Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH2:25][N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH:24]=2)[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:34])[CH3:33])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:28]1([N:26]([CH2:25][C:23]2[CH:24]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:35])=[O:2])=[CH:8][CH:9]=3)[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:33])[CH3:34])[CH3:27])[CH2:30][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(C#Cc2ccc(C(C)(C)C(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Yield: 20.7 %

Procedure:
A solution of 2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionic acid methyl ester (Intermediate 15, 0.040 g, 0.084 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Preparative reverse phase HPLC on a partisil 10 ODS-3 column using 10% water in acetonitrile as the mobile phase afforded the title compound (0.008 g, 27%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[F:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=3)[O:14][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c([N+](=O)[O-])c3)n2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 11 (12.46 g; 47.13 mmol) was dissolved in DCM (200 mL) and n,n′-dicyclohexylcarbodiimide (11.67 g; 56.56 mmol) was added. Then Intermediate 1 was added (10 g; 47.13 mmol) and the suspension was stirred at RT for 12 hours. The precipitate was filtered off and the solvent evaporated to give a yellow solid. The residue was dissolved in Toluene (300 mL) and Py (150 mL) and the solution was heated to 130° C. for 12 hours. The reaction mixture was concentrated to afford a yellow sticky oil which was precipitated from ACN affording the title compound as a yellow solid. LC/MS (Method B): 441.3 (M+H)+ HPLC: Rt 5.86 min (Purity: 95.1%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.C(#N)C>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C17) (1.95 g, 4.83 mmol) in methanol (25 mL) was added sodium hydroxide (2 N, 10 mL, 20.0 mmol) and the solution was stirred at room temperature overnight. The methanol was evaporated off under reduced pressure, the reagents were diluted with acetonitrile, and additional sodium hydroxide (2 N, 20 mL, 40.0 mmol) was added. The reaction was stirred at room temperature for 5 hours and then acidified with hydrogen chloride (2 N). The white precipitate was vacuum-filtered to afford the title compound as a white solid (1.72 g, 94%): mp 239-241° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.44 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.12-8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.69-7.59 (m, 3H), 6.61 (d, J=16.0 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 376 ([M+H]+).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[C:1]([N:62]1[CH2:63][CH2:64][N:59]([C:56]2[CH:57]=[CH:58][C:53]([C:45]3[NH:44][C:43](=[O:65])[C:42]4[C:47](=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:41]=4[O:40][CH3:39])[N:46]=3)=[CH:54][CH:55]=2)[CH2:60][CH2:61]1)(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccncc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of isonicotinic acid (0.083 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.110 g, 34%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.58-8.79 (m, 2H), 8.12 (d, J=9.0 Hz, 2H), 7.45 (d, J=6.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.64-4.06 (m, 9H), 3.22-3.54 (m, 5H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:7]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Product: Clc1ccnc(-n2ccnc2)n1
Yield: 22.2 %

Procedure:
In anhydrous tetrahydrofuran, 1500 mg of 2,4-dichloropyrimidine was substituted with 680 mg of imidazole. The reaction mixture was treated according to the procedure of Example 5 to yield 401 mg of 4-chloro-2-(1-imidazolyl)pyrimidine recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[C:6]=1[O:7][CH2:8]C(O)=O)=[O:4].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[O:7]1[C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:16]=[CH:8]1
Reactant: COC(=O)c1cccc(C=O)c1OCC(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc2ccoc12
Yield: 25.2 %

Procedure:
A mixture of 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid, 1.48 g of sodium acetate and 7 ml of acetic anhydride is refluxed for 1.5 hours. After cooling, water is added to the reaction mixture, and the aqueous mixture is alkalized with potassium carbonate and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 0.39 g of methyl benzofuran-7-carboxylate as colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([OH:21])[CH:15]=3)=[N:8][CH:7]=1)=[O:5])C>S(=O)(=O)(O)O>[OH:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=3)[C:12](=[O:22])[O:13]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnc(-c2cc3ccc(O)cc3oc2=O)s1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cnc(-c2cc3ccc(O)cc3oc2=O)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A suspension of 2-(7-hydroxy-2-oxo-2H-chromen-3-yl)-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.16 mmol) in 70% (w/w) sulfuric acid (3 mL) was stirred at 100° C. for 1 h. During heating the solids dissolved and a solid precipitated after 1 h. The precipitate was collected, washed with water and dried in air. In this manner the title compound (30.5 mg, 0.10 mmol, 62.5%) was obtained as a pale brown solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(C=O)c2)cc1
Yield: 45.6 %

Procedure:
The title compound (130 mg, 46%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (265 mg, 0.788 mmol, prepared in example 1), 3-formylbenzeneboronic acid (160 mg, 0.964 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CS([C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([O:16][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCc1nc(C)c(-c2c(O)cccc2Cl)o1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2c(Cl)cccc2Oc2nc(OC)cc(OC)n2)o1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2 ml DMF solution containing 0.24 g 2-propyl 4-methyl-5-(2-chloro-6-hydroxyphenyl)oxazole, 0.2 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.26 g pottasium carbonate was stirred for 14 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and was then extracted with ethyl acetate. The organic layer obtained was washed with water and was then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduce pressure. The residue obtained was purified by using silica gel column chromatography, where hexane-ethyl acetate solution in a mixing ratio of 4:1 is used, affording the objective substance in an amount of 0.26 g.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:14][CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][CH:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=2)=[N:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(COc1ccc(Oc2ccc(OC(C)C)cn2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(N)COc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
tert-Butyl {2-[4-(5-isopropoxypyridin-2-yloxy)phenoxy]-1-methylethyl}carbamate (414 mg, 1.03 mmol) was treated with 90% strength trifluoroacetic acid for 4 h. The trifluoroacetic acid was distilled off and the aqueous phase was freeze dried. The crude product contains excess trifluoroacetic acid and was further reacted without purification.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:39]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:39].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=1
Reactant: CSc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine (117) (8.7 mmol) using the procedure described for compound (9) (2.29 g, 68%).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:6]1
Reactant: CC1(C)OB(/C=C/CCl)OC1(C)C
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(/C=C/CN2CCCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (E)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 4.94 mmol) in acetonitrile (10 mL) was treated with potassium carbonate (1.366 g, 9.88 mmol) and pyrrolidine (0.531 mL, 6.42 mmol). The suspension was stirred at ambient temperature for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator to provide the title compound. MS ESI(+) m/z 238.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][NH2:14]>CO>[CH3:12][N:13]1[C:10]([NH2:11])=[CH:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14]1
Reactant: CNN
Reactant: N#CCC(=O)c1ccccc1
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1N
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A mixture of benzoyl acetonitrile (2.0 g, 13.778 mmol) and methyl hydrazine (0.698, 15.156 mmol) in methanol (10 mL) was irradiated under microwave conditions at 110° C. for 90 min. The reaction mixture was cooled to rt and poured into rapidly stirred ice cold water. The obtained solid was collected by filtration, dried under vacuum and triturated with a mixture of pentane-hexane (˜10 mL) to yield a white solid (1.7 g, 71%). [1H-NMR (CDCl3, 300 MHz) δ 7.82-7.65 (m, 2H), 7.45-7.20 (m, 3H), 5.90 (s, 1H), 3.75 (s, 3H), 3.55 (s, 2H); LCMS RtA=0.824 min; [M+H]+=174.1]
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15][OH:16])=[N:7][C:6]=2[CH:20]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH:15]=[O:16])=[N:7][C:6]=2[CH:20]=1
Reactant: OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Temperature: -60 °C
Reaction time: 0.58 h

Procedure:
To a solution of 1.5 g of 3-(5-fluorobenzothiazol-2-yl-trans-ethenyl)benzyl alcohol (Preparation H2) in 40 ml of methylene chloride and 25 ml of dimethylsulfoxide at -60° C. was added a solution of 0.64 ml of oxalyl chloride in 20 ml of dry methylene chloride containing 0.74 ml of dimethylsulfoxide. After stirring at -60° C. for 35 minutes the reaction mixture was allowed to warm to -35° C. for 25 minutes. The mixture was again cooled to -60° C. and 3.65 ml of triethylamine was added over a period of 5 minutes. The mixture was allowed to warm to room temperature and was treated with 200 ml of water. The organic phase was washed with a brine solution, dried over sodium sulfate and concentrated in vacuo to give after trituration with ethyl acetate--hexane 1.2 g. A sample was recrystallized from ethyl acetate--hexane, m.p. 151°-152° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h

Procedure:
240 mmol of imidazole, 240 mmol of 2-amino4-chloronitrobenzene and 240 mmol of potassium carbonate in 450 ml of dimethylformamide (DMF) are stirred in a 1 litre round-bottomed flask. The mixture is maintained at 130° C. with stirring for 48 hours. After the DMF has been removed by evaporation, the residue is taken up in water. The precipitate that forms is filtered off and then washed with water. It is then dissolved in 550 ml of 1N hydrochloric acid. After insoluble material has been filtered off, the filtrate is rendered alkaline and the precipitate that forms is filtered off and washed with water. After drying, the expected product is obtained after purification by chromatography on silica gel using a dichloromethane/methanol mixture(95/5).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)oc1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (93 mg, 0.24 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.21 ml, 1.20 mmol) in dichloromethane (2.4 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (124 mg, 0.26 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (113 mg, 0.21 mmol, 85% yield) as a white foam: LCMS (ES) m/e 551 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]2[CH:15]=[C:16]([C:18](=[O:20])[CH3:19])[S:17][C:9]=2[CH:8]1[N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])(=O)C.O.[K+].[Br-]>CO>[C:18]([C:16]1[S:17][C:9]2[CH:8]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[CH:7]([OH:6])[C:12]([CH3:14])([CH3:13])[O:11][C:10]=2[CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC1C(N2CCCC2=O)c2sc(C(C)=O)cc2OC1(C)C
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc2c(s1)C(N1CCCC1=O)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide (50%, 0.15 g, 1.87 mmol) was added to a solution of 6-acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (0.45 g, 1.28 mmol) in methanol (20 mL) and stirred at rt for 1h. The solution was poured into water (100 mL) and extracted into dichloromethane. The dichloromethane solution was washed with water (3x) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resultant oil was crystallized from diethyl ether and hexanes to give the product, 0.327 g (83%), as a colorless solid: mp 102°-106° C.; IR (KBr): 1665 and 1561 cm-1 ; MS: m/z 310 (MH+); 1H NMR (CDCl3): δ 1.31 (s, 3H), 1.51 (s, 3H), 2.07 (m, 2H), 2.48 (s, 3H), 2.51 (m, 2H), 3.34 (m, 2H), 3.45 (d, J=6.2 Hz, 1H, exchanges with D2O), 3.80 (dd, J=6.2 Hz and J=9.4 Hz, 1H, simplifies to d, J=9.4 Hz, with D2O), 5.29 (d, J=9.4 Hz, 1H) and 7.14 (s, 1H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[C:47]1([CH2:53][CH2:54][OH:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCCc1ccccc1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCc2ccccc2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-phenylethanol, the title compound was obtained as a colorless solid (0.06 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.36 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.87 (s, 6H); MS (ES−) m/z 399.1, 401.1 (M−1).