Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8]O)[CH:7]=1.O=S(Cl)[Cl:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8][Cl:13])[CH:7]=1
Reactant: OCc1cc(Br)ccc1I
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of (5-bromo-2-iodophenyl)methanol (1.4 g, 4.5 mmol) in DCM (20 mL) was added SOCl2 (3.2 g, 26.9 mmol) at 0° C., and the reaction was stirred at rt overnight. The solution was concentrated, and the residue was purified silica gel chromatography (PE) to give 1.2 g (81%) of the title compound as a brown solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH:13]([Cl:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:35][CH:13]([Cl:12])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Reaction time: 20 h
Yield: 76.4 %

Procedure:
1.2 ml (0.0129 mol) of acetic anhydride and 0.6 ml (0.0143 mol) of 98% strength nitric acid are added in succession to 5 g (0.0113 mol) of 5-dichloroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 10 ml of glacial acetic acid at room temperature. The mixture is stirred for 20 hours, after which it is evaporated down in vacuo, the residue is taken up in 50 ml of dichloromethane and the solution is washed in succession with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent in vacuo. 4.2 g (76.4% of theory) of 5-dichloroacetamido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 112° C.-120° C. are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 19.5 g. (0.0468 mol.) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone, 12.3 g. of sodium bicarbonate, 3.00 g. of 10% palladium-on-carbon and 250 ml. of ethanol was stirred under one atmosphere of hydrogen pressure for 1.5 hours. The reaction mixture was then filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to a solid. The crude solid was purified via column chromatography on 280 g. of silica gel eluted with 20% ethercyclohexane to yield a solid. Recrystallization of this solid from aqueous methanol gave 9.1 g. (62%) of the title product, m.p. 87° C., principally in the hemiketal form.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N+:4]([O-])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl-].[NH4+].C(O)(=O)C>O.[Zn]>[Cl:1][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2nc(Cl)nnc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 21,8 g (0.1 mole) of 3,7-dichlorobenzo-1,2,4-triazine 1-oxide, 7.5 g of zinc dust and 5.5 g of ammonium chloride in 400 ml of water was stirred vigorously at room temperature for 24 hours. 50 ml of glacial acetic acid were then added, the mixture was stirred for a further hour and the insoluble constituents were then filtered off. The latter were extracted twice with methylene chloride. The combined methylene chloride solutions were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from wash benzine. 7.5 g, that is to say 37% of theory, of 3,7-dichloro-benzo-1,2,4-triazine with a melting point of 113°-115° C were obtained. ##STR36## (Preparation according to process variant (a))
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]([CH2:19][CH3:20])=[C:8]([CH2:21][CH3:22])[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH2:21][CH3:22])=[C:9]([CH2:19][CH3:20])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: CCc1nc(O)c(Cc2ccccc2)nc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CCc1nc(Cc2ccccc2)c(=O)n(CCO)c1CC
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Ethylene chlorohydrin (20.15 g, 0.25M) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethyl-pyrazine (12.10 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added thereto and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 230 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 640 (12.31 g, yield: 58.7%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:33]2[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]2[CH:29]([CH3:31])[CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
4-(8-((4-tert-Butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (80 mg) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 31.4 mg 471 following reverse phase purification. MS (Q1) 532.4 (M)+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15](=O)[C:14]2[C:13]([C:24]([O:26]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.CN1C=CN=C1C1C(C2C=CC=CC=2)C(=O)C2C(C(OCC)=O)=CC=CC=2N1.O.[NH2:57][NH2:58]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:57][NH:58][C:24](=[O:26])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of methyl 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (87 mg) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) was stirred at room temperature for overnight. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude. The crude product was purified by pre-HPLC to give 8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (34 mg, yield 42%) as a yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.41 (s, 3H), 4.49 (d, 1H), 5.35 (d, 1H), 7.18-7.20 (m, 2H), 7.26-7.29 (m, 1H), 7.33-7.35 (m, 3H), 7.40 (d, 1H), 7.61 (d, 1H), 7.71-7.75 (m, 2H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>CN(C)C=O>[N:11]1([CH2:10][C:2]2[N:1]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CNC(=O)CCl
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(Cn2nnc3ccccc32)nc2ccccc21
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1-(1H-Benzimidazol-2-ylmethyl)-1H-benzotriazole (500 mg, 2.00 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Potassium carbonate (1.11 g, 8.00 mmol) and 2–Chloro-N-methylacetamide (237 mg, 2.20 mmol) were added. The reaction mixture was allowed to stir overnight at reflux. The solvent was evaporated under vacuum, and the white waxy residue taken up in methylene chloride (300 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (CH2Cl2/MeOH=15:1) to give 304 mg (47%) of the title compound as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][N:13]=1.N>>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Clc1ccc(-c2nc(-c3cccnc3)no2)cn1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Tyger) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J=7.6, 5.3 Hz, 1 H), 7.57 (d, J=8.5 Hz, 1 H), 8.40-8.48 (m, 2 H), 8.80 (dd, J=4.7, 1.7 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 9.40 (d, J=2.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 261 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:27])[C:20](=[O:26])[NH:21]2>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:27])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:26])[NH:21]2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (4.86 g, 22.0 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of isopropyl magnesium chloride (49.6 mmol, 24.8 mL, 2.0 M solution in tetrahydrofuran) over 10 min at 0° C. The reaction mixture was stirred for 30 min upon which time 4-chloroisatin (4.00 g, 22.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h and quenched by the addition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture was concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with hot diethyl ether to afford 4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (6.70 g, 95%) as a beige solid: mp 250-253° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30, (s, 1H), 9.04 (s, 1H), 7.20 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.45 (s, 1H), 6.17 (s, 1H), 5.88 (d, J=6.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.1, 148.6, 147.0, 145.6, 139.6, 130.6, 130.1, 129.6, 122.3, 118.6, 108.9, 108.4, 101.1, 97.4, 75.8; MS (ES−) m/z 304.2 (M−17), 302.2 (M−17).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10]C(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH:23]=[CH2:24])[CH2:19][CH:20]=O)[CH3:15]>C1(C)C=CC=CC=1.CO>[C:1]1([C@H:7]([N:9]2[CH:20]3[CH2:19][N:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])[CH2:22][CH:23]3[CH2:24][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Temperature: 90 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of (1-(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 mL of toluene was heated to 90° C. To this 170 g (1.1 equivalents) of a 15.84 wt. % solution of allyl-(2-oxo-ethyl)-carbamic acid ethyl ester (U.S. Pat. No. 5,071,999) in toluene, was added over 20 minutes and the mixture was stirred at 90° C. for 14 hours then at 95° C. for 12 hours. After cooling, the product was extracted with 2×115 g of 20% citric acid solution. The citric acid solution was diluted with 205 mL of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 120 g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 mL of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 mL of MeOH to provide 140 g (100% yield) of the title compound as a 30% by weight solution in MeOH.
Reaction SMILES: [Cl-].[C:2]1([PH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>[NH4+].[Cl-]>[C:9]1([P:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Diphenylphosphine chloride (5 mmol, 0.92 ml) was dissolved in TIM (25 ml). The solution was cooled to 0° C. 4-Methoxyphenyl magnesium bromide (6.5 mmol, 19 ml, 1.3 eq) was added dropwise to the solution over 20 minutes. The mixture was stirred for 3 hours. The mixture was allowed to warm to room temperature, and then stirred for another 5 hours after which saturated NH4Cl (20 ml) was added thereto to terminate the reaction. The inorganic salt was removed by suction filtration and the filtrate was extracted with dichloromethane (40 ml×3). The extract was dried over sodium sulfate and concentrated using an evaporator and an oil pump to give diphenyl-4-methoxyphenylphosphine.
Reaction SMILES: CC1C=CC(S([O-])=O)=CC=1.[NH2:11][C:12]1[C:21]([C:22]([O:24]CC=C)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1>CS(C)=O.O.Cl.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>[NH2:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: C=CCOC(=O)c1c(N)nn2cc(F)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: Nc1nn2cc(F)cnc2c1C(=O)O
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
In an alternative method, 4-methylbenzenesulfinate (anhydrous, 1.2 eqv, 22.6 g, 127 mmol) was suspended in dry DMSO (20 vol, 500 ml). The stirred mixture was warmed to 30° C. under a nitrogen atmosphere. Upon complete dissolution Pd(PPh3)4 (2 mol %, 2.4 g, 2.1 mmol) was added. The mixture was stirred for 10 min at 25-30° C. after which time a turbid yellow solution was present. Allyl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (25 g, 105.8 mmol) was added portionwise, maintaining the temperature at 25-30° C. Once addition was complete the cloudy solution was stirred until the reaction was complete by HPLC (2-3 hrs). A heavy precipitate formed after 15 minutes post addition of the substrate. The mixture became thicker as the reaction proceeded. The reaction mixture was diluted with water (125 ml) and 2M HCl (66 ml) was added slowly, maintaining the temperature at 25-30° C. The slurry was stirred for 30 minutes, then filtered. The filtration was slow (2 hrs). The resulting solid was washed with water, then dried on the sinter. The solid was slurried in DCM (8 vol) for 1 hr. The solid was filtered (rapid filtration) and washed with DCM. The solid was re-slurried in chloroform (8 vol) for 1 hr. The acid was filtered and dried on the sinter. It was further dried in a vacuum oven at 50° C. for 24 hrs. The product was obtained as an off-white solid (18.6 g, 85%); 1H NMR (500 MHz, DMSO-d6) δ 12.14 (1H, brs), 9.31 (1H, dd), 8.69 (1H, m), 6.47 (2H, brS); 19F NMR (500 MHz, DMSO-d6) δ−153.65; MS (ES+) 197.1.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:32]4[C:33]([F:40])=[CH:34][C:35]([S:37]([CH3:39])=[O:38])=[CH:36][C:31]=4[F:30])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (10.0 mg, 0.025 mmol), 6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylic acid (9.4 mg, 0.03 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL) and DIPEA (9.6 mg, 0.074 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (3.0 mg, 17%). LCMS calc. for C34H39F3N5O6S (M+H)+: m/z=702.3. Found: 702.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 98.8 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (45.3 g, 217 mmol), β-alanine ethyl ester hydrochloride (40.0 g, 240 mmol), and triethylamine (54.8 g, 542 mmol) in dichloromethane for 15 hours to provide ethyl 3-(3-nitroquinolin-4-ylamino)propionate (62.0 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[O:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl) methanol (0.55 g, 1.92 mol) in DCM (20 mL) was added Dess-Martin periodinane (1.6 g, 3.84 mol) at room temperature. The resulting solution was stirred for 1 h. To the reaction mixture was added NaHCO3 solution (20 mL) and ethyl acetate (50 mL). The organic layer was extracted with ethyl acetate (2×20 mL), washed with brine solution (2×20 mL), dried over anhydrous sodium sulfate and the solvent removed via distillation under reduced pressure. The crude was purified through silica gel (100-200 mesh) column chromatography using 10% methanol in DCM) to obtain (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone as off-white solid (0.4 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, 2H), 8.51 (s, 1H), 8.19 (dd, 2H), 7.82 (d, 2H), 7.45 (t, 2H); LC-MS m/z calculated for [M+H]+285.04 found 284.98.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[F:7][C:8]([F:28])([F:27])[C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:27][C:8]([F:7])([F:28])[C:9]1[C:18]([C:19]([NH:1][C:2]2[NH:6][N:5]=[N:4][N:3]=2)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1nnn[nH]1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 52.9 %

Procedure:
5.03 g of anhydrous 5-amino-tetrazole were suspended with stirring at 8° C. in 230 ml of ethyl acetate and a solution of 21.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 230 ml of ethyl acetate and a solution of 18 g of triethylamine in 180 ml of ethyl acetate were simultaneously added to the reaction mixture over 15 minutes. The mixture returned to room temperature and was refluxed for one hour and cooled. The mixture was vacuum filtered and the recovered product was dissolved in one liter of water. The filtrate wash waters were added to the solution and the pH was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was dissolved in 50 ml of 2 N sodium hydroxide. 150 ml of water were added to the solution and the mixture was heated to reflux and cooled. The mixture was acidified with 100 ml of 20% hydrochloric acid and was vacuum filtered. The product was dried and crystallized from 250 ml of acetic acid to obtain 12.279 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(1H-tetrazol-5-yl)-3-quinolinecarboxamide melting at >260° C.