Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:2]1
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Yield: 71.4 %

Procedure:
Using 4-{[1-benzothiophen-3-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized in Example A1(3) and ethyl 3-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4), the title object compound (220 mg, 71%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16][CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC2(CCSCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Yield: 91 %

Procedure:
To a solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.200 g, 0.910 mmol) and tetrahydrothiopyran-4-one (0.528 g, 4.55 mmol) in glacial acetic acid (6 mL) was added p-toluenesulfonic acid monohydrate (0.017 g, 0.091 mmol). The mixture was heated at 80° C. overnight. Then, the mixture was concentrated, and then the residue was dissolved in methanol (20 mL). Solid NaHCO3 (1.00 g, 11.9 mmol) was added, and the mixture was stirred briefly. The solvent was then removed, and the obtained residue was chromatographed (Combiflash, silica gel, dichloromethane to 93:7 dichloromethane/methanol) to give the title compound (0.263 g, 91%) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C2=NC3COCC3N2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate (compound 466.5, 100 mg, 0.330 mmol, 1.00 equiv, 90%) and sodium hydroxide (73 mg, 1.82 mmol, 5.00 equiv) in methanol/H2O (3/3 mL). The resulting solution was stirred overnight at 70° C., then concentrated in vacuum. The residue was diluted with H2O (5 mL) and the pH of the solution was adjusted to 2-3 with hydrogen chloride (12 N), then extracted with ethyl acetate (3×10 mL). The combined organics was concentrated in vacuo to obtain the title compound as a yellow solid (80.0 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 178.8 %

Procedure:
tert-Butyl {[1-[(2-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:5 to give the title compound as colorless crystals (yield 78 mg, 90%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([C:30]6[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, white solid (109 mg, 85%), MS (ISP) m/z=512.6 [(M+H)+], mp 235° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(pyridin-3-yl)-benzoic acid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:15]([O-])(O)=O.[Na+]>>[CH:3]1[N:2]=[CH:15][N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=12
Reactant: CCOC(=O)c1cccnc1CN
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cccn2cncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60° C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([NH:25][CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNC(C)(C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-amine (113 mg, 0.33 mmol, 1.0 eq.) and methyl acrylate (86 mg, 0.99 mmol, 3.0 eq.) was dissolved in MeOH (2 mL). The mixture was reflux for 16 h. The mixture was concentrated and purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (100 mg, 71%) as a slight yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.73-7.68 (m, 3H), 7.60 (dd, 1H), 7.13-7.16 (m, 2H), 4.26-4.23 (m, 1H), 3.66 (s, 3H), 2.62 (t, 2H), 2.50 (t, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.58 (s, 6H), 1.45-1.38 (m, 2H), 1.19-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH:15]2[CH2:19][CH2:18][C@@H:17]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH:15]2[CH2:19][CH2:18][C@@H:17]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc([C@@H]2CCC(N[C@H](C)c3ccc(F)c4ccccc34)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](NC1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1ccc(F)c2ccccc12

Procedure:
A solution of methyl {4-[(1R)-3-{[(1R)-1-(4-fluoronaphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetate (72 mg, 0.17 mmol) and potassium hydroxide (56 mg, 1.0 mmol) in methanol (2 mL) and water (0.5 mL) was heated under reflux for 2 hours. 2N hydrochloric acid was added to the reaction solution to make the pH 7, and the solution was purified by high performance liquid chromatography (water:acetonitrile) to give the title compound (a mixture of diastereomers) (36 mg, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OCCCCl)c1
Temperature: 25 °C

Procedure:
A mixture of 3′-hydroxyacetophenone (5 g) and 1-bromo-3-chloropropane (5.0 mL) in acetone (40 mL) was treated with potassium carbonate (8.1 g). The mixture was stirred at reflux temperature for 17 hours. The reaction was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (50 mL) and H2O (50 mL). The aqueous phase was washed with two fresh portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound (8.6 g) which was used without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, supplier Aldrich) in DCM (200 ml) was added DIPEA (9.85 ml) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, supplier Aldrich). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to give 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCCC1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccc2[nH]ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc2[nH]ccc2c1

Procedure:
51.1 g (0.347 mole) of 6c are stirred analogously to Example 1b in 1,900 ml of CH2Cl2 and 200 ml of tetrahydrofuran with 190 g (2.18 moles) of manganese(IV) oxide at 20° C. overnight.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1([NH:11][C:12]2[C:17]([CH:18]=[N:19][OH:20])=[CH:16][N:15]=[C:14]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:13]=23)[CH2:10][CH2:9]1.Cl[O-].[Na+]>O1CCCC1>[CH:8]1([NH:11][C:12]2[C:17]([C:18]3[CH2:3][C:2]([CH3:4])([C:1]([O:6][CH3:7])=[O:5])[O:20][N:19]=3)=[CH:16][N:15]=[C:14]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:13]=23)[CH2:9][CH2:10]1
Reactant: C=C(C)C(=O)OC
Reactant: CCn1ncc2c(NC3CC3)c(C=NO)cnc21
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CC3)c(C3=NOC(C)(C(=O)OC)C3)cnc21
Temperature: 25 °C

Procedure:
Methyl methacrylate (0.3 ml, 0.0028 mole) was added to 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (70 mg, 0.00028 mol) in tetrahydrofuran. The reaction mixture was stirred at room temperature. Sodium hypochlorite (2 ml) was added slowly to the mixture thus obtained over a period of about 5 minutes and the reaction mixture was allowed to stir at room temperature for about 4 hours. Tetrahydrofuran was evaporated and the organic layer was extracted with ethyl acetate. It was concentrated and purified by column chromatography to yield the title compound. Yield: 50 mg (51%). m/z: (M++1) 344.1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)Nc1cc(CCc2cccc(C(F)(F)F)c2)ccn1
Yield: 33.8 %

Procedure:
{4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-yl}-urea (210 mg, 0.68 mmol) is dissolved in methanol (3 mL) and DCM (3 mL). Then 5% palladium on carbon (145 mg, 0.068 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 71 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Nc1cc2[nH]c(=O)ccc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cnc(N)cc21
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of (XII) (2.1 g, 13 mmol) in dry DMF (65 mL) was added cesium carbonate (6.4 g, 19.6 mmol), followed by ethyl iodine (1.71 mL, 21.4 mmol), and the mixture was stirred at 60° C. for 4.5 hours. The cooled mixture was filtered, and the filtrate was diluted with ethyl acetate. The solution was washed with brine, dried, and concentrated to give an orange residue that was purified by silica gel chromatography, eluting with 1:1 ethyl acetate: hexanes and then ethyl acetate. Concentration of product fractions gave 7-amino-1-ethyl-1H-[1,6]naphthyridin-2-one (XIII) (1.3 g, 53%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[N:14]([O-])=O.[Na+].O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=2)[NH:6][N:14]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1CC(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Temperature: 15 °C

Procedure:
18 parts of 2-(2,2,2-trifluoro-ethyl)-4-bromo-aniline are dissolved in 490 parts by volume of glacial acetic acid. To this solution, well stirred at 15° C., is added all at once a solution of 4.9 parts of sodium nitrite in 11.9 parts of water. At the end of 3 days, the acetic acid is evaporated and the residue is taken up in 40 parts of water, the solid filtered off, washed and dried. 18 parts of 3-trifluoromethyl-5-bromo-indazole are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:4]1[CH:5]=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (300 mg, 1.12 mmol) in THF (50 mL) was added NaH (95 mg, 60%, 2.36 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of ethyl bromoacetate (0.262 mL, 2.36 mmol). The reaction was heated at 70° C. overnight. After the cooling of the reaction solution to room temperature, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified using reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 320 mg of the title compound in 81% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.25 (s 1H), 7.78 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.6, 7.6 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.64 (dd, J=2.4, 8.8 Hz, 1H), 5.00 (s, 2H), 4.97 (s, 2H), 4.13 (q, J=6.8 Hz, 2H), 1.16 (t, 6.8 Hz, 3H); MS (ES) m/z: 354 (M+H)+; HPLC purity: 99.11% (220 nm), 99.14% (254 nm).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>ClCCl.C(O)CCC>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCCCO
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(C(F)(F)F)c1)c1ccc2c(c1)CNCC2

Procedure:
2-Acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3-trifluoromethylaniline in dichloromethane according to the method generally described in EP No. 0038177-A. The resulting product was deacetylated by heating with aqueous hydrochloric acid in butanol to give 7-(3-trifluoromethylphenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.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>[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:2]3[C:3]([CH3:19])=[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 100 °C
Yield: 7.2 %

Procedure:
To a stirred solution of 5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (159 mg, 0.14 mmol), in degassed DMF (3.0 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (184 mg, 0.55 mmol), K2CO3 (153 mg, 1.10 mmol), and H2O (0.5 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 15 mg (7%) of the desired product. 1H-NMR (DMSO-d6) 8.56 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.54 (s, 1H), 7.32-7.38 (m, 5H), 7.02 (d, 1H), 5.65 (s, 2H), 3.81 (s, 2H), 2.53-2.50 (m, 4H), 2.43-2.40 (m, 4H), 2.10 (s, 3H); LC-MS [M+H]+=454, RT=2.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (0.5 g, 0.0016 mole), methyl iodide (0.5 g, 0.0035 mole) and potassium carbonate (0.23 g, 0.0017 mole) in dimethyl formamide (25 ml) was stirred at 100° for 3 hrs. under nitrogen. The reaction mixture was cooled. The product, which precipitated, was filtered, washed with water and dried. Recrystallization from DMF gave white crystals (0.47 g, 90%), m.p. 295°-297°.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[NH2:23]Cl.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:23][N:14]1[CH:15]=[CH:16][C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[C:13]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: NCl
Agent: O=S([O-])S(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Solid methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (1.33 μm, 4.50 mmole) was added in portions to an ice-cooled suspension of NaH (60% in mineral oil, 234 mg, 5.85 mmole) in dry DMF (15 mL) under a dry N2 atmosphere. Upon completion of the addition, the reaction was removed from the bath and left stirring at RT. After 1 hr, a solution of NH2Cl (59 mL; 0.1 M in Et2O prepared according to J. Chem. Soc. C, 1971, 824; 5.85 mmole) was added and the reaction was left stirring for 1.3 hr. It was then cooled to −5° C. and an aqueous solution of Na2S2O4 (20 mL, 1.0 M) was slowly added over 5 min. Water (60 mL) was added and the bath was removed. After 10 min, this was extracted with EtOAc (2×200 mL) and the organic extracts were washed with brine and dried (Na2SO4). Removal of the solvents followed by flash chromatography on silica gel using step gradient elution (hexane:EtOAc from 100:0 to 70:30) afforded the title compound (1.22 gm, 88% yield) as a solid. 1H NMR (CDCl3): 2.39 (s, 2H), 3.62 (s, 3H), 5.44 (s, 2H), 5.76 (m, 1H), 6.73 (m, 1H), 7.26 (m, 2H), 7.66 (m, 2H); MS: 311 (M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).