Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.62-6.70 (m, 12H), 5.10-5.00 (m, 1H), 3.71-3.56 (m, br, 2H), 3.04-2.82 (br, 2H), 2.78-2.64 (m, br, 3H), 2.64-2.48 (m, br, 3H), 2.05-1.82 (m, br, 6H), 1.62-1.42 (m, br, 2H), 1.25 (d, 6H, J=6.0 Hz); ESMS m/e: 521.2 (M+H)+.
Reaction SMILES: [Si]([O:8][N:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[O:11])(C(C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:30][C:31](=O)[C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:35]([O:42]COC)=[C:34]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1.Cl>C1COCC1.CC(C)=O.C(OCC)(=O)C>[OH:8][N:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][CH:14]([C:31](=[O:30])[C:32]2[CH:37]=[C:36]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:35]([OH:42])=[C:34]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=2)[C:13]1=[O:17])=[O:11]
Reactant: COCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Reactant: CN(O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(O)C(=O)N1CCC(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 10 %

Procedure:
To a chilled solution (-78° C.) of 2 g (7.34 mmol) of the thus obtained 1-(N-tert-butyldimethylsilyloxy-N-methylcarbamoyl)pyrrolidin-2-one in THF (5 ml) was added 8.1 ml (8.1 mmol) of a THF solution of 1.0M lithium bis(trimethylsilyl)amide under a nitrogen atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was dropwise added 5 ml of a THF solution of 1.55 g (5 mmol) of methyl-3,5-di-tert-butyl-4-methoxymethyloxybenzoate while being stirred at room temperature for 20 hours. The reaction mixture was poured into ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was dissolved in 12 ml of acetone and added with 0.6 ml of conc. hydrochloric acid. The reaction mixture was stirred at room temperature for 20 hours, and poured into ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was chromatographed on silica gel (toluene/ethyl acetate=10/1) to give 200 mg of the objective compound (Ia-20) as white amorphous in 10% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N+:5]([O-])=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21].P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)pyridine 1-oxide in methylene chloride was added PCl3 and the resulting mixture was heated at reflux for 20 min, cooled to rt. The mixture was concentrated to dryness. The residue was worked-up using standard procedure to give the title compound. After silica gel purification, the title compound was prepared as a white solid, mp. 42-44° C. Anal. For C17H20ClNO calc. C, 70.46; H, 6.96; N. 4.83; found, C, 70.35; H, 7.13; N, 4.58.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][NH2:29])=[N:26][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([NH:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Reactant: Cc1ccc(CN)nc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CNc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 95).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:39]2[CH:38]=[CH:37][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccc5ccccc5c4)cc3C)c2cc1OC
Yield: 102.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-naphthylmethanol (87 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (160 mg, yield 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCCC2=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-oxopyrrolidin-1-yl)benzoic acid (19.94 mg, 0.097 mmol) in DCM (5 ml) was added oxalyl chloride (2M solution in DCM, 0.058 ml, 0.117 mmol) and 2 drops of DMF. The resulting mixture was stirred at r.t for 1 hr., then concentrated in vacuo. The residue (off white solid) was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)(=O)[CH3:2].Cl.[NH2:10][OH:11].N1C=CC=CC=1.O>C(O)C>[S:5]1[CH:6]=[CH:7][N:8]=[C:4]1[C:1](=[N:10][OH:11])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1nccs1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(=NO)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Commercially available 2-acetyl thiazole (1.27 g) and commercially available hydroxylamine hydrochloride (830 mg) were dissolved in ethanol (40 ml) to prepare a solution. Pyridine (0.97 ml) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and was dried over sodium sulfate. The solvent was removed by evaporation and was dried by means of a vacuum pump to give the title compound (1.25 g, 88%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21]([C:23]4[NH:27][C:26]([S:28]([CH3:31])(=[O:30])=[O:29])=[N:25][C:24]=4[C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:22])[CH:17]=[CH:16][C:15]=3[CH3:39])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40].CC(O)C>>[NH2:40][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21]([C:23]4[NH:27][C:26]([S:28]([CH3:31])(=[O:30])=[O:29])=[N:25][C:24]=4[C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:22])[CH:17]=[CH:16][C:15]=3[CH3:39])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(NC(=O)c2[nH]c(S(C)(=O)=O)nc2-c2ccc(F)cc2)cc1NC(=O)c1csc2c(Cl)ncnc12
Reactant: N
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2[nH]c(S(C)(=O)=O)nc2-c2ccc(F)cc2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 80 °C
Yield: 59 %

Procedure:
Compound 4-chloro-N-(5-(4-(4-fluorophenyl)-2-(methylsulfonyl)-1H-imidazole-5-carboxamido)-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (7.0 mg, 0.01 mmol) was dissolved into 2M ammonia in IPA (1.0 mL, 1.99 mmol ammonia). The resulting solution was heated in a sealed vial at 80° C. for 6 hrs. The solvent was removed under reduced pressure and the crude material was purified by SiO2 chromatography (DCM to 8% MeOH gradient, desired product elutes in 6% MeOH) (4 mg, 59% yield). 1HNMR (400 MHz, MeOD/CDCl3): d 8.64 (s, 1H), 8.42 (s, 1H), 8.26 (m, 1H), 7.66 (m, 2H), 7.56 (m, 2H), 7.51 (s, 1H), 7.41 (m, 2H), 7.07 (d, 1H, J=9.2 Hz), 7.01 (t, 2H, J=8.4 Hz), 3.20 (s, 3H), 2.33 (s, 3H). MS (ESI): m/z 565.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])[CH2:13][OH:14])[CH:8]=[CH:7]2.CO[C:18](OC)([CH3:20])[CH3:19].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]1[CH2:13][O:14][C:18]([CH3:20])([CH3:19])[O:15]1)[CH:8]=[CH:7]2
Reactant: COC(C)(C)OC
Reactant: OCC(O)c1ccc2cccc(Br)c2n1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(c2ccc3cccc(Br)c3n2)O1
Reaction time: 2 h

Procedure:
To 1-(8-bromoquinolin-2-yl)ethane-1,2-diol (505 mg, 1.88 mmol) in acetone (5 mL) and 2,2-dimethoxypropane (5 mL, 1.88 mmol) was added Montmorillonite K 10 (1 g). The reaction mixture was stirred for 2 hours, then filtered and concentrated to give crude product.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28]I>CN(C=O)C.[H-].[Na+]>[CH3:28][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: CI
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCOCC2)c2nc(-c3cnn4ccc(C#N)cc34)ncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.5 %

Procedure:
To a solution of example 1 (48 mg, 0.13 mmol) in DMF (6 mL), 55-65% NaH dispersion in mineral oil (7.3 mg, 0.18 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then MeI (0.015 mL, 0.25 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was quenched with saturated NaCl aqueous solution (10 mL) and extracted with EtOAc (3×10 mL) and CH2Cl2 (2×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH2Cl2 mixtures of increasing polarity as eluent, to afford 50 mg of the desired compound (quantitative yield).
Reaction SMILES: F[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].CCN(C(C)C)C(C)C.[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=2)[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH:31][C:2]3[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=3)[C:5]#[N:6])[CH:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)cc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.8 %

Procedure:
To a solution of 3,5-difluoro-2-nitrobenzonitrile (Method 99, 5.8 g, 31.5 mmol) and DIEA (5.5 ml, 31.5 mmol) in THF (50 ml) was added drop wise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (4.66 g, 37.8 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 20 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (DCM-EtOAc=10:1) to give the title compound as a yellow solid (5.5 g, 61%). 1H NMR (400 MHz) 12.43 (s, 1H), 9.70 (s, 1H), 8.22 (dd, J=11.2 and 2.0 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H), 5.92 (s, 1H), 1.90 (m, 1H), 0.95 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 287; Found: [M+H]+ 288.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 36 g of 5-bromopentan-1-ol were added 24.72 ml of 2,3-dihydropyran and 3 drops of phosphorus oxychloride under cooling in an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with 5% aqueous potassium hydroxide, water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:19) as eluent to give 49.5 g of the subtitle compound having the following physical characteristics:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[O:28]=[C:29]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:31][C@H:30]1[NH2:46]>O1CCCC1.C(N(CC)CC)C>[O:28]=[C:29]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:31][C@H:30]1[NH:46][C:5]([NH:27][C:24]1[CH:25]=[CH:26][C:14]([CH3:13])=[C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH:23]=1)=[O:11]
Reactant: N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(N)cc1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3NC2=O)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 256.3 %

Procedure:
Under ice-cooling, triphosgene (456 mg) was added to a solution of tert-butyl 2-methyl-5-aminobenzoate (850 mg) in anhydrous tetrahydrofuran (50 ml), triethylamine (1.85 ml) was added thereto five times each 0.37 ml over a 15 minutes after divided into five portions. After the mixture was stirred at room temperature for 5 minutes, (R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.04 g) was added under ice-cooling. The resultant mixture was stirred at room temperature for one hour, the reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, crystals so precipitated were washed with diisopropyl ether, to thereby obtain 1.94 g of the title compound (Yield: 98%).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C(OCC)C.Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:18](=[O:20])[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]([C:2]2[S:1][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)=[O:10])[CH:12]=1)[CH3:21]
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCOCC
Product: CC(C(=O)NCCN(C)C)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reaction time: 20 h
Yield: 37.3 %

Procedure:
N,N'-Carbonyldiimidazole (3.8 g) is added to 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.25 g) [prepared as described in a previous Example] in solution in diethyl ether (70 cc). When the evolution of gas has ceased, 2-dimethylaminoethylamine (2.1 g) in solution in diethyl ether (25 cc) is then added. After 20 hours at 25° C., the reaction mixture is evaporated. The residue, dissolved in methylene chloride (100 cc), is washed four times with a 5% (w/v) aqueous sodium chloride solution (total 400 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. The oil obtained (5.4 g) is dissolved in N aqueous hydrochloric acid solution (50 cc). This solution is washed three times with diethyl ether (total 150 cc) and then rendered alkaline to pH 11 by the addition of 1 N aqueous sodium hydroxide solution (55 cc). The resulting precipitate is extracted three times with methylene chloride (total 150 cc). The combined methylene chloride solutions are washed three timmes with distilled water (total 150 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. N-(2-Dimethylaminoethyl) 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionamide (3.3 g), in the form of an oil, is thus obtained.
Reaction SMILES: [C:1]([C:8]([NH2:39])([CH2:19][CH2:20][CH2:21][C:22]1([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([C:8]([NH2:39])([CH2:19][CH2:20][CH2:21][C:22]1([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Yield: 97.5 %

Procedure:
The Boc-diester (I) (1.27 g, 2.36 mmol) was dissolved in dioxane (15 ml) and treated with 2.6 ml 1N sodium hydroxide solution at room temperature under argon for 4 hours. The reaction mixture was acidified (pH =2) with 3N hydrochloric acid and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, washed with 3N hydrochloric acid, dried over MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol/chloroform) to give 1.03 g of the title product: MS: MH+ =448); 1HNMR (CDCl3): 7.33 (S, 5H), 5.07 (S, 2H), 5.20-4.80 (m, 1H), 4.42-4.05 (m, 1H), 2.32 (S, 2H), 1.43 (S, 9H) and 2.08-1.07 (m, 16H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(CCOc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z=595.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]([CH2:26][OH:27])[CH2:23][CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH2:23][CH2:24][CH3:25])[CH2:26][OH:27])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CCC[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 120 °C

Procedure:
1.4 g 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (II) are placed in 9 ml dioxane, then first 3.5 ml diisopropylethylamine, then 0.9 g D-norvalinol are added. The reaction mixture is heated in the microwave at 120° C., until there is no further reaction, and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].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.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([CH3:33])=[CH:35][CH:36]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)c2ccccc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
Tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (7), (4-methyl-1-naphthyl)boronic acid (46), tetrakis(triphenylphosphine)palladium(0), and sodium carbonate were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70° C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, purified by preparative layer chromatography (10% ethyl acetate/Hexane) then treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 47A as a white powder (12.0 mg, 26%). 1H NMR (500 MHz, DMSO d6) δ=12.80 (br, 1 H), 12.60 (s, 1 H), 8.04 (d, 1 H), 7.88 (s, 1 H), 7.87 (d, 1 H), 7.74 (d, 1 H), 7.57-7.52 (m, 3 H), 7.46-740 (m, 2 H), 7.37 (d 1 H), 7.28 (d, 1 H), 7.04 (s, 1 H), 2.68 (s, 3 H) ppm. ESI MS [M+H] 428.21.