Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([OH:49])[CH:33](O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].O>C1(C)C=CC=CC=1>[CH2:32]1[O:49][C:11]2([CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[O:13][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CCCCCCCCCCCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)NC(c3ccccc3)C2)O1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 14.6 g (58.0 mmol) of 2,6-diphenyl-4-piperidone and 12.2 g (64 mmol) of p-toluenesulfonic acid monohydrate in 500 mL of toluene is refluxed and the azeotroping water is collected in a Dean Stark trap. When 1 mL of water is collected, 15.0 g (58.0 mmol) of 1,2-hexadecanediol (Aldrich) is added and the reaction is refluxed until another 1 mL of water is collected. The reaction mixture is cooled to room temperature and made basic with 50% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous phase is extracted with toluene (2×100 mL). The combined organic phases are dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. 11.0 g (38% yield) of the title compound is isolated after purification by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) followed by recrystallization from ethanol: mp 63°-70° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:22]=[C:11]2[C:12]([CH:16]3[CH2:18][CH:17]3[CH:19]=[N:20]O)=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[N:22]=[C:11]2[C:12]([CH:16]3[CH2:18][CH:17]3[CH2:19][NH2:20])=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1
Reactant: Cc1nc2c(C3CC3C=NO)cccn2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(C3CC3CN)cccn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a suspension of lithium aluminum hydride (150 mg, 3.24 mmol) in tetrahydrofuran (8 mL) was added a solution of 2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-8-yl)cyclopropanecarbaldehyde oxime (175 mg, 0.809 mmol) obtained in Reference Example 24 in tetrahydrofuran (8 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium sulfate decahydrate (1.8 g) was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), the solution was added to a suspension of lithium aluminum hydride (150 mg, 3.24 mmol) in tetrahydrofuran (8 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. Sodium sulfate decahydrate (1.8 g) was added under ice-cooling, and the mixture was filtered through celite to give the title compound (98.9 mg, yield 60%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To a stirred mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (4.99 mmol, 1.170 g), tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (4.99 mmol, 1 g) and triethylamine (11.98 mmol, 1.670 mL, 1.213 g) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.99 mmol, 1.149 g). The reaction was stirred for 20 hours. Chromatography on silica (eluting with a gradient of dichloromethane to ethyl acetate) gave the intermediate tert-butyl 3-(4-(3-(cyclopropylmethyl)ureido)-N-methylbenzamido)-pyrrolidine-1-carboxylate (2 g).
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.[Br:13][C:14]1[C:19]2[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:22][C:18]=2[C:17]([C:27](O)=[O:28])=[CH:16][C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.OC1C2N=NNC=2C=CC=1.N>CN(C)C=O>[Br:13][C:14]1[C:19]2[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:22][C:18]=2[C:17]([C:27]([NH2:4])=[O:28])=[CH:16][C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(=O)O)c2o1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(N)=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (1.61 g, 8.42 mmol) was added to an N,N-dimethylformamide (80 ml) solution of 4-bromo-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylic acid (I-256) (2.62 g, 7.02 mmol) and hydroxybenzotriazole (1.14 g, 8.42 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was cooled at 0° C., then aqueous 28% ammonia (1.42 ml, 21.1 mmol) was put into it, followed by further stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, then saturated sodium bicarbonate water (200 ml) was added, the product was extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated brine (50 ml), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3:2) to obtain the entitled compound (2.59 g, 99%) as a yellow white solid.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[C:18]([C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([Si](C(C)(C)C)(C)C)[C:28]=3[N:29]=[CH:30][CH:31]=2)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)CC1C=CC(OC)=CC=1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:17]1[C:18]([C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[NH:32][CH:33]=[CH:34][C:27]=23)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(Cl)cnc2C(=O)c2ccnc3c2ccn3[Si](C)(C)C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
0.97 g of {2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-pyridin-3-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester and desilylated analog mixture was dissolved in 5 mL of TFA, stirred at r.t. for 2 h and evaporated. The residue was partitioned into a mixture of aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was evaporated under reduced pressure. The solid residue was triturated with 200 mL of a 1:3 mixture of ethyl acetate-hexanes to afford 372 mg of the product as a brown solid. LC-MSD, m/z for C13H9ClN4O [M+H]+=273.0, 275.0;
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-].Cl[CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]>CN(C=O)C.CCOC(C)=O>[OH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCCOCCCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1ccc(OCCOCCO)cc1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
To a solution of 4,4′-dihydroxybenzophenone (3.0 g, 13.9 mmol) in DMF (30 mL) was added Cs2CO3 (13.55 g, 41.6 mmol). The mixture was heated at 80° C. under nitrogen for 1 h. The stirred reaction was cooled to room temperature and NaI (2.08 g, 13.9 mmol) was added, followed by dropwise addition of a solution of 2-(2-chloroethoxy) ethanol (1.63 mL, 15.3 mmol) in DMF (7 mL). The reaction mixture was heated at 80° C. under nitrogen overnight. The mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl (100 mL), then extracted with EtOAc (3×60 mL). The organic layers were combined and washed with water, brine, and dried over Na2SO4, then concentrated to a light brown oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 95% EtOAc:hexanes to give a light brown oil which contained some DMF. The residue was dissolved in EtOAc (100 mL) and further washed with water (2×50 mL), saturated aqueous CuSO4 (50 mL), water (50 mL) and brine (50 mL). The EtOAc solution was dried (Na2SO4) and concentrated to 15 mL and 30 mL of hexanes added. A white solid precipitated and was washed with 1:1 hexanes:EtOAc to afford compound 61 (1.90 g, 45%). mp 126-127° C. 1H NMR (400 MHz, CD3OD): δ 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.85-3.90 (m, 2H), 4.20-4.25 (m, 2H), 6.87 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H). LRMS (APCI): m/z, 303 (M+H)+, 301 (M−H)−.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CCCc2ccccc21

Procedure:
1,2,3,4-Tetrahydro-1-naphthylamine is stirred with acetic anhydride to afford N-(1,2,3,4-tetrahydro-1-naphthyl)-acetamide, which is oxidized to N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide by the method of Example 1.
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10](Cl)([Cl:13])(=[O:12])=[O:11]>CN(C)C=O>[C:1]1([C:7]([CH3:9])=[CH:8][S:10]([Cl:13])(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(C)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=CS(=O)(=O)Cl)c1ccccc1

Procedure:
Following the procedure of Preparation A, 2-phenylpropene is reacted with sulfuryl chloride in N,N-dimethylformamide to give 2-phenylpropene-1-sulfonyl chloride, which is then treated with ammonia to give 2-phenylpropene-1-sulfonamide, m.p. 101-102.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)(O)[O-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C.[I-].[Na+]>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][NH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:25]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(OC)c(OC)cc1C#N
Temperature: 25 °C
Yield: 20.4 %

Procedure:
Under N2 suspend 2-amino-4,5-dimethoxybenzonitrile (2.0 g, 12.25 mmol) in ethanol (50 mL), and add sodium bicarbonate (3.09 g, 36.78 mmol) in one portion. By syringe, slowly add ethyl bromoacetate (2.72 mL, 24.5 mmol), and then sodium iodide (10 mg). Heat the reaction at 65° C. and then cool to ambient temperature. Filter the resulting solid and wash with ethyl acetate to dissolve the organics. Concentrate the filtrate to obtain 0.66 g (23%) of the title compound; MS 265(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1.Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)[C:28](=[O:29])[CH:27]=[CH:26][C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2ccn(C)c2c1
Agent: Cl
Product: CN(Cc1ccc2ccn(C)c2c1)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 65 %

Procedure:
According to the procedure of Example 35g methyl-(1-methyl-1H-indol-6-ylmethyl)-amine (129 mg, 0.74 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (190 mg, 0.75 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (180 mg, 65%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.07-8.06 (m, 1H), 7.55-7.47 (m, 2H), 7.39-7.21 (m, 3H), 6.95-6.88 (m, 1H), 6.38-6.37 (m, 1H), 4.89-4.71 (m, 2H), 3.76-3.74 (m, 3H), 3.08-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21].O>COCCO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:23][S:20]([NH2:24])(=[O:22])=[O:21])=[CH:14][CH:13]=1
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Reactant: NS(N)(=O)=O
Solvent: COCCO
Solvent: O
Product: NC(N)=Nc1nc(-c2nc(N)ccc2C=NS(N)(=O)=O)cs1
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (2.1 g) and sulfamide (2.9 g) in 2-methoxyethanol (10.5 ml) was stirred for 3 hours at 70°-75° C. The mixture was added to water, isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(aminosulfonylimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=2)[N:13]=1.[C:24]([CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][N:31]=1)(=[O:26])[CH3:25].[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][CH2:28][CH2:27][C:24](=[O:26])[CH3:25])=[N:31][CH:32]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CC(=O)CCNc1ccc(I)cn1
Reactant: C[Sn](C)(C)c1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)CCNc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-trimethylstannylphenyl)oxazoline (0.84 g, 2.0 mmol) was mixed with 2-(N-acetylethylamino)-5-iodopyridine (0.93 g, 3.2 mmol), Pd(PPh3)4 (0.12 g) and lithium chloride (0.15 g) in dioxane (10 ml) and the mixture was refluxed for 8 hours. After separation by chromatography (eluent: ethyl acetate), 2-(2,6-difluorophenyl)-4-[4-(2-(N-acetylethylamino)pyridin-5-yl)phenyl]oxazoline was obtained, 0.31 g, pale oil.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][N:21]([C:42](=[NH:37])[NH2:43])[CH2:22][CH2:23]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1=C(C2CCN(C(=N)N)CC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g), and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([O:24]CC)=[O:23])[CH:15]=1.O>Cl.C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([OH:24])=[O:23])[CH:15]=1
Reactant: CCCn1nc(C(=O)OCC)cc1CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCn1nc(C(=O)O)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 10 °C
Yield: 69.4 %

Procedure:
A stirred solution of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylate (45.1 g, 127 mmol) in 1 M aqueous hydrochloric acid (157 mL) and acetic acid (157 mL) was heated at 95° C. (internal temperature) for 10 hours and then cooled to 10° C. Water (300 mL) was added and a white solid was isolated by filtration, washed with water and diethyl ether, and dried. The solid was treated with toluene (150 mL) and heated at reflux for 3 hours with a Dean-Stark trap. The mixture was cooled in an ice bath to 10° C. and a solid was isolated by filtration and dried to provide 28.85 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][O:6][P:5](=[O:16])([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[O:4][CH2:3]1.C(OO)(=[O:20])C.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:3][O:4][P:5](=[O:16])([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]3[CH:12]([O:20]3)[CH2:11]2)[O:6][CH2:7]1
Reactant: CC1(C)COP(=O)(OCC2C=CCCC2)OC1
Reactant: CC(=O)OO
Solvent: O
Solvent: ClCCl
Product: CC1(C)COP(=O)(OCC2CCC3OC3C2)OC1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 15.5 g (0.058 mol) 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinanoxymethyl)-1-cyclohexene, and 100 mL of methylene chloride. Peracetic acid (13.76 g, 35 wt. % in acetic acid; 0.058 mol) in methylene chloride (60 mL) was added dropwise to above mixture over 20 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 100 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×100 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1C

Procedure:
58.3 mg of the target compound (0.16 mmol, 20.0%) was obtained using 1-(2,3-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Br:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.Cl[C:37](OCC)=[O:38]>O1CCCC1.CN(C)C=O>[Br:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]2[NH:1][C:37](=[O:38])[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2N)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc32)CC1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
A stirred solution of 1,1-dimethylethyl 4-{[2-amino-5-bromo-4-(trifluoromethyl)phenyl]amino}-1-piperidinecarboxylate (D67, 0.98 g, 2.2 mmol) in tetrahydrofuran (25 ml) at room temperature under argon was treated with diisopropylethylamine (0.78 ml, 4.4 mmol) followed by ethyl chloroformate (0.24 ml, 2.5 mmol) and maintained for 20 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to leave a beige solid, which was dissolved in dimethylformamide (20 ml) and heated with stirring under argon for 1.5 hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a light brown solid (0.95 g, 91%).