Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCCCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 98.9 %

Procedure:
A suspension of morpholine (3.30 mL, 3.30 g, 37.8 mmol), 6-bromo-1-hexanol (6.72 g, 72.3 mmol), ethanol (20 mL), and potassium carbonate (6.23 g, 45.1 mmol) was stirred for 36 hours at 25° C., after a slight exotherm at the beginning. The reaction mixture was diluted with ethyl acetate (30 mL), filtered and concentrated. The residue was taken up in ethyl acetate, filtered and concentrated. The 7.0 g of 4-(6-hydroxyhexyl)morpholine was isolated as a yellow oil and used as is.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[O:8]1.Cl[C:20]1[S:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:28][O:27][C:25]([C:22]1[S:21][C:20]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])[CH2:16][CH2:15]3)=[N:24][CH:23]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)s1
Reactant: Cc1ccccc1C1CCc2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCC(c2ccccc2C)O3)s1
Temperature: 50 °C
Reaction time: 10 h
Yield: 97.6 %

Procedure:
A suspension of 2-o-Tolyl-chroman-6-ol (2.5 g, 10.4 mmol), methyl 2-chloro-thiazole-5-carboxylate (1.9 g, 10.6 mmol, 1.02 eq) and potassium carbonate (1.9 g, 1.3 eq) in dimethylformamide (30 ml) was stirred at 50° C. for 10 h. The suspension was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water, dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). The product was obtained as a pale yellow solid (3.87 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)=[O:14].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[F:23][C:22]([F:25])([F:24])[C:18]1[N:17]=[C:16]([NH:15][C:13](=[O:14])[NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=4)[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
1.500 g of 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea (3.65 mmol), 1.692 g of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.47 mmol), 0.422 g of tetrakis(triphenylphosphine)palladium(0) (0.365 mmol) and 8.21 ml of a 2M sodium carbonate solution (16.42 mmol) were dissolved/suspended in 32 ml DMF in a microwave vessel, flushed with vacuum/argon, and subsequently heated in the microwave for 1 h at 80° C. HPLC/MSD indicated almost complete formation of the desired product. The reaction mixture was poured on ice, stirred for 1 h, and the precipitation formed was filtered off and dried in vacuum for 24 h. 2 g of the desired product were obtained as an off white powder (yield: quant.). The quite pure raw material was used without further purification in the next step.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CS(O[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)(=O)=O>C(O)C.C(OCC)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2
Reactant: NCCO
Reactant: CS(=O)(=O)OCCc1cccc2cc[nH]c12
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCNCCc1cccc2cc[nH]c12
Yield: 84.6 %

Procedure:
Add ethanolamine (5 mL, 82 mmol) to a solution of 7-(2-(methanesulfonyloxy)eth-1-yl)indole (0.79 g, 3.3 mmol) in ethanol (50 mL) and stir the reaction mixture at reflux overnight Dilute with ethyl acetate (150 mL), wash sequentially with water (3×50 mL) and saturated aqueous sodium chloride (2×50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to provide 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole as a light-brown solid (0.57 g, 85%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: CCc1ccccc1NC(=O)CC#N
Product: CCc1ccccc1NC(=O)C(C#N)=CN(C)C

Procedure:
As for Example 1, 2-cyano-2'-ethylacetanilide as long needles, m.p. 128°-130° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-3-dimethylamino-2'-ethylacrylanilide as colorless prisms, m.p. 102.5°-104° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:38]1.C1(C)C=CC=CC=1>C[C-]1C=CC=C1.[C-]1(C)C=CC=C1.[Ti+2].C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][C:15]([C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=2)=[CH2:38])[C@@H:9]1[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Fc1ccc([C@H]2[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OCCN2Cc2ccccc2)cc1
Agent: [Ti+2]
Agent: C[c-]1cccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 4-benzyl-2-(R)-[3,5-bis(trifluoromethyl)benzyloxy]-3-(S)-(4-fluorophenyl)morpholine (2.50 g, 4.9 mmol) and dimethyl titanocene (2.50 g, 12.0 mmol) in 35 ml of a 1:1 v/v tetrahydrofuran:toluene mixture is stirred in an oil bath at 80° C. for sixteen hours. The reaction mixture is cooled and centrated in vacuo. Flash chromatography on 150 grams of silica gel using 3:1 v/v hexanes:methylene chloride as the eluant affords 1.71 grams (69%) of the title compound as a solid. If desired, an anlytical sample may be obtained by recrystallization from isopropanol.
Reaction SMILES: [CH2:1]([Si:4](Cl)(Cl)Cl)[CH:2]=[CH2:3].[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC>[CH2:1]([Si:4]([O:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:15][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:15][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccccc1
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=CC[Si](OC(=O)c1ccccc1)(OC(=O)c1ccccc1)OC(=O)c1ccccc1
Yield: 74 %

Procedure:
878 g (5 moles) of allyltrichlorosilane and 1000 ml of hexane are placed in the apparatus of Example 1. The reaction with 1855 g of benzoic acid (=15.2 mol) is performed as described in Example 1, as is also the distilling of the raw product. At a pressure of 0.4 mbar and a head temperature of 137° C., 1599 g (3.7 mol) of a colorless liquid is distilled out, which several days later transforms to a sticky-crystalline state. The yield of 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2cc(Cl)ccc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 6.5 parts of 5-chloro-2-methyl-1H-benzimidazole-1-propanol and 120 parts of trichloromethane are added dropwise 12 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the mixture is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromaethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1-(3-chloropropyl)-2-methyl-1H-benzimidazole.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:59]=[CH:60][CH:61]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([O:46]CC2C=CC=C(CN3CCC3)C=2)=[O:45])[CH2:25][CH2:24][CH2:23]1.[OH-].[Na+]>O1CCCC1>[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:59]=[CH:60][CH:61]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([OH:46])=[O:45])[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CN5CCC5)c4)n3Cc3cccc(CN4CCC4)c3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(CN4CCC4)c3)n12
Reaction time: 1 h

Procedure:
3-(Azetidin-1-ylmethyl)benzyl 6-[3-(azetidin-1-ylmethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate tris(trifluoroacetate) (0.15 g, 0.17 mmol, from Step 6) was dissolved in tetrahydrofuran (5 mL) and 1.0 M NaOH (5 mL, 5 mmol) was added. The reaction was stirred for 1 hour. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) Yield: (0.033 g, 51%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>C(O)C>[N:7]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1cccc(CBr)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1cccc(CN2CCCC2)c1
Temperature: 65 °C
Yield: 88.5 %

Procedure:
A suspension of K2CO3 (2.09 g, 15.2 mmol, 3.00 equiv) in absolute ethanol (20 mL) was treated with pyrrolidine (439 μL, 5.05 mmol, 1.00 equiv). 3-(bromomethyl)-benzaldehyde (1.00 g, 5.05 mmol, 1.00 equiv) was introduced, and the reaction was heated to 65° C. for 1 h. The reaction was cooled and filtered. The cake was washed with more ethanol. The filtrate was concentrated to a cloudy oil and partitioned between DCM (50 mL) and 2% w/v aq NaHCO3 (50 mL). The organic phase was collected, and the aq layer was extracted with DCM (2×50 mL). All organic layers were combined, dried (Na2SO4), filtered, and concentrated, giving 3-(pyrrolidin-1-ylmethyl)-benzaldehyde (846 mg, 88% yield) as a pale yellow oil, which was used without further purification. 1H-NMR: 300 MHz, (CDCl3) δ: 10.00 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.47 (dd, J=7.6 Hz, 7.6 Hz, 1H), 3.69 (s, 2H), 2.52 (m, 4H), 1.79 (m, 4H). LCMS-ESI+: calc'd for C12H16NO: 190.1 (M+H+). Found: 190.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].C(O)(=O)C.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:22]([O-:24])=[O:23])[C:6]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1c(C)cccc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Yield: 94.7 %

Procedure:
To a mixture of 30.1 g of N-acetyl-2,6-xylidine (0.18 mole) and 40 ml of acetic acid (0.70 mole) was added gradually 80 ml of concentrated sulfuric acid (0.50 mole) with stirring under ice-cooling. Then, to the mixture was added slowly 10 ml of fuming nitric acid (0.24 mole) in a manner such that the temperature of the reaction mixture did not exceed 10° C. The reaction mixture was returned to room temperature and, after stirring for 2 hours, poured onto ice. The resulting crystalline precipitate was collected by filtration and recrystallized from ethanol to give 35.5 g (92%) of the title compound (m.p. 171°-173° C.; pale yellow needles).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>CO>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:31][CH2:30]1
Reactant: CN1CCC(=O)CC1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Solvent: CO
Product: CN1CCC(Nc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1

Procedure:
This was similarly prepared 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide and 1-methylpiperidin-4-one. MS (ESI) m/z 468.30 (M+H); HPLC retention time of 1.85 min with Xbridge S10 4.6×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 95% MeOH—5% H2O—0.1% TFA; Solvent B: 5% MeOH—95% H2O—0.1% TFA.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[P:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[CH:1]([NH:4][P:6]([NH:4][CH:1]([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: ClP(Cl)c1ccccc1
Solvent: CCOCC
Product: CC(C)NP(NC(C)C)c1ccccc1
Reaction time: 72 h
Yield: 33 %

Procedure:
To a stirred solution of isopropylamine (30 ml, 352 mmol) in diethylether (250 ml), dichlorophenylphosphine (9.63 ml, 71 mmol, dissolved in 50 ml diethylether) was added at 0° C. over a period of 30 min. After stirring for a total of 72 hrs the solution was filtrated. The residue was washed with diethylether and the solvent was removed in vacuum. The remaining oil was distilled at 0.2 Torr/76-78° C. to give a colorless liquid with 33% yield (5.3 g). 31P{H} NMR: 49.0 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=[C:36]=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CNC>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:35]([CH3:36])[CH3:33])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N(C)C)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), dimethylamine (2M solution in tetrahydrofuran, 1.1 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (370 mg, 69%) as pale yellow prisms. MS 489 (MH+). mp 206-207° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CN=C1>[Si:9]([O:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C1CC[C@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)O1

Procedure:
The methodology of Taniguchi et al. (Tetrahedron, 30, 3532, 1974) and Farina et al. (Tetrahedron Lett., 29, 1239, 1988) for the syntheses of D-ribose derivatives provided a model for our synthetic approach to the syntheses of the corresponding L-ribose derivatives. Nitrous acid deamination of D-glutamic acid (1) gave lactone 2, which was then converted to the corresponding ester 3 by treatment of compound 2, with ethanol and catalytic amount of p-toluenesulfonic acid (See Scheme 1). Reduction of compound 3 with NaBH4 in ethanol gave (R)-4-(hydroxymethyl)-4-butyrolactone (4). Protection of the hydroxy group of compound 4 with tert-butyldimethylsilyl chloride in methylene chloride using imidazole as catalyst produced (R)-4-([(tert-butyldimethylsilyl)oxy]methyl)-4-butyrolactone (5), which was then converted to the corresponding lactol 6 by reduction with diisobutyaluminum hydride (DIBAL) in toluene at -78° C. Acetylation of 6 with acetic anhydride and triethylamine afforded the key sugar intermediate, 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (7) as a mixture of alpha and beta anomers: MS, m/e 231 (M+ --CH3CO), 215 M+ --CH3COO); NMR(CDCl3)) delta 0.10 (s, 6H, SiMe2), 0.95 (s, 9H, tert-butyl), 1.85-2.15 (m, 7H, CH2CH2 and COCH3), 3.50-3.65 (M, 2H, 5-H), 4.10-4.30 (m, 1H, 4-H), 6.20-6.30 (m, 1H, 1-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: N#Cc1ccc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([CH3:25])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:17]=1>>[CH3:24][N:22]([CH3:23])[C:18]1[CH:17]=[C:16]([C:15]2[NH:14][N:13]=[C:12]([CH3:25])[C:11]=2[NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1n[nH]c(-c2cccc(N(C)C)c2)c1N
Product: Cc1n[nH]c(-c2cccc(N(C)C)c2)c1NC(=O)c1ccccc1
Reaction time: 16 h

Procedure:
The preparation was carried out as in Example 22A, using 460 mg of benzoyl chloride and 700 mg of 4-amino-5-(3-dimethylamino-phenyl)-3-methylpyrazole, except the reaction mixture was stirred for 16 h and the residue was purified by MPLC (ethyl acetate as eluant) to give the title compound as a tan solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][N:50]1[CH2:54][CH2:53][C@H:52]([NH:55]C(=O)OC(C)(C)C)[CH2:51]1>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:48][CH2:49][N:50]3[CH2:54][CH2:53][C@H:52]([NH2:55])[CH2:51]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCO)C1
Agent: c1ccc2[nH]ccc2c1
Product: N[C@H]1CCN(CCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-tert-butyl 1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.91 (s, 2 H), 8.37 (s, 1H), 8.08 (d, J=1.6 Hz, 2 H), 7.40-7.29 (m, 4 H), 4.43-4.33 (m, 2 H), 3.88-3.78 (m, 1 H), 3.09-2.96 (m, 2H), 2.95-2.74 (3 H), 2.61 (dd, J=9.6, 5.0 Hz, 1 H), 2.43-2.31 (m, 1 H), 1.79-1.68 (m, 1 H); MS (ESI) m/z 451.1 (M−H)−; MS (ESI) m/z 453.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH3:33])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 50 °C
Yield: 29.1 %

Procedure:
To a solution of 2-(4-(4-fluorophenoxy)benzylthio)-5-((2-methoxypyrimidin-5-yl)methyl) pyrimidin-4(1H)-one (100 mg, 0.222 mmol) and Hunig's base (0.058 mL, 0.333 mmol) in DCM (4 mL) was added MeI (0.021 mL, 0.333 mmol). The mixture was heated at 50° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (30 mg, 29.1% yield). LCMS: rt=3.05 min, [M+H]=465.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[N:8]([O:10]CCC(C)C)=[O:9]>>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)CCON=O
Reactant: Cn1nccc1N
Product: Cn1ncc([N+](=O)[O-])c1N

Procedure:
Total yields of up to 46 percent are obtained when the 5-amino-1-methylpyrazole is converted with isoamyl nitrite to produce 5-amino-1-methyl-4-nitropyrazole and reduced with zinc(II)chloride to give 4,5-diamino-1-methylpyrazole according to H. Dorn, et al., Liebigs Ann. Chem. 717, p. 118 (1968).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([OH:3])=[O:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:3][CH2:15][CH3:16])=[O:2]
Reactant: O=C(O)CCCCC1CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCC1CCCC1=O

Procedure:
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, diluted sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109° C. (0.23 mm).