Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[CH2:5][CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[C:21](Cl)(=[O:25])[C:22](Cl)=[O:23].[CH3:27][O-:28].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:28][C:21](=[O:25])[C:22]([C:17]1[C:16]2[C:20](=[C:12]([CH2:11][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][OH:7])[CH:13]=[CH:14][CH:15]=2)[NH:19][CH:18]=1)=[O:23].[CH3:27][O:28][C:21](=[O:25])[C:22]([C:17]1[C:16]2[C:20](=[C:12]([CH2:11][N:4]([CH2:5][CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][CH:15]=2)[NH:19][CH:18]=1)=[O:23]
Reactant: C[O-]
Reactant: CC(=O)OCCN(Cc1cccc2cc[nH]c12)C(C)=O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(CN(CCO)C(C)=O)cccc12
Product: COC(=O)C(=O)c1c[nH]c2c(CN(CCOC(C)=O)C(C)=O)cccc12
Temperature: 25 °C
Yield: 48 %
Yield: 20 %

Procedure:
A solution of acetic acid 2-[acetyl-(1H-indol-7-ylmethyl)-amino]-ethyl ester (4.76 g, 17.36 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. Oxalyl chloride (3.27 g, 26.04 mmol) was added and the reaction was warmed to room temperature. Upon completion, the reaction was cooled to −78° C. and sodium methoxide (4.14 mmol, 18.1 mmol, 25% w/v in methanol) was added. The solution was warmed to 20–24° C., and the mixture was diluted with ethyl acetate (400 mL), washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and concentrated. SiO2 chromatography afforded the title compound (1.12 g, 20%) and (7-{[(2-Acetoxy-ethyl)-acetyl-amino]-methyl}-1H-indol-3-yl)-oxo-acetic acid methyl ester (3.0 g, 48%). MS (electrospray, m/z) 319.2 (M++1), 317.2 (M−−1).
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=O.C(C1C=CC(S([N:33]2[C:37]3=[N:38][CH:39]=[C:40]([NH:42][NH2:43])[N:41]=[C:36]3[CH:35]=[CH:34]2)(=O)=O)=CC=1)(C)(C)C.CCN(C(C)C)C(C)C.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:2]1([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[N:41]2[C:36]3[CH:35]=[CH:34][NH:33][C:37]=3[N:38]=[CH:39][C:40]2=[N:42][N:43]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate (0.41 g, 1.4 mmol, Preparation #5) was added to a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.50 g, 1.4 mmol, Preparation #3) and DIEA (0.25 mL, 1.4 mmol) in 1,4-dioxane (15 mL) at about 0° C. After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.53 mL, 7.2 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature then aqueous Na2CO3 (2 M, 14.5 mL, 29.0 mmol) was added and the reaction was heated at about 90° C. for about 3 days. The reaction was partitioned with EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified over silica gel (12 g) eluting with 50-100% EtOAc in heptane to afford benzyl 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate as a yellow solid (0.34 g, 61%): LC/MS (Table 2, Method a) Rt=1.89 min; MS m/z: 377 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16](Cl)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:32])[CH2:28][N:29]([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:31][N:29]([CH3:30])[CH2:28][CH:27]([NH:32][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: COc1ccccc1C(N)CN(C)C
Reactant: O=C(Cl)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(CN(C)C)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Yield: 14.4 %

Procedure:
To a 40-mL vial with magnetic stir bar at 25° C. under a nitrogen atmosphere was added 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl chloride (0.26 g, 0.94 mmol) and anhydrous DCM (8 mL). 1-(2-Methoxy-phenyl)-N*2*,N*2*-dimethyl-ethane-1,2-diamine (0.2 g, 1.0 mmol) was then added followed by the diisopropylethylamine (0.6 g, 0.8 mL, 4.7 mmol) and stirring continued×16 hours. The solvent was evaporated under a nitrogen stream and the resulting residue purified via preparative HPLC (0.1% triethylamine/1% acetonitrile mixture in water and methanol) afforded the desired product as a white solid (59.1 mg, 14% yield). LCMS m/e 436 (M+H). 1H NMR (400 MHz, DMSO-d6) ppm 2.12 (s, 6H) 2.25 (dd, J=12.38, 4.27 Hz, 1H) 2.60 (dd, J=12.34, 9.78 Hz, 1H) 3.77 (s, 3H) 5.44-5.52 (m, 1H) 6.41 (dd, J=3.36, 1.18 Hz, 1H) 6.66 (d, J=5.44 Hz, 1H) 6.84 (td, J=7.42, 0.71 Hz, 1H) 6.92-6.97 (m, 1H) 7.16-7.22 (m, 1H) 7.24 (dd, J=7.57, 1.56 Hz, 1H) 7.26-7.28 (m, 1H) 7.39 (d, J=5.39 Hz, 1H) 7.81 (d, J=5.38 Hz, 1H) 7.98 (d, J=5.41 Hz, 1H) 8.23 (d, J=7.92 Hz, 1H) 9.89 (s, 1H) 11.49 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:37][C:36]3[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[CH:17]4[CH2:26][CH2:25][C:24]5[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=5[CH2:18]4)=[CH:3][C:2]=3[F:1])[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C4CCC3CC4)c(F)c2)c1
Yield: 52.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:16]4[N:17]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:18][CH2:19][C:15]=4[C:14]([CH3:25])=[N:13][C:12]=23)=[CH:6][C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]1=2.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:6]1[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[O:3][C:7]=1[C:8]1[C:9]([CH3:26])=[N:10][N:11]2[C:16]3[N:17]([CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[CH2:18][CH2:19][C:15]=3[C:14]([CH3:25])=[N:13][C:12]=12
Reactant: BrBr
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4cc5ccccc5o4)c(C)nn3c21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4oc5ccccc5c4Br)c(C)nn3c21
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Bromine (1.0 M solution in carbon tetrachloride 0.3 mL, 0.30 mmol) was added to a solution of 3-benzo[b]furan-2-yl-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (50 mg, 0.13 mmol) in N,N-dimethylformamide (0.3 mL) at 0° C., followed by stirring for one hour. Hypo water was added thereto, and the mixture was diluted with ethyl acetate, washed with an aqueous saturated solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (57 mg) as white crystals.
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:42][CH2:41][C:39]1[CH:38]=[C:37]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=2)[N:36]=[C:35]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[CH:40]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A solution of acid 4B (0.15 g, 0.53 mmol) in THF (10 mL) was added with DEPC (0.10 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.17 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (90 mg) after crystallization from ethyl ether. Yield=32%. 1HNMR (DMSO, 200 MHz) δ 1.092 (t, 3H, J=5.6), 1.95 (m, 4H), 3.4-3.46 (m, 6H), 4.39 (d, 2H, J=6), 5.13 (s, 1H), 6.12 (s, 1H), 6.47 (s, 1H), 7.20 (s, 1H), 7.51 (t, 2H, J=7.9), 7.80-7.90 (m, 4H), 8.27 (d, 2H, J=8.1), 8.78 (bt, 1H). [M+1] 576.28 (C28H28F4N4O3S requires 576.60).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=[O:23].[CH2:27]([C:29]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]3[CH2:38][CH2:39][NH:40][CH2:41][CH:32]3[C:31]=2[CH:30]=1)[CH3:28]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:7][CH2:8][C:9]([N:40]2[CH2:39][CH2:38][CH:33]3[NH:34][C:35]4[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[CH:30][C:31]=4[CH:32]3[CH2:41]2)=[O:11])=[O:23])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: CCc1ccc2c(c1)C1CNCCC1N2
Reactant: O=C(O)CCCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C1CN(C(=O)CCC(=O)c3ccc(F)cc3)CCC1N2
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of β-(p-fluorobenzyl)propionic acid (3.0 g) and triethylamine (1.7 g) in dry tetrahydrofuran (90 ml) is added dropwise ethyl chloroformate (1.8 g) under maintaining the temperature of the system at 0° - 2°C. The mixture is stirred at the same temperature for 30 minutes. The mixture is added in portions of 8-ethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (3.3 g) in dry tetrahydrofuran (50 ml) so that the temperature in the system is maintained at 0° - 2°C. After the addition, the mixture is stirred at room temperature for one hour and then refluxed for one hour. After cooling, the precipitated crystals are filtered off and the filtrate is concentrated. The resulting residue is recrystallized from ethanol to give the titled compound (4.2 g), m.p. 120° - 124°C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=C(C=CC=1)N>C(O)(=O)C>[F:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(F)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(F)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 3-fluoroaniline (44.3 mg, 0.4 mmol), and acetic acid (0.06 ml) were used to give 8.1 mg (0.025 mmol, 12% yield) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4].C1(OC)C=CC=CC=1.ClC(Cl)(Cl)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([OH:27])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Yield: 103.4 %

Procedure:
A mixture of 7.65 g of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl]-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, 25 ml of methylene chloride, 5 ml of anisole and 20 ml of trichloroacetic acid was allowed to react at room temperature for 30 minutes. At the end of this time, 300 ml of diisopropyl ether were added to the reacton mixture and the resulting precipitates were collected by filtration, giving 5.95 g of 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][O:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:20])[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1>O>[OH:22][CH2:21][C:13]1[C:14]2[C:19](=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][O:7][CH3:6])=[CH:11][CH:12]=1
Reactant: COCOc1ccc(C=O)c2cccc(C)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(CO)c2cccc(C)c12
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
1.23 g of sodium borohydride was added to an ethanol (100 ml) solution of 15 g of 4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde at room temperature and agitated for 30 minutes. Water was added to the reaction solution and the resultant crystals were collected by filtration and dried to obtain 14 g of the captioned compound as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([S:8]([N:11]([CH2:33][O:32][CH2:30][CH3:31])[C:12]2[N:13]=[CH:14][C:15]([F:18])=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Nc1ncc(F)cn1)c1cc(Cl)c(F)cc1F
Reactant: CCOCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.7 %

Procedure:
To a solution of 5-chloro-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 12, 0.28 g, 0.86 mmol) in dichloromethane (7 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.32 mmol) and chloromethyl ethyl ether (0.088 mL, 0.95 mmol). The reaction mixture was stirred for 20 hours allowing the solution to gradually warm to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution, water, and brine and then dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes to ethyl acetate gradient elution) to afford the title compound as a white solid (173 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:24][N+:21]([O-:23])=[O:22])=[C:7]([CH3:15])[C:8]([O:13][CH3:14])=[C:9]([CH3:12])[C:10]=1[CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1c(C)c(C)c(OC)c(C=C[N+](=O)[O-])c1C
Temperature: 80 °C

Procedure:
In a 500 mL round bottom flask was placed 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (2.5 g, 12 mmol) and ammonium acetate (1.3 g, 17 mmol). The solids were taken up in nitromethane (240 mL), and the mixture warmed to 80° C. for 90 min. After the reaction was complete, volatiles were removed in vacuo, the residue was dissolved in ethyl acetate (200 mL), washed with water and brine (50 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3.3 g 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene as a yellow solid. Further purification was performed by digesting the solid product in cyclohexane for 3 hrs, after which the 2.5 g pure compound 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene was obtained. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H), 7.95 (d, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: O=c1[nH]nc(-c2cc3ccc(F)cc3c(N[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a mixture of (S)-3-(7-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 0.35 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (122 mg, 1.15 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (45 mg, 0.49 mmol) was added dropwise and the reaction mixture was stirred at −40° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (79 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 11.70 (s, 1H), 8.25-8.22 (d, J=10.8 Hz, 1H), 7.97-7.96 (m, 1H), 7.63-7.60 (m, 2H), 7.55-7.54 (m, 1H), 6.59-6.57 (m, 1H), 6.21-6.15 (m, 1H), 5.68-5.65 (dd, J1=10.4 Hz, J2=2.4 Hz, 1H), 5.20-5.18 (m, 1H), 4.19-4.15 (m, 0.5H), 3.70-3.67 (m, 2H), 3.69-3.45 (m, 1.5H), 3.25 (m, 0.5H), 2.26-2.24 (m, 1H), 2.08-2.03 (m, 1H).
Reaction SMILES: C(OC(C1C=N[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=1N)=O)C.C(O[C:21]([C:23]1[CH:24]=[N:25][N:26]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:27]=1[N:28]([C:39](=[O:48])[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1[Cl:47])C(=O)C1C=CC(Cl)=CC=1Cl)=[O:22])C.[Cl:55]CCl>>[Cl:55][C:15]1[CH:16]=[CH:17][C:12]([NH:9][C:21]([C:23]2[CH:24]=[N:25][N:26]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:27]=2[NH:28][C:39](=[O:48])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[Cl:47])=[O:22])=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N(C(=O)c1ccc(Cl)cc1Cl)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Product: O=C(Nc1c(C(=O)Nc2ccc(Cl)cc2)cnn1-c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromoaniline (1, 60.0 mg, 0.35 mmol) in dichloromethane (1.5 mL) is added p-toluoyl chloride (2, 46.1 μL, 0.35 mmol) and TEA (97.2 μL, 0.70 mmol). The reaction mixture is stirred at room temperature for 30 minutes to provide N-(4-bromo-phenyl)-4-methylbenzamide (3). After removal of the solvent, without further purification, 3 is taken by thionyl chloride (0.5 mL) and the mixture is heated at 80° C. for 1 hour before thionyl chloride is removed in vacuo to provide imidoyl chloride 4. Without further purification, the crude 4 is dissolved in dichloroethane (1.0 mL), and ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate (5, 96.8 mg, 0.42 mmol) and TiCl4 (153.0 μL, 1.40 mmol) are added. The reaction mixture is heated at 160° C. in a microwave for 20 minutes, cooled down, diluted with dichloroethane (5 mL), and quenched with H2O (5 mL). The two layers are separated. The aqueous layer is extracted with dichloroethane. The combined dichloroethane layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography followed by reverse phase HPLC to provide 5-(4-bromo-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as a white solid product: 1H NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 8.16 (d, 2H), 7.50 (t, 2H), 7.47 (d, 2H), 7.34 (t, 1H), 7.22 (d, 2H), 7.06 (d, 2H), 7.02 (d, 2H), 2.32 (s, 3H); HPLC-MS calculated for C24H17BrN4O(M+H+) 457.1. Found: 457.1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=O)(C)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]([NH2:24])[CH3:23]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]([NH:24][CH2:10][C@@H:9]([NH2:8])[CH3:11])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccccc1[C@H](C)N
Product: COc1ccccc1[C@H](C)NC[C@H](C)N
Yield: 12.2 %

Procedure:
By using N-t-butoxycarbonyl-(L)-alanine (431 mg), and (1S)-1-(2-methoxyphenyl)ethanamine (200 mg) obtained by the method described in the publication (Japanese Patent Unexamined Publication No. 54/154724) as starting materials, the title compound (33.6 mg) was obtained in the same manners as those of Reference Example 10, (1), (2), and Reference Example 3, (2).
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](C(NCCC)=O)[CH:19]=3)[CH:17]=2)=[O:11])[C:5]2[CH:6]=[CH:7]C=CC=2N=N1.[CH:31]1([CH2:34][NH2:35])[CH2:33][CH2:32]1.C1C[O:39][CH2:38]C1>>[CH:31]1([CH2:34][NH:35][C:38]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[C:15]([CH3:30])=[CH:14][CH:13]=[C:12]([C:10]([NH:1][CH2:5][CH2:6][CH3:7])=[O:11])[CH:17]=3)=[CH:23][CH:22]=2)=[O:39])[CH2:33][CH2:32]1
Reactant: C1CCOC1
Reactant: NCC1CC1
Reactant: CCCNC(=O)c1cccc(-c2cc(C(=O)n3nnc4ccccc43)ccc2C)c1
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5′-[(1H-1,2,3-Benzotriazol-1-yl)carbonyl]-2′-methyl-N-propyl-1,1′-biphenyl-3-carboxamide (25 mg, 0.062 mmol) in THF (1 ml) was mixed with cyclopropylmethylamine (7.2 μl) in THF (0.6 ml) and the reaction stirred at room temperature for 4 h. The reaction was loaded onto an SPE (aminopropyl, 1 g) and eluted with chloroform, ethyl acetate and methanol. The solvent was evaporated from the product fractions to give N4′-cyclopropylmethyl-6-methyl-N3-propyl-1,1′-biphenyl-3,4′-dicarboxamide. NMR: δH CDCl3 7.84, (2H, d), 7.68, (1H, dd), 7.62, (1H, d), 7.38, (2H, d), 7.33, (1H, d), 6.37, (1H, t), 6.26, (1H, t), 3.42, (2H, m), 3.35, (2H, m), 2.28, (3H, s), 1.64, (2H, m), 1.09, (1H, m), 0.98, (3H, t), 0.58, (2H, m), 0.30, (2H, m). LCMS: retention time 3.13 min, MH+351.