Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:39]([NH:38][C:34]6[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=6)=[O:40])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(NC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cn2)CC1
Temperature: 25 °C

Procedure:
Combine the amine (0.164 g, 0.425 mmol), 3-trifluoromethylphenyl isocyanate (0.060 mL, 0.425 mmol) and triethylamine (0.119 mL, 0.851 mmol) in DMSO (5 mL). Stir the mixture at room temperature for ninety minutes. Extract the mixture with ethyl acetate versus water. Wash the organic layer with saturated aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→10% methanol in dichloromethane) to afford product (0.056 g, 13%, two steps). MS(ES), m/z 573 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[CH:14]([Mg]Br)([CH3:16])[CH3:15].Cl>O1CCCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:7]([C:8]#[N:9])[C:10]#[N:11])[CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1
Reactant: CC(C)[Mg]Br
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(Cl)cc1)C(C#N)C#N
Yield: 52 %

Procedure:
First, 1.02 g of (4-chlorobenzylidene)malononitrile was dissolved in 20 ml of tetrahydrofuran, to which a catalytic amount of copper (I) iodide was added, and while stirring under ice cooling, a solution of isopropyl magnesium bromide in tetrahydrofuran (prepared from 0.34 g of magnesium, 10 ml of tetrahydrofuran, and 1.46 ml of isopropyl bromide) was added dropwise, followed by stirring for 30 minutes under ice cooling. Then, 10% hydrochloric acid was added to the reaction mixture, which became acidic and was extracted with ethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.66 g of (1-(4-chlorophenyl)-2-methylpropyl)malononitrile (the intermediate (3)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>[OH-].[K+]>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Temperature: 60 °C
Yield: 80 %

Procedure:
Monomers in which the bulky organic group was a t-butyl group and the alkyl groups were hexyl groups were made as follows. 4-hydroxybenzoic acid was dissolved in 30% ethanolic KOH. About 1% of KI was added as a catalyst. The mixture was heated to about 60° C. and a stoichiometric amount of 6-chloro-1-hexanol was slowly added over about ½ hour. After refluxing the reaction mixture for extended period of time (2–15 hrs) the contents was cooled, the reaction mixture was filtered off, and the filtrate solvent was evaporated under vacuum. Water was added into the residue and acidified with HCl and the precipitate was filtered and crystallized with ethanol, yielding approximately an 80% 4-(6-hydroxyhexyloxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[C:4]([N+:20]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([N:12]([CH3:13])[CH3:14])=[O:11]
Reactant: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 68 %

Procedure:
The product from Example 168c (1.5 g, 4.6 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.91 g, 68%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.[NH4+].[OH-].[CH:14](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:14]=[N:9][C:4]=2[C:3]=1[CH3:10]
Reactant: Cc1c(Br)ccc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(Br)ccc2[nH]cnc12
Temperature: 60 °C
Yield: 98 %

Procedure:
A mixture of 156 (28 g, 140 mmol), formic acid (240 mL) and 37% concentrated HCl (400 mL) was heated to 60° C. for 12 h, cooled in an ice-water bath, and the pH slowly adjusted to 8-9 with 28% concentrated NH4OH. The solid was collected by filtration, washed with water and dried in air to afford 25 g (98%) of 5-bromo-4-methyl-1H-benzo[d]imidazole (158) as a yellow solid: MS (ESI) m/z=213 [M+1]+.
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[C:23]([CH3:30])=[C:24]([CH3:29])[N:25]([CH2:26][CH:27]=[CH2:28])[C:18]=12)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:1].[CH2:26]([N:25]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:23]([CH3:30])=[C:24]1[CH3:29])[CH:27]=[CH2:28]
Reactant: C=CCn1c(C)c(C)c2nccc(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)c21
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCn1c(C)c(C)c2nccc(NCc3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of (1-allyl-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)carbamic acid tert-butyl ester hydrochloride (101.3 mg) prepared in Step 1 in ethyl acetate (10 ml) was saturated with hydrochloric acid gas and then stirred for 1 hour at room temperature. The resulting precipitate was filtered and then dried to give the titled compound as a white solid (35.3 mg, 44.1%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH2:21][C:20]([CH3:22])=[CH2:19])[CH:11]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 104.6 parts of methyl 2-hydroxy-4-(acetylamino)benzoate in 470 parts of N,N-dimethylformamide were added portionwise 24 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour at room temperature, there was added a solution of 55.2 parts of 3-chloro-2-methyl-1-propene in 47 parts of N,N-dimethylformamide. Stirring was continued for 3 days at 50° C. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was washed with water, sodium hydroxide 10% and water and was then dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 65.8 parts (50.0%) of methyl 4-(acetylamino)-2-[(2-methyl-2-propenyl)oxy]benzoate (interm. 15).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:3]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([CH:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)[C:5]=3[N:7]=2)[CH2:16][CH2:17]1
Reactant: Cc1cc(N)n(C2CCN(C)CC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCN(C)CC1
Temperature: 70 °C

Procedure:
3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=343.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 4 H), 1.38 (t, J=7.07 Hz, 3 H), 1.83 (d, J=6.06 Hz, 2 H), 2.12-2.22 (m, 4 H), 2.27 (s, 3 H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1 H), 2.54 (s, 3 H), 2.94 (d, J=6.57 Hz, 2 H), 4.42 (q, J=7.16 Hz, 2 H), 4.57-4.73 (m, 1 H), 7.46 (s, 1 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>CO.O1CCOCC1.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Yield: 91.1 %

Procedure:
To a solution of dimethyl 4-[2-(6-quinolinoxy)ethoxy]benzylidenemalonate (2.23 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.04 g, 90%). HRMS calcd for C23H27NO6: 413.4670. Found: 413.4672. MA calcd for C23H27NO6: C, 66.81%; H, 6.58%; N, 3.39%. Found: C, 66.53%; H, 6.55%; N, 3.36%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1>ClC(Cl)C.ClCCl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.4 %

Procedure:
N-Bromosuccinimide (58.62 g, 329.34 mmol) was added in portions over a period of 5-10 min to a well stirred solution of 4-methyl-2-methoxy-1-nitro benzene (50.0 g, 299.4 mmol) and 1,1′-Azobis(cyclohexane carbonitrile) (1.0 g, 4.1 mmol) in dichloroethane (600 mL) and the resulting mixture was heated to reflux under a UV light for a maximum 7-8 hr. After cooling to rt, the reaction mixture was diluted with dichloromethane (400 mL) and washed with aqueous Na2S2O4 solution, water and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid (102.0 g) which was triturated with diisopropyl ether to afford 43.0 g of the desired product. The diisopropyl ether filtrate was concentrated and purified by silica-gel column chromatography (5-40% EtOAc/Hexanes) to obtain an additional 5.5 g of the desired product (48.5 g, 66%). 1H NMR (CDCl3-300 MHz): δ=3.98 (s, 3H), 4.46 (s, 2H), 7.05 (dd, J=6.60 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH:7]2[C:5]1(Cl)[O:6]2)[CH:2]=[CH2:3].N1C=CC=CC=1.[ClH:20]>>[CH2:1]([C:4]1([Cl:20])[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Reactant: Cl
Solvent: c1ccncc1
Product: C=CCC1(Cl)C(=O)CCCC1(Cl)Cl

Procedure:
1.60 g (6.62 mmol) of epoxide 2j and 2 cm3 (25 mmol) of pyridine were heated to reflux for 24 h. After cooling, the mixture was acidified to pH=1 with 3N HCl, extracted with ether (3×30 cm3), dried over MgSO4 filtered and evaporated down. The crude product was purified by flash chromatography on silica (eluent: ether/petroleum ether=1/99). The following were isolated (in the order of elution): starting epoxide 2j, 0.40 g of transposition ketone 6a (Yld=40%), traces of 2-allyl-2,3-dichloro-3-cyclohexenone 7 (evidence based on GC/mass) and phenol 4f.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a slightly yellow oil (yield: 79.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]=[C:32]=[O:33])=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]3)=[O:33])=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene (0.201 g, 0.95 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 4.15 (M+H)+; MS (ESI−) m/z 413 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.95 (s, 3H), 4.36 (d, J 5.6, 2H), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m, 2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, 1H); Anal. Calcd for Cl9H16BrN3O3: C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N, 9.84.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:30][C@H:31]1[CH2:36][C@H:35]2[CH2:37][C@@H:32]1[CH2:33][C@H:34]2O)([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:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:13]([O:30][C@H:31]1[CH2:36][C@H:35]2[CH2:37][C@@H:32]1[CH2:33][C@@H:34]2[N:43]1[C:39](=[O:49])[C:40]2[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:42]1=[O:44])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@H]2O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2N1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Reaction time: 32 h

Procedure:
A solution of diethyl azodicarboxylate (2.58 mL, 16.4 mmol) in anhydrous THF (10.0 mL) was added dropwise to a mixture of (1R,2R,4R,5S)-5-(tert-butyldiphenylsilyloxy)bicyclo[2.2.1 ]heptan-2-ol (5.00 g, 13.6 mmol), phthalimide (2.31 g, 15.7 mmol), and triphenyl phosphine (4.11 g, 15.7 mmol) in anhydrous THF (60 mL) at ambient temp. under nitrogen. After stirring for 32 h, the solvents were removed in vacuo. The residue was purified by flash column chromatography (0 to 20% of ethyl acetate in hexanes) to give the title compound as a white solid. MS m/z: 496.3 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][N+:21]([O-:23])=[O:22])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To an acetic acid (5.5 mL) and dimethyl sulfoxide (94 mL) solution of 1-benzyloxy-3-((E)-2-nitro-vinyl)-benzene (5.5 g, 21.5 mmol) described in Manufacturing Example 61-1-2 was added sodium borohydride (1.3 g, 34.4 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (3.14 g, 57%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.84 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[-1-(2-fluorophenyl)ethoxy]thiophene-2-carboxamide in 35 ml THF is cooled to 0° C. At 0° C., 1.27 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 2-hydroxy-4-methoxy-1-nitrobenzene (520 mg, 3.08 mmol), benzyl bromide (522 mg, 3.08 mmol) and potassium carbonate (637 mg, 4.61 mmol) in DMF (3 mL) is stirred at 65° C. for 18 h. The mixture is poured into water and the mixture extracted with EtOAc. The organic phase is washed with water (3×) and brine (1×) and is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.Cl.[F:28][CH:29]1[CH2:32][NH:31][CH2:30]1>>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:31]1[CH2:32][CH:29]([F:28])[CH2:30]1)=[O:25])=[O:23]
Reactant: FC1CNC1
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CC(F)C2)cnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) and 3-fluoroazetidine hydrochloride (15.1 mg, 135 μmol) according to the method described in example 37, step 3 as white solid (39 mg, 94.8 μmol, 84.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24](O)=[O:25])[N:22]=1)=[CH:5]2.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([NH:39][CH3:37])=[O:25])[N:22]=1)=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
The compound (44 mg, 0.11 mmol) prepared in Example 31 was dissolved in N,N-dimethylformamide (2 ml). Methylamine (0.08 ml, 2M in THF, 0.17 mmol), EDC (36 mg, 0.19 mmol) and HOBT (30 mg, 0.22 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18 mg, Yield 37%).
Reaction SMILES: O1CCOCC1.Cl.Cl.[Cl:9][C:10]1[C:11]([CH:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[N:14][CH:15]=1.C(N(CC)CC)C.Cl[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:31])=[O:32])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:48]2[N:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:14][CH:15]=1
Reactant: Clc1ncccn1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCCCNc2ncccn2)ncc1Cl
Temperature: 80 °C
Reaction time: 19 h
Yield: 65.1 %

Procedure:
To a 1,4-dioxane solution (1.0 ml) of the N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (76 mg, 0.136 mmol) obtained in Example 173 were added triethylamine (76 μl, 0.54 mmol) and 2-chloropyrimidine (23 mg, 0.20 mmol). The resulting mixture was stirred at 80° C. for 19 hours. The reaction mixture was allowed to cool to room temperature, followed by dilution with ethyl acetate. The diluted mixture was washed with water and brine, dried and concentrated. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to give the title compound (50 mg, 65%). The compound was crystallized in ethanol to afford a white solid (36 mg).