Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].F[C:33]1(C2N(C)N=CC=2[N+]([O-])=O)[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]([OH:48])[CH2:35][CH2:34]1>>[C:19]([O:18][C:17]([NH:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:33]12[O:48][CH:36]([CH2:35][CH2:34]1)[CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][CH2:39]2)=[O:10])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(NC(=O)OC(C)(C)C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2

Procedure:
Following the procedure for Intermediate 1 starting from tert-butyl N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)carbamate gave tert-butyl N-(5-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]-8-oxabicyclo[3.2.1]octan-2-yl]carbamate as a pale pink solid (172 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 10.45 (s, 1H), 8.29 (s, 1H), 7.35-7.27 (m, 1H), 7.18-7.08 (m, 2H), 4.76 (br s, 1H), 4.29 (br s, 1H), 4.04 (br s, 1H), 3.85 (s, 3H), 2.38-2.33 (m, 1H), 2.19-1.86 (m, 7H), 1.55 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:25])(=[O:24])[CH2:2]1.[ClH:26].C(O)C>>[ClH:26].[CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])(=[O:25])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCS3(=O)=O
Agent: Cl
Solvent: CCO
Product: O=S1(=O)CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
The tert-butyl(6bR,10aS)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (130 mg) was mixed with cold ethanol hydrochloride (4M) (5 mL), and the solution was stirred for 10 min at 0° C. The solvent was removed under reduced pressure and the residue was dissolved in hot acetonitrile with a small amount of methanol. Upon cooling to room temperature, the title compound (78 mg, 73%) was obtained as white crystalline material. 1H NMR (CD3OD, 500 MHz) δ2.13-2.22 (m, 1H), 2.23-2.32 (m, 1H), 2.88 (t, 1H, J=11.3 Hz), 3.19-3.35 (m, 4H), 3.45-3.66 (m, 4H), 3.78-3.88 (m, 2H), 6.92 (t, 1H, J=7.8 Hz), 7.39 (d, 1H, J=7.8 Hz), 7.49 (d, 1H, J=8.5 Hz) ppm. CIMS (Methane) m/z=265 [C13H16N2O2S+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:20][CH3:21])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.Br[CH:23]([CH3:27])[C:24](=O)[CH3:25].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:27][C:23]1[N:1]=[C:2]2[C:10]([O:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]2[C:24]=1[CH3:25]
Reactant: CC(=O)C(C)Br
Reactant: CCc1cccc(C)c1COc1cc(C(N)=O)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cccc(C)c1COc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 35.1 %

Procedure:
6-amino-5-(2-ethyl-6-methylbenzyloxy)nicotinamide (0.14 g, 0.49 mmol), 3-bromo-2-butanone (0.075 g, 0.49 mmol) and sodium bicarbonate (0.1 g, 1.2 mmol) was added to acetonitrile (3 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from acetonitrile gave 0.058 g (35%) of the title compound.
Reaction SMILES: [Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[CH2:14]([N:18]([CH2:26][C:27]([N:29]1[CH2:37][C:36]2[CH:35]=[N:34][C:33]([NH:38][CH:39]3[CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40]3)=[N:32][C:31]=2[CH2:30]1)=[O:28])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][C:16]#[CH:17].C1(C)C=CC=CC=1.[N:55]([Si](C)(C)C)=[N+:56]=[N-:57]>CN(C)C=O.O.C(OCC)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:47][CH:39]1[NH:38][C:33]1[N:34]=[CH:35][C:36]2[CH2:37][N:29]([C:27](=[O:28])[CH2:26][N:18]([CH2:14][CH2:15][C:16]3[NH:57][N:56]=[N:55][CH:17]=3)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:30][C:31]=2[N:32]=1
Reactant: C#CCCN(CC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1cnn[nH]1)CC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
Add copper(II)sulfate pentahydrate (0.022 g; 0.2 equiv; 0.088 mmoles) and L-ascorbic acid sodium salt (0.175 g; 2.0 equiv; 0.88 mmoles) to a deoxygenated solution of tert-butyl N-but-3-ynyl-N-[2-[2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-oxo-ethyl]carbamate (0.204 g; 1.0 equiv; 0.44 mmoles) in dimethylformamide (6 mL) and water (3 mL) (including toluene (0.05 mL) as an internal standard). Heat to 90° C. and then add azidotrimethylsilane (0.47 mL; 8 equiv; 3.54 mmoles) dropwise with continued stirring at 90° C. Stir for 3 hours, then dilute the reaction mixture with water (100 mL) and ethyl acetate (50 mL). Extract with ethyl acetate (3×50 mL), and wash the combined organic extracts with brine. Dry the organics over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in ethyl acetate) to give tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-5-yl)ethyl]carbamate (0.157 g; 70%) as a yellowish foam: MS (m/z): 505(M+1).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][Br:13])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1ccccc1C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)Oc1ccccc1CBr
Yield: 65 %

Procedure:
To a solution of 0.1 mol of o-cresol propionate in 150 cc of CCl4 are added, with ultraviolet irradiation, in small fractions, and in proportion with the decoloration, 0.22 mol of bromine in 30 cc of CCl4, the solvent is removed and the residue is distilled under reduced pressure. The 1-propionoxy-2-bromomethylbenzene is obtained:
Reaction SMILES: CSC.B.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([I:15])=[C:10]([CH:14]=1)[C:11](O)=[O:12].CO>C1COCC1.COB(OC)OC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([I:15])=[C:10]([CH:14]=1)[CH2:11][OH:12]
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: B
Agent: COB(OC)OC
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cc(Cl)ccc1I
Temperature: 22.5 °C
Yield: 74.8 %

Procedure:
Borane methylsulfide (7.3 mL, 73 mmol) was added to a stirred solution of 5-chloro-2-iodobenzoic acid (17.17 g, 60.79 mmol) in THF (40 mL) and trimethylborate (20 mL), maintaining the internal temperature at 20-25° C. After 16 h methanol (8.87 mL, 0.219 mol) was added cautiously and the solution was evaporated in vacuo, azeotroping with methanol (3×50 mL). The resulting solid was recrystallized (hexanes/ethyl acetate, 5:1, 120 mL) to give 5-chloro-2-iodobenzyl alcohol (12.2 g): 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 4.64 (s, 2H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 7.49 (d, J=2.4, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of ethyl {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (16.1 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (58 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (58 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (15 g, yield 98%) as a brown amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[C@@H:13]([CH3:14])[CH2:12][N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]2=S)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[C@@H:13]([CH3:14])[CH2:12][N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2C(=S)N([C@@H](C)c3ccccc3)C[C@@H]2C)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@@H]2C)CC1
Yield: 34.1 %

Procedure:
(3S,4R)-3-(1-Ethoxycarbonylcyclopropyl)-4-methyl-1-[(S)-1-phenylethyl]-2-pyrrolidinethion (1.80 g, 5.43 mmol) was dissolved in ethanol (100 ml), and the solution was mixed with Raney nickel (10 ml) and heated under reflux for 1.5 hours. After completing the reaction, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in chloroform (100 ml), washed with 10% ammonia water (100 ml), water (100 ml) and saturated brine (100 ml) in that order and then dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was purified by silica gel column chromatography (silica gel, 160 ml; ethyl acetate:hexane=1:1), to thereby obtain 558 mg (34%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C>CN(C)C=O>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([OH:27])=[C:19]([OH:18])[CH:20]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccc(O)c(O)c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 195.7 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (846 mg, 3 mmol) in N,N-dimethylformamide (7.5 mL) is added 3,4-dihydroxy benzylamine hydrobromide (660 mg, 3 mmol) and triethylamine (630 μL, 4.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.38 g of 6-Bromo-4-[(3,4-dihydroxy-benzylamino)-methylene]-4H-isoquinoline-1,3-dione hydrobromide.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(=O)([O-])[O-].[K+].[K+].C(O)CCC>CO.O.C(OCC)C>[ClH:2].[F:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[CH:15][CH:16]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Solvent: CO
Product: Fc1cccc(N2CCNCC2)c1
Yield: 35.9 %

Procedure:
This compound was prepared according to the procedure of Preparation 1. A mixture of 8.0 g (0.045 mol) of bis(2-chloroethyl)amine hydrochloride, 5.0 g (0.045 mol) of m-fluoroaniline and 12.5 g (0.09 mol) of solid potassium carbonate in a total volume of 50 mL of n-butanol gave 3.5 g (35%) of white solid, mp 205°-207° C. (methanol-water-ethyl ether).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11](=[O:19])[CH2:12][C@@H:13]([NH2:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC(=O)C[C@@H](C(O)=O)NC(OC(C)(C)C)=O)C1C=CC=CC=1>>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11](=[O:19])[CH2:12][C@H:13]([NH2:18])[CH2:14][N:15]([CH3:16])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CN(C)C[C@@H](N)CC(=O)OCc1ccccc1

Procedure:
(S)-3-Amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride was prepared in analogy with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (intermediate 1), starting from Boc-L-aspartic acid 4-benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[S:10][C:9]=2[CH:16]=1)=[O:4].CCN=C=NCCCN(C)C.[CH:28]1[CH:29]=[CH:30][C:31]2[N:36](O)N=[N:34][C:32]=2[CH:33]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:34][C:32]1[CH:33]=[CH:28][CH:29]=[CH:30][C:31]=1[NH:36][C:13]([C:11]1[S:10][C:9]2[CH:16]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH:12]=1)=[O:15]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1ccc2cc(C(=O)O)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C(=O)Nc3ccccc3N)sc2c1
Reaction time: 0.33 h

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid 6-methyl ester (129 mg, 0.543 mmol) in DMF (4 mL) was added EDCI (125 mg, 0.652 mmol), HOBt (88 mg, 0.652 mmol). The reaction mixture was stirred for 20 min and phenylene diamine (147 mg, 1.36 mmol) was added. After 18 h, the solvent was removed and EtOAc and H2O were added. The resultant solid was filtered yielding the desired product. 1H NMR (CDCl3, 600 MHz) δ 8.53 (s, 1H), 8.01 (s, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.23 (d, J=6.8 Hz, 1H), 7.05 (t, J=6.8 Hz, 1H), 6.81 (d, J=6.8 Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 3.90 (s, 3H). MS: cal'd 327 (MH+), exp 327 (MH+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:34])([F:33])[S:20](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:22])=[O:21].CCOC(C)=O>CN(C=O)C>[F:18][C:19]([F:34])([F:33])[S:20]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of vanillin (20.0 g, 131 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (36 g, 263 mmol) and 4-nitrophenyl trifluoromethanesulfonate (54.0 g, 197 mmol) and the reaction mixture was stirred for 8 h. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-formyl-2-methoxyphenyl trifluoromethanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CNc1c(N)cnc2ccccc12
Product: Cn1c(-c2ccccc2)nc2cnc3ccccc3c21

Procedure:
Following the general method of Example 195, Step B, 3-amino-4-(methylamino)quinoline was reacted with benzaldehyde to provide 1-methyl-2-phenyl-1H-imidazo[4,5-c]quinoline, melting point 168-170° C. Analysis: Calculated for C17H13N3 : % C, 78.7; % H, 5.1; % N, 16.2. Found: % C, 78.9; % H, 5.0; % N, 16.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[CH2:21][CH2:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C1(C2N=C(C3[C@H](CC4C=CC=C(O)C=4)CCC=3)OC=2C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:74]([O:76][CH3:77])=[O:75].[I-].[K+]>C(Cl)Cl.C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=4)[O:30][CH2:31][C:74]([O:76][CH3:77])=[O:75])[CH2:21][CH2:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: Oc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 3.5 h
Yield: 78.9 %

Procedure:
To a solution of (+)-(5S)-1-(4,5-diphenyloxazol-2-yl)-5-(3-methoxybenzyl)cyclopentene (2.33 g) in methylene chloride (10 ml), was added boron tribromide in methylene chloride (1M, 9 ml) at 0C. After 3.5 hours stirring at the same temperature, the reaction mixture was washed with water and saturated aqueous sodium hydrogencarbonate. Drying (sodium sulfate) and removal of solvent afforded a yellow syrup containing (+)-(5S)-1-(4,5-diphenyloxazol-2-yl)-5-(3-hydroxybenzyl)cyclopentene. An acetonitrile solution (20 ml) of the yellow syrup, potassium carbonate (1.30 g), methyl bromoacetate (0.98 g) and potassium iodide (a catalytic amount) was stirred under reflux for 3.5 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with 1N hydrochloric acid, water and brine. Drying (sodium sulfate) and removal of solvent at reduced pressure followed by flash chromatography over 50 g of silica afforded (+)-methyl [3-[[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (2.10 g, 98.2% ee) as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]=O)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:15])=[C:5]1[CH3:16])[CH:2]=[CH2:3].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]=[N:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:15])=[C:5]1[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C)c(C)c2ccnc(C=O)c21
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: C=CCn1c(C)c(C)c2ccnc(C=Nc3ccc(F)cc3)c21
Temperature: 25 °C
Yield: 132 %

Procedure:
A solution of 1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-carbaldehyde (1.214 g, 5.67 mmol) prepared in Preparation 3 and 4-fluoroaniline (0.54 ml, 5.67 mmol) in ethanol (10 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give 2.3 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COc1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.6 mmol of 2-methoxybenzenethiol, and 1.6 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 170°-172° C. dec.). 1H NMR (DMSO-d6) δ3.76 (bs, 5H), 5.44 (dd, 1H), 6.26 (t, 1H), 6.85 (m, 1H), 6.91 (t, 1H), 7.34-7.50 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)=[CH:15][CH:14]=1)[CH3:12]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cccc3cc[nH]c23)cc1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 4-ethylphenylboronic acid: ESMS m/e: 222.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25]>>[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:34])=[O:25]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN(C)C)c1C
Yield: 103.5 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (30 mg, 0.13 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (30 mg) to give 0.06 g (100%) of the title compound as a yellow-orange gum.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[Cl:59])[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C>O1CCCC1>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[N:50]1[C:46]2[N:47]=[CH:48][N:49]=[C:44]([O:43][C@@H:32]([CH2:31][N:29]3[CH2:30][CH:27]([OH:26])[CH2:28]3)[C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:34])[C:45]=2[CH:52]=[N:51]1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C(=O)Nc2ccc(F)cn2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cn1)[C@H](CN1CC(O)C1)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (7.14 mL, 7.14 mmol) was added in one portion to a stirred solution of (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate AX1) (4.27 g, 7.14 mmol) in tetrahydrofuran (100 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (30 mL), concentrated to approximately 50 mL and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford the product (2.54 g, 73.6%). 1H NMR (400 MHz, CDCl3) δ 2.35 (1H, s), 3.15-3.21 (3H, m), 3.27-3.31 (1H, m), 3.84-3.91 (2H, m), 4.50-4.57 (1H, m), 5.90-5.93 (1H, m), 7.41-7.54 (4H, m), 7.61-7.63 (1H, m), 8.14 (1H, d), 8.23-8.26 (1H, m), 8.37 (1H, s), 8.59 (1H, s), 9.74 (1H, s); m/z (ES+) (M+H)+=484.17; HPLC tR=1.65 min.