Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[N:28]([C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)[N:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].O>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][N:28]([C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]4)[C:24]=3[CH3:23])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.16/541.16 (100/50) [MH+]. HPLC: tR=3.98 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][C:35]([NH2:41])=[CH:36][CH:37]=2)[CH2:32]1>CC(O)C.Cl>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:35]4[CH:34]=[C:33]5[C:38]([CH2:39][CH2:40][N:31]([CH3:30])[CH2:32]5)=[CH:37][CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: CN1CCc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)C(F)(F)F)c5)nn5ccccc45)n3)cc2C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (310 mg, 0.74 mmol, which may be prepared according to Example 11, Step C) and 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (150 mg, 0.92 mmol) in 2-propanol (10 mL) was added 6 drops concentrated HCl. The reaction was stirred for 18 h at 80° C., then partitioned between saturated aqueous NaHCO3 and 20% (v/v) MeOH in EtOAc. The aqueous layer was extracted with 20% (v/v) MeOH in EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 72% yield (290 mg, 0.53 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.39 (s, 1H), 9.45 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.44-7.55 (m, 4H), 7.38 (d, J=8.2 Hz, 1H), 7.14 (t, J=6.9 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.50 (d, J=5.3 Hz, 1H), 3.39 (s, 2H), 2.75 (t, J=5.7 Hz, 2H), 2.59 (t, J=5.7 Hz, 2H), 2.32 (s, 3H). MS (ESI) m/z=544 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 28.3 %

Procedure:
Following General Procedure I, (R)-tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (220 mg, 0.39 mmol) was reacted with NBS (90 mg, 0.51 mmol) to afford the desired product (60 mg, 28%) as a reddish oil: ESI MS m/z 543 [C26H27BrN2O4S+H]+.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1.CN(C1SC=CN=1)CCNC(=O)C#CC1C=CC=C(Cl)C=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cnc(N(C)CCN)s1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Agent: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nccs1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1cnc(N(C)CCNC(=O)C#Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.19 g (˜2.6 mmol) of PS carbodiimide were added to a solution of 232 mg (1.35 mmol) of N1-methyl-N1-(5-methylthiazol-2-yl)ethane-1,2-diamine and 367 mg (2.03 mmol) of (3-chlorophenyl)propiolic acid in DCM (40 ml). The mixture was then shaken for 16 h at RT, after which the resin was filtered out and rinsed with DCM and EtOH. The filtrate was evaporated under a vacuum and CC (DCE/EtOH 5:1) was carried out with the residue, 169 mg (0.51 mmol, 37%) of N-(2-(methyl(thiazol-2-yl)amino)ethyl)-3-(3-chlorophenyl)-propiolamide being obtained. MS [MH+] 334.1
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][C:74](=[O:76])[CH3:75])[CH:68]=1>>[C:74]([NH:73][C:69]1[N:70]=[CH:71][N:72]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[CH:68]=1)(=[O:76])[CH3:75]
Reactant: CC(=O)Nc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CC(=O)Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 141 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for N-(6-chloropyrimidin-4-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=7.78 Hz, 1H), 6.56 (t, J=1.88 Hz, 1H), 6.47 (d, J=1.76 Hz, 2H), 4.02 (br. s., 1H), 3.79 (br. s., 1H), 3.61 (d, J=9.29 Hz, 3H), 2.84-3.17 (m, 2H), 2.00 (s, 3H), 1.75 (br. s., 2H), 1.33-1.57 (m, 2H). EIMS (m/z): calcd. for C19H22Cl2N6O2 (M+1H) 437. found 437.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CN(C)CCCN
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)CCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 26 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and an aqueous solution of 3-(dimethylamino)-propylamine (prepared from 51 gm of diamine and 70 cc of water) with a yield of 26% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>C(N(C(C)C)C(C)C)C>[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC1CC1
Yield: 94.7 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (8.92 g, 30.0 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (7.91 g, 33.0 mmol) were refluxed in N-ethyldiisopropylamine (20 ml) for 8 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:3), to give N-cyclopropyl-6-[4-[bis(4-fluorophenyl)methyl]1-piperazinyl]hexanesulfonamide (13.97 g) as a crystalline substance (yield based on 1-[bis(4-fluorophenyl)methyl]piperazine: 94.7%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Yield: 86.7 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (0.72 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (4.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.6 g of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid as a colorless solid, mp 161°-162° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[CH3:18][O-:19].[Na+]>CN(C)C=O.CO>[CH3:18][O:19][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 120 °C

Procedure:
First, the intermediate 2-methoxy-9,10-anthraquinone was prepared. A solution of 2-chloro-9,10-anthraquinone (10.08 g, 42 mmol) in 100 mL of N,N-dimethylformamide was treated with 25 mL of 25% sodium methoxide in methanol. The stirred reaction mixture was heated in a 120° C. oil bath for 6 h under nitrogen, then cooled to ambient. The product was precipitated into aqueous HCl (0.5 M, 250 mL), collected, washed with water and dried. The product was purified by recrystallization from a mixture of toluene and heptane to provide 1.6 g (16%) of a light yellow solid. This intermediate was characterized by 1H NMR: (300 MHz, CDCl3) δ 4.00 (s, 3H), 7.28 (d, 1H), 7.29 (d, 1H), 7.70 (m, 2H), 8.26 (s, 1H), 8.30 (m, 2H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C@@H:22]2[C@@H:23]([O:6]2)[CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Add a solution of m-chloroperoxybenzoic acid (0.77 mol, 133.1 g) in dichloromethane (200 mL) drop wise to a solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.64 mol, 117.8 g) in dichloromethane (1 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 16 h. Dilute the reaction mixture with dichloromethane and wash with 4 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (112 g, 87%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.87-1.93 (m s, 1H), 2.04 (br s, 1H), 3.11 (br s, 1H), 3.20 (br s, 1H), 3.28 (s, 1H), 3.44 (br s, 1H), 3.68 (br s 1H). 3.81-3.92 (m, 1H). ES-MS m/z 204 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (363 mg) synthesized in Example A189 was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the mixture, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (283 mg, 83%) as a colorless solid.
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].C([C:28]1[S:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:29]=1)=O>CCCCCC>[CH3:3][O:2][CH:1]([O:4][CH3:5])[C:28]1[S:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CCCCCC
Product: COC(OC)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethyl orthoformate (7.5 ml) and montmorillonite K-10 (5.0 g) (Aldrich Chem. Co., Milwaukee, Wis.) were mixed and stirred at room temperature for 10 minutes. A solution of 5-formyl-2,2'-bithiophene (5.0 g) (Aldrich Chem. Co., Milwaukee, Wis.) in n-hexane (10 ml) was added and was stirred at room temperature. The reaction was monitored with thin layer chromatography until the reaction was completed. Montmorillonite K-10 was filtered. The filtrate was added to a saturated sodium bicarbonate aqueous solution and extracted with ethyl, acetate (15 ml×3). The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give light yellowish oily product (6.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:40])[CH2:37]CO>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:40])[CH3:37])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: CN(C)CCO
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN(C)CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.035 g, 0.067 mmol) with N,N-dimethylethanolamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.50-8.07 min) afforded 2-(dimethylamino)ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate as an off-white solid (0.008 g, 0.014 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.48 (t, 1H), 7.32 (m, 3H), 5.23 (s, 2H), 4.29 (t, 2H), 2.86 (m, 2H), 2.39 (s, 6H); MS: (M−H)− 580.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:24])=[O:2])=[O:18]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 5-(furan-2-carbonyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (100 mg, 0.3 mmol) in methanol (10 mL). Add dropwise 2 N NaOH (0.225 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute the residue with ethyl acetate and wash by saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12](=O)[CH2:13]Br)=[N:10][CH:11]=1)=[O:5])C.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:9]3[N:10]=[CH:11][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOC(=O)c1cnc(C(=O)CBr)nc1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)cn3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-pyrimidyl)thiazole.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:20][C:10]1[C:9]([C:21]#[N:22])=[C:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:5][C:6]2=[C:12]([F:13])[C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(CBr)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Yield: 81.9 %

Procedure:
Under nitrogen atmosphere, a carbon tetrachloride (12 ml) solution of 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (1.00 g, 3.42 mmol), N-bromosuccinimide (913 mg, 5.13 mmol) and 2,2′-azobis(isobutyronitrile) (56 mg, 342 μmol) was stirred at 80° C. for 13 hours. After cooling, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=5:1, v/v) to obtain the entitled compound (1.04 g, 82%) as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:12])[CH2:9][CH2:10][CH3:11].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=2[O:15]1>>[CH3:13][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:3][CH2:2][O:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][O:18][C:17]=2[CH:19]=1
Reactant: CCCC(C)=CCCC(C)=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Product: CCCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCO2

Procedure:
By the procedure of Example 1, 1-bromo-3,7-dimethyl-2,6-decadien is reacted with sesamol to obtain 4-[(3,7-dimethyl-2,6-decadienyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 140° C./0.025 mm Hg.; nD23 = 1.5237.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.I[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CC#N>[CH:14]1([C:8]2[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: IC1CCCC1
Solvent: CC#N
Product: Nc1ccc2c(C3CCCC3)c[nH]c2c1

Procedure:
3-Cyclopentyl-1H-indol-6-ylamine (B-15) was synthesized following the general scheme above starting from 6-nitroindole and iodo-cyclopentane. Overall yield (16%). HPLC ret. time 2.39 min, 10-99% CH3CN, 5 min run; ESI-MS 201.5 m/z (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH2:3]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1(C)C=CC=CC=1>O>[O:15]=[C:4]1[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:7][C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:3]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(N2CCNCC2)CC(c2ccccc2Cl)C1

Procedure:
A mixture of 24.0 g (0.108 mol) of 1,3-dioxo-5-(o-chlorophenyl)-cyclohexane, 28.4 g (0.33 mol) of anhydrous piperazine and 270 ml of toluene is heated at the boiling point under reflux for 5 hours, using a water separator. The toluene is distilled off, while still warm, in vacuo and the residue is dissolved in chloroform. This solution is extracted three times by shaking with water, to remove the excess piperazine, and dried with sodium sulphate. The concentrated solution is purified by means of column chromatography (corresponding to Example 2). Some of the fractions contain 6.5 g of the base [3-oxo-5-(o-chlorophenyl)-1-cyclohexen-1-yl]-piperazine in pure form, of melting point 159°-160° C., and another portion is still contaminated. The latter is purified by the oxalate: 6.2 g of a white salt of melting point 225°-227° C. (decomposition). After converting back into the base, a further 5.0 g are obtained. Total yield: 11.5 g (=36.7%). RF value: 0.38 (conditions corresponding to Example 1).