Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[NH2:12][CH2:13][CH2:14][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1

Procedure:
1 mmol of 2-amino-6-chloro-3-nitropyridine and 15 mmol of 1,2-diaminoethane were stirred at reflux for fourteen hours. The reaction mixture was concentrated in vacuo and solution of 1.5 mmol of NaOH in water was added. This solution was extracted twice with 95%/5% methylene chloride/ methanol. The aqueous was then saturated with salt and extracted twice with 95%/5% acetonitrile/ methanol and then finally extrated twice with 95%/5% ethylacetate/methanol. All organic fractions were combined and dried over sodium sulfate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:9]=[C:10]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:5]2=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[NH:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:3][CH:4]=2)[N:8]([CH2:20][CH2:21][CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2nc(Nc3c(Cl)cccc3Cl)c3cnc(Cl)nc32)CC1
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Clc1cccc(Cl)c1Nc1nn(CCC2CCNCC2)c2nc(Nc3ccccc3)ncc12

Procedure:
A solution of 48.5 mg (0.09 mmol) of tert-butyl 4-(2-(6-chloro-3-(2,6-dichlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)piperidine-1-carboxylate 93 in 5 mL 1,4-dioxane was treated sequentially with 17 μl (0.2 mmol) of aniline and 525 μl (7.1 mmol) of TFA. The resulting orange solution was heated at reflux for 22 h, and then was concentrated. The residue was purified by chromatography on silica gel (CH2Cl2:MeOH, 9:1) to give the title compound 94. 1H-NMR (CD3OD) δ 1.22-1.45 (m, 3H), 1.66-1.78 (m, 2H), 1.91-2.02 (m, 2H), 2.10 (s, 1H), 2.62-2.74 (m, 2H), 3.10-3.23 (m, 2H), 4.15 (t, J=6.3 Hz, 2H), 6.99 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 7.23-7.31 (m, 2H), 7.42 (t, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 8.56 (s, 1H). Mass Spectrum (ESI) m/e=482.0 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:26])[C:32]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.782 g, 0.00217 mol) in THF (30.0 mL) was added NaH (0.156 g, 0.00650 mol) and the mixture was stirred for 1 h. To this was added 2-amino-4-chloro-3-nitropyridine (0.376 g, 0.00217 mol) and the mixture was stirred overnight. The solution was concentrated and the residue was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound (0.381 g, 35%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[CH2:16]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL of methanol under inert atmosphere, 35.2 g (0.592 moles) of glacial acetic acid and 50 mL of methanol was added followed by a solution of 62.83 g (0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture was cooled to approximately 15° C. and a solution of 134.6 g (2.14 moles) of sodium cyanoborohydride in 700 mL of methanol was added in approximately 40 minutes, keeping the temperature between 15° C. and 25° C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and partitioned between 1 L of 2M ammonium hydroxide solution and 2 L of ether. The ether layer was washed with 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500 mL of brine and dried over magnesium sulfate for 1 hour. The ether layer was filtered, concentrated under reduced pressure and the crude solid product was recrystallized from 110 mL of ethyl acetate and 1.3 L of hexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[C:10]=2[N:11]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:8](=[O:28])[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[N:11][C:10]2=3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1

Procedure:
tert-Butyl {1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 80) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:28][N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6cn[nH]c6)cn45)CC3)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-{1-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline (6 mg, 0.017 mmol) in N,N-dimethylformamide (200 μL) was added potassium carbonate (4.0 mg, 0.029 mmol) and methyl iodide (3 μL, 0.048 mmol). After stirring at RT for 16 h, the reaction mixture was purified by RP-HPLC to afford the desired product. LCMS: (M+H)=367.0.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed acid-free with about 2 liters of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:25]=[C:26]([CH:36]([NH:38][C:39]([C:41]2[O:42][C:43](Br)=[CH:44][CH:45]=2)=[O:40])[CH3:37])[CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([CH:36]([NH:38][C:39]([C:41]2[O:42][C:43]([C:6]3[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)=[CH:44][CH:45]=2)=[O:40])[CH3:37])[CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32]
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cc(C3CC3)cc(C(F)(F)F)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 18.2 %

Procedure:
2-(3-Cyclopropyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (120 mg, 0.26 mmol) and 5-Bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (18 mg, 0.03 mmol), Cs2CO3 (250 mg, 0.77 mmol) as described in example 102 to give the title compound (25 mg, 18%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[C:16]([Br:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:14]1[CH:15]=[C:16]([Br:17])[C:4]2[O:3][C:2]([Br:1])=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:13]=1
Reactant: Cc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
A mixture containing 68.7 g. (0.19 mole) of 2,7-dibromo-5-methyl-3-phenylbenzofuran and 35.5 g. (0.19 mole) of N-bromosuccinimide in one liter of carbon tetrachloride is irradiated with a bulb simulating sunlight for two hours. An additional 10 g. of N-bromosuccinimide is added, and irradiation is continued for one hour. The mixture is cooled and filtered. The filtrate is evaporated to a brown oil which crystallizes when triturated with hexane to provide solid 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].C(#N)C.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Br-:14].[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([CH3:10])[S:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1sc(CO)c(C)c1C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Temperature: 50 °C

Procedure:
2.2 G. of 2-hydroxymethyl-3,4,5-trimethyl-thiophene were dissolved in 25 ml. of acetonitrile and 4.6 g. of triphenylphosphonium bromide were added. The resulting reaction mixture was heated to 50° C. for 3 hours. After evaporation of the solvent, the residue which formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5-trimethyl-2-thenyl)-triphenyl phosphonium bromide obtained was dried at 50° C. under high vacuum and had m.p. 208°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12](I)=[CH:11][N:10]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1CCCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:11][N:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(-c2cnc(I)cn2)c(Cl)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cnc(-c2ccc(Cl)cc2Cl)cn1

Procedure:
The product was prepared analogously to Example 48.1c from 450 mg (1.28 mmol) of 2-(2,4-dichlorophenyl)-5-iodopyrazine and 0.20 mL (1.41 mmol) of trimethylsilylacetylene (using triethylamine as base). Yield: 300 mg (73% of theoretical); C15H14Cl2N2Si (M=321.276); calc.: molpeak (M+H)+:321/323/325 (2 Cl); found: molpeak (M+H)+:321/323/325 (2 Cl); Rf value: 0.6 (silica gel, cyclohexane/EtOAc 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[CH3:1][C:2]1[C:10]2[C:5]([N:6]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(-c2ccccc2)[nH]c2ncccc12
Product: Cc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1

Procedure:
The title compound was prepared from 3-methyl-2-phenylpyrrolo[2,3-b]pyridine and phenacylbromide on a 4 mmol scale according to the procedure described in example 8 yielding 1.58 g (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:4][C:3]=1[F:10]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)c(F)c1
Product: O=C(C=Cc1ccc(Cl)c(F)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chloro-3-fluorobenzaldehyde and acetophenone, 3-(4-chloro-3-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1)=O>O1CCCC1>[C:7]([CH:9]=[CH:18][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1)#[N:8]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(C=CC#N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.0 M potassium tert-butoxide in THF (2.0 mL, 2.0 mmol) was added diethyl cyanomethylphosphonate (0.30 mL, 1.8 mmol) dropwise at 0° C. and the mixture was stirred at 0° C. for 1 h. A solution of tert-butyl (3-formylcyclohexyl)carbamate (0.30 g, 1.3 mmol) in tetrahydrofuran (9.3 mL) was added dropwise, then cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, concentrated and purified on silica gel column (eluting with 0-30% EtOAc in hexanes) to give the desired product as a mixture of cis- and trans-isomer mixtures (0.12 g, 36%). LCMS calculated for C14H22N2O2Na (M+Na)+: m/z=273.2. Found: 273.1.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([Cl:12])[CH:10]=2)[N:5]([C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(C3C=CC(C)=CC=3)=O)[C@@H:16]([O:17]C(C3C=CC(C)=CC=3)=O)[CH2:15]2)[C:4]=1Cl)=[O:2].[CH3:41][O-:42].[Na+].CO.C(Cl)(Cl)Cl>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:13])[N:5]([C@@H:14]1[O:28][C@H:27]([CH2:16][OH:17])[C@@H:29]([OH:30])[CH2:15]1)[C:4]([O:42][CH3:41])=[C:3]2[CH:1]=[O:2]
Reactant: C[O-]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3c(Cl)c(C=O)c4cc(Cl)c(Cl)cc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-Formyl-2,5,6-trichloro-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.113, 198 mg, 0.33 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (75 mg, 1.4 mmol). The suspension was stirred at room temperature for 16 h, after which time the solution clarified. The solvent was then removed under vacuum, and the residue was suspended in water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated to yield a damp solid. The crude material was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid. The solid was recrystallized from warm MeOH to yield 82 mg (68%) of 4.114 as a white crystalline solid: mp 186-187° C.; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 6.32 (dd, 1H), 5.37 (b, 1H, D2O exch.), 5.15 (b, 1H, D2O exch.), 4.43 (s, 3H), 4.41 (m, 1H), 3.83 (d, 1H), 3.68 (m, 2H), 2.53 (m, 1H), 2.11 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 183.22, 159.16, 129.40, 125.04, 124.73, 124.66, 121.11, 114.24, 100.02, 87.29, 82.99, 70.07, 64.16, 61.03, 38.43. HRMS (EI) m/z calcd. for C15H15Cl2NO5 359.0327, found 359.0320. Anal calcd for C15H15Cl2NO5·½H2O: C, 48.80; H, 4.37; N, 3.79. Found: C, 48.48; H, 4.61; N, 3.61.
Reaction SMILES: [CH2:1]([N:3]([C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:22][CH2:21]1
Reactant: BrCCCCBr
Reactant: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CCN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibromobutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide as colorless oil, MS 470 (M−CH3, 1Br).
Reaction SMILES: O[C@@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:27]([OH:30])(=[S:29])[CH3:28].Cl>O1CCCC1>[C:27]([S:29][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1)(=[O:30])[CH3:28]
Reactant: CCOC(=O)C1=CCOC[C@@H]1O
Reactant: CC(O)=S
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCOC[C@H]1SC(C)=O
Temperature: -45 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, to a solution (500 mL) of ethyl (3R)-3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (23.5 g) in tetrahydrofuran was added dropwise N,N-diisopropylethylamine (35.7 mL) at −70° C. Then, methanesulfonyl chloride (13.7 mL) was added dropwise, and the mixture was stirred at −45° C. for 2 hr. The mixture was again cooled to −70° C., N,N-diisopropylethylamine (14.6 mL) and thioacetic acid (35.7 mL) were respectively added, and the mixture was stirred at −45° C. for 2 hr. The reaction mixture was treated with 1N hydrochloric acid (300 mL) and extracted with diisopropyl ether (300 mL×2). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and water (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=6:1→4:1) to give the title compound (19.5 g, 62%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25]
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: Cc1cccc(C)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,6-dimethylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (22%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](O)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.ClC([N:20](C)C)=C(C)C>C(Cl)Cl>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([NH2:20])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(S)n2ncc(C(=O)O)c2n1
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: Cc1cc(S)n2ncc(C(N)=O)c2n1

Procedure:
A suspension of 105 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 400 ml of methylene chloride was treated with 6.3 ml of 1-chloro-N,N,2-trimethyl-1-propenamine and treated in an ultrasound bath until the majority has passed into solution. The mixture was suction filtered over a glass fiber filter, and ammonia was conducted into the clear filtrate at 20°. A crystalline precipitate formed which was filtered off under suction, dried and subsequently triturated in 100 ml of H2O for 5 minutes. The insoluble material was filtered off and the filtrate was concentrated in a vacuum to half of the volume. Upon allowing to stand at 0°, there was-obtained 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide as the ammonium salt in the form of white crystals.