Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.C(Cl)Cl.[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
4-(2-Hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (0.4 g, 1.0 mmol, 1.0 eq.) and triethylenediamine (220 mg, 2.0 mmol, 1.4 eq.) were dissolved in DCM (11 mL, 170 mmol). The mixture was cooled at 0° C. under nitrogen, TsCl (290 mg, 1.5 mmol, 1.1 eq.) was added, and the mixture was stirred at 0° C. for an additional 60 minutes. The mixture was diluted with EtOAc (50 mL) and washed with water (2×25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (500 mg), which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH:26]=[C:25]2[C:16]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:32]4[C:33]([F:38])=[N:34][CH:35]=[CH:36][CH:37]=4)=[CH:22][C:23]=3[C@:24]32[CH2:30][O:29][C:28]([NH2:31])=[N:27]3)=[C:15]([F:39])[CH:14]=1)(=O)=O.[O:42]1[CH2:47][CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:42]1[CH2:47][CH2:46][CH:45]=[C:44]([C:13]2[CH:14]=[C:15]([F:39])[C:16]3[O:17][C:18]4[C:23](=[CH:22][C:21]([C:32]5[C:33]([F:38])=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:20][CH:19]=4)[C@@:24]4([CH2:30][O:29][C:28]([NH2:31])=[N:27]4)[C:25]=3[CH:26]=2)[CH2:43]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated) (1 ml), Pd(PPh3)4 (53.5 mg, 0.046 mmol), (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (475 mg, 0.925 mmol; prepared from the alcohol by steps analogous to those described in Method BB40 and Example 2), and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389 mg, 1.850 mmol) were combined in DMF (5 ml). The solution was heated at 85° C. for three hours before being cooled to rt. The solution was concentrated and the derived residue was purified via silica gel column chromatography (RediSep 40 g column) using 20-70% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=448.0 [M+H]+. Chemical Formula: C25H19F2N3O3. Exact Mass: 447.14. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18-2.36 (m, 2 H) 3.75 (t, J=5.5 Hz, 2 H) 4.24 (m, 2 H) 4.30-4.48 (m, 2 H) 6.22-6.36 (m, 1 H) 6.52 (s, 2 H) 7.07-7.15 (m, 1 H) 7.38 (m, J=8.5 Hz, 2 H) 7.50 (ddd, J=7.4, 4.9, 1.9 Hz, 1 H) 7.53-7.66 (m, 2 H) 8.12 (ddd, J=10.4, 7.5, 1.9 Hz, 1 H) 8.20-8.30 (m, 1 H)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30]([C:27]5([OH:26])[CH2:29][CH2:28]5)=[O:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (18.3 mg, 64.8%), MS (ISP) m/z=415.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 1-hydroxycyclopropanecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9](O)=O)[CH:7]=1.[C@@H]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31]3[S:32][C:33](CC)=[CH:34][CH:35]=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][CH2:9][C:33]2[S:32][C:31]([C:30]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=3)=[CH:35][CH:34]=2)[CH:7]=1
Reactant: O=C(O)Cc1cc(Br)ccc1Cl
Reactant: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Product: Clc1ccc(Br)cc1CCc1ccc(-c2ccccc2)s1

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification. (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H). (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH:33]([NH:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][CH2:30][C:29]=2[C:39]=1[O:40][CH3:41]>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:34][CH:33]([NH:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][CH2:30][C:29]=3[C:39]=2[O:40][CH3:41])=[N:3][CH:4]=1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine (110 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a tan foam. Mp: 79-82° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.59 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.61 (t, J=8 Hz, 1H), 7.51 (s, 1H), 7.27 (m, 1H), 6.86 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.63 (m, 2H), 3.29 (m, 4H), 3.00-2.67 (m, 7H) 2.05 (m, 1H), 1.80 (m, 8H), 1.60 (m, 1H).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([S:58]([CH2:61][CH3:62])(=[O:60])=[O:59])=[C:46]([CH:57]=2)[CH2:47][N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:40])=[CH:32][CH:31]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.B(O)O>>[C:51]([O:50][C:49]([N:48]([CH2:47][C:46]1[CH:57]=[C:42]([NH:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][CH:32]=2)[CH:43]=[CH:44][C:45]=1[S:58]([CH2:61][CH3:62])(=[O:60])=[O:59])[CH3:56])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: OBO
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 17C (0.428 g, 0.76 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (0.202 g, 0.894 mmol) and then hydrolyzed to the free boronic acid to give 17D (0.260 g, 76%) as a white solid. MS (ESI) m/z 519.0 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:31]2[S:30][CH:29]=[CH:33][CH:32]=2)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1c(Br)sc(Br)c1CCCCCCCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCc1c(-c2cccs2)sc(-c2cccs2)c1CCCCCCCC
Yield: 145.7 %

Procedure:
In a dry box under an inert atmosphere, Pd(PPh3)2Cl2 (0.15 gram, 0.2 mmol) was added to a mixture of 2,5-dibromo-3,4-dioctylthiophene (4.2 grams, 9 mmol) and 2-(tributylstannyl)-thiophene (7.4 grams, 19.8 mmol) in anhydrous tetrahydrofuran (50 milliliters) in a 250 milliliter round bottom flask. The mixture was then refluxed for 12 hours and the solvent was removed by evaporation. The crude product thus obtained was purified by flash chromatography on silica gel using hexane as eluent to provide 3.1 grams of 2,5-bis(2-thienyl)-3,4-dioctylthiophene.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].Br[CH2:8][CH:9]=[O:10].[OH-].[Na+]>CO>[CH3:1][C:2]([NH:6][CH2:8][CH:9]=[O:10])([CH3:5])[C:3]#[CH:4]
Reactant: O=CCBr
Reactant: C#CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(C)(C)NCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylprop-2-ynylamine (2.0 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-(1,1-dimethylprop-2-ynylamino)acetaldehyde.
Reaction SMILES: [OH-].[Na+].Cl.C([O:6][C:7]([CH2:9][C:10]1([C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([CH2:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][CH:27]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])C>O.C(O)C>[C:7]([CH2:9][C:10]1([C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH2:32])=[NH:31])=[CH:33][CH:34]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([OH:8])=[O:6]
Reactant: CCOC(=O)CC1(C(=O)c2ccc3c(c2)nc(Cc2ccc(C(=N)N)cc2)n3C)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(Cc2ccc(C(=N)N)cc2)nc2cc(C(=O)C3(CC(=O)O)CCCCC3)ccc21

Procedure:
To a solution of 160 mg (4 mmol) of sodium hydroxide in 5 ml water and 20 ml ethanol are added 400 mg (0.8 mmol) of 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride. After two hours at ambient temperature the solution is evaporated down, the residue is dissolved in water and acidified with glacial acetic acid. The precipitate is suction filtered and dried.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([F:14])([CH2:11][CH2:12][CH3:13])CC[N:6]1[C:15](OC(C)(C)C)=O)=[O:4].O.[OH-].[Li+].[CH2:25]1COCC1>O>[F:14][C:9]1([CH2:11][CH2:12][CH2:13][CH3:25])[CH2:15][NH:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10]1
Reactant: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(F)CN[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 12c (0.27 g, 0.89 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide monohydrate (45 mg, 1.06 mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was purified by column chromatography using 10% MeOH in DCM as eluant to obtain 4-Fluoro-4-butylproline 12d (P=Boc, m=1, R9=n-butyl) (0.26 g, 100%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 4.30 (m, 1), 3.72 (m, 1), 3.49 (m, 1), 3.39 (m, 1), 2.58 (m, 1), 2.02 (m, 2), 1.72 (m, 13), 0.93 (t, J=6.6, 3); MS (ESNEG): 288 [M−1]−.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[C:32]([C:35]1[S:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:34])[CH3:33]>CCCCCC.C(OCC)(=O)C>[C:32]([C:35]1[S:36][CH:37]=[C:38]([C:11]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:9]=3[C:8]([CH3:29])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:24]=2[CH3:25])[CH:39]=1)(=[O:34])[CH3:33]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: CC(=O)c1cc(Br)cs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cs1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-acetyl-4-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([N:1]([S:31]([CH3:30])(=[O:33])=[O:32])[C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Yield: 131.4 %

Procedure:
To a mixture of 1.00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione, 0.63 g of triethylamine and 10 ml of dichloromethane, 0.48 g of methanesulfonylchloride was added at a temperature of not more than 5° C. The resultant mixture was stirred overnight. After washing twice the reaction mixture with water, the reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dichloromethane was distilled off to obtain a crude product. The obtained product was washed with diisopropylether to obtain 1.36 g of the objective product as white crystals.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]\[C:26]#[N:27]>>[CH3:17][S:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:25]=[C:26]([NH2:27])[N:12]2[N:13]=1
Reactant: N#C/C=C\c1ccccn1
Reactant: CSc1nc(CS(=O)(=O)c2ccccc2)n[nH]1
Product: CSc1nc2cc(-c3ccccn3)cc(N)n2n1

Procedure:
The title compound, MS m/e (%):258 (M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-methylsulfanyl-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16]O)([CH3:4])[CH3:3].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][Cl:20])([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(CCO)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCCl)c(C(C)(C)C)c1

Procedure:
A solution of the title product of Example 10 (2.0 grams, 8.5 mmoles) and thionyl chloride (2.03 g, 17.1 mmoles) in toluene (50 ml) is heated at reflux for one hour. After cooling, the mixture is evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(Cl)coc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(Cl)coc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Ethyl 3-chloro-1-benzofuran-6-carboxylate (110 mg, 0.49 mmol) is dissolved in MeOH (3 ml) and water (0.75 ml), treated drop-wise with 2N NaOH (0.27 ml, 0.54 mmol) and stirred overnight at RT. The volatiles are removed in vacuo, the residue is dissolved in water (3 ml) and the pH is adjusted to 3 with concentrated HCl. The resulting solid is filtered and dried overnight in a vacuum oven to afford 88 mg (92%) of 3-chloro-1-benzofuran-6-carboxylic acid as a white solid. MS for C9H5ClO3 (EI) m/z: 196(M)+.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH:4]=[CH:3][NH:2]1.[Br:15]Br.O>CC(O)=O>[Br:15][C:4]1[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:1](=[O:14])[NH:2][CH:3]=1
Reactant: O=c1[nH]ccc2sc3ccccc3c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [1]benzothieno[3,2-c]pyridin-1(2H)-one in AcOH (0.52 M) was added Br2 (1.1 equiv) at room temperature. The mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into H2O and stirred for 30 min. The mixture was filtered and washed with H2O to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC(C)C(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)C)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, isobutyryl chloride (21 mg, 107 μmol, 3 eq.) was added. After 12 h of stirring, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (24.5 mg, 76% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 63 %

Procedure:
Upon boiling a solution of 15.1 g 3-nitrobenzaldehyde and 26.0 g amidinoacetic acid ethyl ester in 250 ml ethanol for two hours, 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 175° - 176° C (ethanol) is obtained.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>CO>[CH2:15]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Under a nitrogen atmosphere add sodium cyanoborohydride (5.77 g, 91.6 mmol) to 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-butylamine (3.34 g, 45.8 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (40 mL), saturated aqueous K2CO3 (30 mL) and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (3.63 g, 84%). MS (APCI+) m/z: 189 (M+H)+.