Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[OH:42][CH2:41][CH2:40][N:34]1[CH2:39][CH2:38][N:37]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:36][CH2:35]1
Reactant: OCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CCO)CC1
Yield: 2 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.2 equivalent of 2-(piperazin-1-yl)ethanol as secondary amine. The product was purified by preparative TLC (eluent: petrolether/DCM/MeOH 2:3:1 containing 2% of a 7 M NH3 solution in MeOH).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 43 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 2-aminoethanol (8.52 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to a vial. It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.1 min) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.040 mmol, 43.2% yield): LCMS=474.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.50-7.73 (7 H, m), 5.13 (1 H, s), 3.58-3.69 (2 H, m), 3.35-3.40 (2 H, m); HPLC peak RT=6.8 min (Method A).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([CH2:10][Cl:11])[N:4]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15]>>[NH2:2][C:3]1[N:4]=[C:5]([CH2:10][Cl:11])[CH:6]=[C:7]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[N:8]=1
Reactant: OCC(F)(F)F
Reactant: Nc1nc(Cl)cc(CCl)n1
Agent: [Na]
Product: Nc1nc(CCl)cc(OCC(F)(F)F)n1
Reaction time: 24 h

Procedure:
0.23 Parts of sodium metal was added to 10 parts of 2,2,2-trifluoroethanol with stirring and ice-bath cooling. The mixture was then stirred for several hours at room temperature until the sodium dissolved. This solution was added dropwise, over 30 minutes, to a stirred suspension of 1.78 parts of 2-amino-4-chloro-6-chloromethyl-pyrimidine in 25 parts of 2,2,2-trifluoro-ethanol and the resulting mixture was stirred at 60° C. for 18 hours. A further 0.1 parts of sodium was dissolved in 10 parts of 2,2,2-trifluoroethanol and added to the reaction mixture. Stirring at 60° C. was continued for a further 24 hours then the reaction mixture was cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The crude product was purified by chromatography on silica (Merck Kieselgel 60 using a 50:50 mixture of ether and 40°-60° petroleum ether as eluent followed by recrystallisation from a mixture of 60°-80° petroleum ether and ethyl acetate to give 2-amino-4-chloromethyl-6-(2,2,2-trifluoroethoxy)pyrimidine m.p. 77°-78° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18](Cl)(=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Yield: 97.3 %

Procedure:
To (S)-(+)-4-phenyl-2-oxazolidinone (9.88 g, 60 mmol) in THF (150 mL) at −78° C., was added n-butyl lithium (37.7 mL, 1.6M in hexanes, 60 mmol) over a period of 30 minutes. THF (50 mL) was added to the resultant thick suspension and the reaction mixture allowed to warm up to facilitate stirring. Trans-cinnamoylchloride (11.5 g, 69 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated ammonium chloride solution (50 mL) and stirred for 0.5h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with water (300 mL), 5% sodium bicarbonate (200 mL) and brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give a pale yellow solid. The compound was crystallized from ethylacetate and washed with hexanes to give 17.12 g (97%) of (S)-4-phenyl-3-[(E)-(3-phenyl-acryloyl)]-oxazolidin-2-one.
Reaction SMILES: [C:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Ni].C(O)C>[CH:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(CO)C1=CCCCCCCCCCC1
Agent: [Ni]
Solvent: CCO
Product: CC(CO)C1CCCCCCCCCCC1

Procedure:
45 g of the mixture of isomers of 2-cyclododecenylpropan-l-ol from Example 1 were heated for 7 hours at 200° with 2 g of Raney nickel and 10 ml of ethanol in a shaken autoclave with 200 bar of hydrogen After removal of catalyst and solvent, the reaction mixture was distilled. At 105-110° C. and 0.7 mbar, 35 g of 2-cyclododecylpropan-l-ol were obtained.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:14])[NH:12][CH2:11][CH:10]([CH3:13])[O:9]1.C(N(CC)CC)C.[Br:22][CH:23]([CH2:27][Br:28])[C:24](Cl)=[O:25]>O>[CH3:7][C:8]1([CH3:14])[N:12]([C:24](=[O:25])[CH:23]([Br:22])[CH2:27][Br:28])[CH2:11][CH:10]([CH3:13])[O:9]1
Reactant: O=C(Cl)C(Br)CBr
Reactant: CC1CNC(C)(C)O1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)C(Br)CBr)C(C)(C)O1

Procedure:
Fourteen (14 ml.) milliliters of a benzene solution containing 3.5 g. of 2,2,5-trimethyl oxazolidine was added to 25 ml. of benzene and 3.5 g. of triethylamine. Seven and one-half (7.5 g.) grams of 2,3-dibromopropionyl chloride was added dropwise with stirring and cooling in an ice bath. When reaction was complete, the mixture was poured into water and the benzene layer separated, dried over anhydrous magnesium sulfate and the solvent stripped under vacuum. The yield was 5.7 g. of an oil, nD30 =1.5060.
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 93.7 %

Procedure:
A solution of 75 mg of 8e, 35 mg of pyridine-3-boronic acid, 60 mg of K2CO3 in 2 ml of degassed 90% aq. dimethoxyethane was heated at 90° C. for 16 h The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was once washed with 1M K2CO3, once with water, dried and concentrated. The crude material was chromatographed over silica gel using a gradient of toluene/acetone. The isolated material was treated with diethyl ether and provided 70 mg of 8f; Mp 200-201° C.; Rf 0.15 (toluene/acetone 7/3). MS-ESI: [M+1] 529.3.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][N:3](C(OC(C)(C)C)=O)[CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H]2CCNC[C@H]21
Reaction time: 2 h

Procedure:
To (1S,6R)-8-benzyl 3-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3,8-dicarboxylate (300 mg, 0.9 mmol) in CH2Cl2 was added TFA (1:1). After 2 h, the reaction was concentrated and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.Br[CH2:37][CH:38]1[CH2:40][C:39]1([F:42])[F:41]>>[F:41][C:39]1([F:42])[CH2:40][CH:38]1[CH2:37][N:34]1[CH:35]=[C:31]([C:9]2[C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=3[NH:11][N:10]=2)[CH:32]=[N:33]1
Reactant: FC1(F)CC1CBr
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1nccc2[nH]nc(-c3cnn(CC4CC4(F)F)c3)c12
Yield: 55 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 1-bromomethyl-2,2-difluorocyclopropane to give the title compound (29.4 mg, 55% over two steps). LC-MS (Method G): m/z=306.0 [M+H]+, 3.49 min. 1H-NMR (400 MHz, DMSO): δ 13.28 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.86 (d, J=5.8, 1H), 7.09 (d, J=5.9, 1H), 4.43-4.26 (m, 2H), 4.06 (s, 3H), 2.37-2.23 (m, 1H), 1.79-1.67 (m, 1H), 1.60-1.49 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.C(O[C:24]([CH3:33])([CH3:32])[CH:25]([OH:31])[C:26]([O:28]CC)=O)C.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:26](=[O:28])[C:25](=[C:24]([CH3:32])[CH3:33])[O:31][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(O)C(C)(C)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 205 °C
Yield: 46.1 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (10.0 g, 33.1 mmol), ethyl 3-ethoxy-2-hydroxy-3-methylbutanoate (9.44 g, 49.7 mmol), ferric chloride hexahydrate (90.2 mg, 0.03 mmol) and tributylamine (309.5 mg, 1.7 mmol) were introduced into a two-necked eggplant type flask (200 cc) equipped with a Dean Stark and a Dimroth condenser and heated at 205° C. (oil bath) for 10 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, toluene (60 mL) was added, and the reaction solution was washed with water (100 mL). The organic layer was concentrated under reduced pressure, and ethanol (35 mL) acidified with hydrochloric acid was added to the resulting oily substance to form a homogeneous solution. The solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with ethanol acidified with hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione as white crystals (5.40 g, yield 46.1%).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH3:35][NH:36][CH3:37].C1COCC1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH3:35][N:36]([CH3:37])[CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10]
Reactant: CNC
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 13 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (0.09 mmol) and 2M dimethyl amine in THF (0.225 mL, 0.45 mmol) were allowed to react in the presence of K2CO3 (44 mg, 0.45 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (5.5 mg, 13%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[O:14])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[BH4-].[Na+].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([O:14][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCn2c1cc1cc(Br)ccc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCn2c1cc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (1.1 g, 4.4 mmol) in MeOH (20 mL), cooled to 0° C., was added NaBH4 (0.33 g, 8.8 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with H2O and then extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford a white solid which was used without further purification. The crude solid was dissolved in CH2Cl2 (20 mL) and TBSCl (0.7 g, 4.4 mmol) and imidazole (0.33 g, 4.4 mmol) were added. After stirring at room temperature for 1 h, the reaction mixture was poured into H2O and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid (1.26 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH3:11].[C:13]([Cu])#[N:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][C:5]=1[CH3:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(Br)cc1C
Product: COC(=O)c1ccc(C#N)cc1C
Temperature: 180 °C
Yield: 63 %

Procedure:
A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180° C. for 5 hours before it was poured into ice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63%) as a solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[O:15]C)[N:5]=[C:4]([N:17]2[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[N:18]2)[CH:3]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[OH:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([N:17]2[C:21]([C:22]([F:24])([F:23])[F:25])=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[N:18]2)[CH:3]=[C:2]([I:1])[CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2cc(I)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(I)cc(-c3cc(C)ccc3O)n2)c1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of the title compound from Example 19 Step F (1 g, 1.88 mmol) and iodotrimethylsilane (3.6 mL) in 15 mL chloroform was heated at 80° C. for 7 h. A second portion of iodotrimethylsilane (2 mL) was added and heating was continued at 90° C. overnight. The volatiles were removed in vacuo. Toluene was added, and the volatiles were removed in vacuo. Finally, dry MeOH was added, and the volatiles were removed in vacuo. Silica gel flash chromatography using hexanes:EtOAc (20:1 to pure EtOAc) gave the title compound: LCMS m/z 518.6 [M+H]+; 1H NMR (400 MHz, acetone-d6) δ 8.87 (d, J=1.1 Hz, 1H), 8.24 (s, 1H), 8.12 (d, J=1.1 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.30 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[NH2-].[Na+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)([CH2:20][CH:19]([O:22][CH2:23][CH3:24])[O:18][CH2:16][CH3:17])[C:10]#[N:11])[CH3:17]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(CBr)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(CC(C#N)(CC(OCC)OCC)c1cccc(C(F)(F)F)c1)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A mixture of 30 g of 3-(trifluoromethyl)-phenylacetonitrile and 14.4 g of sodium amide in 400 ml of toluene is left with stirring at AT for 5 minutes, 66 ml of bromoacetaldehyde diethyl acetal are added and then the mixture is heated at 60° C. for 3 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/AcOEt (100/5; v/v) mixture. This gives 26 g of the expected product.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].C[S+](C)(C)=O.O=C1C[CH:19]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]([CH2:17][CH2:18]2)C1>O1CCCC1.C1(C)C=CC=CC=1.O>[O:4]1[CH2:1][C:2]21[CH2:5][CH:19]1[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]([CH2:17][CH2:18]1)[CH2:3]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1C2CCC1CC1(CO1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C@:10]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:16][C@H:15]2[C@:11]1([CH3:17])[CH:12]=[CH:13][CH2:14]2)=O)(C)(C)C.C(N(CC)CC)C>Cl.C(OCC)(=O)C>[NH2:8][CH2:9][C@:10]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][C@H:15]2[C@:11]1([CH3:17])[CH:12]=[CH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@@H]2CC=C[C@@]21C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@]12C=CC[C@H]1C[C@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
Tert-butyl(±)-[(1S,5R,6S)-6-(tert-butoxycarbonylaminomethyl)-5-methylbicyclo[3.2.0]hept-3-en-6-yl]acetate (120 mg, 0.34 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (2 mL), and the solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (2 mL). To the solution, triethylamine (0.048 mL, 0.34 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The resulting powder was collected by filtration and dried to obtain the compound of interest as a white solid (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:4]=1[CH:5]=[O:6]>S(=O)(=O)(O)O>[OH:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COc1ccc(OC)c(C=O)c1
Agent: O=S(=O)(O)O
Product: COc1ccc(O)cc1C=O
Temperature: 50 °C
Reaction time: 46 h
Yield: 31.8 %

Procedure:
Concentrated sulfuric acid (110 ml) was added to 2,5-dimethoxybenzaldehyde (20.17 g, 0.121 mol) with cooling in an ice water bath. The resulting red suspension was stirred at 50° C. for 46 h. The reaction contents were poured over ice and extracted with diethyl ether. The ether layer was extracted with 1N sodium hydroxide (200 ml). The basic extract was acidified by addition of 3N hydrochloric acid and extracted with diethyl ether (2×). The ether extracts were combined and dried over MgSO4. After filtration, the solvent was removed in vacuo to give 5-hydroxy-2-methoxybenzaldehyde (5.85 g, 32%) as an orange solid.
Reaction SMILES: O[CH:2]1[CH2:7]SC(O)C[S:3]1.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].CO>O.C(N(CC)CC)C>[NH2:10][C:9]1[S:3][CH:2]=[CH:7][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(N)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: NC(=O)c1ccsc1N
Temperature: 37.5 °C
Yield: 141.7 %

Procedure:
2,5-Dihydroxy-1,4-dithiane (76 g) and cyanoacetamide (84 g) were added to a mixture of methanol (180 mL), water (10 mL) and triethylamine (10 g). The resulting mixture was heated at 35-40° C. for about 30 minutes while stirring, and then heated to 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to room temperature and poured into a mixture of ice (100 g)/water (360 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give 100.6 g of the title compound as a pale gray powder ((M+H)+=143, M.P.=159.0-159.6° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of 4-hydroxy-2-fluoro-benzonitrile (1.0 g, 7.3 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (2.09, 15 mmol) and benzyl bromide (0.87 mL, 7.3 mmol), and the solution was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution, which was then extracted, washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (1.5 g, 6.7 mmol, 92%) was obtained as a white solid.