Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19](OC)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: COC(=O)c1cccc(-n2cccc2C#N)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccn1-c1cccc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
28% Methanolic sodium methoxide (122.2 ml) was added to a solution of guanidine hydrochloride (63.7 g) in dry N,N-dimethylformamide (300 ml) and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.5 g), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water under stirring. The isolated precipitate was collected by filtration to give 2-[3-(2-cyanopyrrol-1-yl)benzoyl]guanidine (21.66 g).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][SH:5].[OH-].[K+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CO.C(O)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)=CCC/C(C)=C/CS
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 54.6 %

Procedure:
To a stirred solution of (E)-3,7-dimethylocta-2,6-dienylmercaptan (1.00 g=5.9 mmol) in methanol (40 ml) was added potassium hydroxide (0.33 g=5.8 mmol) and 1-chloro-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethane (1.62 g=5.9 mmol) in ethanol at room temperature, and then the reaction mixture was refluxed for 90 minutes. After cooling, the methanol was evaporated, and then the residue was diluted with chloroform. The chloroform layer was washed with water, followed by drying over anhydrous sodium sulfate. Concentration followed by column chromatography on silica gel (ethyl acetate:hexane=2:3) gave 1.32 g of Compound 10 as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.[H+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH:22]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH:24]=[CH:23]1.O>C(O)(=O)C>[O:29]1[C:28](=[O:30])[CH2:27][C@@H:22]2[CH2:26][CH:25]=[CH:24][C@H:23]12
Reactant: O=C(O)CC1C=CCC1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: Ic1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1C[C@@H]2CC=C[C@@H]2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrafluoroboric acid (2.50 mL, 15.9 mmol) was added to a solution of iodobenzene diacetate (5.10 g, 15.9 mmol) in acetic acid (13.2 mL). 2-Cyclopentene-1-acetic acid (955 μL, 7.93 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was then added to water and extracted with chloroform. The chloroform layer was extracted with water. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CHCl3) δ 2.22-2.31 (m, 2H), 2.67-2.84 (m, 2H), 3.05-3.15 (m, 1H), 5.44-5.51 (m, 1H), 5.79-5.86 (m, 1H), 6.01-6.07 (m, 1H).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[O:12]([CH2:30][CH2:31][C:32]1(CCO)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:41](O)(=[O:43])[CH3:42].C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[O:12]([CH2:30][CH2:31][C:32]1([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(=O)C1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 160.2 %

Procedure:
After adding 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (31 mg, 0.20 mmol) to a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (810 mg, 1.97 mmol) and iodobenzene diacetate (700 mg, 2.17 mmol) in methylene chloride (10 mL), the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.29 g). This was used without purification for the following step.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH2:24][C:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:27])[NH2:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)CCCl
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(N(N)CCC(=O)NC(C)(C)C)cc1
Reaction time: 14 h
Yield: 64.3 %

Procedure:
To a solution of tert-butyl amine (1.0 gm, 13.6 mmol) in dichloromethane (50 ml) was added 3-chloropropionyl chloride (2.06 g, 16.3 mmol) and NaOH (650 mg, 16.25 in 2.0 ml H2O) solution simultaneously at −20 deg C. for 1 h. The reaction mixture was allowed to stir for 1 h at RT. The organic layer was washed with 5% HCl followed by 5% aqueous sodium bicarbonate. The organic layer was dried and concentrated to get 2.23 g (yield: 99%) N-tert-butyl-3-chloropropanamide as white solid. To a solution of p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol) in ethanol (15 ml) was added triethylamine (1.31 ml, 9.4 mmol) and N-tert-butyl-3-chloropropanamide (510 mg, 3.12 mmol). The resulting reaction mixture was heated at 90 deg C. for 14 hrs. The reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain the crude, which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to obtain 500 mg (yield: 63.3%) of 3-(1-p-tolylhydrazinyl)-N-tert-butylpropanamide. The amide obtained (500 mg, 2.0 mmol) and N-methyl-4-piperidone hydrochloride (298 mg, 2.0 mmol) were dissolved in ethanolic HCl (20 ml) and stirred at RT for 15 minutes. The solvent was removed in vacuo. The reaction mixture obtained was dissolved in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated. The crude obtained was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 1.12%) of the desired product as TFA salt. 1H NMR (DMSO-D2O) TFA SALT 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.0-6.95 (d, 1H), 4.5 (m, 1H), 4.30-4.15 (m, 3H), 3.70-3.65 (m, 1H), 3.50-3.30 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (s, 3H), 2.50-2.40 (d, 2H), 2.30 (s, 3H), 1.10 (s, 9H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](F)(F)F)[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16])([CH3:3])[CH3:2].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.[NH2:29][C:30]1[C:35]2[O:36][CH2:37][C:38](=[O:40])[NH:39][C:34]=2[CH:33]=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:22]([NH:29][C:30]1[C:35]2[O:36][CH2:37][C:38](=[O:40])[NH:39][C:34]=2[CH:33]=[CH:32][CH:31]=1)=[O:23])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1CN
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)Nc2cccc3c2OCC(=O)N3)c(OC(C)C)c1
Temperature: 70 °C
Yield: 24 %

Procedure:
To a solution of 31a (0.95 g, 5.20 mmol) in THF (20 mL) was added CDI (2.1 mol eq, 1.80 g) and the mixture was heated at 70° C. for 6 h. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×35 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (yellow oil, 1.4 g, 97% yield). The oil obtained (0.7 g, 2.56 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.24 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtOAc:Petroleum ether) to obtain the product as a white solid (0.104 g, 24% Yield). 1HNMR (DMSO, 400 MHz) δ 1.26 (s, 3H), 1.29 (s, 3H), 2.26 (s, 3H), 4.18 (d, 2H, J=6), 4.60 (m, 3H), 6.44 (dd, 1H), 6.76 (m, 2H), 6.99 (m, 3H), 7.76 (dd, 1H), 8.13 (s, 1H), 10.64 (s, 1H). [M+1] 370.00 (C20H23N3O4 requires 369.41).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>CN(C)C=O>[ClH:14].[NH:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]1=[CH:4][N:5]([CH3:10])[CH3:6]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=N)N(C)C(=O)N(C)C1=O
Product: Cl
Reaction time: 0.5 h

Procedure:
20 g (129 mmol) of 6-amino-1,3-dimethyluracil was suspended in 550 ml of dimethylformamide. 216 g of phosphorus oxychloride was added to the suspension at a temperature below 20° C., and the reaction mixture was stirred for 30 minutes. The resulting precipitate was filtered off and washed with acetone to give 6-imino-1,3-dimethyl-5-dimethylaminomethylene-5,6-dihydrouracil hydrochloride (compound 1) in a 95% yield. The product may also be used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:5]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C=Nc2ccccc2)cc1
Yield: 77 %

Procedure:
A mixture of 7.2 g (0.040 mol) of 4-butoxybenzaldehyde, 4.0 g (0.044 mol) of aniline, 0.10 g of p-toluenesulfonic acid, and 75 mL of toluene was heated at reflux for 16 hr, with continuous azeotropic separation of the water evolved. Upon cooling, the contents of the flask were chromatographed on silica gel using dichloromethane as the eluent to give 7.8 g (77%) of N-(4-butoxylbenzylidene)aniline as a viscous oil. Crystallization from heptane afforded an analytical sample of a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: COCCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are dissolved in 15 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 15 ml of ethanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to said mixture and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol=5:2:1). 1.2 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[O:9][C:8]2=[O:17])=[CH:4][CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29](B(O)O)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[N:27]1([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:2]2[CH:19]=[CH:18][C:5]([CH2:6][N:7]3[CH2:11][C:10]4([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[O:9][C:8]3=[O:17])=[CH:4][CH:3]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(I)cc1
Reactant: OB(O)C1CN(Cc2ccccc2)CCO1
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: COCCOC
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccccc2CN2CCOCC2)cc1
Yield: 83.5 %

Procedure:
3-(4-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (55 mg, 0.148 mmol) and benzylmopholine-2-boronic acid (49 mg, 0.222 mmol) were mixed in ethylene glycol dimethyl ether (1 mL) and sodium carbonate (2M) aqueous solution (1 mL). Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (17 mg, 0.0148 mmol) was added and the reaction mixture was heated at 100˜110° C. for 1˜1.5 hours. The reaction was diluted with dichloromethane (DCM), washed with water (4 mL) and brine (4 mL). The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 5-30% ethyl acetate in hexane to give the product as off-white solid (52 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 7.49 (m, 1H), 7.42 (d, 2H), 7.32 (m, 5H), 4.5 (s, 2H), 3.65 (t, 4H), 3.39 (s, 2H), 3.18 (s, 2H), 2.36 (t, 4H), 1.82 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:16][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7](I)=[CH:8]1.C[Si](N[Si](C)(C)C)(C)C.C[N:28](C)[CH:29]=[O:30]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]1[CH2:16][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:29]([NH2:28])=[O:30])=[CH:8]1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1C1CC2C1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 9-bromo-4-iodo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene (65 g, 162.08 mmol, 1.00 equiv), N,N-dimethylformamide (1.2 L), HMDS (208 g, 1.29 mol, 8.00 equiv), and Pd(PPh3)2C1 (9.1 g, 0.08 equiv). To the above CO (2 atm) was introduced in. The resulting solution was stirred at 60° C. for 2 h. This reaction was repeated for 3 more times. The reaction mixture was cooled to 40° C. and quenched by the addition of 1500 mL of water. The solids were collected by filtration and washed with 3×500 mL of water. The solids were diluted with 2 L of EA and stirred at room temperature for 1 h. The solids were collected by filtration. The filter cake was diluted with 2 L of EA and stirred at 50° C. for 1 h. The solids were collected by filtration and dried to afford 172 g (83%) of 9-bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide as a brown solid. LC-MS: 318 [M+1]+1H-NMR (DMSO, 300 MHz, ppm): □ 18.75 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.44-4.44 (dd, 1H), 7.23-7.25 (dd, 1H), 7.14 (s, 1H), 4.89-4.95 (m, 1H), 3.67-3.73 (m, 1H), 3.04-3.12 (m, 2H), 1.64-1.68 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.O.[C:26]([OH:30])(=[O:29])[CH:27]=O.C(O)(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([CH:27]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:26]([OH:30])=[O:29])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: O
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(C(=O)O)c2ccccc2F)C1
Temperature: 120 °C

Procedure:
tert-Butyl (3R)-piperidin-3-ylcarbamate (0.1 g, 0.499 mmol), (2-fluorophenyl)boronic acid (0.070 g, 0.499 mmol) and glyoxilic acid monohydrate (0.045 g, 0.499 mmol) were taken up in DCM (2.25 mL)/HFIP (0.25 mL) in a 5 mL microwave vial. The reaction mixture was heated to 120° C. for 15 minutes under microwave irradiation. The solvent was removed in vacuo to give 2-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-2-(2-fluorophenyl)acetic acid as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[C:36]([CH3:37])=[N:35][CH:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[C:36]([CH3:37])=[N:35][CH:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.64 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:14])=[O:10]
Reactant: O=C(O)CCCCCCBr
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
to a suspension of 7-bromoheptanoic acid (1.7 g, 8.13 mmol) obtained above in CH2Cl2 (30 mL) were added oxalylchloride (2.13 mL, 24.39 mmol) and a catalytic amount of DMF. The mixture was stirred overnight at room temperature. The solvent was removed by evaporation in vacuo to give 1.84 g (100%) of the 7-bromoheptanoyl chloride as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:20][CH2:19]1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCC1CC1
Product: Cc1cc(C#Cc2cn(CC3CC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=252.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromomethyl-cyclopropane.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11](O)=[O:12])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:18][CH:19]([OH:21])[CH3:20]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:9]([O:21][CH:19]([CH3:20])[CH3:18])=[O:8]
Reactant: CC(C)O
Reactant: O=C(O)CCOCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)OC(=O)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-benzyloxypropanoic acid (27.7 mmol) in propan-2-ol (40 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (30.5 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried on Na2SO4, filtered and concentrated under reduced pressure. The crude was diluted with isopropanol (80 mL) and Pd(OH)2 (20%, 1 g) in isopropanol was added. The system (reaction in a stainless steel reactor) was purged with nitrogen, vacuum and H2 and the reaction mixture was stirred under H2 atmosphere (3 bars) overnight at room temperature. The reaction mixture was filtered through autocup and the precipitate was washed with isopropanol. The filtrates were concentrated under reduced pressure and dried under vacuum pump to give the expected compound in 78% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.26 (d, J=6.31 Hz, 6H), 2.19 (brs, 1H), 2.54 (t, J=5.56 Hz, 2H), 3.86 (t, J=5.56 Hz, 2H), 5.06 (heptuplet, J=6.25 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22][CH3:23])[NH:11][C:10]=2[CH:9]=1>>[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22][CH3:23])[N:11]([CH2:2][CH2:3][CH2:4][Cl:5])[C:10]=2[CH:9]=1
Reactant: ClCCCBr
Reactant: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Product: COc1ccc2c(c1)N(CCCCl)c1cccc(SC)c1S2
Yield: 35.9 %

Procedure:
2-Methoxy-6-methylthio-10-(3-chloropropyl)-phenothiazine (10.1 g.) is prepared by reacting 1-bromo-3-chloropropane (47.5 g.) with 2-methoxy-6-methylthiophenothiazine (22.0 g.).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[Cl:8][SiH:9]([Cl:11])[Cl:10]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[Cl:8][Si:9]([Cl:11])([Cl:10])[C@H:2]1[CH2:3][C@H:4]2[CH2:7][C@@H:1]1[CH2:6][CH2:5]2
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CC2CCC1C2
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)[C@H]1C[C@@H]2CC[C@H]1C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
(R)-2-Methoxy-2'-di(4-chlorophenyl)phosphino-1,1'-binaphthyl prepared in Example 3 (7.93 mg, 14.78 mmol) and allylpalladium chloride dimer (1.35 mg, 3.69 μmol=7.38 μmol of palladium) were dissolved in toluene (6.95 g). In the solution, norbornene (6.95 g, 73.81 mmol) was added. After adding trichlorosilane (12.00 g, 88.59 mmol) at 0° C., the mixture was warmed to room temperature, followed by stirring at room temperature for 12 hours. Thereafter, from the reaction mixture, the solvent was evaporated off at 100° C. under reduced pressure of 1 Torr to obtain (1S, 2S, 4R)-2-trichlorosilylnorbornane (16.41 g). Isolation yield, 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(O)=O>[Pd].C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cc(F)cc(C2=CCNCC2)c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=CO
Product: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Reaction time: 24 h
Yield: 81.7 %

Procedure:
A mixture of 4-[3-fluoro-5-(methylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine (2.02 g, 7.9 mmol), palladium on carbon (0.56 g) and formic acid (1.9 ml) in isopropyl alcohol (60 ml) was hydrogenated at 50 psi for 24 h under hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 1.66 g of crude product. MS m/z (relative intensity, 70 eV) 257 (M+, bp), 256 (80), 133 (21), 69 (25) 56 (99).