Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@@H:39]([NH2:41])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@@H:39]([NH:41][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: C[C@H](N)COCc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N[C@@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—((S)-2-benzyloxy-1-methyl-ethyl)-amine as described for example 1.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([C@@H:24]([NH2:27])[CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][C:5]2([CH2:4][CH2:3][C:2]([CH2:15][CH2:16][NH:27][C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH3:26])([OH:1])[CH2:14][CH2:13]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: CC[C@H](N)c1ccccc1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1
Yield: 50 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-phenyl-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 50% of theory; LC (method 8): tR=1.16 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5](/[CH:6]=[CH:7]/[CH2:8][C:9]3[S:10][CH:11]=[CH:12][C:13]=3[S:14](N3C=CC=C3)(=[O:16])=[O:15])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].S(Cl)([Cl:31])(=O)=O>C(O)(C)C>[Cl:31][S:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[CH2:8]/[CH:7]=[CH:6]/[C:5]1[CH:22]=[CH:23][C:24]2[O:25][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1ccsc1C/C=C/c1ccc2c(c1)OCO2)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2

Procedure:
3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene was prepared in the same manner as described in Example 15E from N-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding potassium sulfonate (100%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 31% overall yield.
Reaction SMILES: [C:1]1([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][O:19][C:15]=2[CH:14]=1>C(O)(C)C>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH3:11])[C:8]([OH:10])=[O:9])[CH2:24][CH2:25]3)=[N:18][O:19][C:15]=2[CH:14]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: C=C(C(=O)O)c1ccccc1
Solvent: CC(C)O
Product: CC(C(=O)O)(c1ccccc1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
2-phenylacrylic acid (1.8 g, 12 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.4 g, 11 mmol) in 100 ml dry isopropanol was refluxed for 3 h. The mixture was concentrated in vacuo and taken up in water whereupon NaHCO3 was added until pH 8-9. The formed crystals were isolated, washed with ethyl acetate and dried to give 2.0 g 3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino-2-phenylpropanoic acid. M.p. 194°-200° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCCO
Product: CN(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(methylamino)ethanol (1.2 equiv) to give 154 (10.4 mg, M+1 371.1)
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1.O=[CH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:22]([O:23][CH3:24])[C:20]=1[OH:21]>CC(O)=O>[OH:21][C:20]1[C:22]([O:23][CH3:24])=[CH:25][CH:26]=[CH:27][C:19]=1[CH:18]=[CH:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1nc(C)n(-c2ccccc2)c(=O)c1C
Reactant: COc1cccc(C=O)c1O
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc(C)c(C)c(=O)n2-c2ccccc2)c1O
Temperature: 150 °C
Yield: 58 %

Procedure:
A mixture of 2,5,6-trimethyl-3-phenylpyrimidin-4(3H)-one (4) (403 mg, 1.88 mmol) and O-vanillin (286 mg, 1.88 mmol) in AcOH (4 mL) was heated at 150° C. for 2 h in a microwave oven. Acetic acid was evaporated under reduced pressure, and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 5 as a yellow solid (380 mg, 58%); MS m/z: 349 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C:14]1([CH3:20])[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>CCC(C)=O.ClCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][NH:15][C:14]([CH3:20])([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: CC1(C)CNCCN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC1(C)CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C

Procedure:
1,4-dichlorophthalazine (1 g, 5 mmol) and 2,2-dimethyl piperazine (1.75 g, 15 mmol, 3 eq) were slurried in 5 mL of MEK for 3 h at 45° C. After cooling to rt, the reaction was diluted with 150 mL of dichloromethane and washed with 1×20 mL of sat. NaHCO3 and 1×20 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (100:5→8:1 dichloromethane:methanol:triethylamine) afforded 1-chloro-4-(3,3-dimethylpiperazin-1-yl)phthalazine. MS (M+H)+=277.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(#N)C>[OH:26][CH2:25][CH2:27][NH:28][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: NCCO
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Solvent: CC#N
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCO)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) in acetonitrile (3.4 mL) is treated with ethanolamine (103 μL, 1.71 mmol) and stirred at ambient temperature for 18 h. Solvent is removed under reduced pressure, and the crude product is triturated and filtered from hot ethyl acetate to give the title compound, mp 217–219° C.; MS (ESI+) for C14H15N3O5S m/z 338 (M+H)+; [α]25D−43 (c 0.99, DMSO).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[OH:6][C:7]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[OH:6][C:7]1[CH:20]=[C:19]([OH:21])[C:18]([C:2]([CH3:3])([CH3:1])[CH2:4][CH3:5])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CC=C(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Reaction time: 6 h
Yield: 89.8 %

Procedure:
42 g (0.6 mol) of 2-methyl-2-butene are added dropwise to a solution of 45 g (0.21 mol) of 2,4-dihydroxybenzophenone and 6.1 g (63 mmol) of methanesulfonic acid in 90 ml of toluene and the mixture is held at 75° C. with stirring for 6 h. The reaction mixture is cooled, then treated with 100 ml of NaHCO3 and extracted with ethyl acetate. The resulting solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is recrystallized from CH2Cl2 /hexane. 53.6 g (89.9%) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone are obtained as beige crystals having a melting point of 100°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[ClH:23].CO>CO>[ClH:23].[ClH:23].[CH3:1][C:2]1[CH:22]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)cccn2n1
Agent: Cl
Solvent: CO
Product: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {[(1R,2R)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methyl}carbamate (1.71 g, 5.67 mmol) in methanol (6 mL) was added hydrochloric acid-methanol reagent (manufactured by TCI, 18 mL) solution and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure to give the title compound (1.61 g, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>S(Cl)(Cl)=O>[F:20][C:15]1[C:14]2[S:13][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:11])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(CSc1ccccc1F)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C1c2cccc(F)c2SCC1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
The acid from Step C (4.5 g, 15 mmole) was dissolved in 30 ml of thionyl chloride and refluxed for four hours. After cooling the thionyl chloride was concentrated and the residue taken up in carbon tetrachloride. The carbon tetrachloride was concentrated and the residue was taken up in 30 ml of dichloroethane. To the dichloroethane solution being cooled in an ice bath, was added aluminum trichloride (total of 2.1 g, 16 mmole) in three portions every 15 min. After stirring the black solution for an additional 30 min at 0° C., a 5% aqueous HCl solution was added. The aqueous phase was separated and extracted twice with methylene chloride. The organic phases were combined, dried (MgSO4), and concentrated to give the crude product as a yellow oil (3.4 g, 82% yield). 1H NMR (CDCl3) δ: 7.97 (1H, dd, J=3, 9 Hz), 7.19 (6H, m), 4.12 (1H, dd, J=4, 12 Hz), 3.58 (1H, m), 3.32 (1H, ddm J=4, 12 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][Si:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][CH2:34]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][Si:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][CH2:34][O:24][C:23]([C:18]1([C:20]([O:22][CH2:34][CH2:33][CH2:32][Si:31]([CH3:37])([CH3:36])[CH3:30])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: C[Si](C)(C)CCCO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC[Si](C)(C)C)(C(=O)OCCC[Si](C)(C)C)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-trimethylsilylpropanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.01 (s, 18H), 0.46 (m, 4H), 1.33 (d, J=6.3 Hz, 3H), 1.70 (m, 4H), 2.80 (m, 1H), 3.18 (m, 2H), 3.46(m 2H), 4.24(t, J=7.0 Hz, 4H), 5.47 (bd, J=9.7 Hz, I H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (ES) m/z 650 (MH+); [α]D25 -22° (c, 1.0, CHCl3). Anal. Calcd. for C32H48ClNO7Si2 ·HCl: C, 55.96; H, 7.04; N, 2.04 Cl, 10.32; Si, 8.18. Found: C, 55.82; H, 7.21; N, 1.87; Cl, 10.22; Si, 7.76.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=3[C:12]3[CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:11]2=3)[CH2:27][CH2:26]4)=[CH:4][CH:3]=1>CO.[Pt]=O>[CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:14][C:13]=3[C:12]3[CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:11]2=3)[CH2:29][CH2:30]4)[CH2:4][CH2:3]1
Reactant: Cc1ccc(/C=C\n2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)cn1
Agent: O=[Pt]
Solvent: CO
Product: CC1CCC(CCn2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)CN1

Procedure:
A solution of 6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (65 mg, 0.157 mmol; Example 177) in methanol was treated with platinum oxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours to afford the title compound as the minor product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.02-1.14 (m, 3H), 1.46-1.86 (m, 4H), 1.98-2.21 (m, 4H), 2.64-2.79 (m, 2H), 2.96-3.12 (m, 3H), 3.17-3.28 (m, 3H), 4.15-4.25 (m, 4H), 6.99 (ddd, J=9, 2, 1 Hz, 1H), 7.19 (s, 1H), 7.33-7.40 (m, 1H); MS (DCI/NH3) m/z 422 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+].C(=O)(O)[O-].[Na+].[F:52][CH2:53][C:54]1[N:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C(Cl)Cl>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:18])[F:19])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:60]([C:57]3[CH:56]=[N:55][C:54]([CH2:53][F:52])=[CH:59][N:58]=3)=[O:61])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-fluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. Details of an actual preparation are as follows:-tert-Butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (500 mg) was dissolved in DCM (10 mL) and 5-fluoromethyl-pyrazine-2-carboxylic acid (223 mg), N,N-diisopropylethylamine (521 mg) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophophate (750 mg) were added. The reaction mixture was stirred at RT for 1 h, and sodium bicarbonate (sat., aq., 50 mL) was added. The mixture was extracted with EtOAc (2×75 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 30% EtOAc/hexanes gradient) to afford the amide (613 mg) as a white solid. The amide was dissolved in DCM (2 mL) and TFA (1 mL) was added. After stirring at RT for 2 h, the reaction mixture was evaporated and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (3×25 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound as a white solid
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:9]N(C)C)[C:6](=O)[CH3:7])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[N:22][N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[C:6]=1[CH3:7])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: NNc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccncc2)c1C
Yield: 76 %

Procedure:
Dissolve 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (0.550 g, 2.96 mmol), pyridin-4-yl-hydrazine hydrochloride (0.454 g, 3.12 mmol) and triethylamine (0.435 mL, 3.12 mmol) in ethanol (12 mL) and reflux for 2 hr. Evaporate the mixture then dilute with saturated sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate) the solution, filter and concentrate. Purify using silica gel chromatography, eluting with 50:50 ethyl acetate:hexane to give 5-methyl-1-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a tan solid (0.520 g, 76%). MS (ES): m/z=232 [M+H]+.
Reaction SMILES: [CH:1]([O:4][P:5]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12](O)=[O:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH3:25].C(Cl)(Cl)Cl>C(Cl)(=O)C(Cl)=O>[CH:1]([O:4][P:5]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]([NH2:25])=[O:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCCCCCCCCCC(C(=O)O)P(=O)(OC(C)C)OC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(C(N)=O)P(=O)(OC(C)C)OC(C)C
Temperature: 35 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
553 g (1.57 moles) of alpha-(diisopropyl phosphono)lauric acid was placed in a 3 liter flask. 791 g (6.28 moles) of distilled oxalyl chloride was carefully added while maintaining the temperature at or slightly below 35° C. (Temperatures much above 35° C. result in oxalyl chloride attack on the phosphonate esters, and too rapid addition results in foaming.) The temperature was maintained at 35° C. for 4 hours, after which I.R. analysis revealed all the acid had converted to the acid chloride. Excess oxalyl chloride was distilled off while maintaining the temperature at 35° C. or below. The product was then diluted with an equal volume of freshly distilled THF and added to a 3 liter flask containing about 1 liter of condensed ammonia. Following a vigorous reaction, the mixture was allowed to stand and warm overnight. Excess ammonia was driven off using a steam bath, and 1 liter of chloroform was added and heated to reflux. The hot chloroform solution was filtered to remove insoluble ammonium chloride and then flash evaporated. The solid residue was dissolved as a 30% solution in pentane, chilled to -78° C. and then placed in a refrigerator. After standing overnight, a crystalline product was collected, dried and ground to a powder. The product weighed 417 g (70% yield) and was pure as verified by TLC and 1H NMR.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:31]#[N:32])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33].CCOCC>O1CCOCC1>[ClH:33].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:31]#[N:32])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C#N)CC3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CC1(c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (30 mg, 0.07 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 1 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 0.5 mL and ether (10 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product, (17 mg, 85%); LCMS; 90%, ESI+ Calcd: 334.4, found m/z: 335.7 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 1.41-1.44 (m, 2H), 1.64-1.68 (m, 3H), 1.86-1.95 (m, 1H), 2.05-2.37 (m, 4H), 3.98-4.15 (m, 2H), 4.30-4.35 (m, 1H), 6.90-6.93 (m, 2H), 6.98-7.04 (m, 4H), 7.29-7.36 (m, 2H)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:28][CH3:29])[C:20]3=[O:30])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:28][CH3:29])[C:20]3=[O:30])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3ccccc3[nH]2)c2ncccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCn1c(=O)n(-c2ccc3c(ccn3-c3nc4ccccc4[nH]3)c2)c2ncccc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
A mixture of 3-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and manganese dioxide (439 mg) in toluene (8 mL) was stirred at 100° C. for 5 h, filtered, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (28.0 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+]>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])[CH2:14][CH2:13]1
Reactant: CC(=O)c1ccccc1F
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccccc1N1CCN(C)CC1

Procedure:
A mixture of 55.2 g. of o-fluoroacetophenone and 100 ml. of N-methyl-piperazine is heated at 95°-100° for 19 hours, then cooled and poured into 1600 ml. of water containing 22 ml. of 50% aqueous sodium hydroxide. The mixture is extracted with three 300 ml. portions of ether. The combined ether extract is washed thoroughly with water, then with saturated aqueous sodium chloride, dried and evaporated to give o-(4-methyl-1-piperazinyl)acetophenone as a viscous oil, suitable for use without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: O=C1CC(c2cccc(-c3ccncn3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K4) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (96 mg).
Reaction SMILES: [F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>>[F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(C)c1F
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C(=O)c2cccc(C)c2F)cc1

Procedure:
Prepared according to Method A step 2-fluoro-N-methoxy-N,3-dimethylbenzamide (4.8 g, 24 mmol) and 4-methoxyphenylmagnesium bromide (50 mL, 0.5 M in THF) to give 3.7 g of the title compound as a white solid.