Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCCC1.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCc1cc(Cc2ccccc2)c(Br)cn1
Yield: 24.7 %

Procedure:
200 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine (Example 189a) and 10 mg of platinum (IV) oxide were added to 10 ml of methanol, 10 ml of tetrahydrofuran and 10 ml of ethyl acetate, followed by stirring at room temperature at normal pressure in a hydrogen atmosphere overnight. The catalyst was filtered off and the filtrate was evaporated, to give 50 mg of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:31]([O:30][C:29]([N:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19])=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COC(=O)c1ccc2ccn(CCCBr)c(=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ccn(CCCN(C(=O)OC(C)(C)C)c3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.3 %

Procedure:
To a solution of methyl 2-(3-bromopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.19 g, 0.60 mmol) dissolved in DMF (10 mL) was added tert-butyl (4-methoxyphenyl)carbamate (0.20 g, 0.89 mmol), tetra-n-butylammonium iodide (0.44 g, 1.19 mmol) and cesium carbonate (0.39 g, 1.19 mmol). The reaction mixture was stirred at rt for 6 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 60% EtOAc/hexanes) to afford methyl 2-{3-[(tert-butoxycarbonyl)(4-methoxyphenyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.11 g, 38%). LC-MS: (FA) ES+ 467.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.C[Si](C)(C)[O:10][C:11]([CH:13]=[CH2:14])=[CH2:12].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[O:10]=[C:11]([CH3:12])[CH2:13][CH2:14][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: Oc1cc(Cl)sn1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CCn1sc(Cl)cc1=O

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 2-trimethylsiloxy-1,3-butadiene (5.6 g, 0.04 mole) and 0.5 g of hydroquinone in 20 ml of toluene was heated at 80° C. for 96 hours. After cooling, the mixture was concentrated in vacuo. The residual oil was dissolved in diethyl ether and washed with saturated NaHCO3 solution and then with water. After drying (MgSO4) and concentrating the solution, the residual oil was purified by column chromatography on silica gel, using diethyl ether/methanol (9/1) as eluant. Compound 1 was obtained as an oil, 0.3 g; IR (neat) 1625,1650 cm-1 ; NMR (CDCl3) δ6.25 (s,1H); 4.0 (t, 2H); 2.9 (t,2H); 2.2 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCCNCC1
Product: CCOc1cc(N2CCCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 58 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and methylhomopiperazine was used in place of N-methylpiperazine. In this manner, 94 mg (58%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)CC)C.[K+].[Br-]>CCOCC>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH:16][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cccc(N)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 15.5 g (0.1 mol) portion of o-methylbenzoyl chloride was added dropwise to a stirred solution of 11.9 g (0.1 mol) of m-methoxyaniline and 10.1 g (0.1 mol) of triethylamine in 250 ml of ether and the resulting solution was cooled. After addition of the o-methylbenzoylchloride, the mixture was stirred at room temperature for an additional 5 hours, and the reaction mixture was washed with water to remove triethylamine hydrochloride. The ether layer was dried over anhydrous sodium sulfate and the ether was removed whereby 23.9 g (99%) of fine white prisms having a melting point of 142°-143° C were obtained. IR cm-1 (KBr-tablet), νNH 3250 (S), νCO 1655(S), 1610(S).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH:24](=[N:26][OH:27])[CH3:25]>Cl.S([O-])([O-])(=O)=O.[Cu+2].O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([C:24](=[N:26][OH:27])[CH3:25])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: CC=NO
Reactant: COC(=O)NCc1cc(N)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C(C)=NO)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
10.7 g of methyl N-[5-amino-2-chlorobenzyl]carbamate was dissolved in 33 g of 14% hydrochloric acid, followed by stirring at room temperature for 1 hour. 7 ml of an aqueous solution of 3.8 g of sodium nitrite was dropwise added to the solution with stirring at from 0 to 5° C. The formed diazonium salt was dropwise added to a mixed solvent of water/ethyl acetate/toluene (80 ml/40 ml/40 ml) of 21.7 g of sodium acetate, 2.6 g of copper sulfate and 5.9 g of acetaldoxime with vigorously stirring at from 0 to 5° C. over a period of 15 minutes, followed by stirring at room temperature further for 2 hours. The reaction solution was acidified with hydrochloric acid, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained crude crystals were washed with a mixed solvent of ether/ethyl acetate to obtain 2.8 g of methyl N-[2-chloro-5-(1-hydroxyiminoethyl)benzyl]carbamate as colorless crystals (m.p. 124-127° C.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCC)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-iodopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.5 g, 90%).
Reaction SMILES: [ClH:1].[O:2]=[C:3]([N:6]1[CH2:10]CC[CH2:7]1)[CH2:4][NH2:5].Cl.CNC.CN1CCO[CH2:18][CH2:17]1>>[ClH:1].[NH2:5][C@@H:4]([CH2:17][CH3:18])[C:3]([N:6]([CH3:7])[CH3:10])=[O:2]
Reactant: NCC(=O)N1CCCC1
Reactant: CN1CCOCC1
Agent: CNC
Agent: Cl
Product: CC[C@H](N)C(=O)N(C)C

Procedure:
(2S)-2-Amino-N,N-dimethylbutanamide, hydrochloride salt was prepared in a manner similar to 2-oxo-2-(1-pyrrolidinyl)ethanamine, hydrochloride salt (Example 69), utilizing N-CBZ-L-2-aminobutyric acid in place of N-CBZ-glycine, utilizing dimethylamine, hydrochloride salt in place of pyrrolidine, and using 3 equivalents of NMM in Part A. (M+H)+: 130.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:28])=[CH:5][C:6]2[CH2:15][CH2:14][CH:13]([NH:16]C(C3C=CC=CC=3)C)[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=3[C:7]=2[C:25]=1[O:26][CH3:27].CO.C(O)(=O)C.C>[OH-].[Pd+2].[OH-].O>[NH2:16][CH:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]2[C:25]([O:26][CH3:27])=[C:3]([O:2][CH3:1])[C:4]([OH:28])=[CH:5][C:6]=2[CH2:15][CH2:14]1
Reactant: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(NC(C)c1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(N)CC2
Yield: 82.7 %

Procedure:
5 g of the product of Stage A, 50 ml of methanol, 25 ml of acetic acid and 150 ml of water were stirred for 30 hours at ambient temperature under a hydrogen atmosphere (400 mbar) in the presence of 2 g of 20% palladium hydroxide on wet activated charcoal (50% water). Filtration was carried out followed by washing with methanol, then concentrating to dryness under reduced pressure at 40° C. After crystallization from ethyl acetate, 3 g of the expected product were obtained.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].S(=O)(=O)(O)[O-:30].[Na+]>O1CCCC1.O>[OH:30][C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(F)n2)CC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(O)n2)CC1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
Part C″: To a solution of tert-butyl 4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.349 g, 1.00 mmol) in 20 mL of tetrahydrofuran at 25° C. was added a solution of lithium hydroxide monohydrate (0.084 g, 2.00 mmol) in 5 mL of water, and the resulting mixture was stirred at 25° C. for 11 days. The reaction mixture was diluted with water, the pH of the solution was adjusted to ˜pH 6 employing aqueous sodium bisulfate solution, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-50% diethyl ether/methylene chloride) to afford tert-butyl 4-(1-(6-hydroxypyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.090 g); Mass Spec.: m/e: 348.24 (M+H)+ [calc'd: 348.18]; 1H NMR (300 MHz, CDCl3) δ 7.84 (m, 1H), 7.21 (m, 1H), 6.89 (m, 1H), 3.52 (m, 4H), 3.32 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:17][OH:18].O>C(O)C>[OH:18][N:17]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C=NO)cc([N+](=O)[O-])c1
Yield: 49.1 %

Procedure:
A mixture of methyl 3-formyl-5-nitrobenzoate (0.418 g, 2.0 mmol), hydroxylamine hydrochloride (0.209 g, 3.0 mmol) in ethanol (5.0 mL) was heated at reflux for 2 h. On cooling, the mixture was poured into water and the precipitate collected by filtration. The cake was recrystallized from ethyl acetate-hexane and dried to give 0.22 g (49%) of methyl 3-[(N-hydroxylimino)methyl]-5-nitrobenzoate as an off-white solid, mp 144°-145° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1)[NH2:6].ClCCl.C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][C:29](=[O:30])[CH2:28][Cl:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H](N)Cc1ccc(C)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.60 g) in a mixed solvent of dichloromethane (7 ml) and water (9 ml) was added potassium carbonate (1.70 g) in small portions under ice cooling. Chloroacetyl chloride (0.66 ml) was added to the mixture at 5° C. or below over 15 minutes and then the total mixture was stirred for 30 minutes. The organic layer was separated, washed with an aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester in the form of an oily substance.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([N:18]([CH2:36][CH3:37])[CH2:19][CH2:20][NH:21][C:22]1[N:23]=[N+:24]([O-:35])[C:25]2[CH:31]=[C:30]3[CH2:32][CH2:33][O:34][C:29]3=[CH:28][C:26]=2[N:27]=1)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O-:35][N+:24]1[C:25]2[CH:31]=[C:30]3[CH2:32][CH2:33][O:34][C:29]3=[CH:28][C:26]=2[N+:27]([O-:4])=[C:22]([NH:21][CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:36][CH3:37])[N:23]=1
Reactant: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
H2O2 (70%, 0.38 mL, ca. 2.8 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 2.8 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 209 (235 mg, 0.78 mmol) and TFA (0.13 mL, 1.7 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×25 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM, to give 1,4-dioxide 210 (95 mg, 38%) as a red solid: mp 187-190° C.; 1H NMR (CD3OD) δ 8.16 (t, J=1.7 Hz, 1H, H-9), 7.30 (s, 1H, H-5), 4.85 (t, J=8.4 Hz, 2H, H-7), 3.90-3.94 (m, 2H, CH2), 3.40-3.49 (m, 4H, H-8, CH2), 3.36 (q, J=7.3 Hz, 4H, CH2), 1.37 (t, J=7.3 Hz, 6H, CH3), NH not observed; 13C NMR δ 169.8, 151.5, 142.3, 135.5, 128.2, 119.0, 93.7, 75.6, 51.7, 49.0 (2), 37.3, 29.4, 9.1 (2); HRMS (FAB+) calcd for C15H22N5O3 (MH+) m/z 320.1723, found 320.1726.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[C:11]3[O:16][C:17]([CH3:21])([CH3:20])[O:18][CH2:19][C:10]=23)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(C)C=CC=CC=1>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C(C)C>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[C:11]3[O:16][C:17]([CH3:21])([CH3:20])[O:18][CH2:19][C:10]=23)=[CH:4][CH:3]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Cc1ncc(Nc2ccc(Br)cn2)c2c1OC(C)(C)OC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(Nc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cn2)c2c1OC(C)(C)OC2
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
A mixture of (5-bromo-pyridin-2-yl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-amine (10) (564 mg, 1.55 mmol), tetrakis(triphenylphosphine) palladium(0) (174 mg, 0.15 mmol), cesium carbonate (1.56 g, 4.8 mmol), 2-tert-butylsulfamoyl-phenylboronic acid (438 mg, 1.7 mmol) in a solution of toluene (20 mL), iso-butyl alcohol (15 mL) and water (5 mL) was stirred at 80° C. under nitrogen for 5 h. The reaction was diluted with water and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel to give N-tert-butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylamino)-pyridin-3-yl]-benzenesulfonamide (11) as a colorless solid (554 mg, 74% yield).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH:15]1([C:2]2[CH:14]=[CH:13][C:5]3[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)[CH2:17][CH2:16]1
Reactant: OB(O)C1CC1
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCC(=O)c2ccc(C3CC3)cc2N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 23.2 %

Procedure:
To a solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.6 g, 2.0 mmol) in toluene (9 mL) and H2O (1 mL) under an atmosphere of N2 was added cyclopropylboronic acid (0.34 g, 4.0 mmol), K3PO4 (1.27 g, 6.0 mmol), PCy3 (1.2 mL, 0.8 mmol), and Pd(OAc)2 (90 mg, 0.4 mmol). The reaction mixture was allowed to stir at 80° C. for 12 h and then allowed to cool to rt. To the mixture were added EtOAc (50 mL) and H2O (50 mL), and the resulting solids were filtered over Celite®. The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to provide 8-cyclopropyl-3,4-dihydro-1H-1-benzazepine-2,5-dione (100 mg, 23%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1)(O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[OH:2][CH2:1][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][CH:15]([O:21][CH:22]([CH3:23])[CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: CCOC(=O)C(Cc1cn(CC(=O)O)c2ccccc12)OC(C)C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cn(CCO)c2ccccc12)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
0.3 g of Ethyl 3-(1-carboxymethyl-1H-indol-3-yl)-2-isopropoxypropionate was dissolved in 10 ml of tetrahydrofuran, and 0.2 ml of triethylamine was added under ice-cooling, followed by 0.1 ml of ethyl chloroformate, then the mixture was stirred at 0° C. for 15 minutes. After filtering off the precipitated insoluble substances, the reaction solution was again cooled with ice, and 60 mg of sodium borohydride and water were added, and stirring was continued at room temperature for 1 hour. The reaction solution was cooled with ice, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (33% ethyl acetate-hexane), to give 143 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[F:11][C:12]([F:17])([F:16])[C:13](N)=[NH:14].FC(F)(F)C(O)=O>CCO>[F:11][C:12]([F:17])([F:16])[C:13]1[NH:14][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1
Reactant: COC(=O)c1sccc1N
Reactant: N=C(N)C(F)(F)F
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(C(F)(F)F)nc2ccsc12
Temperature: 150 °C
Yield: 27.7 %

Procedure:
To a stirring solution of methyl 3-aminothiophene-2-carboxylate (45a, 1.57, 10.0 mmol) in EtOH (10 mL) was added trifluoroacetamidine (2.24 g, 2 eq) and trifluoroacetic acid (1.54 ml, 2 eq). The resulting mixture was heated to 150° C. for 1 hour in microwave reactor. The reaction mixture was cool and filtered to provide 2-(trifluoromethyl)thieno[3,2-d]pyrimidine-4(3H)-one 45b as a solid (0.61 g). 1H NMR (400 MHz, MeOD) δ ppm: 7.49 (d, J=5.29 Hz, 2H), 8.18 (d, J=5.29 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:20]#[N:21])[CH:3]=1.[NH2:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C([O-])([O-])=O.[K+].[K+].CC#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH2:22])=[O:24])[N:7]=[N:6][C:5]=1[NH:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])#[N:21]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(CNc1nnc(Cl)cc1C#N)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(CNc1nnc(-c2cccc(C(N)=O)c2)cc1C#N)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 4.3 %

Procedure:
To a solution of 6-chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carbonitrile (550 mg, 1.8 mmol, 1.0 equiv), 3-aminocarbonylphenylboronic acid, pinacol ester (330 mg, 2.0 mmol, 1.1 equiv) and aqueous K2CO3 (2.0 M, 5.0 mL, 5.4 mmol, 3.0 equiv) in dioxane (18 mL) was added Pd(dppf)Cl2 (150 mg, 0.18 mmol, 0.1 equiv). The mixture was stirred at 120° C. for 10 minutes in a microwave and allowed to cool to room temperature. The solvents were evaporated in vacuo, and the residue was dissolved in dichloromethane. The solution was filtered and the solvent dried over Na2SO4. Purification over silica gel using a gradient of 40-80% EtOAc/hexanes gave a yellow solid that was slurried with CH3CN to give the desired product (30 mg, 4.3%) as a yellow solid. m/z=390.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1>CO.[Pd]>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[N:4]2[CH2:5][CH2:6][NH:7][CH2:2][C:3]2=[CH:10][N:9]=1
Reactant: Fc1ccc(-c2ncc3c(Cl)nccn23)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(-c2ncc3n2CCNC3)c(F)c1
Reaction time: 20 h

Procedure:
To a solution of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Step C, 200 mg) in methanol, at 0° C. and under a nitrogen atmosphere was added palladium on carbon (75 mgs, 10 wt % Pd) and the contents hydrogenated at 50 psi for 20 hours. The reaction mixture was filtered and the filter cake washed with methanol (2×10 mL). The filtrate was concentrated under reduced pressure to yield a solid d (175 mgs) that was used as such for the subsequent step without further purification.