Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>CN(C)C=O>[C:1]1([C:7]2[N:17]=[C:18]([SH:19])[NH:20][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: CN(C)C=O
Product: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1

Procedure:
21.2 g (0.10 mol) of benzoin were dissolved in DMF (dimethylformamide) with 10.8 g (0.15 mol) of thiourea with warming and the mixture was heated under reflux for 15 hours. After cooling, the DMF was stripped off and the residue was treated with ethanol. The precipitate resulting in the course of this was filtered off with suction, washed with cold ethanol, dried and reused without further purification. The yield was 18.4 g.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[CH3:20][O:21][C:22]1[C:23](=O)[C:24](=[O:28])[C:25]=1[O:26]C.C(N(CC)C(C)C)(C)C>CO>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:23]3[C:24](=[O:28])[C:25](=[O:26])[C:22]=3[O:21][CH3:20])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1c(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A vial containing a solution of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 0.020 g, 0.075 mmol), 3,4-dimethoxy-3-cyclobutene-1,2-dione (0.011 g, 0.077 mmol), N,N-diisopropylethylamine (14 μL, 0.080 mmol) and MeOH (1.5 mL) was shaken at ambient temperature for about 16 hours then filtered to give 3-(7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamino)-4-methoxy-cyclobut-3-ene-1,2-dione (0.022 g, 78%) as a tan solid; RP-HPLC (Table 1, Method e) Rt 1.80 min, m/z (ESI+) 375.9 (M+H)+.
Reaction SMILES: Cl.N1CCCCC1.C(O)=O.C([N:18]1[CH2:27][CH:26]2[CH2:28][CH:20]([C:21]3[CH:22]=[N:23][N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:25]=32)[CH2:19]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CO.C(OCC)C.[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:24]2[N:23]=[CH:22][C:21]3[CH:20]4[CH2:28][CH:26]([CH2:27][NH:18][CH2:19]4)[C:25]2=3)=[CH:34][CH:33]=1
Reactant: Fc1ccc(-n2ncc3c2C2CC3CN(Cc3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CO
Product: Fc1ccc(-n2ncc3c2C2CNCC3C2)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 9-benzyl-3-(4-fluoro-phenyl)-3,4,9-triaza-tricyclo[5.3.1.020.6]undeca-2(6),4-diene (0.23 mmol) in methanol (2 ml) was added a solution of 1N HCl in diethyl ether (2 mL). The mixture was stirred for 45 min. and the solvent was removed to yield a solid. In a separate flask piperdine (1.5 mmol) and formic acid (0.69 mmol) were combined in methanol (2 ml). To this solution is added a solution of the HCl salt of 9-benzyl-3-(4-fluoro-phenyl)-3,4,9-triaza-tricyclo[5.3.1.02,6]undeca-2(6),4-diene in methanol (3 ml). To this resulting solution was added Pearlman's catalyst (8 mg, 10% wt. on carbon). The reaction mixture was heated under reflux under a nitrogen atmosphere for 18 h then it was cooled and filtered through a plug of Celite™ to remove solids and the pad was washed with methanol. The resulting filtrate was condensed to a gum, which is taken up in ethyl acetate and saturated aqueous sodium bicarbonate solution (20 ml). The mixture was extracted with ethyl acetate (3×20 mL) and the resulting organic layer was dried over MgSO4. The solids were removed by vacuum filtration and the solvent was removed to provide an oil which was purified by chromatography on silica gel eluting with 0.1% ammonium hydroxide solution in 10% methanol/dichloromethane to produce an oil that was treated with 1N HCl in ethyl ether. Trituration of the solids produced a gummy solid (0.082 mmol). 1H NMR (CD3OD, 400 MHz) δ 7.60 (m, 2H), 7.40 (s, 1H), 7.20 (br, 2H), 3.25 (m, 1H), 2.90–2.60 (m, 5H), 2.20 (m, 1H), 0.80 (br s, 1H); APCl MS m/z 244.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCCN2CCCCC2)cc1
Yield: 99.9 %

Procedure:
Following the procedure described in example 1§E, but starting from 1-(3-chloropropoxy)-4-iodobenzene (3 g), potassium carbonate (4.15 g) and piperidine (1.7 g) in N,N-dimethylformamide (30 mL) affords 3.49 g of 1-[3-(4-iodophenoxy)propyl]piperidine used without further purification.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[NH:33][NH2:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[N:33]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:34]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cc(Cl)ccc3Cl)c3cc(O)ccc23)c(O)c1
Yield: 20.5 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.4 g, 1.6 mmol), sodium acetate (0.27 g, 3 mmol) and 2,5-dichlorophenylhydrazine hydrochloride (0.45 g, 2.5 mmol) to give 0.127 g of product as a beige solid (mp 78–80° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:48]3[N:49]=[CH:50][N:51]([CH3:53])[CH:52]=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:48]3[N:49]=[CH:50][N:51]([CH3:53])[CH:52]=3)[S:17][C:10]=12
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1

Procedure:
Following the procedure described for compound 5a (example 1, step 5) but substituting amine 9 for compound 12, title compound 5c was obtained as a white solid (78% yield). MS (m/z): 502.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[CH2:14][CH2:15]CSCCS)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[CH2:14][CH:15]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(CCCCOCc1ccccc1)CCCSCCS
Product: O=CCC(=O)CCCCOCc1ccccc1

Procedure:
0.135 mole=44 g of 7-benzyloxy-1-(2,5-dithiapentyl)-heptane-3-one were heated for 1 hour under nitrogen and under reflux in 1 liter of acetone with [0.275 mole]=47 g of CuCl2 . 2 H2O and [0.57 mole]=44 g of CuO, the copper salts were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether, washed twice with 2N- HCl and thrice with water, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled under reduced pressure. B.p.0.5 mm 185°-192° C.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)(=[O:51])=[O:50]>>[CH3:4][CH:2]([CH2:1][N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:53]([NH:52][S:49]([C:45]1[S:44][CH:48]=[CH:47][CH:46]=1)(=[O:51])=[O:50])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:13])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(2-thiophenesulfonyl)-L-phenylalanine (300 mg, 1.2 mmol) which was prepared in step A of example 24. The final product was purified by preparative HPLC to yield 46 mg (54%) of the desired material.
Reaction SMILES: [N+](C1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:12]3)([O-])=O.C=O.Cl.[CH3:19][N:20]([CH3:22])[CH3:21]>[Ni].C(O)C>[CH3:19][N:20]([CH3:22])[C:21]1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:12][CH2:13]3
Reactant: CN(C)C
Reactant: O=C1c2cccc([N+](=O)[O-])c2OC12CC2
Agent: [Ni]
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)c1cccc2c1OC1(CC1)C2=O
Reaction time: 3 h
Yield: 138 %

Procedure:
A mixture of 7-nitrospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (10 g.), formalin (37% formaldehyde, 10 ml.), trimethylamine hydrochloride (2 g.) and Raney nickel (10 g.) in ethanol (500 ml.) was subjected to reduction at 49°-56° C. for 3 hours under hydrogen pressure of 50 kg/cm2. After removing the catalyst by filtration, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and the solution was washed with 5% aqueous solution of sodium hydrogen carbonate then with water, followed by drying. The solvent was evaporated off and the residue was subjected to column-chromatography on silica-gel. The first fraction eluted with hexane-ethyl acetate (9:1) was recrystallized from ethanol to give 7-dimethylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (5.87 g.) as yellow needles melting at 68.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1.[H-].[Na+].[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:21]([CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)n2CCN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
A suspension of 0.62 g (2 mmol) of 2-(2,5-dimethoxyphenylmethyl)-6-methyl-4(3H)-quinazolinone and 0.19 g (2 mmol) of 50% sodium hydride in dioxane (10 ml) were stirred at room temperature for 1 hour. Then, to the resulting reaction mixture was added 0.22 g (2 mmol) of dimethylaminoethyl chloride dissolved in dioxane (10 ml), followed by heating at 60° C. for 5 hours. After cooling, to the mixture obtained were added 30 ml of water. The resulting mixture was extracted with dichloromethane and the dichloromethane layer was concentrated under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: ethanol=97:3) to obtain 0.10 g (yield 13 %) of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone as an oily substance. The thus obtained quinazolinone was dissolved in ether and to the resulting solution was added a 5% hydrogen chloride-ethanol solution and the precipitated crystals were collected by filtration to obtain 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone hydrochloride. The melting point and infrared absorption spectrum of this hydrochloride were identical with those of Compound 24 obtained in Example 24, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:24])[C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:18])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCCOC(=O)c1ccc(O)cc1
Product: CCCOC(=O)c1ccc(OC(=O)c2ccccc2C(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
Propyl p-hydroxybenzoate and phthalic dichloride are allowed to react and treated in a similar procedure to Example 4. The residue obtained is recrystallized from hexane and recrystallized from ethyl acetate-chloroform (1:1) to yield di(p-propoxycarbonylphenyl)phthalate, m.p. 87°-89° C., as white crystals.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (13.9 mg, 49.6%), MS (ISP) m/z=401.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and isobutyric acid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:7]=[C:8]2[N:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]2[C:26]=1[CH2:27]O>C(Cl)Cl>[Cl:3][CH2:27][C:26]1[N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[N:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]2=[N:7][C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(-n2c3ncccc3n3c(CO)c(C)nc23)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(-n2c3ncccc3n3c(CCl)c(C)nc23)c(C)c1
Reaction time: 2 h

Procedure:
Thionyl chloride (0.164 mL, 2.25 mmol) was added at 0° C. to a solution of [2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol (0.36 g, 1.12 mmol) in CH2Cl2 (10 mL). After 2 h, solvents was removed and the title compound was obtained as a brownish oil (100% yield). Mass spec.: 335.24 (M−Cl+OMe+H)+.
Reaction SMILES: ClCCl.C(N(CC)CC)C.[NH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)(Cl)Cl>[N:19]1[CH:18]=[CH:17][N:16]2[C:15]=1[CH2:14][C:13]1[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=1[NH:11][C:24]2=[S:25]
Reactant: Nc1ccccc1Cc1ncc[nH]1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: S=C1Nc2ccccc2Cc2nccn21

Procedure:
Dichloromethane (42,000 ml) and 5,120 g (50.65 moles) of triethylamine were charged into a 20 gallon flask. The solution was stirred under nitrogen atmosphere and 4,370 g (25.23 moles) of 2-(2-aminobenzyl)imidazole were added. The suspension was cooled to 0°-5° and 3,421 g (29.75 moles) of 85% thiophosgene in carbon tetrachloride were added over 3 hours, during which time the reaction temperature rose slowly to 15°. The suspension was then stirred at 10° for 4 hours and at ambient temperature overnight. The precipitated product was collected, washed with 2×3000 ml of dichloromethane and 5×4000 ml of water, and dried (5 mm Hg/60°) to give 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione, m.p. 182°-183°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 1-methylsulfonylpiperazine (HCl salt), using 2.8 equiv of triethylamine, via General Procedure C to give crude 5-chloro-2-(4-methylsulfonylpiperazin-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 135 after purification by reverse HPLC. MS (Q1) 478 (M+)
Reaction SMILES: B.CSC.[CH:5]1([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N)CN>C1COCC1>[NH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc(CSC2CCCC2)cn1
Agent: B
Solvent: NCCN
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1ccc(CSC2CCCC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Add borane-dimethylsulfide complex (6.9 mL, 13.7 mmol, 2M solution in THF) to a solution of 5-cyclopentylthiomethyl-pyridine-2-carbonitrile (1 g, 4 mmol) in THF (12 mL) at room temperature under a nitrogen atmosphere. Stir the solution at room temperature for 16 h. Concentrate the solution in vacuo, dissolve the residue in chloroform (50 mL), add ethylenediamine (0.72 g, 12 mmol) and stir at 50° C. for 1 h. Wash the mixture with water (10 mL), dry the organic phase over Na2SO4 and concentrate in vacuo. Purify the residue by SCX chromatography followed by chromatography on silica gel (10 g) eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient) to obtain the title compound (0.24 g, 27%). MS (ES+) m/z: 223.1 (M+H)+.
Reaction SMILES: B1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5]2.C=CCCCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[K+].[Br-].O.[CH:29]1[C:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:40])[C:33]=2[CH:32]=[CH:31][C:30]=1OS(C(F)(F)F)(=O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:30]1[CH:31]=[CH:32][C:33]2[C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[CH:29]=1)[CH2:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: B1C2CCCC1CCC2
Reactant: O=C1CCCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C=CCCCCCC
Solvent: O
Product: CCCCCCCCc1ccc2c(c1)CCCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
(7-octyl-1-benzosuberone). 9-BBN (0.5 M solution in THF, 20.2 mL, 10.1 mmol) was added to 1-octene (1.6 mL, 10.1 mmol) at rt. The solution was then stirred at room temperature overnight. After this time, K3PO4 (2.93 g, 13.8 mmol), Pd(Ph3P)4 (191 mg, 0.17 mmol, 1.8 mol %), KBr (1.2 g, 10.1 mmol) and degassed H2O (0.18 mL, 10 mmol) were added followed by a solution of 2 (2.7 g, 9.2 mmol) in dry degassed THF (10 mL). The reaction mixture was then heated to 65° C. under argon for 2 h. After cooling the solution was acidified to pH 1 and extracted into EtOAc (100 mL). The aqueous layer was re-extracted with EtOAc (50 mL) and the combined organics washed with H2O (20 mL) and brine (40 mL). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 5% EtOAc in hexanes) to give 1.45 g compound 3 (72%). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.95 Hz), 1.24 (bs, 10H), 1.58 (p, 2H, J=6.95 Hz), 2.06 (m, 4H, J=5.85 Hz), 2.57 (t, 4H, J=6.95 Hz), 2.87 (t, 2H, J=6.22 Hz), 7.01 (s, 1H), 7.06 (d, 1H, J=8.05 Hz), 7.91 (d, 1H, J=8.06 Hz).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)\[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[C:12]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:13][S:14](=O)[C@H:9]12)=[O:6].O.O.Cl[Sn]Cl.C(Cl)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)\[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[C:12]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS(=O)[C@H]12)c1cscn1
Agent: Cl[Sn]Cl
Solvent: CC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
The 1-oxide derivative (85 mg) from Example 4 was dissolved in dimethylformamide (2 ml, followed by addition of SnCl2.2H2O (84 mg) and cooling with ice. Acetyl chloride (0.38 ml) was added dropwise to the mixture. Then the ice bath was removed to raise the temperature to 20° C. After stirring for 15 minutes, the reaction mixture was added to cold water (10 ml). The mixture was extracted three times with ethyl acetate (15 ml×3). The ethyl acetate layers, combined together, were washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (0.5 ml) and the solution was added dropwise to petroleum ether (30 ml) with stirring. Resulting crystals were filtered, and dried under reduce pressure to give the title compound (35 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][C:10]1[CH:30]=[CH:29][C:13]2[C@@H:14]3[CH2:20][CH2:19][C@@H:18]([CH:21]4[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]4)[CH2:17][C@H:15]3[O:16][C:12]=2[C:11]=1[F:31])[CH3:8].O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([O:9][C:10]1[CH:30]=[CH:29][C:13]2[C@@H:14]3[CH2:20][CH2:19][C@@H:18]([CH:21]4[CH2:22][CH2:23][CH:24]([CH:27]=[CH2:1])[CH2:25][CH2:26]4)[CH2:17][C@H:15]3[O:16][C:12]=2[C:11]=1[F:31])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC(C=O)CC3)CC[C@@H]21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1CCC([C@@H]2CC[C@H]3c4ccc(OCC)c(F)c4O[C@@H]3C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.65 g (27.0 mmol) of methyltriphenylphosphonium bromide are initially introduced in 100 ml of THF, and 3.09 g (27.0 mmol) of potassium tert-butoxide in 60 ml of THF are added at −5° C. After 1 h at this temperature, 8.40 g (about 24 mmol) of crude (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanecarbaldehyde as a solution in 90 ml of THF are added dropwise, and the batch is stirred at room temperature for 3 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are dried using sodium sulfate. The crude product remaining after removal of the solvents is filtered adsorptively (SiO2, toluene), and the filtrate is concentrated to dryness. Repeated recrystallisation of the residue from ethanol gives (±)-(3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-3-(4-vinylcyclohexyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (m.p. 132° C.).