Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]2[CH2:16][CH2:17][C:12]1([C:18]([OH:20])=O)[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[NH2:21][C:18]([C:12]12[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:20]
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A stirred solution of 7-[(benzyloxy)carbonyl]-7-azabicyclo[2.2.1]heptane-1-carboxylic acid (C-35) in dioxane was treated with pyridine (0.8 eq.) and Boc2O (1.5 eq.), then ammonium bicarbonate (1.46 eq.) was added and the mixture was stirred at room temperature for 15 hours. Dioxane was concentrated and the residue was taken up in ethyl acetate, washed with HCl 1N and brine and dried over Na2SO4 to give, after filtration and concentration, the titled compound (C-36).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].ClC1C=C(C=CC=1)C(OO)=[O:35]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH2:26][CH2:27][CH2:28][OH:29])=[O:35])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCSCCCO)ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCS(=O)CCCO)ccc1Cl
Yield: 56.3 %

Procedure:
Prepared according to the method of Example 14 using 2-chloro-5-[2-(3-hydroxypropylthio)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 15, 0.12 g) and 3-chloroperoxybenzoic acid (0.07 g, 70%) to give the title compound (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:32][CH2:33][C:34](=O)[CH2:35][CH3:36].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][CH:34]([CH2:35][CH3:36])[CH2:33][CH3:32])[CH:5]=1
Reactant: CCC(=O)CC
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)Nc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (200 mg, 0.87 mmol, 1 equiv) in (CH2Cl)2 (5 ml) were added sodium triacetoxyborohydride (1.536 g, 5.22 mmol, 6 equiv), 3-pentanone (0.546 ml, 5.22 mmol, 6 equiv) and AcOH (0.050 ml, 0.87 mmol, 1 equiv). The resulting mixture was stirred at room temperature for 48 h, diluted with CH2Cl2 (20 ml), washed with saturated aqueous NaHCO3 solution (20 ml), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOH: 3/2) gave 3-(1-ethyl-propylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B43) (106 mg, 40%) as a colourless oil. [M+H]+=305.0 RT=3.19
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[C:37]([C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[F:46])[NH2:42])#[CH:38]>ClCCCl>[C:37]([C:39]1[CH:40]=[C:41]([NH:42][C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:43]=[CH:44][C:45]=1[F:46])#[CH:38]
Reactant: C#Cc1cc(N)ccc1F
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C#Cc1cc(Nc2ncnc3cnc(C)cc23)ccc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 13.3 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4-one (44 mg, 0.27 mmol), polymer -supported triphenylphosphine (0.462 g of about 3.0 mmol P/g resin, 1.55 mmol) and anhydrous carbon tetrachloride (0.261 mL, 2.71 mmol) were combined in 1,2-dichloroethane (1.25 mL). The reaction mixture was heated to 60° C. under an atmosphere of dry nitrogen for 2 hours. 3-Ethynyl-4-fluoro-aniline (55 mg, 0.407 mmol) was added and heating was continued at 60° C. for 6 hours. The polymer was filtered off and washed several times with 50% methanol/chloroform. The filtrate and washings were concentrated in vacuo and flash chromatographed on silica with gradient from 0 to 10% methanol/methylene chloride to afford the title product (10 mg; M.P. 225° C.; LC-MS: 279 (MH+); anal. RP-HPLC: 3.94 min.).
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=O)[CH2:5][CH2:4]1.[C:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH2:32])[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]([S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[NH:32][C:27]3[CH:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:30]=[CH:29][C:28]=3[N:31]=2)[CH2:5][CH2:4]1
Reactant: Nc1ccc(-c2ccccc2)cc1N
Reactant: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)C(C)(C)C
Product: CN([C@H]1CC[C@H](c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1)S(=O)(=O)C(C)(C)C

Procedure:
Trans-4-(N-methyl-tert-butylsulfonylamino)cyclohexanecarboxylic acid and 4-phenyl-1,2-phenylenediamine were allowed to undergo ring closure condensation under the same conditions as described in Example 1-3), followed by separatory purification on a collective thin-layer chromatograph (chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: CCI
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cccc(Cl)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-chloro-6-hydroxybenzaldehyde (2.000 g; 12.80 mmol), iodoethane (3.985 g; 25.50 mmol), and K2CO3 (2.119 g; 15.30 mmol) in anh. DMF (35 ml) was heated to 80° C., under nitrogen, for 1 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-6-ethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 185.39 g/mol.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)[CH3:21].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([CH2:3][C:4]2[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[C:24]([OH:36])[N:23]=1)[CH3:21]
Reactant: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 (323 mg, 1.07 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 94:6) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided, after evaporation, 60 mg of 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.04 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 43 as a yellow solid (69 mg, 12% yield).
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Amino-2-methylbenzoic acid (6.16 g) was heated at reflux for 30 minutes in concentrated HBr. The mixture was cooled to 0° C. and treated with a solution of NaNO2 at 0° C. (2.8 g in 5.6 mL H2O). The resultant diazonium salt solution was slowly added to a preheated (60-70° C.) solution of CuBr (3.8 g) in 3.2 mL concentrated HBr. After the addition, the mixture was stirred overnight at room temperature and filtered. The recovered filter cake was washed first with water and then with 10% HCl, and dried in air to yield 6.93 g of 3-bromo-2-methylbenzoic acid as a light purple powdery solid. This material was dissolved in ethyl acetate, washed twice with 5% HCl dried over Na2SO4, and recrystallized from 4:1 hexanes:ethyl acetate first at room temperature and then under refrigeration. 1H NMR (DMSO, 200 MHz), δ (ppm): 7.72 (dd, 2H), 7.2 (t, 1H), 2.5 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O>CC(C)=O>[CH2:15]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][O:4][C:2]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[O:3])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC(CCCCCC)COC(=O)Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCC(CCCCCC)COC(=O)n1cncn1
Reaction time: 16 h
Yield: 67.4 %

Procedure:
2-Hexyldecyl chloroformate (90 g) was added during 30 minutes to a stirred suspension of potassium carbonate (41 g), and 1,2,4-triazole (21 g) in acetone (350 ml). During addition the temperature of the reaction mixture rose from ambient (22°) to 40°. The mixture was stirred for 16 hours and then poured into water (750 ml) and extracted with toluene. The toluene solution was distilled giving 1-(2'-hexyldecyloxycarbonyl)-1,2,4-triazole (67.1 g), b.p. 165°-175° at 0.4 mm of mercury.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nn1ccc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
A solution of pyrrolo[2,3-c]pyridine (8.47 mmol) and potassium tert-butoxide (16.9 mmol) in DMF (38 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (84.6 mL) is added drop-wise at rt, and the reaction mixture is stirring at rt for 2 h., quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford pyrrolo [2,3-c]pyridin-1-ylamine (226 mg, 11%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.96 (br, 2N—H), 6.43 (d, H), 7.29 (m, H), 7.50 (d, H), 8.29 (d, H), 8.89 (s, H).
Reaction SMILES: N1C=CN=C1.[C@@H:6]1([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:12][CH2:11][C@H:10]1[O:13][C@@H:6]([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:7][C@@H:8]1[OH:9])([CH3:24])[CH3:23]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (0.183 g, 2.69 mmol) was added to a solution of 2′-deoxyuridine (0.272 g, 1.19 mmol) in dry DMF (5 mL) under nitrogen. The mixture was cooled in an ice-salt bath before drop-wise addition of triisopropylsilyl chloride (0.28 mL, 1.31 mmol) via a syringe. The reaction mixture was kept at 0° C. for 3 h, allowed to warm up to room temperature and then stirred at room temperature for 22 h. After addition of water (5 mL), the crude mixture was extracted with CHCl3 (2×10 mL). The organic layers were combined and dried over MgSO4. Removal of the solvent under reduced pressure afforded a crude transparent oil which was further purified by flash chromatography eluting the column (ISOLUTE SI) a gradient of 0→10% CH3OH in CHCl3. The title compound was obtained from the fractions with Rf=0.25 (10% CH3OH in CHCl3) as a crystalline white solid (0.366 g, 74%). M.p. 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[N+](C1C=CC([O:19][C:20]([C:22]2[C:30]3[S:29][C:28]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:27][C:26]=3[C:25]([O:37][CH3:38])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O>CN(C)C=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:20]([C:22]1[C:30]2[S:29][C:28]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[N:27][C:26]=2[C:25]([O:37][CH3:38])=[CH:24][CH:23]=1)=[O:19])#[N:9]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCCCC3)nc12
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCCCC3)nc12
Yield: 75.5 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (125 mg) in dimethyl formamide (10 ml), sodium hexamethyldisilazide in tetrahydrofuran (1.1 ml, 1.0 M), and 4-methoxy-2-(piperidin-1-yl)benzothiazole-7-carboxylic acid 4-nitrophenyl ester (210 mg). Purification by flash chromatography (eluent 5% methanol in dichloromethane) followed by trituration with ethyl acetate yielded the title compound as an off-white solid (152 mg). TLC Rf 0.48 (ethyl acetate); Mpt 290-291° C.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[F:9][C:10]([F:20])([F:19])[CH2:11][I+]C1C=CC=CC=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[F:9][C:10]([F:20])([F:19])[CH2:11][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)C[I+]c1ccccc1
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)CNc1ccccc1
Yield: 90.8 %

Procedure:
250 mg (0.573 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate, 107 mg (1.15 mmol) of aniline and 5 ml of methylene chloride were reacted and worked up in the same manner as described in Reference Example 4 to obtain 91.1 mg of N-(2,2,2-trifluoroethyl)aniline as an oily substance. Yield, 92%.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][OH:7])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: OCCNCCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCNCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a solution of diethanolamine (1.097 g, 10.43 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.216 g, 56%). Mass (m/z): 385.2 (M++1), 383.1 (M+−1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:34][CH2:33][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:31])[C:21]=4[C:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[O:24][CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].C[Si](C)(C)[NH:37][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]1[CH2:34][CH2:33][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:37][C:20](=[O:31])[C:21]=4[C:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[O:24][CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4coc5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1CCn2c(c(C3=C(c4coc5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)furan-2,5-dione in 100 ml of chloroform was treated with 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and the solution obtained was heated to 50° C. while stirring under a nitrogen atmosphere for 6 hours. An additional 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol were added and the heating was continued for 16 hours. Two more additions of the same quantities of hexamethyldisilazane and methanol were effected and the temperature of the mixture was held at 50° C. for an additional 24 hours. Then, 20 ml of methanol were added and the mixture was heated to reflux for 15 minutes, cooled and concentrated. The precipitate was filtered off and triturated in succession with ethyl acetate and methanol. There were obtained 630 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-1H-pyrrole-2,5-dione of melting point 234°-237° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C1COCC1.Cl>[Br:15][C:13]1[CH:12]=[CH:11][C:7]2[C:8](=[O:10])[O:9][C:1](=[O:2])[NH:5][C:6]=2[CH:14]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reaction time: 2 h

Procedure:
Phosgene (1.9 M in toluene, 18.4 mL, 35 mmol) was added dropwise over 1 h to a solution of 2-amino-4-bromobenzoic acid from Step A (2.5 g, 11.7 mmol) in THF (30 mL) and 1 N HCl (20 mL). After 2 h, the precipitate was collected by filtration, washed with H2O, then ethyl acetate, and dried in vacuo to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[CH:15]([CH3:17])[CH3:16].CCO>[Pd].C(N(CC)CC)C>[ClH:1].[CH:15]([CH:8]1[C:9]2[C:4](=[CH:3][CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:5][CH2:6][NH:7]1)([CH3:17])[CH3:16]
Reactant: COc1ccc(Br)c2c1C(C(C)C)NCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(C(C)C)NCC2
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To 5-bromo-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.0 g) were added EtOH (30 mL), triethylamine (1.3 mL), and 10% palladium-supported carbon (0.30 g), followed by stirring under a hydrogen atmosphere for 2 hours. The reaction liquid was filtered through celite and the solvent was evaporated. An aqueous 1 M NaOH solution was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in EtOAc (30 mL). 4 M HCl/EtOAc (5 mL) was added to the mixture, and the precipitated solid was collected to obtain 1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-:14]#[N:15].[Na+]>CS(C)=O>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]=2[O:9]1
Reactant: [C-]#N
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[C:19](OCC)(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCO
Product: CC(=O)CC(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 145 °C
Yield: 48.7 %

Procedure:
A mixture of 22.1 g (0.09 mol) of N-(6-hydroxyhexyl) phthalimide and 10.2 g (0.08 mol) of ethyl acetoacetate was heated in an oil bath at 145° C. under nitrogen for 15 hours. After drying on high vacuum the residue was subjected to flash chromatography (silica gel, 7:3 petroleum ether/ether). The product was isolated as 12.9 g (75%) of a pale yellow oil b.p. 218°-226° C./0.15 mm. NMR: (CDCl3) w 1.5 (8H, m), 2.21 (3H, s), 3.35 (2H, s), 3.55 (2H, m), 3.99 (2H, t), 7.5 (4H, m).
Reaction SMILES: [C:1]([C:4](CC(O)=S)=[S:5])(=[O:3])[NH2:2].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>C(O)C.O>[C:1]([C:4]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:12]([O:11][CH3:10])[CH:13]=1)=[S:5])(=[O:3])[NH2:2]
Reactant: COc1ccc(N)cc1OC
Reactant: NC(=O)C(=S)CC(O)=S
Solvent: CCO
Solvent: O
Product: COc1ccc(NC(=S)C(N)=O)cc1OC
Reaction time: 2 h

Procedure:
The solution of carbamoyl-thiocarbonyl thioacetic acid prepared above was added to a solution of 3,4-dimethoxy-aniline (20 g) in ethanol (100 ml) and water (100 ml). The mixture was allowed to stand in a sealed vessel for 2 hr. The ethanol was evaporated under reduced pressure until crystallisation occurred. The product was collected by filtration, washed with cold ethanol, and dried to give N-(carbamoyl-thiocarbonyl-)-3,4-dimethoxy-aniline (14.13 g); m.p. 149°-151° C.