Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[S-:18][C:19]#[N:20].[K+]>CN(C=O)C.O1CCCC1.CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:20]=[C:19]=[S:18])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(N=C=S)c1ccc2ccccc2c1
Yield: 84.1 %

Procedure:
To a mixture of 2-naphthyl carboxylic acid (5.0 g, 29.0 mmol) and 2 drops of N,N'-dimethylformamide in dry tetrahydrofuran (50 ml) was added dropwise thionyl chloride (6.3 ml, 87 mmol) and the resulting reaction mixture was stirred at reflux temperature for 3 h. The volatiles were evaporated in vacuo and the solid residue was redissolved in dry tetrahydrofuran (30 ml) and added dropwise to a solution of potassium thiocyanate (2.9 g, 30 mmol) in acetone (40 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (250 ml) and extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (2×80 ml), dried (MgSO4), filtered and evaporated in vacuo affording 5.2 g (84%) of naphthalene-2-carbonyl isothiocyanate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].II.C(I)[I:18].N(OCCC(C)C)=O.C(=O)(O)[O-].[Na+]>C1COCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([I:18])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13]
Reactant: ICI
Reactant: CC(C)n1cnc2c(Cl)nc(N)nc21
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(I)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-chloro-9-isopropyl-9H-purin-2-amine (2.68 g, 12.7 mmol) was dissolved in THF (64 mL) at rt. Iodine (1.61 g, 6.25 mmol), CH2I2 (10.6 mL) and CuI (1.27 g, 6.66 mmol) were added. The mixture was stirred for 5 min at room temperature. Isopentyl nitrite (5.33 mL) was added. The reaction mixture was refluxed for 45 min, and was then cooled to room temperature. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with EtOAc three times. The combined organic phase was washed with brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0 to 30% ethyl acetate in hexane to afford the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 4.95-4.88 (m, 1H), 1.65 (d, 6H). MS m/z 323.0 (M+1).
Reaction SMILES: OCC(CCCCC)CCC(C1C=CC(OCC)=CC=1)O.C(C(C(OCC)=O)C(OCC)=O)CCCC.BrCCC(OCC)=O.[C:46]([C:51]([CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])([CH2:57][CH2:58][C:59]([O:61]CC)=[O:60])C(OCC)=O)([O:48]CC)=[O:47]>>[CH2:64]([CH:51]([CH2:57][CH2:58][C:59]([OH:61])=[O:60])[C:46]([OH:48])=[O:47])[CH2:65][CH2:66][CH2:67][CH3:68]
Reactant: CCCCCC(CCC(=O)OCC)(C(=O)OCC)C(=O)OCC
Agent: CCCCCC(C(=O)OCC)C(=O)OCC
Agent: CCCCCC(CO)CCC(O)c1ccc(OCC)cc1
Agent: CCOC(=O)CCBr
Product: CCCCCC(CCC(=O)O)C(=O)O

Procedure:
A solution of 29.4 g of 4-hydroxymethyl-1-p-ethoxyphenyl-1-nonanol [obtainable by reaction of diethyl 2-pentylmalonate (boiling point 127°/13 mbar) with ethyl 3-bromopropionate to give diethyl 2-carboethoxy-2-pentylglutarate (boiling point 160°/0.4 mbar), hydrolysis and decarboxylation to give 2-pentylglutaric acid, heating to form the anhydride (boiling point 120°/0.7 mbar), reaction with phenetol/AlCl3 to give 4-p-ethoxybenzoyl-2-pentylbutyric acid (m.p. 61°) and reduction with LiAlH4 ] and 1 g of p-toluenesulfonic acid in 400 ml of benzene is boiled under a water separator for 6 hours, then the mixture is washed with NaHCO3 solution, dried, evaporated and 2-p-ethoxyphenyl-5-pentyltetrahydropyran is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([NH:18][C:19]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)=[O:20])[CH2:15][CH2:14][N:13]1[C:31](OC(C)(C)C)=O)=O.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C.O.CO.C1COCC1>[CH3:31][N:13]1[CH2:14][CH2:15][C@@H:16]([NH:18][C:19]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)=[O:20])[CH2:17][C@@H:12]1[C:10]1[NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[N:9]=1
Reactant: Cc1ccc(NC(=O)[C@H]2C[C@H](NC(=O)c3ccc4c(c3)OCCO4)CCN2C(=O)OC(C)(C)C)c(N)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2nc([C@H]3C[C@H](NC(=O)c4ccc5c(c4)OCCO5)CCN3C)[nH]c2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
The (2R,4R)-tert-butyl 2-((2-amino-4-methylphenyl)carbamoyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate (4.8 g, 9.4 mmol) was dissolved in acetic acid (10 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Then TFA (10 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and did next reaction without further purification. 37% formaldehyde solution (3.5 mL, 47 mmol) in water was added to a solution of the residue in methanol (50 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (29 mL) was added carefully at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then solvent was evaporated in vacuum. Saturated sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL) were added and the mixture was stirred about 30 minutes. The organic layer was separated, dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep 120 g, silica gel packed) with CH3OH/CH2Cl2 from 2%-6-8% to give the title compound as an off-white solid 3.0 g (78%). LC-MS: 407.3, 405.3 (t=1.2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([B:22]([OH:27])[OH:23])=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)cc(F)c1B(O)O
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A RBF was charged with 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (513 mg, 2.168 mmol) and THF (7225 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (1.8M in hexanes) (1445 μA, 2.60 mmol) was added dropwise. After 30 min, triisopropyl borate (597 μl, 2.60 mmol) was added dropwise, and the cooling bath was removed. After 10 min, the mixture was diluted with 2N aq. NaOH, and the resulting biphasic mixture was stirred for 40 min. The mixture was diluted with water and ether. The layers were separated, and the organic layer was extracted with water (1×). The combined aq. extracts were acidified with 2N aq. HCl (30 mL). The resulting suspension was stirred for 20 min then filtered. The collected solid was washed with water (3×), then dried under a stream of N2 (g) for 1 h to give (3′-chloro-3-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (147 mg, 0.524 mmol, 24.18% yield) as an off-white solid. m/z (ESI) 281.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH2:27]([Mg])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(OC)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: [Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of (R)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (1.09 g, 2.68 mmol) in anhydrous TBME (45 mL) at −78° C. under argon was added BF3Et2O (0.57 mL, 5.38 mmol). After 5 min, benzylmagnesium grignard (5.38 mL, 5.38 mmol, 1.0M in ether) was added dropwise with stirring. After 40 min, LCMS indicated that the reaction was complete and the cold solution was quenched with saturated NaCl (ca 20 mL), transferred to a separation funnel and the organic phase extracted with EtOAc (3×20 mL). The combined organic portions were dried, decanted, concentrated and purified by silica gel ISCO chromatography.2×120 g cartridge columns were used 0-60% EtOAc/hexanes over 20 min. A trace amount of minor diastereomer eluted first followed by the major diastereomer (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.97 g, 72% yield). Rf0.4 (Hexane:EtOAc 2:1) LCMS: 2.15 min [M+1] 499.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 4.15 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.65 ppm, d, 1H, J=2.6 Hz; 7.62 ppm, dd, 1H, J=2.6 and J=8.8 Hz; 7.36 ppm, 4H, m; 7.29 ppm, 1H, m; 7.24 ppm, 1H, m; 7.14 ppm, 2H, m; 6.99 ppm, 1H, d, J=10.1 Hz; 6.81 ppm, 1H, d, J=6.6 Hz; 4.09 ppm, 1H, d, J=13.2 Hz; 3.69 ppm, 1H, d, J=13.2 Hz; 1.18 ppm, 9H, s.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:25]=[CH:24][C:15]2[S:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:18]([CH3:19])[C:14]=2[CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:20]([C:17]2[S:16][C:15]3[CH:24]=[CH:25][C:12]([F:11])=[CH:13][C:14]=3[C:18]=2[CH3:19])(=[O:22])=[O:21])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: CCc1cc(Br)ccc1N
Solvent: c1ccncc1
Product: CCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 46.6 %

Procedure:
This compound was prepared in analogy to Example 1, starting from 4-bromo-2-ethylaniline (CAS:45762-41-2, 2.0 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) in pyridine (2.0 ml) for 4 h to obtain the desired compound (0.20 g) as a colorless solid. MS (ISP): 445.0, 447.0 (M+NH4)+
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.[CH2:39]([N:41]([CH2:45][CH3:46])[CH2:42][CH2:43]S)[CH3:40]>>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH2:40][CH2:39][N:41]([CH2:45][CH3:46])[CH2:42][CH3:43])=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: CCN(CC)CCS
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN(CC)CC)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[CH3:14][CH:15]([CH3:18])[C:16]#[CH:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[C:17]#[C:16][CH:15]([CH3:18])[CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: C#CC(C)C
Reactant: CCOC(=O)c1ccc(I)c(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl3-amino-4-iodobenzoate (Compound 31, 6.87 g, 23.1 mmol) in triethylamine (50 ml) at 25° C. under argon then added CuI (22 mg, 1.16 mmol), Pd(PPh3)2Cl2 (82 mg, 1.16 mmol), and 3-methyl-1-butyne ( 3.18 g, 46.2 mmol). The reaction was stirred for 20 h at 25° C., filtered off brown solid, and then rinsed solid with EtOAc, organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1
Yield: 52 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 4-formylbenzeneboronic acid according to the procedure described in example 8 gave 4-(9-hydroxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)benzaldehyde (509) (I; Ar=4-formylphenyl) in a 52% yield; mp (THF/CH2Cl2/pentane) 276–280° C. 1H NMR [(CD3)2SO] δ 11.84 (br s, 1H), 11.07 (br s, 1H), 10.11 (s, 1H), 9.28 (br s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 68.43; H, 4.16; N, 7.26. C21H12N2O4.3/4H2O requires C, 68.20; H, 3.68; N, 7.57. FABMS found [M+H]+: 357.0841. C21H13N2O4 requires 357.0875.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][CH3:24])[C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53].C(N(CC)CC)C>O1CCCC1.C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH2:23][CH3:24])[C@@H:12]([C:20]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
2.6 g (0.008 mole) of N-benzyloxycarbonyl-N-ethyl-D-phenylalanine (Example 3, Step 2) are dissolved in 10 ml of tetrahydrofuran and at 0° C. 1.6 g (0.008 mole) of 2,4,5-trichlorophenol and 1.65 g (0.008 mole) of dicyclohexylcarbodiimide are added, then the mixture is left to stand at room temperature for 4 hours. The residue is dissolved in 40 ml of benzene, washed twice with 20 ml of a 5 percent solution of sodium hydrogen carbonate, twice with 20 ml of water, then it is dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. The residual oil is dissolved in 10 ml of pyridine, 0.92 g (0.008 mole) of L-proline and 1.12 ml (0.008 mole) of triethylamine are added and the mixture is stirred till the dissolution of proline at room temperature. Then the solution is left to stand for 4 to 5 hours, subsequently it is evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. The residue is dissolved in a mixture of 25 ml of water and 10 ml of diethyl ether. The aqueous layer is washed twice with 10 ml of diethyl ether and the combined ether extracts are washed with 10 ml of a 5 percent solution of sodium hydrogen carbonate. The aqueous layers are combined and acidified to pH 2 with 3N hydrochloric acid. The separated product is extracted three times with 15 ml of benzene, the benzene layers are combined, washed three times with 5 ml of water, dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. Yield 2.2 g (64%) of an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]>C(OCC)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:7])[CH2:13][CH2:12]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C(=O)c5ccco5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and 1-(furan-2-yl-methanoyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 114–115° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:50])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH2:49][C:33]4([CH2:36][C:35]([C:43]([O:45]C(C)C)=[O:44])([C:37]([O:39]C(C)C)=[O:38])[CH2:34]4)[CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.CO>[C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:50])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH2:49][C:33]4([CH2:36][C:35]([C:43]([OH:45])=[O:44])([C:37]([OH:39])=[O:38])[CH2:34]4)[CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (15 mg, 0.019 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 4 h. The solvent was removed in vacuo. The crude product was dissolved in dioxane (1 mL) and MeOH (1 mL). H2O was added dropwise, the solid formed was collected by filtration to give desired product in 88% yield. MS: m/e 688.6 (M−H)−, 2.72 min (method 5). 1H NMR (400 MHz, METHANOL-d4) δ 5.88 (s, 1H), 5.57-5.52 (m, 1H), 4.74 (d, J=1.8 Hz, 1H), 4.61 (s, 1H), 2.69 (s, 2H), 2.68-2.48 (m, 4H), 2.33-2.25 (m, 1H), 2.14 (dd, J=17.9, 6.7 Hz, 1H), 1.99-1.83 (m, 2H), 1.77-0.81 (m, 19H), 1.70 (s, 3H), 1.45 (s, 9H), 1.16 (s, 3H), 1.09 (s, 3H), 1.08 (s., 3H), 1.00 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][C:12]([O:26][CH3:27])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.CO.CCOC(C)=O>CCO.[Pd]>[CH3:27][O:26][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:17][NH:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3cc(OC)ccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A suspension of 10% Pd/C (3.80 g) and 2-benzyl-7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (3.87 g, 10.8 mmol, see Example 80) in EtOH (160 ml) was hydrogenated at 50 p.s.i. for 12 hours. The catalyst was removed via filtration through diatomaceous earth and the filtrate was concentrated in vacuo. Purification via flash chromatography (Biotage , SiO2, 9:1 EtOAc:MeOH then 1:1 EtOAc:MeOH) gave the title product (2.19 g, 8.13 mmol, 76% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][S:42]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.20 g, 0.35 mmol) from Example 2 in CH2Cl2 (20 mL) was added methanesulfonoyl chloride (0.045 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant to give the title compound as an amorphous solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[CH:6]=1)([CH3:3])[CH3:2]>CC(O)C.[Ni]>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:12])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(OC(C)C)cc[n+]1[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: Cc1cc(OC(C)C)ccn1
Yield: 78.7 %

Procedure:
A suspension of 4-isopropyloxy-2-methylpyridine N-oxide (0.78 g) in 2-propanol (10 ml) was hydrogenated over Raney-nickel (50% suspension in water, 1 ml) under a hydrogen atmosphere for 48 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 4-isopropyloxy-2-methylpyridine (555 mg).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].N12CCCCC1C=NCCC2.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: C1=NCCCN2CCCCC12
Solvent: CCO
Product: Nc1ccnc(SCCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A mixture of 2-thiocytosine (0.25 g.), 1,5-diazabicyclo[5,4,0]undec-5-ene (0.33 g.), ethanol (10 ml.) and N-(4-bromobutyl)phthalimide (0.62 g.) was stirred at room temperature for 18 hours and then evaporated to dryness. The residue was partitioned between water and ethyl acetate and the ethyl acetate phase was dried and evaporated to dryness. The residue was recrystallised from acetonitrile to give 4-amino-2-(4-phthalimidobutylthio)pyrimidine (0.56 g.), m.p. 164°-167°.