Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[C@H:23]1[C@H:30]2[C@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]2)[CH2:25][S:24]1)(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C[Si](C)(C)N[Si](C)(C)C.ClC=CCl.ClCCCl.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:23]2[C@H:30]3[C@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[CH2:25][S:24]2)=[C:4]([Cl:11])[N:3]=1
Reactant: CC(=O)O[C@@H]1SC[C@H]2OC(C)(C)O[C@@H]12
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: ClC=CCl
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(Cl)nc(Cl)nc43)SC[C@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of 2,6-dichloropurine (2.29 g, 22.12 mmol) and ammonium sulfate (438 mg, 3.32 mmol) in hexamethyldisilazane (HMDS, 50 ml) was fluxed overnight under inert, dry conditions. The resulting reaction mixture was concentrated in a vacuum and the solid mixture thus formed was re-dissolved in cold 1,2-dichloroethene (20 ml). To this solution were dropwise added a solution of (3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl acetate (1.41 g, 11.06 mmol), obtained in Preparation Example 1, in 1,2-dichloroethane (20 ml), and then trimethylsilyl trifluoromethanesulfonate (TMSOTf, 4.0 ml, 22.12 mmol). The resulting solution was stirred at 0° C. for 30 min and then at room temperature for 1 hr, and heated at 80° C. for 2 hrs with stirring. The reaction mixture was cooled, diluted in dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate (NaHCO3) solution. The organic solvent was dried over anhydrous magnesium sulfate (MgSO4) and concentrated in a vacuum to give a residue in the form of a yellow syrup. The residue was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (50:1, v/v) as an elution solvent to afford the object compound in the form of a foam (3.03 g, 79%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][N:42]([CH:40]=[O:41])[CH2:43][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: O=CN1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCN(C=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 6.2 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-formylpiperazine(20.6 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-(4-formylpiperazine-1-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (5.6 mg, 6%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]([CH2:9][OH:10])[CH2:6][CH:7]=[CH2:8].B(F)(F)F.CCOCC.CO[C:30](OC)([CH3:32])[CH3:31]>CC(C)=O>[OH:10][CH2:9][C@H:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][C@H:3]1[CH2:2][O:1][C:30]([CH3:32])([CH3:31])[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (6.8 g, 26.2 mmol) was dissolved in acetone (150 mL) followed by the addition of BF3.Et2O (2.62 mmol). The reaction mixture was cooled to 0° C. and 2,2-dimethoxypropane (4.1 g, 39.4 mmol) was added. The resulting mixture was stirred at rt for 1 h, TEA (0.5 mL) was added and stirred for another 5 min before evaporating under reduced pressure. The residue was dissolved in Et2O (300 mL), washed with 1 N HCl (80 mL), sat. aq. NaHCO3 (80 mL), brine (80 mL) successively, and dried, filtered, and concentrated under vacuum to give crude (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (7.5 g, 96%). It was used for the next step without further purification. 1H NMR (CD3OD) δ 1.4-1.5 (m, 13H), 1.5-1.6 (d, 6H), 1.6-1.9 (m, 2H), 2.0-2.1 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 4.1-4.2 (m, 1H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:27])([F:26])[CH2:23][CH2:24]I>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:22]([F:27])([F:26])[F:21])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(F)c2F)CCN(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation according to Example 43: Enantiomer E2 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1,1,1-trifluoro-3-iodopropane (0.32 mL, 3.1 mmol). Stirred 2 h at ambient temperature and 2×5 min at 40° C.; Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1) Yield: 0.2 g. [α]D=−14.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 144° C.; MS m/z (relative intensity, 70 eV) 295 (M+, 24), 212 (31), 182 (12), 139 (bp), 127 (20).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CN(C=O)C.O>[Si:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of hydroquinone (1.0 g, 0.9 mmol) and tert-butyldimethylsilylchloride (1.4 g, 0.9 mmol) in 5 mL of dry DMF was gradually added imidazole(1.2 g, 1.8 mmol) and the solution was stirred for 1 hour. TLC analysis (silica gel, 20% ethyl acetate/hexane) showed completion of reaction. The solution was poured into 25 mL of water and extracted with 3×25 mL of ether. The combined ether solutions were dried over anhydrous MgSO4. Evaporation of solvent gave an oil which was chromatographed on silica using 20% ethyl acetate/hexane to give the product as a white solid in 70% yield: 1H NMR (CDCl3) δ0.145 (s, 6H), 0.956 (s, 9H), 4.47 (bs, 1H), 6.68 (s, 4H); 13C NMR (CDCl3) δ-4.48, 18.21, 25.74, 115.93, 120.55, 120.81, 149.78.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[N:8][C:6]=2[N:7]=1.[BrH:15]>CC(O)=O>[Br:15][CH2:12][C:10]1[CH:9]=[N:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:14])[C:5]=2[CH:11]=1
Reactant: Br
Reactant: Nc1nc(N)c2cc(CO)cnc2n1
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(CBr)cnc2n1

Procedure:
The intermediate III-2 was prepared from 2,4-diaminopyrido [2,3-d]pyrimidine-6-methanol (III-1) by the procedure described in J. Med. Chem., 35:332 (1992). This particular preparation analyzed for a 1.75 HBr° 0.25 CH3COOH salt (formula wt. 406.7). The material was suitable for conversions to compound 33.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[P:5](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[K].[CH2:18]([O:20][C:21]([O:23][NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28])=[O:22])[CH3:19].C(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([O:26][C:25]([N:24]([CH2:2]/[CH:3]=[CH:4]/[P:5](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:23][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[O:29])[CH3:28]
Reactant: CC(C)(C)OP(=O)(/C=C/CBr)OC(C)(C)C
Reactant: CCOC(=O)NOC(=O)OCC
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)ON(C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
To a solution of di-tert-butyl 3-bromo-trans- 1-propenylphosphonate (17.1 g.) in dry N,N-dimethylformamide (55 ml.) was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (11.03 g.). The reaction mixture was stirred for 10 minutes under ice-cooling and for 1.5 hours at ambient temperature. The reaction mixture was poured into ice water (400 ml.) and then the resultant mixture was extracted three times with ethyl acetate (300 ml., 200 ml. and 100 ml.). The combined ethyl acetate layer was washed three times with water (100 ml.), dried over magnesium sulfate and then concentrated under reduced pressure to give an oily residue (20.23 g.). The residue was subjected to column chromatography on silica gel (200 g.) [developing solvent: a mixture of chloroform and ethyl acetate (4:1)]. The fractions containing the object compound were collected and concentrated under reduced pressure to give an oily di-tert-butyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonate (8.84 g.).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:13])[CH3:12])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31]C)=[O:30])[CH:27]=3)[C:22]([S:33][CH3:34])=[CH:21]2)=[N:18][CH:19]=1>C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:13])[CH3:12])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([OH:31])=[O:30])[CH:27]=3)[C:22]([S:33][CH3:34])=[CH:21]2)=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C(C)O)ccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)O)ccc12
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.30 g, 7.07 mmol) was added at room temperature to a solution of 300a) (1.0 g, 2.36 mmol) in THF/water (1:1, 40 mL). The reaction mixture was stirred at this temperature for 16 h and then concentrated. The residue was diluted with water (20 mL) and washed with ethyl acetate (2×30 mL). The aqueous phase was adjusted with sodium hydrogen sulfate to a pH value of 2. The precipitating solid was filtered off through a sintered funnel and residual water was removed by azeotropic distillation with toluene. Light brown solid. Yield: 0.75 g (75% of theory)
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][O:24][Si](C(C)C)(C(C)C)C(C)C)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:36])[CH3:35])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OC(=O)C)C>[F:37][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][OH:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:35])[CH3:36])=[O:4]
Reactant: CC(C)[Si](OCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(2-((triisopropylsilyloxy)methyl)thiazol-5-yl)phenyl)oxazolidin-3-yl)ethanone (2.6 g, 4.8 mmol) in tetrahydrofuran (50 mL) is added tetrabutylammonium fluoride (5.2 mL of a 1M solution). The reaction is stirred at room temperature for 1 hour. The reaction is diluted with ethylacetate (100 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude material is chromatographed eluting from 100% hexanes to 75:25 ethylacetate:hexanes to afford the title compound (1.8 g): m/z (Cl) M+H 401.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:25]=[CH:26]/[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1/[CH:25]=[CH:26]/[CH3:27])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 111.1 %

Procedure:
The mixture 5-fluoro-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (153) (260 mg, 0.68 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (0.2 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 2.5 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The filtered compound is purified by HPLC to give a pure product (154) as white solid (267 mg, 100%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:9][C:8]2([C:12]2[N:13]=[N:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>N.CCO.[Ni]>[CH:1]1([CH:7]2[CH2:9][C:8]2([CH2:10][NH2:11])[C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CC1(c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1C1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCC1(c2nnn[nH]2)CC1C1CCCCC1
Reaction time: 60 h
Yield: 35.9 %

Procedure:
To a solution of the 2-cyclohexyl-1-(2-trityl-2H-tetrazol-5-yl)-cyclopropanecarbonitrile (1.10 g, 2.39 mmol) in 50 mL 2.0M NH3 in EtOH was added RaNi (1.4 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 60 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2) furnished 0.19 g (36%) of C-[2-cyclohexyl-1-(1H-tetrazol-5-yl)-cyclopropyl]-methylamine as a colorless solid. 1H NMR (CD3OD) δ 3.97 (d, J=13.2 Hz, 1H, —CH2NH2), 2.96 (d, J=13.2 Hz, 1H, —CH2NH2), 1.87 (m, 1H), 1.77 (m, 1H), 1.68 (m, 2H), 1.47 (m, 1H), 1.38 (m, 1H), 1.12-1.31 (m, 6H), 1.07 (m, 1H), 0.91 (dd, J=4.6, 6.6 Hz, 1H, cyclopropyl —CHH). LRMS: m/z 220.2 (M−1). Anal. Calc'd for C11H19N5: C, 59.70; H, 8.65; N, 31.65. Found: C, 58.39; H, 8.54; N, 31.20.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][C:16]#N)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][C:16]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
A mixture of cyanomethyl 3-(t-butyloxycarbonylamino)benzoate (20 g), triethylamine (10.6 g), 4-dimethylaminopyridine (0.1 g) and benzyl alcohol (11.4 g) is stirred at a bath temperature of 55° C. for 15 hours. The reaction mixture is extracted with ethyl acetate (200 ml), and the extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 80% aqueous acetonitrile solution to give the title compound (22.0 g, 93%) as white short needles.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH2:5][Cl:27])[CH2:15][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CCl)CC1
Temperature: 0 °C

Procedure:
To a solution of 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (8.5 g) in chloroform (85 ml) is added thionyl chloride (2.7 ml) at room temperature. The mixture is stirred at the same temperature for 30 mintues, and the reaction mixture is poured into ice water, and then neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrobenzyl chloride (8.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>C(Cl)Cl>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(N=C=S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 5-amino-2-chlorobenzotrifluoride (0.932 g, 4.76 mmol) in 30 mL CH2Cl2 was added 1,1′-thiocarbonyldiimidazole (0.976 g, 1.15 mmol). The reaction was warmed to RT and stirred for 45 min. The reaction was stirred for an additional 1 h, during which additional 1,1′-thiocarbonyldiimidazole (0.50 g and 0.20 g) was added at 30 min intervals. The reaction was concentrated down to a small volume and purified by short column silica gel chromatography using EtOAc:hexanes (15:75), to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccncc2)nc2cc(F)ccc2c1Cl

Procedure:
Prepared according to procedure E using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.17 mmol), palladium tetrakistriphenylphosphine (0.251 mg, 0.22 mmol) and 4-tributylstannylpyridine (800 mg, 4.35 mmol) in toluene (15 mL). After purification 4-chloro-7-fluoro-3-methyl-2-(pyridin-4-yl)quinoline was obtained as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(OCC)C>[O:8]1[CH:12]2[CH:11]=[CH:10][CH:9]1[CH:3]1[C:4](=[O:6])[NH:5][C:1](=[O:7])[CH:2]12
Reactant: c1ccoc1
Reactant: O=C1C=CC(=O)N1
Solvent: CCOCC
Product: O=C1NC(=O)C2C3C=CC(O3)C12
Temperature: 25 °C
Reaction time: 70 h
Yield: 46.1 %

Procedure:
A mixture of maleimide (Sigma-Aldrich, St. Louis Mo.; 2.0 g, 0.0206 moles) and furan (Sigma-Aldrich, St. Louis Mo.; 7.49 mL, 0.103 moles) in anhydrous ethyl ether (50 mL) was stirred for 70 hours at room temperature under an argon atmosphere. A white precipitate formed during the reaction and was filtered off and dried under reduced pressure giving 1.57 g of white crystals. NM (d6-DMSO): Mixture of exo- and endo-isomers (37:63) of ETPI: Exo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 2.85 ppm (s, —CH, 2H), 5.25 ppm (s, —CH, 1H), 6.55 ppm (s, —CH═CH—, 2H), Endo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 3.48 ppm (s, —CH, 2H), 5.11 ppm (s, —CH, 2H), 6.49 ppm (s, —CH═CH, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.[F-].[Cs+].C(OC([N:35]1[CH2:40][CH2:39][CH:38](OS(C)(=O)=O)[CH2:37][CH2:36]1)=O)(C)(C)C.CO>CC(N(C)C)=O.C(OCC)(=O)C.Cl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:38]5[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]5)=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OC3CCNCC3)cc2c1=O

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (200 mg) was stirred with cesium fluoride (364 mg) and 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (251 mg) in DMA (1.5 ml) at 85° C. for 24 hours (during this time further additions (4×125 mg) of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester took place). The reaction mixture was diluted with ethyl acetate and washed with 1N NaOH (2×), water (3×), brine, dried (magnesium sulfate) and concentrated to a brown oil. Purification by column chromatography with a gradient of 50% ethyl acetate/iso-hexane to 100% ethyl acetate gave a cream coloured solid. The solid was dissolved in 4M HCl in dioxane solution (1 ml) and methanol (0.5 ml) and stirred for 16 hours at room temperature. The reaction mixture was concentrated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide as a cream coloured foam solid (146 mg); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.50 (m, 2H), 1.95 (m, 2H), 2.10 (s, 3H), 2.60 (m, 2H), 2.84 (m, 1H), 2.96 (m, 2H), 4.54 (m, 1H), 6.71 (d, 1H), 7.20 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.67 (s, 1H), 7.80 (d, 1H), 7.83 (s, 1H), 7.87 (d, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]=[C:6]([C:8]1[S:9][CH:10]=[C:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:12]=12)[CH3:7]>CO.[Pd]>[CH3:7][CH:6]([C:8]1[S:9][CH:10]=[C:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][C:12]=12)[CH3:5]
Reactant: C=C(C)c1scc2c1CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1scc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 63.2 %

Procedure:
3.7 g (59 mmol) of ammonium formate and then 0.9 g of 10% palladium-on-charcoal are added to a solution of 0.78 g (2.9 mmol) of 1-(1-propen-2-yl)-5-(1,1-dimethylethoxy)carbonyl-5,6-dihydro-4H-thieno[3, 4-c]pyrrole in 40 ml of methanol. The reaction mixture is heated at reflux for 8 hours, then filtered on a Celite column and evaporated to dryness. The residue is taken up in 50 ml of ethyl acetate, washed with 20 ml of water, dried over sodium sulphate and evaporated to dryness. After purification on a silica column using the 1/4 ethyl acetate/hexane eluent mixture, 0.49 g of an oily product is obtained. Yield 63%.