate of 30 ml/min. at -78° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 34.8 mmoles. Subsequent to the fluorine introduction, 20 ml of anhydrous acetonitrile and 2.2 g (12.8 mmoles) of sodium trifluoro-methanesulfonate as a XM reactant were added to the reaction solution after which the temperature of the solution was raised to -40° C., while removing the solvent with the aid of an aspirator. The solvent, after filtering sodium fluoride formed as a byproduct, was distilled off and the resultant residue was recrystallized from THF to give 1.75 g (yield: 67%) of N-fluoropyridinium trifluoromethanesulfonate, the physical properties of which are shown in Table 6.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4]#[N:5].[SH2:12]>N1C=CC=CC=1.C(N(CC)CC)C>[NH2:1][C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4](=[S:12])[NH2:5]
Reactant: S
Reactant: N#CC=C(N)c1cccnc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C=C(N)c1cccnc1
Reaction time: 672 h

Procedure:
A solution of 20 g of 3-amino-3-(3-pyridinyl)-2-propenenitrile [J. Med. Chem., 18, 441 (1975)] in 100 ml of pyridine and 14 ml of triethylamine was saturated with hydrogen sulfide and set aside under nitrogen at room temperature for 28 days. The solution was kept saturated by passing hydrogen sulfide into the reaction mixture at intervals during this time. After evaporation the crude product was purified by chromatography and crystallization from ethyl acetate to give 3.65 g of 3-amino-3-(3-pyridinyl)-2-propenethioamide, which was suspended in 80 ml of diethyl ether together with 5.21 g of potassium carbonate. A solution of 5.21 g of iodine in 80 ml of diethyl ether was added dropwise in 10 min to this suspension, keeping the temperature at 3±2° C. After 45 min the reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed, dried, and evaporated to give 2.19 g of 3-(3-pyridinyl)-5-isothiazolamine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cn1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-methoxypyridine-3-carbaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 500.
Reaction SMILES: [CH:1]([OH:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH:10]=[O:11])([O-:6])=[O:5].C(OC(=O)C)(=O)C>O>[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH:15][CH:1]=[O:3])[CH:10]=[O:11])([O-:6])=[O:5]
Reactant: O=CO
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To 56.6 ml (1.50 mol) of HCOOH was added 24.9 g (150 mmol) of 3-nitro-4-aminobenzaldehyde. The solution was heated to reflux, 28.4 ml (300 mmol) of acetic anhydride was added dropwise and the solution was refluxed for 30 minutes. The resulting suspension was cooled and poured into 400 ml of cold H2O with rapid stirring. The product was filtered, air dried, and recrystallized from isopropanol to yield 23.2 g (80%) of 3-nitro-4-formamidobenzaldehyde as a bright yellow powder: melting point=183°-191°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C)C=O>[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([Cl:10])[C:4]=1[Cl:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COc1ccc(S)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccc(F)cc2F)c(Cl)c1Cl
Reaction time: 0.42 h

Procedure:
To 1.26 g of sodium hydride in 25 ml dimethylformamide (sieve dried) is added dropwise a solution of 10 of 2,3-dichloro-4-methoxythiophenol in 25 ml dimethylformamide. After the addition is complete, the reaction mixture is stirred for 25 mins and a solution of 10 g of 2,4-difluorobenzyl bromide in 25 ml dimethylformamide is added dropwise. After this addition is complete, the mixture is stirred for 20 mins and cautiously poured onto ice-water. The aqueous mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil which crystallizes with cooling and trituration with hexane. Two recrystallizations with ethyl acetate-hexane give 5.1 g of (2,3-dichloro-4-methoxyphenyl) 2,4-difluorobenzyl sulfide, mp 86°-88°.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.N1CCCCC1>C(O)(=O)C>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:11]2[CH2:1][CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1CCCc2ccccc21
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccncc2)CCc2ccccc21

Procedure:
A mixture of 73.0 grams (0.50 moles) of α-tetralone, 64.2 grams (0.60 moles) of 4-pyridinecarboxaldehyde, 10 grams of piperidine and 10 grams of acetic acid are heated at 80° for 19 hours. The resultant solid is crystallized from about 400 ml. of ethanol to give 2-(4-pyridylmethylene)- 1-tetralone; (m.p. 112°-114°C).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.28 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:24]>O1CCOCC1>[NH2:24][C:6]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(Cl)ncnc2Cl)c1
Reactant: N
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
3-Hydroxy-5-(methylsulfonamido)phenyl 4,6-dichloropyrimidine-5-carboxylate (110 mg, 0.29 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia (0.86 ml, 7N in MeOH) was dropwise added and the mixture was stirred at 0° C. and overnight at room temperature. After dilution with ethyl acetate, this organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil as a residue (148 mg, 49% purity, 70% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
Azetidine (0.25 g, 4.35 mmol) was added to a solution of sodium hexamethyldisilylazide (0.85 g, 4.6 mmol) in THF (10 mL) at 0° C. and reaction mixture stirred for 10 minutes. 4-fluorobenzenesulfonyl chloride (0.85 g, 4.35 mmol) was subsequently added and the reaction mixture was allowed to warm up to ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated and then dried (MgSO4), filtered and evaporated to give a waxy, yellow solid (75 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 2-amino-5-fluoro-6-methylpyridine (Sanchez & al., J. Heterocycl. Chem. 24, 215(1987); CAS:[110919-71-6]) instead of 2-chloro-4-aminopyridine to yield [2-(5-Fluoro-6-methyl-pyridin-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester, white solid, MS (ISP): m/e=361.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide, white solid, MS (ISP): m/e=261.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, (ISP): m/e=338.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.[NH3:28].CO>>[NH2:28][C:21]1[CH:20]=[C:19]([C:11]2[S:12][C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[C:26]#[N:27])[CH:24]=[CH:23][N:22]=1
Reactant: N
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Solvent: CO
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Yield: 44 %

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.600 g, 0.00144 mol) and 7 M ammonia in methanol (40 mL, 0.280 mol) was irradiated in a microwave at 150° C. for 8 hours. Solvent was evaporated and the residue was purified by column chromatography on silica gel (40 g), gradient DCM to 6% MeOH in DCM over 30 minutes to afford the title compound as yellow solid (0.26 g, 44%). LCMS: (FA) ES+, 413, 415. 1H NMR (400 MHz, d4-Methanol) 8.40 (s, 1H), 8.05 (dd, J=5.16, 1.10 Hz, 1H), 7.61 (dd, J=1.54, 0.76 Hz, 1H), 7.46-7.42 (m, 2H), 7.03-7.00 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: COc1ccc(C=CCCl)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 10 %

Procedure:
Prepared from 4-methoxy-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in the presence of 1 equivalent of potassium carbonate in chloroform. Yield: 10% of theory, Melting point: 155-160° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].OS(O)(=O)=O.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 120 °C
Yield: 40 %

Procedure:
To a suspension of 2,6-dichloro-9H-purine (8.00 g, 40 mmol, 1.00 eq) and Na2SO4 (96.2 g, 677 mmol, 16.0 eq) in tert-butanol (380 mL) was added concentrated H2SO4 (11.3 mL, 211 mmol, 5 eq). The reaction mixture was heated at 120° C. with vigorous stirring under a reflux condenser [Caution: Gas evolution]. During the following 10 hr, additional H2SO4 (26 mL), Na2SO4 (75 g), and tert-butanol (350 mL) were added to the reaction mixture in several portions. After a further 6 hr of heating, the reaction mixture was cooled to ambient temperature, quenched with NaHCO3(s) added portionwise [Caution: Gas evolution], and diluted with water (300 mL) and EtOAc (300 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×300 mL). The combined organics were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified via flash chromatography eluting with a gradient of 0-50% EtOAc in heptane to give the title compound (4.09 g, 40% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H) 1.73 (s, 9H). m/z (APCI+) for C9H10Cl2N4 245.1/247.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:27][CH3:28])[C:11]1[C:16]([O:17][CH2:18][O:19][CH3:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:12]=1[CH2:25][OH:26].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(OCC)(=O)C>[CH3:29][S:30]([O:26][CH2:25][C:12]1[CH:13]=[CH:14][C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:17][CH2:18][O:19][CH3:20])[C:11]=1[CH:10]([O:9][CH3:8])[O:27][CH3:28])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Reaction time: 0.5 h

Procedure:
Triethylamine (2.74 ml, 19.7 mmol) was added to a solution of [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (5.09 g, 16.4 mmol) obtained in Example (6-6) in ethyl acetate (50 ml). After methanesulfonyl chloride (1.33 ml, 17.2 mmol) was added dropwise to the mixture under ice-cooling, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. n-Hexane was added to the residue obtained by removing the solvent under reduced pressure. The precipitated crystals were filtered to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate as a pale yellow compound (5.37 g, yield: 84%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:29]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:30])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1CCCCC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 438.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[N:36]1.N1CCCCC1>CO>[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](/[CH:44]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[C:9]([O:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0720 g, 0.154 mmol) in methanol (1 mL) was added with 1H-indazole-3-carboxaldehyde (0.0225 g, 0.154 mmol) and piperidine (0.00131 g, 0.0154 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 43%).