Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:40])[NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:26][C@H:25]2[CH3:39])=[O:23])=CC=1)([O-])=O>CO>[NH2:24][CH2:25][CH2:26][NH:27][C:11]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]([N:24]1[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:26][C@H:25]1[CH3:39])=[O:23])=[O:40]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NC(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.3 %

Procedure:
To a solution of (2R, 5S)-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamic acid 4-nitro-phenyl ester (0.206 g, 0.37 mmol) in dry methanol (6 ml) was added ethyldiamine (0.05 ml, 0.814 mmol). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and chromatagraphed on silica gel to give the title compound (0.115 g, 63% yield).
Reaction SMILES: ClC1C=C(N[C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])C=CC=1SC1N(C)C=CN=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O>>[N:30]1([CH:29]2[CH2:21][CH2:20][N:19]([C:22]3[CH:21]=[C:20]4[C:25]([CH:16]=[C:17]([C:27]#[N:28])[CH:18]=[N:19]4)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl
Reactant: CN1CCCC1=O
Product: N#Cc1cnc2cc(N3CCC(N4CCCC4)CC3)ccc2c1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.37 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile and 339 mg (2.20 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 9:1 methylene chloride/methanol) gives 66 mg of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 125-130° C.
Reaction SMILES: O1CCCC1.[O:6]([CH2:14][C@H:15]([O:25][CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:28][O:27][CH2:26][O:25][C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:14][OH:6]
Reactant: COCO[C@@H](CO[Si](C)(C)C(C)(C)C)Cc1ccccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCO[C@@H](CO)Cc1ccccc1OC
Reaction time: 2 h
Yield: 103.3 %

Procedure:
Under ice-cooling, to a tetrahydrofuran solution of (R)-1-t-butyldimethylsiloxy-2-methoxymethoxy-3-(2-methoxyphenyl)propane (2.2 g) was added a solution of n tetrabutylammoniumfluoride (1 mol/l, 6.46 ml) in tetrahydrofuranand stirred for 2 hours successively. After tetrahydrofuran wasevaporated in vacuo, water was added, extracted with ethyl acetate,and dried over magnesium sulfate. The solvent was evaporated invacuo, the gained crude product was purified by silica gel columnchromatography, and eluted with a mixed solvent of hexane andethyl acetate (1:1, v/v). The fractions containing the desiredproduct were combined and evaporated in vacuo to obtain (R)-2-methoxymethoxy-3-(2-methoxyphenyl)-1-propanol(1.51 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:35])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:28][C:27]1[C:22]([NH:21][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)=[O:14])=[CH:23][C:24]([F:35])=[C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3ccc(F)cc23)cc1F
Temperature: 0 °C
Yield: 46.6 %

Procedure:
In methylene chloride (30 ml) was dissolved 5-fluoro-1-methylindole-3-carboxylic acid (885 mg, 4.58 mmol). To the resulting solution was added oxalyl chloride (600 μl, 6.87 mmol) under stirring at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (50 ml). The resulting solution was added dropwise to a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (1.06 g, 4.58 mmol) in methylene chloride (20 ml), followed by heating under reflux for 15 minutes. The reaction mixture was cooled and triethylamine (3.19 ml, 22.9 mmol) was added thereto. The resulting mixture was heated under reflux for 18 hours. The reaction mixture was cooled and poured in 1N HCl, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (2/1) eluate fractions, ethyl (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetate (868 mg, 47%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15]C(C)(C)[O:17][C@@:13]32[C@@H:8]([C@H:9]([C:21]([CH3:25])=[C:22]([Cl:24])[Cl:23])[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CO.CO>[C:1]([O:4][CH:5]1[C:6]([CH3:26])=[CH:7][CH:8]2[C:13]([OH:17])([CH:12]([CH3:20])[CH2:11][CH2:10][CH:9]2[C:21]([CH3:25])=[C:22]([Cl:24])[Cl:23])[CH:14]1[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)=C(Cl)Cl)CC[C@@H](C)[C@@]23OC(C)(C)O[C@@H]13
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: OCCO
Product: CC(=O)OC1C(C)=CC2C(C(C)=C(Cl)Cl)CCC(C)C2(O)C1O
Temperature: 75 °C

Procedure:
To a stirred solution of (3aS,4R,6aR,7R,10R,10aR)-7-(2,2-dichloro-1-methylethenyl)-2,2,5,10-tetramethyl-4,6a,7,8, 9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 170, 0.95 g) in ethylene glycol (40 ml) and methanol (10 ml) was added para-toluenesulphonic acid (95 mg). The reaction mixture was heated to 75° C., after 1.5 h the reaction mixture was concentrated in vacuo to remove the methanol. The resultant solution was diluted with diethyl ether (30 ml) and water (30 ml) and the organic layer separated and washed with sodium hydrogen carbonate (3×30 ml). The aqueous layers were back extracted with diethyl ether (2×20 ml) and the combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a white solid.
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][OH:19].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:14])([CH3:13])[CH3:15])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][O:19][CH2:1][O:2][CH3:3]
Reactant: COCCl
Reactant: COc1nc([Si](C)(C)C)cc(I)c1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1c(I)cc([Si](C)(C)C)nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
MOMCl (2.0 mL, 26.7 mmol) was added dropwise to a 0° C. solution of 2a (3 g, 8.9 mmol) and iPr2EtN (4.6 mL, 26.7 mmol) in dry CH2Cl2 (35 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 5% aq. NaHCO3 solution and the product was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 3.0 g (88% yield) of the crude product 3a as an orange oil. The crude product was sufficiently pure for the subsequent reaction. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 3.46 (s, 3H), 3.98 (s, 3H), 4.71 (s, 2H), 4.75 (s, 2H), 7.51 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−2.08, 53.79, 55.53, 67.85, 96.39, 113.84, 122.6, 132.98, 161.43, 166.37; IR (film, NaCl, cm−1) 2946, 1528, 1340, 1042, 840; LRMS (70 eV, EI) m/z (rel int %) 381 (M+), 366, 336, 320, 306, 169, 128, 84 (100), 73. HRMS m/z calcd for C12H20NO3SiI (M+) 381.0257, found 381.0241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Yield: 71.1 %

Procedure:
A mixture of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (9.13 g, 0.0316 mol), hydroxylamine hydrochloride (2.64 g, 0.0380 mol), and sodium carbonate (4.04 g, 0.0381 mol) in absolute ethanol was refluxed under nitrogen for 13.5 hours and allowed to cool. The resulting suspension was filtered, and the filter cake was washed with ethanol followed by diethyl ether. The filter cake was dried under house vacuum to give a white solid. The solid was dissolved in methanol (450 mL), and the cloudy solution was filtered to remove fines. The filtrate was stirred while one equivalent of 1 M HCl was added dropwise followed by dropwise addition of deionized water (200 mL). The mixture was gently rotary evaporated (bath temperature=40° C.) to a volume of 150 mL. The solids that precipitated were chilled at 5° C. for 10 minutes and filtered. The filter cake was washed with water and dried in vacuo to give 6.82 g of 4-(4′-chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 155-157° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:30])[CH:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH:19]([CH3:29])[C:18]([OH:30])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: CC(Cc1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1)C(=O)O
Yield: 78.5 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (37 mg, 0.16 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (51 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1.Br[C:12]1C=C(C)C(I)=C(C)C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:12])[C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: C=Cc1ccc(Br)cc1C
Agent: C=C[Si](C)(C)C
Product: C=Cc1c(C)cc(Br)cc1C
Yield: 94 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 5-bromo-2-iodo-1,3-dimethylbenzene (15.6 g, 48 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h to yield 32A (10.0 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.26 (s, 6 H) 5.24 (dd, J=17.86, 1.92 Hz, 1 H) 5.55 (dd, J=11.54, 2.20 Hz, 1 H) 7.18 (s, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:15].Cl.[F:17][C:18]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:19]=1[C:20](=[N:27][OH:28])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>C(#N)C.[I-].[K+]>[F:17][C:18]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:19]=1[C:20](=[N:27][OH:28])[CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]3=[N:6][C:5]=2[CH3:15])[CH2:23][CH2:22]1
Reactant: ON=C(c1ccc(F)cc1F)C1CCNCC1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 36.0 g (0.16 mole) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in 800 ml of acetonitrile 44.3 g of 4-(2,4-difluoro-benzoyl)-piperidine-oxime-hydrochloride, 33.6 g of sodium hydrogen carbonate and 0.66 g (4 millimoles) of potassium iodide are added. The reaction mixture is refluxed for 5 hours, cooled to room temperature and the solvent is removed in vacuo. The residue is taken up in 700 ml of water and extracted twice with 600 ml of dichloromethane each. The combined organic layers are dried over sodium sulfate and evaporated in vacuo. Thus 63.7 g of the title compound are obtained. Yield 92.5%. M.p.: 180-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:13][N:14]([CH3:26])[CH:15]=[N:16][S:17]([C:20]1[S:21][C:22](Br)=[CH:23][CH:24]=1)(=[O:19])=[O:18]>CN(C=O)C.O>[CH3:13][N:14]([CH3:26])[CH:15]=[N:16][S:17]([C:20]1[S:21][C:22]([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18]
Reactant: COc1ccc(CS)cc1
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc(S(=O)(=O)N=CN(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxy-α-toluenethiol (7.7 g, 0.05 mol) in DMF (10 ml) was added dropwise to a stirred mixture of sodium hydride (2.50 g, 50% oil dispersion, 0.054 mol) in DMF (40 ml). When gas evolution was complete, N,N-dimethyl-N'-(5-bromothiophene-2-sulfonyl)formamidine (14.85 g; 0.05 mol) was added and the resulting mixture was stirred for 1 hour at 25° C. The reaction mixture was diluted with water and the solid that separated was collected, washed with water and dried to give 15.36 g., m.p. 92°-101° C. Recrystallization from 1-chlorobutane gave material with m.p. 110°-111.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([C:18]([OH:20])=O)=[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:54][C:55]1[CH:56]=[CH:57][C:58]([O:67][CH:68]([F:70])[F:69])=[C:59]([C:61]2[NH:65][N:64]=[CH:63][C:62]=2[NH2:66])[CH:60]=1>CN(C=O)C.O>[Cl:54][C:55]1[CH:56]=[CH:57][C:58]([O:67][CH:68]([F:70])[F:69])=[C:59]([C:61]2[C:62]([NH:66][C:18]([C:17]3[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[N:13][C:12]=34)=[O:20])=[CH:63][NH:64][N:65]=2)[CH:60]=1
Reactant: Nc1cn[nH]c1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76939.6 %

Procedure:
To a solution of compound 2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.78 g, 0.01 mol) in DMF (40 mL) was added DIPEA (3.9 g, 0.03 mol), HATU (3.8 g, 0.01 mol) and 5-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-ylamine (2.6 g, 0.01 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the precipitate was collected to give the target compound as a solid (4 g, 77%). LCMS (Method 7) [M+Na]+=541.9, RT=1.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 13.13 (s, 1H), 9.58 (s, 2H), 9.2 (dd, 1H, J=7.2, 1.6 Hz), 8.58 (d, 1H, J=2), 8.27 (s, 1H), 7.60 (m, 2H), 7.23-7.04 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1/[CH:13]=[CH:14]/[C:15]([O:17]CC)=O>Cl.O1CCOCC1>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:15](=[O:17])[CH:14]=[CH:13]2
Reactant: CCOC(=O)/C=C/c1cc(OC(F)(F)F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(OC(F)(F)F)ccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate (2.2 mmol) in 4N HCl in dioxane (25 mL) was added concentrated HCl (2 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. The product was extracted with EtOAc and used without further purification. Retention time (min)=1.804, method [1], MS (ESI) 230.1 (M+H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=O>>[CH2:1]([NH:3][CH2:14][C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCN
Product: CCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of ethylamine with quinoline-2-carbaldehyde
Reaction SMILES: [Br:1][C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=O.C(O)(=O)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:10][C:3]2[CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]=2[Br:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)CCC(Br)=C(C=O)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)CCC(Br)=C(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of 2-bromo-5,5-dimethyl-cyclohex-1-ene carbaldehyde (1 g, 4.61 mmol) in dichloromethane (70 ml) at rt under nitrogen was added glacial acetic acid (0.29 ml, 5.1 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (0.94 g, 5.07 mmol). The reaction was stirred for 1 h before sodium triacetoxyborohydride (2.05 g, 9.68 mmol) was introduced. After 16 h, a solution of 5% NaOH (20 ml) was added and the mixture was extracted with dichloromethane. The organic layer was separated and washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica eluting with 5% EtOAc/heptane provided 4-(2-bromo-5,5-dimethyl-cyclohex-1-enylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 73%).-1H NMR (MeOD) δ 3.44 (4H, br t), 3.14 (2H, br s), 2.55 (2H, br m), 2.40 (4H, br t), 2.08 (2H, br s), 1.51 (2H, t), 1.48 (9H, s), 0.93 (6H, s).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>CO.O1CCCC1>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A 1:2 methanol/tetrahydrofuran (60 mL) solution of (4-benzyloxy-phenyl)-acetic acid methyl ester (1.35 g, 5.27 mmol) was combined with 2M aqueous lithium hydroxide (20 mL) at room temperature and the reaction was stirred overnight. The reaction was acidified to pH 1 with 1N hydrochloric acid and extracted with ethyl acetate (2×50 mL). The organic portions were dried over sodium sulfate and the solvent removed in vacuo to give the title compound as a white crystalline solid (1.25 g, 98%). 1H NMR (300 MHz, CDCl3) δ 3.63 (s, 2H), 5.09 (s, 2H), 6.96-6.99 (d, 2H), 7.22-7.25 (d, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:10]=1[OH:11])[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5]2>C(Cl)Cl>[Br:1][C:2]1[C:10]2[O:11][C:13]([CH3:15])([CH3:14])[CH2:12][C:9]=2[C:8]2[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=C(C)Cc1c(O)c(Br)cc2c1C(CCNC(=O)CC)CC2
Solvent: ClCCl
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)CC(C)(C)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A solution of N-[2-(5-bromo-6-hydroxy-7-(2-methyl-2-propenyl)indan-1-yl)ethyl]propionamide (2.4 g, 6.5 mmol.) in methylene chloride (40 mL) was cooled with ice. To the solution was added dropwise gradually a diethyl ether boron trifluoride complex (4.0 mL, 32.5 mmol.). The reaction mixture was stirred for 3 hours under ice-cooling, which was poured into ice-water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to afford the title compound (yield 2.1 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])(=[O:15])=[O:14])=[O:11])[N:3]=1.Cl>C(O)C.[OH-].[Na+].O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2C(=O)O)n1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of methyl 3-[[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-2-thiophenecarboxylate in 10 ml of ethanol and 1 ml of 50% sodium hydroxide in water was stirred overnight at room temperature. To this was added ice-water and aqueous hydrochloric acid until acidic, and the precipitate was filtered and washed first with acetone and then with methylene chloride. The product, 0.8 g, melted at 127°.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:30]([C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:25][C:23]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:24])[CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc(OCC(=O)N2CCOCC2)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCC(=O)N4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.87 g), 3-[4-morpholinylcarbonylmethoxy]benzaldehyde (2.1 g, 8.43 mmol) and xylenes (20 ml) was heated at 160° C. for about 2 days. The solvent was removed, then methanol was added to the residue and the product was collected by filtration. Additional product was obtained from the filtrates and the product fractions were pooled and recrystallized from CH3CN/CHCl3 to afford 1-cyclopentyl-3-ethyl-6-[3-(4-morpholinylcarbonylmethoxy)-phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212°-213° C.