Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[N:18]([CH3:22])[CH3:17])=[CH:4][C:3]=1[CH3:9]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)N(C)C)ccc1Br
Yield: 36.2 %

Procedure:
4-Bromo-3-methylaniline (5.00 g, 27 mmol), triethylamine (3.9 ml, 28 mmol), 4-(dimethylamino)pyridine (0.5 g, 4 mmol) and dimethylcarbamyl chloride (2.6 ml, 28 mmol) were mixed in dichloromethane (100 ml), and left to stand for 2 weeks. The solution was then washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to give a solid. This was triturated with ether, and the solid was filtered off and dried, affording the title compound (2.51 g, 36%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>O.CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: COc1cc(Cl)cc(CBr)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)cc(CC#N)c1Cl
Yield: 97.4 %

Procedure:
By the method of Example 1, Step C, 15.40 grams (0.057 mole) of 2,5-dichloro-3-methoxyphenylmethyl bromide and 3.63 grams (0.074 mole ) of sodium cyanide were reacted in 70 mL of water and 65 mL of methanol, yielding 12.0 g of 2,5-dichloro-3-methoxyphenylacetonitrile as an oil that solidified on standing, m.p. 53°-57° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:22]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH2Cl2 (8 mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8 g, 3.0 mmol), EDCl (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037 g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 1.2 g of ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate. Mass calculated for C235H27NO6=413.46; found: [M+Na]+=437.1.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11]OS(=O)(=O)[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:21][N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:11][C@@H:7]([NH:8][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)COS1(=O)=O
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C[C@@H](NC(=O)OC(C)(C)C)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
tert-Butyl (45)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1 g; 3.34 mmol), N-methyl-4-nitrobenzenesulfonamide (722 mg; 3.34 mmol), and Cs2CO3 (0.40 ml; 5.01 mmol) were dissolved in CH3CN (25 ml), and stirred overnight. The reaction mixture was filtered, washed with H2O (50 ml), and dried under vacuum to provide the desired intermediate (1.12 g; 77%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=3)[C@H:9]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:10]2)=[CH:36][CH:37]=1)(=[O:43])[CH3:42]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Yield: 102 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (228 mg), 1-[4-(bromomethyl)phenyl]ethanone (107 mg) and potassium carbonate (42 mg) in acetonitrile (2 ml) was refluxed for 4.5 hours. After cooling, the mixture was evaporated in vacuo. Ethyl acetate and water were added to the residue and the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and methanol as an eluent to give (2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.30 g). To a solution of this piperazine (0.30 g) in ethyl acetate was added 4N hydrogen chloride in ethyl acetate solution (0.13 ml) and the whole was evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and ether to give (2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (283.5 mg) as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:22](O)=[O:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)(=O)C>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:22]([C@@H:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:23]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid (0.192 g, 0.5 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.205 g, 1.5 mmol) were dissolved in dried dichloromethane (5 ml) under nitrogen at 0° C., and triethylamine (0.63 ml, 4.5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.382 g, 1.5 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 7:3 petroleum spirit: ethyl acetate as eluent to provide a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].[CH2:10]([O:12][C:13]([C:15]1([C:18]2([NH2:21])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1([C:18]2([NH:21][C:6](=[O:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)C1(C2(N)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NC1(C2(C(=O)OCC)CC2)CC1
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
Chlorocarbonyl-acetic acid ethyl ester (1.24 ml; 11.2 mmol) in CH2Cl2 (5 ml) is added dropwise under stirring within 15 minutes at room temperature to a solution of 1′-amino-bicyclopropyl-1-carboxylic acid ethyl ester (1.38 g; 8.16 mmol) (Synlett. 2003, 2, 265) and triethylamine (1.02 ml; 10.4 mmol) in CH2Cl2 (100 ml). Stirring is continued for 5 minutes, then the reaction mixture is poured on water, acidified with 2N HCl and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; acetone/heptane 9:92>2/8) to yield the title compound as off-white crystals (1.9 g; 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CC(C1C=C(S[C@@H]2CCCC[C@H]2S[CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])C=C(C(C)(C)C)C=1)(C)C>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:32](=[O:33])[CH3:31])=[CH:4][CH:5]=1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: NCc1ccncc1
Product: CC(=O)NCc1ccncc1

Procedure:
Substituting 4-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(4-pyridinylmethyl)-acetamide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:11]=[C:12]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:42])[F:41])[CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([S:24]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)(=[O:26])=[O:25])=[C:19]([F:33])[CH:18]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.C(O)(=O)C>[Cl:23][C:22]1[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:42])([F:43])[F:41])=[CH:11][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH3:46])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)=[CH:18][C:19]([F:33])=[C:20]([S:24]([NH:27][C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3C(F)(F)F)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(n2nccc2-c2cc(-c3ccccc3C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 132.3 %

Procedure:
To a suspension of 4-{[3-(1-azetidin-3-yl-1H-pyrazol-5-yl)-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 46, 42.9 mg, 0.0659 mmol) in methanol (0.10 mL), dichloromethane (1.72 mL) and acetic acid (0.10 mL) was added formaldehyde (37% w/w, 16.7 μL, 0.224 mmol). The reaction was then stirred under nitrogen at room temperature for 45 minutes. Sodium triacetoxyborohydride (42.6 mg, 0.201 mmol) was added to the reaction which was stirred for 18 hours at room temperature. The reaction was diluted with dichloromethane (20 mL) and washed with water (3×2 mL). The combined aqueous phases were extracted with dichloromethane (3×5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a white solid (58.0 mg). The solid was purified by B-HPLC to afford the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(-c3ccc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a light brown solid (0.055 g, 21%). MS (ISP) 412.1 [(M+H)+], 414.2 [(M+2+H)+] and 416.2 [(M+4+H)+]; mp 180° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]([C:5]1[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:3]([NH:1][NH:2][S:27]([CH3:26])(=[O:29])=[O:28])[N:4]=1)=[O:13]
Reactant: NNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
A mixture of 2-hydrazinothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (110 mg, 0.4 mmol) and Et3N (61 μL, 0.44 mmol) in THF (5 mL) was treated with methanesulphonyl chloride (31 μl, 0.4 mmol), stirred at room temperature for 20 min, poured into water (25 mL), extracted with EtOAc (2×5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography [SiO2: (EtOAc) to give the title compound (92 mg, 65%) as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br)([O-:18])=[O:17]>O1CCCC1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:18])=[O:17]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Reaction time: 0.5 h

Procedure:
Methyl indole-5-carboxylate (10 g) was dissolved in dry tetrahydrofuran (250 ml) and cooled in an ice-bath. To the stirred solution was added sodium hydride (60% suspension in oil) (2.57 g) in portions over 15 minutes. After stirring for a further 30 minutes, 3-nitrobenzyl bromide (11.55 g) in dry tetrahydrofuran (30 ml) was added dropwise over 20 minutes. Stirring was continued at 0° C. for 30 minutes, then at room temperature for 2 hours. Excess sodium hydride was destroyed by cautious addition of acetic acid, then the reaction mixture extracted from brine into ethyl acetate, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Recrystallisation from ethyl acetate/hexane afforded methyl 1-(3-nitrobenzyl)indole-5-carboxylate (m.p. 129°-130° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc2c(Br)cccn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A15), 4.40 g; 20.7 mmol; 1.0 eq.) and benzoyl chloride (5.81 g; 41.3 mmol; 2.0 eq.) as a white solid (4.9 g, 74%). HPLC, Rt: 2.45 min. (purity 90.1%). LC/MS, M+(ESI): 318.9, M−(ESI): 316.9.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:38])(=[O:37])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[N:31]=[CH:30]3)[S:24]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])(=[O:38])=[O:37])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 26).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1.Cl>O1CCOCC1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1
Reactant: CCOC(=O)c1sc(-c2ccc(OCOC)c(-n3cnnn3)c2)nc1C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ccc(O)c(-n3cnnn3)c2)nc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A reaction mixture solution was prepared by dissolving 1.97 g of ethyl [4-(methoxymethoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 25 mL of 1,4-dioxane and adding 5.0 mL of 2 M hydrochloric acid was heated under stirring at 60° C. for 8 hours. After the reaction mixture solution was cooled to room temperature, the precipitated solid was filtered to obtain 1.49 g of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]CC)=[O:33])[CH:26]=[N:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[N:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: CCOC(=O)c1cnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
To a stirred solution of ethyl 6-[4-({[3-(2,6-dichlorophenyl) -5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoxalinecarboxylate (0.112 g, 0.20 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N sodium hydroxide (0.21 mL, 0.21 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3.5 hours. The solvent was removed in vacuo and water (5 mL) was added to the resulting solid. The pH of the aqueous mixture was adjusted to ˜3 (litmus paper) with 1 N HCl. The acidic aqueous mixture was extracted with ethyl acetate. The aqueous phase was separated and extracted a second time with ethyl acetate. The aqueous phase was separated and found to contain product according to thin layer chromatography. The pH of the aqueous phase was adjusted to ˜2 (litmus paper) with 1 N HCl. The acidic aqueous phase was combined with the aforementioned ethyl acetate extracts. The organic phase was separated, washed with water followed by brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a yellow solid which was dried under high vacuum at room temperature to give 0.095 g (89%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoxalinecarboxylic acid. 1H NMR (d6-DMSO, 400 MHz): δ 13.89 (br s, 1H), 9.40 (s, 1H), 8.32 (s, 1H), 8.24 (m, 2H), 7.81 (d, J=9 Hz, 2H), 7.62 (m, 2H), 7.53 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)=[O:33])=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2cccnc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-4-oxo-1-phenyl-3-{[(pyridine-3-carbonyl)-amino]-methyl}-1,4-dihydroquin-oline-2-carboxylic acid methyl ester was prepared starting from intermediate K and pyridine-3-carbonyl chloride. MS calcd. for C25H21N3O5 [(M+H)+] 444.2, obsd. 444.0.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13]([O:20][C:21]1[C:22]([F:31])=[C:23](B(O)O)[C:24]([F:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:13]([O:20][C:21]1[C:22]([F:31])=[C:23]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[F:12])[C:24]([F:27])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1c(F)ccc(OCc2ccccc2)c1F
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)ccc(OCc3ccccc3)c2F)n1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 3-(benzyloxy)-2,6-difluorophenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate as the desired product as a light yellow oil in 96% yield. LC/MS=374.0 (M+H), Rt=1.07 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[I-:12].[Na+].[OH-].[Na+].[O-]Cl.[Na+].Cl>CO>[I:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: Oc1cccc2cccnc12
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: Oc1ccc(I)c2cccnc12
Reaction time: 16 h

Procedure:
A solution of 8-hydroxyquinoline (25.00 g, 172 mmol), sodium iodide (27.10 g, 181 mmol), and 6M NaOH (30.14 mL, 181 mmol) in methanol at 0° C. was treated with 5.25% aqueous NaOCl (13.46 g, 181 mmol) dropwise over 4 hours, stirred for 16 hours, adjusted to pH 7 with 6M HCl and pH 7 buffer, and extracted with 5% methanol in ethyl acetate (3×200 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in 10% methanol/ethyl acetate and filtered. The filtrate was dried (Na2SO4), filtered, and concentrated to provide the desired product.