Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]2[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[NH:48][C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2>O>[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[N:48]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]5[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]5)=[CH:14][CH:13]=4)[C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2
Reactant: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Reaction time: 8 h
Yield: 94.6 %

Procedure:
An N,N-dimethylformamide (2 mL) solution of 7-(4-bromobutoxy)-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.074 mmol) was added with potassium carbonate (20.4 mg, 0.148 mmol) and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione (27.4 mg, 0.111 mmol) and then stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=5:2), and the title compound (40.2 mg, 95%) was obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of (1S,2R,3S,5S)—N2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)bicyclo[3.1.0]hexane-2,3-diamine (42 mg, 0.094 mmol) in dichloromethane (1.9 mL) at 0° C. was added DIEA (0.025 mL, 0.14 mmol) and acryloyl chloride (0.009 mL, 0.11 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R,3S,5S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)bicyclo[3.1.0]hexan-3-yl)acrylamide (36 mg, 76%) as a pale yellow solid. MS (ES+) C25H24Cl2N4O3 requires: 498, found: 499
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[S-:20][C:21]#[N:22].[K+]>CC(C)=O.CCOC(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][S:20][C:21]#[N:22])[C:6]([CH3:19])=[N:7]2)=[CH:12][CH:13]=1
Reactant: N#C[S-]
Reactant: COc1ccc(Cn2cc(C(=O)CBr)c(C)n2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(C(=O)CSC#N)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
According to Scheme 2, Step 3: To a solution of 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (9.28 mmol, 3.00 g) in acetone (19 mL) was added potassium thiocyanate (9.28 mmol, 0.90 g) and the reaction mixture was stirred overnight at room temperature. Then, the reaction mixture was diluted with EtOAc and the organic phase was washed with water. The organic phase was dried over MgSO4, was filtered and was concentrated. The crude residue was purified by flash chromatography over silica gel using cyclohexane/EtOAc (80:20 to 50:50) as eluent to yield 1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone (6.57 mmol, 1.98 g, 71%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34])[C:27](Cl)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:24]([F:23])[CH:25]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(C(F)(F)F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To the stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 3-fluoro-4-trifluoromethylbenzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL) and washed with water (2×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-4-trifluoromethyl-benzamide (0.6 g, 53%) as a white solid: mp 165-167° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=8.20 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.5 Hz, 1H), 7.76-7.84 (m, 3H), 7.95-8.01 (m, 3H), 9.45 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.97, 30.92, 38.54, 48.87, 115.88 (116.17), 118.56 (118.72, 119.00, 119.16), 122.30, 123.94 (123.98), 120.52 (124.13), 127.25, 127.74 (127.80), 131.55, 133.24, 134.83, 138.51, 140.42 (140.52), 157.04 (160.38), 164.19, 166.91, 167.48, 169.81, 172.74; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.00; H, 2.95; N, 8.80; F, 15.92.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.CN1CCNCC1.[CH3:58][C:59]([OH:63])([C:61]#[CH:62])[CH3:60]>>[OH:63][C:59]([CH3:60])([CH3:58])[C:61]#[C:62][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: CN1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(Br)cc2-3)CC1
Reactant: C#CC(C)(C)O
Agent: CN1CCNCC1
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: CN1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(C#CC(C)(C)O)cc2-3)CC1
Yield: 23 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((4-methylpiperazin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with N-methylpiperazine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (12 mg, 23%).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20].N1C=CC=CC=1.Cl>S(Cl)(Cl)=O>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:6]([C:5]3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[O:8][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (2.00 g, 9.38 mmol) in thionyl chloride (8.2 mL) was heated at 80° C. for two hours. The excess of thionyl chloride was removed under vacuum. The resulting yellow solid was dissolved in DMA (15.4 mL), then (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (2.636 g, 11.26 mmol) and pyridine (6.2 mL) were added. The red solution was heated to 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of cc HCl (10 ml) and ice (80 g), then stirred for thirty minutes. The yellow precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from dichloromethane-isopropanol mixture afforded 2.42 g (62%) of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol as yellow crystalline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[Cu][C:33]#[N:34].C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[C:13]([N:11]1[CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]#[N:34])[N:9]=[CH:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#C[Cu]
Reactant: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-bromo-phenyl)-1-trityl-1H-imidazole (73.0 g, 163.3 mmol) in dimethylformamide (500 ml) was added copper (I) cyanide (17.5 g, 195.9 mmol). The reaction was heated to ˜80° C. under nitrogen for 14 h. After cooling to about 50° C., the reaction was diluted with toluene (ca. 300 ml) and slowly poured onto ammonium hydroxide (3N, 1.5 L) while stirring vigorously. The mixture was stirred for 40 min and then filtered in vacuo over a bed of celite (slow filtration, required ˜2 h). The phases were separated and the organic layer was washed with brine (75 ml×3) and dried (sodium sulfate). Concentration of the solvent afforded a light brown solid. The crude product contains ˜10–15% of trityl alcohol (by HPLC) and was used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11].I[CH3:24]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][N:8]([CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11])[CH3:24]
Reactant: COc1ccc(CCNCC(O)c2ccc(C)s2)cc1OC
Reactant: CI
Solvent: c1ccccc1
Product: COc1ccc(CCN(C)CC(O)c2ccc(C)s2)cc1OC

Procedure:
A solution of α-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol (2.29 g, 0.007 mole), described in Example 16, and the lower alkyl halide, iodomethane (9.94 g, 0.07 mole), in 70 ml benzene is stirred at 25° C for 3 days. The mixture is concentrated under reduced pressure. The residual oil is taken up in methanol and made alkaline with 10% NaOH. The mixture is extracted with chloroform. The extract is washed with water, dried (K2CO3) and concentrated to give a yellow oil, which is purified by chromatography to give the title compound; nmr (CDCl3) δ 2.41 (s, 3H), 2.46 (s, 3H), 2.6 - 2.8 (m, 6H), 3.68 (s, 1H), 3.83 (s, 3H), 3.88 (s, 3H), 4.88 (t, 1H), 6.6 - 6.9 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O1CCCCC1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C)C=O>[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: BrCCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.4 g of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g (0.06 mole) of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(3-pyridyl)-3-methylindole.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[CH:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1.[Cu]>[OH:17][CH:11]([CH:6]1[CH:5]([CH:2]=[CH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8][C:7]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC=O
Reactant: CC(C)C1C=CC(=O)CC1
Agent: [Cu]
Solvent: C1CCOC1
Product: CCCCCCC=CC1C(C(C)C)CCC(=O)C1C(O)CCCCC
Reaction time: 2 h
Yield: 82 %

Procedure:
Following the procedure of Example 1, a mixed solution was formed of the cuprate and Me3ZnLi (0.52 mmol) comprising 10 mol-% of copper per mole of enone. The solution was treated with 4-isopropyl-2-cyclohexenone (77 μL, 0.5 mmol) as a neat liquid over 70 minutes and then stirred for an additional 2 hours. Hexanal (0.25 mL, 2.0 mmol), in 1.0 mL THF at -78° C., was then added. After 5 minutes the mixture was quenched with 5 mL of 10% NH4OH in saturated NH4Cl. The product was extracted with 3×20 mL of ether and dried over Na2SO4. The solution was then filtered through flitted filter paper and the solvent removed in vacuo. The resulting residue was submitted to flash chromatography on silica gel (Petroleum Ether/Ethyl Acetate, 30/1) to give an 82% yield of 2-(1-hydroxyhexyl)-3-(1-octen-1-yl)-4-isopropyl cyclohexanone as a colorless oil which gave satisfactory IR, NMR, MS, and HRMS data.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C@H:8]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[CH2:9][N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]2[CH2:44][CH2:43][C:31]3([O:36][CH2:35][CH2:34][N:33](C(=O)C(F)(F)F)[CH2:32]3)[CH2:30][CH2:29]2)=[CH:21][CH:20]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O.CO>[O:36]1[C:31]2([CH2:43][CH2:44][N:28]([CH2:27][CH2:26][O:25][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:10]([CH2:9][C@H:8]([OH:7])[C:45]4[C:53]5[S:52][C:51](=[O:54])[NH:50][C:49]=5[C:48]([OH:55])=[CH:47][CH:46]=4)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CNCCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of potassium carbonate (240 mg) in water (35 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(4-(2-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzyl)carbamate (examples 223-263, step a) (725 mg) in MeOH (35 mL). The resulting mixture was stirred at RT for 5 h. Methanol was removed by evaporation under a stream of nitrogen keeping the reaction mixture at 25° C. Water (20 mL) and brine (30 mL) were added and the mixture was extracted with ethyl acetate (7×30 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% (2M NH3 in MeOH)/DCM to give the subtitled compound as a white solid. Yield 385 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>>[CH:20]1([CH2:19][N:3]2[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:6]([CH3:7])=[C:2]2[CH3:1])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Product: Cc1cc(C(=O)CCc2ccccc2)n(CC2CC2)c1C
Yield: 93 %

Procedure:
The title compound was prepared as an orange oil in 93.0% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and bromomethylcyclopropane.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([NH2:36])[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([NH:36][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:22])[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(Cc1cccs1)c1cccs1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1cccs1)c1cccs1
Yield: 40 %

Procedure:
The title compound was prepared in a yield of 40% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,2-di(2-thienyl)ethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[NH2:23].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[NH:23]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[C:11]4[S:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:4]=2)[CH:1]=[N:24]1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(-c2nc(N3CCOCC3)c3sccc3n2)cc1N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: c1cc2nc(-c3ccc4cn[nH]c4c3)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (99 mg) in chloroform (10 mL) and acetic acid (2 mL) was added isoamyl nitrite (44 μL). The reaction mixture was stirred for 2 days at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 229. MS: ESI MH+ 338
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23]C)=[O:22])[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([OH:23])=[O:22])[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(S(C)(=O)=O)c3)c3ncsc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)c1
Reaction time: 0.15 h
Yield: 40.4 %

Procedure:
Methyl 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (130 mg, 0.29 mmol) and NaOH (130 mg, 3.25 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O were stirred at room temperature for 3 hours and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (50 mg, 40%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.18 (brs, 1H), 10.76 (s, 1H), 9.45 (s, 1H), 8.99-8.95 (m, 2H), 8.72 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz), 8.22-8.18 (m, 1H), 8.08 (dt, 1H, J2=8.1 Hz, J2=1.4 Hz), 7.69-7.61 (m, 3H), 3.24 (s, 3H). LC-MS: 427 [M+H]+, tR=1.48 min. HPLC: 98.42% at 214 nm, 99.23% at 254 nm, tR=5.75 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12](N(CC)CC)C.CI>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Br)ccc2s1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(Br)ccc2s1
Yield: 78.4 %

Procedure:
To a solution of 5-bromobenzo[d]thiazole-2-thiol (24 mg, 0.098 mmol) in EtOH (1.5 mL) was added triethylamine (10 mg, 0.098 mmol) and methyliodide (14 mg, 0.098 mmol). The mixture was heated at reflux for 1.5 h. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 5-bromo-2-(methylthio)benzothiazole 20 mg (80%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])(=[O:21])[CH3:20]
Reactant: CC(O)CCc1ccccc1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)CCc1ccccc1
Yield: 98.3 %

Procedure:
Into a four-necked flask provided with a thermometer and a stirrer, 150 g (1 mol) of 4-phenyl-2-butanol (XXX-35), 500 ml of toluene and 200 ml of pyridine were charged. 122.4 g (1.2 mol) of anhydrous acetic acid and 1 g of 4-dimethylaminopyridine were further added thereto to react them for 4 hours, while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid solution, extracted and fractionated, and then an organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water in the order. The thus-obtained Organic layer was concentrated under a reduced pressure to obtain 189 g of 2-acetoxy-4-phenylbutane (XXIX-35) with yield of 98.5%.
Reaction SMILES: C[Si](C)(C)[N-:3][Si](C)(C)C.[Li+].[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>CCCCCC.C(OCC)C>[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:3])=[NH:15]
Reactant: N#Cc1cccc(F)c1Cl
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
320 ml (0.32 mmol) of a 1 molar solution of lithium hexamethyl disilazide (LiHMDS) in hexane are placed in 800 ml diethyl ether and combined at ambient temperature with 25.0 g (0.161) 2-chloro-3-fluoro-benzonitrile. The mixture is stirred for 2 h at ambient temperature and after cooling to 0° C. it is combined with 280 ml 3 normal hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.