Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH3:12][Si:13]([CH3:22])([CH:20]=[CH2:21])[O:14][Si:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][S:1][CH2:17][CH2:16][Si:15]([CH3:18])([CH3:19])[O:14][Si:13]([CH3:22])([CH3:12])[CH:20]=[CH2:21]
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: CO[Si](CCCS)(OC)OC
Product: C=C[Si](C)(C)O[Si](C)(C)CCSCCC[Si](OC)(OC)OC
Reaction time: 0.17 h

Procedure:
1-(7,7-dimethoxy-8-oxa-3-thia-7-silanonyl)-1,1,3,3-tetramethyl-3-vinyldisiloxane was prepared according to the following process. Two and one-half moles (490 grams) of gamma mercaptopropyltrimethoxy silane was added to a 1-liter flask. A portion of a total quantity of one mole (186 grams) of 1,1,3,3-tetramethyl-1,3-divinyldisiloxane was added to the flask, resulting in the immediate formation of a bluegreen color and generation of heat. The flask was placed in a hood and stirred. The exotherm was measured at 75° C, subsided to about 55° C. and remained there for 10 minutes. The remaining 1,1,3,3-tetramethyl-1,3-divinyldisiloxane was added with no further exotherm. Gas/liquid chromotography revealed consumption of substantially all of the 1,1,3,3-tetramethyl-1,3-divinyldisiloxane reagent and the presence of mono- and diadduct products. The reaction product was distilled through a Vigreaux column to yield 60 g of approximately 95% pure product having a boiling point of 157° C. at 3.0 mm Hg.
Reaction SMILES: C([Li])CCC.O[CH2:7][CH2:8][CH:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.C1C=CC(NC2C=CC(N=NC3C=CC=CC=3)=CC=2)=CC=1.[CH3:37][N:38]([CH2:43][CH2:44][Br:45])[P:39](Cl)([Cl:41])=[O:40]>C1COCC1>[CH3:14][C:11]1([CH3:15])[O:10][CH:9]([CH2:8][CH2:7][P:39]([Cl:41])([N:38]([CH3:37])[CH2:43][CH2:44][Br:45])=[O:40])[CH2:13][O:12]1
Reactant: CC1(C)OCC(CCO)O1
Reactant: CN(CCBr)P(=O)(Cl)Cl
Agent: [Li]CCCC
Agent: c1ccc(N=Nc2ccc(Nc3ccccc3)cc2)cc1
Solvent: C1CCOC1
Product: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Butyllithium (10.8 ml, 21.60 mmol, 2.0M) was added dropwise at 0° C. to a stirred solution of 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (2.87 g, 19.60 mmol) and a crystal of 4-phenylazodiphenylamine indicator in THF (7 ml) under N2. The resulting solution was added dropwise at -78° C. to a stirred solution of N-methyl-N-(2-bromoethyl) phosphoramidic dichloride (5.00 g, 19.60 mmol) in THF (10 ml) under N2. The mixture was allowed to stir under N2 at -78° C. for 3 hr, at which time the purple mixture turned yellow. The mixture was warmed to room temperature and the solvent removed under reduced pressure. The residue was purified by chromatography (1:4 EtOAc: hexanes) and the product 16a isolated as an oil (4.77 g, 67%): Rf 0.61 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.26(dt, 2H, J= 8.44 Hz), 4.17(t, 1H, J=6.53 Hz), 4.06(t, 1H, J=7.06 Hz), 3.54(t, 1H, J=7.10 Hz), 3.44(m, 4H), 2.76(d, 3H, J=12.76 Hz), 1.95(dt, 2H, J=6.24 Hz), 1.67(d, 6H, 15.63 Hz); 31P NMR (CDCl3) -8.07 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([CH2:24][OH:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:24][O:25][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 75.6 %

Procedure:
[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (0.78 g, 2.05 mmol) was treated with methanesulfonyl chloride (0.235 g, 2.05 mmol) and pyridine (0.49 g, 6.15 mmol) in 5 mL of anhydrous dichloromethane at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 4 h. The reaction mixture was diluted with 10 mL of dichloromethane and washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silica gel column chromatography (CH2Cl2:MeOH) gave methanesulfonic acid 2-tert-butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propyl ester (0.71 g).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>C(O)C.[Ru]>[ClH:1].[OH:2][C@@H:3]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1CNCCCC1=O
Reactant: [H][H]
Agent: [Ru]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CNCCC[C@H]1O

Procedure:
As in Example 2, 23.2 g of ethyl 4-oxo-azepan-3-carboxylate hydrochloride in 90 ml of ethanol were hydrogenated with a solution of 36.1 mg of the ruthenium catalyst in 10 ml of ethanol under 40 bar hydrogen pressure at 30° C. for 21 hours and at 50° C. for 3 hours. The residue, consisting of about 80% 3R,4R and 20% 3S,4R isomers, was triturated with tetrahydrofuran and ethanol at 50° C. for half an hour and at room temperature for 4 hours. The crystals were filtered off under suction, washed with a small amount of tetrahydrofuran/ethanol and dried to constant weight at 50° C./20 mbar, to yield 13.3 g of enantiomerically pure ethyl (3R,4R)-4-hydroxy-azepan-3-carboxylate hydrochloride in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1CCCC1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:28])/[CH:27]=[CH:1]/[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CN(C)/C=C/c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-2-nitro-4-(perfluoroethyl)benzene (10.0 g, 39.2 mmol) and pyrollidine (2.79 g, 39.2 mmol) in toluene (250 mL) was added dimethyl formamide dimethyl acetal (4.96 g, 39.2 mmol). The mixture was heated to reflux for 16 hours. After cooling to room temperature the mixture was concentrated under vacuum and the resulting oil was immediately used in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:6]([NH2:7])=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1)#[N:2].O.Cl>[Fe].C(O)C>[C:1]([C:3]1[C:4]([N:13]2[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[CH:5][C:6]([NH2:7])=[C:8]([NH2:10])[CH:9]=1)#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)c(N)cc1-n1ccc(=O)cc1
Yield: 63.3 %

Procedure:
First, a mixture containing 490 mg of 4-cyano-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 642 mg of iron powder, 4 ml of water, 16 ml of ethanol, and 0.2 ml of 2N hydrochloric acid was heated in an oil bath for 1 hour. The subsequent processes were conducted in the same way as in Reference Example 3 to give crude crystals. Then, 405 mg of the crude crystals were recrystallized with methanol/isopropanol to give 274 mg of crystals of 4-cyano-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](=O)[C:32](O)=[O:33])([O-:23])=[O:22].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:32](=[O:33])[C:31]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N+:21]([O-:23])=[O:22])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Cc2ccccc2[N+](=O)[O-])nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 43 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (196 mg) and 3-(2-nitrophenyl)pyruvic acid (188 mg) in ethanol (5 ml) was stirred under reflux for 1 hour. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(2-nitrobenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (140 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (0.5 M, 90 mL) at 0° C. were added p-anisaldehyde (7.9 mL, 65 mmol) and acetic acid (1.2 mL, 22 mmol). Sodium triacetoxyborohydride (18.4 g, 87.0 mmol) was added portion-wise to the solution mixture. The reaction was allowed to warm to room temp and stirred overnight. Upon completion, the reaction was poured into saturated sodium bicarbonate (200 mL). The product was extracted with dichloromethane (3×75 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 1:1 hexanes/dichloromethane) to yield methyl 5-bromo-2-[(4-methoxybenzyl)amino]benzoate. HRMS (M+H)=350.0381. 1H NMR (400 MHz, CDCl3) 8.08 (b, 1H), 8.10 (d, 1H), 7.36 (dd, 1H), 7.24 (d, 2H), 6.88 (d, 2H), 6.54 (d, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:23])[NH2:22])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.60 g), bromomalonaldehyde (0.38 g) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 ml) and methanol (5 ml) was added sodium borohydride (70 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.38 g, yield 54%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 214-215° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH2:12][CH2:13][F:14])(=O)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31](O)[CH:30]=[CH:29][C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[C:29]([O:11][CH2:12][CH2:13][F:14])[C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OCCF
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccc(O)cc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc3c(OCCF)cccc3s2)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
Potassium carbonate (611 mg, 4.42 mmol) and 2-fluoroethyl methane sulfonate (FCH2CH2OMs, 251 mg, 1.77 mmol) were added to 2-(4-nitrophenyl)-6-hydroxybenzothiophene (1-4, 400 mg, 1.47 mmol) obtained in Example 4 dissolved in a solution of dimethylformamide (DMF, 100 mL), heated at 80° C. for 8 hours, cooled to room temperature, followed by adding water. The resulting product was extracted with ethyl acetate, evaporated after a treatment with sodium sulfate under reduced pressure. Purification was performed by column chromatograph to give the target compound 2-(4-nitrophenyl)-4-(2-fluoroethoxy)benzothiophene (1-5, 224 mg, 48%) as a yellow solid. The obtained target compound 1-5 had a melting point of 176.5-178.0° C., and the following physical data;
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=O)[CH2:3][CH2:2]1.[NH2:17][CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)O>>[C:27]1([C:18]2[N:17]=[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[O:9][C:19]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1

Procedure:
Starting from 1.08 g mono-tert-butyl piperidine-1,4-dicarboxylate and 1 g 2-amino-1,2-diphenyl-ethanol the product may be obtained as described in the literature (see Tet. 2001, 4867). The product is purified by chromatography (method B). 560 mg are obtained as an oil. Analytical HPLC-MS (method A): RT=1.72 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[CH3:24]I.O>O1CCOCC1>[CH3:24][O:15][CH2:14][CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CI
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 67 %

Procedure:
6 g of β-[4-(4-trifluoromethylphenoxy)phenoxy]propanol was dissolved in 30 ml of dioxane and 0.46 g of sodium was added to the solution. The mixture was then heated for 3 hours while refluxing. 3.1 g of methyl iodide was added thereto and the resulting mixture was heated for 6 hours while refluxing. The reaction mixture was then poured into an appropriate amount of water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 4.2 g of the desired product having a boiling point of 160° to 165° C./2 mmHg.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.C(O)(=O)C.[C:14]1(=O)[CH2:18][CH2:17][CH2:16]C1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]>O>[C:20]([C:22](=[C:16]1[CH2:17][CH2:18][CH2:14]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
HMDS (69.6 g, 0.43 mol) was added dropwise to 350 mL of acetic acid at ambient temp over 5 minutes. Cyclopentanone (20.3 g, 0.29 mol) and ethyl cyanoacetate (65.0 g, 0.57 mol) were added in single portions to the resulting solution. The mixture was stirred at 70° C. overnight after which it was cooled to ambient temperature and the reacting mixture was poured into 600 mL of water, and extracted with ethyl acetate (500 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give the title compound as a yellow solid (37.0 g, 0.22 mol, 77.2%). LC-MS: m/e=166.2 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCBr)cc1
Temperature: 0 °C

Procedure:
4-(2Hydroxyethyl)benzonitrile (3.0 g, 20 mmol) was combined with triphenylphosphine (6.42 g, 24.5 mmol) imidazole (1.39 g, 20.4 mmol) and carbon tetrabromide (8.11 g, 24.5 mmol) in DCM (10 mL) and stirred at 0° C., monitoring the reaction progress to completion by TLC. Silica gel was added to the mixture and the solvent was removed. Purification by MPLC eluting with 20% ethyl acetate/hexanes afforded the tide compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>C(O)CCC>[O:28]1[C:27]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:22][C:21]=2[O:20][CH2:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: CCCCO
Product: OCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g (5.8 mmol) of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol and 1.58 g (11.5 mmol) 3,4-methylendioxy-aniline in 30 ml n-butanol is stirred for 16 h at 115° C. under N2-atmosphere. After cooling to ambient temperature, the title compound can be filtered off and washed with n-butanol; MS-ES+: (M+H)+=361; HPLC (conditions see Examples 67-78) tR=8.7 min.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4].[NH3:13]>CO>[NH2:13][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(CCl)N[C@H]1CC[C@H](O)CC1
Reactant: N
Solvent: CO
Product: NCC(=O)N[C@H]1CC[C@H](O)CC1

Procedure:
11.5 g. (0.06 mole) trans-2-chloro-N-(4-hydroxycyclohexyl)-acetamide are dissolved in 100 ml. methanol and shaken with 200 ml. liquid ammonia for 20 hours at 50° C. in an autoclave. After concentration of the solvent, suction filtration is carried out. There are obtained 9.7 g. of the title compound, i.e. 94% of theory; m.p. 110°-114° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(N)CN
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 14.97 g (0.196 mol) of 1,2-diamino-2-methylpropane in 300 ml of chloroform and 80 ml pyridine at 0° C. was added 10 g (0.057 mol) of benzenesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to reach room temperature. The mixture was evaporated to dryness in vacuo and the residue was partitioned between water and chloroform. Evaporation of the chloroform gave 10.3 g (79%) of semisolid. The product was identified by NMR and IR spectroscopy and elemental analysis.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:6][C:5]1([CH2:4][CH2:3][C:2](=[O:8])[CH3:1])[O:11][CH2:10][CH2:9][O:7]1
Reactant: OCCO
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)CCC1(C)OCCO1

Procedure:
A commercially available hexan-2,5-dion (137 g) was dissolved in benzene (300 ml). Thereafter, ethylene glycol (100 ml) and p-toluenesulfonic acid (11.4 g) were added to the solution, and the mixture was then dehydrated by heating to reflux for 5 hours. The reaction product was diluted with ethyl acetate, and then washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution. The organic layer was then dried over anhydrous sodium sulfate. The solvent was-distilled off under a reduced pressure, and the residue was subjected to vacuum distillation (80° C. to 82° C./3 mmHg) to obtain 4-(2-methyl[1,3]dioxolan-2-yl)butan-2-one (56.83 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(O)cn1
Reaction time: 1 h

Procedure:
To 5-hydroxypyridine-2-carboxylic acid (5.0 g, 36 mmol) suspended in CH2Cl2 (120 mL) was added DMF (1 mL) followed by oxalyl chloride (4.7 g, 37 mmol). After 1 hour, excess MeOH was added. The resulting mixture was stripped of solvent in vacuo yielding a brown solid that was washed with hot EtOAc. Yielded 4.6 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:16]C(=O)OC(C)(C)C)[C:10]1=[O:24].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]1=[O:24]
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1N1CCCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a round bottom flask was added (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamate (27 mg, 0.081 mmol), DCM (1 mL) and TFA (1 mL). The reaction mixture was stirred at rt for 2 hr. The reaction mixture was concentrated under reduced pressure and then dried under high vacuum to give (S)-3-amino-1-(2-methoxyphenyl)azepan-2-one trifluoroacetate (28 mg, 0.080 mmol, 100% yield) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1>CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:3]5[CH:2]=[N:28][C:6]([CH3:7])=[CH:5][CH:4]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol) 2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (262 mg, 1.2 mmol) Cs2CO3 (650 mg, 2.0 mmol) Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1 1 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 336 (168.7 mg, yield: 36%). 1HNMR (DMSO-d6, 400 MHz): δ9.04 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.91-7.87 (m, 2H), 7.76-7.71 (m, 1H), 7.48-7.45 (m, 2H), 7.36-7.34 (m, 1H), 7.14 (s, 1H), 4.30 (s, 2H), 3.14 (s, 2H), 2.52 (s, 3H). ESI-MS: m/z=474 [M+H+]