Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C=O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:11]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[O:21][CH2:25]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1Cc1ccccc1

Procedure:
Following the procedure of Ben-Ishai (J. Am. Chem. Soc., 1957, 79, 5736), N-Cbz-L-phenylalanine (10.0 gm, 33.4 mmol), paraformaldehyde (3.0 gm, 100.2 mmol), and p-toluenesulfonic acid (0.64 gm, 3.3 mmol) were suspended in toluene (150 ml). The reaction was brought to reflux and water removed azeotropically through the agency of a Dean-Stark trap until collection of water ceased (0.5-2.0 h). After cooling, the reaction mixture was diluted with ethyl ether, washed (1X, saturated aqueous NaHCO3 ; 1X, brine), dried (Na2SO4), filtered, and concentrated in vacuo to provide a solid after cooling. Recrystallization from ethyl acetate/hexanes provided, after the collection of two crops, the pure title compound (9.26 gm, 89%). m.p.=85.5°-86.5° C.; MS (CI) (M+NH4)+ =329, (M+H)+ =312; Anal. Calcd. for C18H17NO4 : C, 69.44; H, 5.50; N, 4.50. Found: C, 69.33; H, 5.48; N, 4.40.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1C1OCCO1
Yield: 116.6 %

Procedure:
2-Chloro-6-fluorobenzaldehyde (100 g), ethylene glycol (192 g) and p-toluenesulphonic acid (17 g) were dissolved in toluene and heated under reflux for four days using a Dean and Stark adapter to collect the water. After cooling the mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-(2-chloro-6-fluorophenyl)-1,3-dioxolane (149 g) as an orange oil , NMR (CDCl3) 4.09(s 4,2H), 4.3(m, 2H), 6.35(s,1H), 7. 2(m,3H).
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C(=O)C2C=CC=CC=2)[CH:9]=1)(=[O:7])=[O:6])[CH3:3].[OH-].[Na+]>O1CCCC1>[CH3:3][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)(=[O:7])=[O:6])[CH3:1]
Reactant: CC(C)NS(=O)(=O)c1cccc(OC(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of stage 2 (0.18 g), 2M aqueous sodium hydroxide solution (15 cm3) and tetrahydrofuran (15 cm3) was stirred for 2 hours at the ambient temperature.
Reaction SMILES: [NH4+].[OH-].ClC(Cl)(Cl)[C:5]([C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)=[O:6].C[N:25](C)C=O.C(OCC)(=O)C>O>[C:5]([C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)(=[O:6])[NH2:25]
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)C(Cl)(Cl)Cl)c1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2cccc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
28% Ammonia aqueous solution (0.4 ml) was added to a mixture of methyl 3-(2-trichloroacetylpyrrol-1-yl)benzoate (1.0 g) and N,N-dimethylformamide (2 ml), and the mixture was stirred for 1.5 hours at ambient temperature. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-carbamoylpyrrol-1-yl)benzoate (0.61 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([CH2:39][CH:40]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)[OH:41])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:45]3[CH:46]=[CH:47][C:42]([CH:40]([OH:41])[CH2:39][CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:43][CH:44]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC1(C)OB(c2ccc(C(O)CC3CCCC3)cc2)OC1(C)C
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(O)CC4CCCC4)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (433 mg, 0.79 mmol) was coupled with 2-cyclopentyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanol according to general procedure G to give {4-[2-[4′-(2-cyclopentyl-1-hydroxy-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester. The product benzyl alcohol was reduced according to general procedure AA and the reduced product was treated following general procedure F to give 5-{4-[2-[4′-(2-cyclopentyl-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidin-3-one-1,1-dioxide.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:29](=[O:30])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: CNC
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Yield: 58 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with dimethylamine to give the title compound as a solid (120 mg, 58%); NMR Spectrum 1.59 (d, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 5.79 (s, 2H), 5.85 (q, 1H), 7.29 (d, 1H), 7.34 (d, 1H), 7.51 (s, 1H), 7.77-7.72 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.52 (m, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[N+:24]([O-])([OH:26])=[O:25].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[N+:24]([C:2]1[S:1][C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCc2sccc2C1
Reactant: O=[N+]([O-])O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCc2sc([N+](=O)[O-])cc2C1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of tert-butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (200 mg, 0.836 mmol) in TFA (6.89 ml, 89 mmol) was added concentrated nitric acid (0.053 ml, 0.836 mmol) dropwise at 0° C. The mixture was next concentrated then dissolved in 20 mL of ethyl acetate and di-tert-butyl dicarbonate (0.194 ml, 0.836 mmol) was added. The mixture was stirred at ambient for 60 minutes then the mixture was poured into a separatory funnel and washed with 20 mL of saturated aqueous sodium bicarbonate and 20 mL of saturated aqueous brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column, 2-50% ethyl acetate/hexane, linear gradient) afforded tert-butyl 2-nitro-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (107 mg, 0.376 mmol). To this intermediate was added palladium on carbon (10% wt) (89 mg, 0.836 mmol) and the flask was capped with septa. The flask was evacuated and backfilled with nitrogen and 10 mL of methanol were added. The mixture was evacuated and backfilled with nitrogen 3 times then evacuated and backfilled with hydrogen. The mixture was stirred under hydrogen (1 atm, balloon) for 3 hours. The mixture was filtered through a celite pad and the filter cake washed with 20 mL of dichloromethane. The mixture was concentrated and the crude material was purified on silica gel flash chromatography (Isco®, Redi-Sep® column, 0-100% ethyl acetate/hexane, linear gradient) to obtain the title compound. MS (ESI) m/z 255.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH2:8][C:9](=[O:13])[NH:10][C:11]=2[N:12]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[O:13]=[C:9]1[CH2:8][S:7][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[N:12][C:11]=2[NH:10]1
Reactant: O=C1CSc2ccc(CO)nc2N1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg, 1.68 mmole) in CH2Cl2 (30 mL) and THF (30 mL) was treated with MnO2 (730 mg, 8.40 mmole), and the mixture was stirred at RT. Additional MnO2 was added after 1 hr (730 mg, 8.40 mmole) and after 16 hr (300 mg, 3.45 mmole). After a total of 20 hr the mixture was filtered through kieselguhr and the filtrate was concentrated to dryness. The reside was triturated with 1:1 EtOAc/hexanes, collected, and dried to afford the title compound (180 mg, 55%) as a solid: MS (APCI−) m/e 195 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[I:24](O)(=O)=O.II>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([I:24])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2n1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 400.7 %

Procedure:
2 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) in 20 ml of glacial acetic acid is combined with 0.5 ml of water, 0.12 ml of concentrated sulfuric acid, 336 mg of iodic acid, and 878 mg of iodine and agitated for 2.5 hours at 90° C. After concentrating the reaction mixture, the latter is combined with 50 ml of water, gently made alkaline with ammonia, and suctioned off, thus obtaining 2.81 g of 8-iodo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 264°-266° C. under decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([N:7]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)c1
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)c1
Yield: 74.1 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(phenyl)benzamide (126.4 mg, 0.28 mmol) and acetic anhydride (0.03 ml, 0.32 mmol), the procedure of Inventive Example 94 was repeated to obtain 101.1 mg (73.1%) of the title compound in a colorless powder form.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([O-:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:45]([O:13][C:12](=[O:14])[C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:29][CH:28]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:15]=1)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C([O-])c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 81 %

Procedure:
Using 3,5-bis(4-nitrophenoxy)benzoate (8) (25.6 g, 64.6 mmol) obtained in Example 4 and n-hexadecyl alcohol (17.3 g, 71.5 mmol), n-hexadecyl[3,5-bis(4-nitrophenoxy)]benzoate was obtained (32.4 g, yield: 81%) in the same manner as in Example 4.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96.6 mg, 74%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1.[CH2:18]([NH2:21])[C:19]#[CH:20].Cl>>[O:1]=[C:2]1[C:7]([C:8]([NH:21][CH2:18][C:19]#[CH:20])=[O:10])=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1
Reactant: C#CCN
Reactant: COC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O
Agent: Cl
Product: C#CCNC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.19 mmol) of methyl 2-oxo-6-(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 3.3 ml (41 mmol) of propargylamine for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 280 mg (85% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=2)[CH:6]=1)=[O:4].C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(F)ccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 4-acetoxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (1 g, 3.8 mmol) in methanol (20 mL) was added sodium methoxide (309 mg, 5.7 mmol). After being stirred at room temperature for 1 hour, the reaction mixture was acidified with 1 N hydrochloric acid to pH 3. The resulting precipitate was collected by filtration and dissolved in ethyl acetate. The organic solution was dried over sodium sulfate, and concentrated in vacuo to afford 900 mg of crude 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester as a pale yellow solid, which was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1
Reactant: O=S(=O)(Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(Nc1cccc([C@@H]2CCNC2)c1)c1cccc(C(F)(F)F)c1
Yield: 66.1 %

Procedure:
A solution of N-[3-((S)-1-benzyl-pyrrolidin-3-yl)-phenyl]-3-trifluoromethyl-benzene sulfonamid (620 mg, 1.34 mmol) (Example 65) in methanol (30 ml) was hydrogenated using the ThalesNano H-Cube® hydrogenation reactor employing a 10% palladium on charcoal catalyst cartridge. After concentration of the solution under reduced pressure, the crude product was purified with silica gel chromatography with ethyl acetate/methanol (1:1; 0:1) as eluent, yielding 328 mg of the purified product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:18][C:19]1[C:27]([NH:28][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=4)[O:10][C:3]=23)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: Cc1cccc(-c2cc3nccc(Cl)c3o2)c1
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1cccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3-methylphenyl)furo[3,2-b]pyridine (23.00 mg; 0.09 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (14.49 mg; 0.10 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (22 mg, 67%). (HPLC (method F): 99%, RT: 4.24 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.55 (s, 1H), 7.96 (d, J=5.5, 1H), 7.75 (d, J=7.5, 1H), 7.69 (s, 1H), 7.44-7.34 (m, 3H), 7.31 (d, J=8.3, 1H), 7.22 (d, J=7.3, 1H), 7.01 (d, J=8.4, 1H), 6.52 (s, 1H), 6.13 (d, J=5.5, 1H), 2.36 (s, 3H), 2.35 (s, 3H); MS (m/z) 354 [M+H]+, RT: 4.1 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.ClCC1N=C2C=CN(C3C=CC(F)=CC=3)C(=O)N2C=1>>[CH2:8]([N:5]1[CH:6]=[CH:7][C:2]2=[N:1][C:18]([CH2:17][Cl:16])=[CH:20][N:3]2[C:4]1=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccn(Cc2ccccc2)c(=O)n1
Agent: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Product: O=c1n(Cc2ccccc2)ccc2nc(CCl)cn12

Procedure:
6-Benzyl-2-chloromethyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-benzyl-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:5]=[C:6]([N:36]([CH3:40])[C:37]([NH2:39])=[O:38])[CH:7]=[C:8]([CH3:35])[C:9]=1/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:34][CH2:33][C:18]2([N:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH3:31])[NH:20][C:19]2=[O:32])[CH2:17][CH2:16]1)(=[O:14])=[O:13].O>CC(C)=O>[CH3:35][C:8]1[CH:7]=[C:6]([N:36]([CH3:40])[C:37]([NH2:39])=[O:38])[CH:5]=[C:4]([CH3:3])[C:9]=1/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:16][CH2:17][C:18]2([N:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH3:31])=[O:1])[NH:20][C:19]2=[O:32])[CH2:33][CH2:34]1)(=[O:13])=[O:14]
Reactant: CCCSCCCCCC1=NC2(CCN(S(=O)(=O)/C=C/c3c(C)cc(N(C)C(N)=O)cc3C)CC2)C(=O)N1
Reactant: OO
Solvent: O
Solvent: CC(C)=O
Product: CCCS(=O)CCCCCC1=NC2(CCN(S(=O)(=O)/C=C/c3c(C)cc(N(C)C(N)=O)cc3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
30% aqueous hydrogen peroxide (0.013 ml) was added to a mixed solution of (E)-1-(3,5-dimethyl-4-(2-((4-oxo-2-(5-(propylthio)pentyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)vinyl)phenyl)-1-methyl-urea (55 mg) and molybdenum(IV) dichloride dioxide (3 mg) in acetone (1.5 ml)-water (0.5 ml), and the mixture was stirred at room temperature for five minutes in a nitrogen stream. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, CH2Cl2-MeOH) to give 1-[3,5-dimethyl-4-((E)-2-{4-oxo-2-[5-(propane-1-sulfinyl)-pentyl]-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-vinyl)-phenyl]-1-methyl-urea (64 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40][CH2:41][C:42]#[CH:43]>O1CCCC1.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:43]#[C:42][CH2:41][S:40][CH3:39])=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#CCSC
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCSC)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL); anhydrous triethylamine (20 mL) and a solution of 3-(methylsulfanyl)propyne (130 mg, 1.51 mmol) in anhydrous tetrahydrofuran (2 mL) were added. Resulting solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added under nitrogen atmosphere. Reaction mixture was stirred at ambient temperature overnight, the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The filtrate was evaporated in vacuo; the obtained residue was dissolved in dichloromethane and the solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(methyl-sulfanyl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.