Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]1[O:38][CH:37]([CH3:39])[CH2:36][NH:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:39][CH:37]1[O:38][CH:33]([CH3:32])[CH2:34][N:35]([CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[CH:26]=[CH:25][CH:24]=2)[CH2:36]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC1CNCC(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CC(C)OC(C)C5)c4)cc23)CC1
Yield: 32.5 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2,6-dimethylmorpholine (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (19.6 mg, 32%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[N:54]=[C:55]=[O:56]>CN(C)C=O>[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[NH:54][C:55]([NH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:37][CH:38]=1)=[O:56]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)Nc4ccc(F)cc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.3 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (65 mg) and anhydrous N,N-dimethylformamide (5 ml) was added 2,4-difluorophenyl isocyanate (81 mg) and the mixture was stirred at room temperature for 4.5 hours and then allowed to stand for 2 days. The reaction mixture was concentrated and diluted with water and tetrahydrofuran and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added ethyl acetate and the precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.2 g, mp 161-164° C.).
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C:28]1[C:33]([OH:34])=[C:32]([CH2:35][OH:36])[C:31]([CH:37]=O)=[CH:30][N:29]=1>O1CCCC1>[CH3:27][C:28]1[C:33]([OH:34])=[C:32]([CH2:35][OH:36])[C:31]([CH:37]=[CH2:1])=[CH:30][N:29]=1
Reactant: [Li]CCCC
Reactant: Cc1ncc(C=O)c(CO)c1O
Agent: [Br-]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1CO
Reaction time: 1 h

Procedure:
67 Ml. of n-butyl lithium (1.9 M in n-hexane) was run into a stirred suspension of triphenylmethylphosphonium bromide (42.7 g., 0.12 M) at room temperature in tetrahydrofuran (300 ml.) under nitrogen. To this stirred solution a solution of the 3,4α-di-O-isopropylidine derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-formylpyridine (24.7 gm. 0.119 M) in tetrahydrofuran (300 ml.) was added dropwise over 1 hour. The reaction was aged 1 hour at room temperature and then refluxed for 4 hours.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[S:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[CH:8]1.O.[OH-].[K+]>C1COCC1>[S:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)=[CH:8]1
Reactant: O=C(O)c1ccc(-c2ccsc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.92 mL, 7.84 mmol) in dry THF (6.0 mL), commercially available 4-(3-thienyl)-benzoic acid (0.4 g, 1.96 mmol) in dry THF (30 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.30 mL), 3.0 M KOH solution (0.30 mL) and H2O (1.0 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness, affording the title compound (0.222 g, 65%), which was used in the next step without any further purification. 1H NMR (DMSO-d6): δ 4.51 (d, J=5.75 Hz, 2H), 5.17 (t, J=5.75 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.52-7.57 (m, 1H), 7.63 (dd, J=2.9, 5.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.81-7.86 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1I)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:1]([O:8][CH2:9][C@@H:10]1[NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1ccccc1I)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1NC(=O)c2ccccc2-c2ccccc21
Temperature: 100 °C

Procedure:
To a mixture of N—[(R)-2-(tert-butyldimethylsilanyloxy)-1-(2-iodophenyl)-ethyl]-2-iodobenzamide (60 mg, 0.159 mmol), hydroquinone (6 mg, 0.054 mmol) and Cs2CO3 (33 mg, 0.10 mmol) is added a homogenous pre-stirred solution of Pd(OAc)2 (1 mg, 0.0044 mmol) and tri-o-tolylphosphine (2 mg, 0.0065 mmol) in DMF (0.5 mL). The reaction mixture is degassed and heated under N2 at 100° C. for 5 h. The reaction mixture is cooled to RT, quenched with 2N HCl, diluted with H2O, and extracted with EtOAc. The organic phase is washed with 1N NaOH, H2O and brine, dried over MgSO4, filtered and concentrated. The crude material is purified by flash chromatography using a gradient of 0-100% . EtOAc/hexane as eluent to give the title compound as a yellow oil: (M+1)+=354.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[S:6]1(=[O:18])=[O:17].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[OH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=[CH:14]4)[CH2:10][CH2:9][CH2:8][N:7]5[S:6]3(=[O:18])=[O:17])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)N(CCCCl)c2cccc3c2N1CCC3
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S1(=O)N(CCCN2CCN(c3ccc(O)cc3)CC2)c2cccc3c2N1CCC3
Yield: 46.8 %

Procedure:
A solution of 1-(3-chloropropyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4 g), 4-(4-hydroxyphenyl)piperazine (4.75 g) and triethylamine (5.88 cc) in dry N,N-dimethylformamide (50 cc) is heated to reflux for 90 minutes and is then cooled and poured into a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The solid is recrystallized from ethyl acetate (300 cc) and dried. 1-[3-(4-(4-Hydroxyphenyl)-1-piperazinyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (2.8 g) is obtained, melting at 182° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:3][CH:4]=2)[C:8](=[O:12])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C=C(Br)c2ccccc21

Procedure:
5-methoxyindanone of formula 20 is dissolved in CCl4, N-bromosuccinimide (2 to 2.2 eq) and 2,2′-azobisisobutyronitrile (0.2 to 0.3 eq) are added thereto. The resulting mixture is further irradiated by a tungsten lamp (375W) for 3 to 5 h with stirring, to obtain the 3-bromoindenone of formula 21.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:27][CH2:26][C:10]3[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:9]=3[CH2:8]2)[O:4]C1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(=O)CC>[C:20]1([N:11]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:9]3[CH2:8][C:5](=[O:4])[CH2:27][CH2:26][C:10]2=3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)COC2(CCc3c(c(=O)c4cccnc4n3-c3ccccc3)C2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCC(C)=O
Product: O=C1CCc2c(c(=O)c3cccnc3n2-c2ccccc2)C1

Procedure:
Reflux 6,8,9,10-tetrahydro-5',5'-dimethyl-10-phenyl-spiro[benzo[b][1,8]naphthyridin-7-(5H) ,2'-[1,3]dioxan]-5-one (32 mmoles) with water (6 ml) and p-toluenesulfonic acid monohydrate (3.2 g) dissolved in 2-butanone (319 ml) for 3 days. Monitor the progress of hydrolysis by thin-layer chromatography. When hydrolysis is complete, cool the solution and evaporate the 2-butanone. Wash a CH2Cl2 solution of the residue with aqueous NaHCO3 solution and with water. Evaporate the CH2Cl2 after drying the organic solution, and crystallize the residue from C2H5OH--CHCl3 to obtain 6,8,9,10-tetrahydro-10-phenyl-benzo[b][1,8]naphthyridin-5,7-dione, m.p. 244°-247° C. (d).
Reaction SMILES: [F:1][C:2]1([C:12](OCC)=[O:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[Li+].[BH4-].CO.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(F)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1(F)CCC2(CC1)OCCO2
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of crude ethyl 8-fluoro-1,4-dioxaspiro[4.5]decane-8-carboxylate, Intermediate 30, (16.26 g, 70 mmol calculated based on previous reaction, 1 equiv) in THF (100 mL) was added LiBH4 (45.5 mL of a 2 M solution in THF, 91 mmol, 1.3 equiv) followed by MeOH (3.68 mL, 91 mmol, 1.3 equiv). Significant warming was observed following MeOH addition. The reaction was stirred 30 min at which time TLC showed no ester remaining. The reaction was poured into a saturated aqueous solution of NaHCO3 and the aqueous solution was extracted with ether (×3). The combined ether layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (30-90% ethyl acetate/hexane) to provide the title compound (7.50 g, 56% yield for 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.90-4.03 (m, 4H), 3.64 (d, J=6.78 Hz, 1H), 3.59 (d, J=6.78 Hz, 1H), 1.97-2.09 (m, 2H), 1.84-1.95 (m, 2H), 1.62-1.80 (m, 4H); 19F NMR (376 MHz, CDCl3) δ ppm −171.25 (br. s., 1F).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10](CC2C=CC(OC)=CC=2)[C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1[Cl:25])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1[Cl:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Temperature: 0 °C
Yield: 99.9 %

Procedure:
A solution of 7-chloro-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (55) (10.40 g, 27.5 mmol) in neat TFA was heated at 70° C. under argon for 36 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 7.08 g (99%) of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as white solids. MP 206° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 7.10 (d, J=5.2 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H) ppm; MS m/z=240 amu (M++1).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]1[CH2:5][O:4]1.[CH3:8][C:9]([NH2:12])([CH3:11])[CH3:10]>CO>[CH3:8][C:9]([NH:12][CH2:5][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])([CH3:11])[CH3:10]
Reactant: ClC(Cl)(Cl)C1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To 200 grams of stirred methanol were added 48.4 grams of 2-(trichloromethyl)oxirane and 21.9 grams of 1,1-dimethylethylamine at equimolar rates, dropwise, at 20° C. during 30 minutes. After stirring 16 hours at ambient temperature, the solvent was removed under reduced pressure of 100 mm. Hg and the white residue recrystallized from 300 grams of hexane to yield 50.7 grams of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol melting 100.5°-102° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.576 ml (6 mmol) 4-fluoroaniline is heated for 2 h at 90° C. The residue is then distributed between acetate and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and 25:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV (6 h, 100° C.); m.p. 129-131° C.; ESI-MS: (M+H)+=331.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]Br)([O-:22])=[O:21]>C(O)C>[C:1]([NH:4][C:5]([CH2:26][CH2:25][C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[N+:20]([O-:22])=[O:21])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl acetamidomalonate (33.2 g) in ethanol (150 ml) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (3.8 g) and ethanol (200 ml)]. The reaction mixture was stirred at room temperature for 30 minutes and a solution of 2-nitrophenethyl bromide (J. Med. Chem. 20, 1020 (1977), 40.0 g) in ethanol (100 ml) was added dropwise during 20 minutes. After addition was complete, the reaction mixture was refluxed for 18 hours, then cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in water (350 ml) and the solution extracted with ethyl acetate (2×350 ml). The combined ethyl acetate extracts were washed with water (200 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave diethyl 2-acetamido-2-(o-nitrophenethyl)malonate as a low melting solid, used without further purification for the next synthetic step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][NH:6]1)=[O:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][N:6]1[S:16]([CH3:15])(=[O:18])=[O:17])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)OC)NC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)OC)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
6-ring: To rac-cis-Piperidine-2,5-dicarboxylic acid dimethyl ester [Frank J., J. Heterocyclic Chem. 32, 857–861 (1995)] (36.2 g) dissolved in dichloromethane (720 ml) were added 4-dimethylaminopyridine (33.0 g) and, dropwise, methanesulphonyl chloride (28.6 g) within 10 minutes and room temperature. The temperature rose to 35° C. The reaction mixture was stirred 1 h at room temperature, washed with 2 molar HCl, sodium carbonate-solution and brine, dried over magnesium sulphate and concentrated to dryness to obtain (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid dimethyl ester (46.8 g) as a syrup, MS: 220 (M+-59).
Reaction SMILES: C1(S(O[CH2:11][CH:12]2[N:24]3[C:15](=[N:16][C:17]4[CH:18]=[C:19]([Br:26])[CH:20]=[CH:21][C:22]=4[C:23]3=[O:25])[CH2:14][CH2:13]2)(=O)=O)C=CC=CC=1.[CH3:27][NH2:28]>C(#N)C>[Br:26][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:25])[N:24]3[CH:12]([CH2:11][NH:28][CH3:27])[CH2:13][CH2:14][C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1C(COS(=O)(=O)c1ccccc1)CC2
Reactant: CN
Solvent: CC#N
Product: CNCC1CCc2nc3cc(Br)ccc3c(=O)n21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To the solution of (6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-yl)methyl benzenesulfonate (100 mg, 0.23 mmol) in acetonitrile (4 mL) was added aq. methylamine (2 mL). The reaction mixture was stirred at 60° C. for 4 h. After concentration, the crude product was purified by column chromatography to give the desired product. MS (ESI): 308, 310 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]2[CH2:22][CH:23]([CH3:25])[CH3:24])(=O)=O.[C-:37]#[N:38].[Na+]>CN(C)C=O>[CH3:20][N:16]1[C:17](=[O:19])[C:18]2=[C:10]([S:9][CH2:8][CH2:7][CH2:6][C:37]#[N:38])[N:11]([CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:12]=[C:13]2[N:14]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]1=[O:21]
Reactant: [C-]#N
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)n(Cc3cccc4ccccc34)cc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Yield: 27.9 %

Procedure:
5-[(3-{Methanesulphonyloxy}propyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (391 mg) was dissolved in dimethyformamide (15 ml) and sodium cyanide (254 mg) was added. The mixture was sonicated for 4 hours and then poured onto sodium bicarbonate (aqueous). The mixture was extracted thrice with ethyl acetate, the extracts were combined, washed twice with water and once with brine, then dried, filtered and evaporated. The resultant oil was chromatographed, eluting with ethyl acetate:isohexane (4:5) and then triturated with cyclohexane-ethyl acetate to give the title compound (95 mg).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:25])([F:24])[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH:14]=[CH:13][N:12]=1>CS(C)=O>[F:25][C:10]([F:9])([F:24])[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][C:20]3([O:23][CH2:4]3)[CH2:19][CH2:18]2)[CH:14]=[CH:13][N:12]=1
Reactant: O=C1CCN(c2ccnc(C(F)(F)F)n2)CC1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)c1nccc(N2CCC3(CC2)CO3)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Sodium hydride (0.48 g of 60% mineral oil dispersion, 12 mmol) in a round bottom flask was washed free of the mineral oil with hexanes before DMSO (20 mL, distilled from calcium hydride) was added. Trimethyloxosulfonium chloride (1.54 g, 12 mmol) was added and the mixture was stirred under dry nitrogen for 20 min at room temperature. A solution of XXVIII (2.45 g, 10 mmol) in DMSO (5 mL) was then added to this milky suspension. The mixture was stirred at room temperature for 30 min, and then heated in a 50° C. oil bath for 1 hr. The reaction was quenched with water (30 mL) and extracted with ether (3×60 mL). The ether extracts were washed with water (3×15 mL), dried over sodium sulfate, and concentrated in vacuo to give the product as a white solid (2.1 g, 81%).
Reaction SMILES: C(O[CH:10]1[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@:11]1([CH3:43])[O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([NH:49][CH:50]=[N:51]2)=[C:47]([Cl:54])[N:46]=1.N12CCCC=C1CCCCN2.FC(F)(F)S(OC[Si](C)(C)C)(=O)=O>C(#N)C>[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([N:49]=[CH:50][N:51]2[C@@H:10]2[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:21]([O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@:11]2([CH3:43])[O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:47]([Cl:54])[N:46]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: C1=C2CCCCNN2CCC1
Agent: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: 65 °C

Procedure:
To a pre-cooled solution of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose [Harry-O'kuru, Rogers E.; Smith, Jennifer M.; Wolfe, Michael S, “A Short, Flexible Route toward 2′-C-Branched Ribonucleosides,” J. Org. Chem., 62:1754-1759 (1997)] (1.74 g, 3.00 mmol) in acetonitrile (15 mL) was added 2-amino-6-chloropurine (0.56 g, 3.30 mmol), then diazabicyclo[5.4.0]undec-7-ene (DBU) (1.37 g, 9.00 mmol), and then dropwise trimethylsilylmethyl trifluoromethanesulfonate (TMS trifate) (2.67 g, 12.00 mmol). The resulting mixture was heated to 65° C. for 4 h, then cooled and partitioned between saturated aqueous sodium bicarbonate (200 mL) and dichloromethane (200 mL). The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was used directly in step B.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23]1([S:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8](=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: ClSc1ccccc1
Reactant: COC(=O)C1SC(=CC(=O)OC(C)(C)C)S1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1SC(=C(Sc2ccccc2)C(=O)OC(C)(C)C)S1

Procedure:
A mixture of methyl 2-(t-butoxycarbonylmethylene)-1,3-dithietane-4-carboxylate (689 mg), pyridine (430 μl) and benzenesulfenyl chloride is allowed to react in methylene chloride at 0° C. until no starting carboxylate is detected. The reaction mixture is washed with water, dried, and vacuum evaporated to give methyl 2-(1-t-butoxycarbonyl-1-phenylthiomethylene)-1,3-dithietane-4-carboxylate. Yield: 713 mg (73%).