Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=C(F)C=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[CH:20][C:21]=2[F:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccc(F)cc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,4-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=410 @ Rt 3.19 min. major peak.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:26][Mg]Br.[ClH:29]>C(OCC)C>[ClH:29].[CH3:26][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: c1ccc(C2=NCCc3ccccc32)cc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC1(c2ccccc2)c2ccccc2CCN1CCc1ccccc1

Procedure:
1-Methyl-1-phenyl-2-phenethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride was prepared by reacting 1-phenyl-3,4-dihydroisoquinoline with phenethyl bromide, then 3M diethyl ether solution of methylmagnesium bromide according to a similar manner to that of Example 26, and then converting the resultant compound to its hydrochloride according to a conventional manner.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2I)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]
Reactant: Clc1ccc(OCC2=CCN(Cc3ccccc3)CC2)c(I)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: Cl
Product: Clc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)CO2

Procedure:
To a refluxing solution of 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c (26.7 g, 0.06 mol) and AIBN (0.05 g, 0.003 mol) in dry benzene was added a solution of Bu3SnH (40 g, 0.137 mol) in benzene (100 mL) over 1 h under nitrogen atmosphere. After addition, the mixture was refluxed for 3 hr and additional AIBN (0.5 g, 0.003 mol) and Bu3SnH (20 g, 0.68 mol) were added. After refluxing for 4 hr, the mixture was concentrated to dryness, and EtOAc (100 mL) and HCl (10%, 40 mL) were added. The precipitate was filtered and washed with petroleum ether to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) as its HCl salt, which was basified by NaHCO3 solution to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>ClCCCl>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:12]([NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:13]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: NCc1ccccc1N
Solvent: ClCCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1ccccc1N
Temperature: 70 °C
Reaction time: 14 h
Yield: 49.2 %

Procedure:
5-tert-Butyl-2-methyl-2H-pyrazol-3-ylamine (10s) (4.8 g, 31 mmol) and carbonyl diimidazole (4.6 g, 32 mmol) were partially dissolved in DCE (100 mL) and heated at 70° C. for 2 hours. The reaction was cooled and 2-aminomethyl-phenylamine (9s) (4.2 g, 34 mmol) was added and the reaction was stirred 14 hours. The reaction was concentrated to remove the solvent and then partitioned between EtOAc and 0.5N HCl (60 mL). The organic phase was washed with NH4Cl and water and dried (MgSO4). The solution was concentrated and recrystallized from EtOAc (200 mL) to provide the desired product (5s) (4.6 g, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.96 (dt, J=7.8, 1.6 Hz, 1H), 6.63 (t, J=6.3 Hz, 1H), 6.59 (d, J=7.0 Hz, 1H), 6.48 (t, J=6.3 Hz, 1H), 5.93 (s, 1H), 5.07 (s, 2H), 4.12 (d, J=6.3 Hz, 2H), 3.51 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].Br[CH2:29][C:30]#[C:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([N:12]1[C:11]2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:8](=[O:25])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:15]=2[N:14]=[CH:13]1)[C:30]#[C:31][CH3:32]
Reactant: CC#CCBr
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2-dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (1.0 g), 1-bromo-2-butyne (0.28 ml), anhydrous potassium carbonate (0.73 g), and N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20–30% ethyl acetate/hexane to give 1.06 g of 2,2-dimethylpropionic acid [7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12](Br)Br)=[CH:7][CH:6]=1.CCCCCC.C([Li])CCC.[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.O>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:27]([CH3:30])([CH3:29])[CH3:26])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=C(Br)Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,2-dibromoethenyl)phenol methoxymethyl ether (16.56 g) in THF (350 ml) was cooled to -78° C., to which was added dropwise, under argon atmosphere, a 1.6M n-butyl lithium hexane solution (70 ml). The mixture was stirred for one hour under the same conditions, which was then warmed and stirred for one hour at room temperature. The reaction mixture was cooled with ice, to which was added dropwise trimethylchlorosilane (7.2 ml). The mixture was then stirred for 3 hours while warming up to room temperature, to which was added water to quench the reaction, followed by extraction with ethyl acetate. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 4-(2-trimethylsilylethynyl)phenol methoxymethyl ether (10.76 g) (Compound B-26). The physical properties are shown in Table 8.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][NH2:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([NH:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)(=[O:23])[CH3:22]
Reactant: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)NCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanamine (1.1 g; 0.004 mol, Example 14) was added to acetic anhydride (3 mL). The mixture was stirred at room temperature for 5 hrs. The solution was then diluted with methanol (50 mL) and refluxed for 1 hr. The solution was concentrated and the residue made basic with aqueous sodium bicarbonate solution. The oily residue was extracted into dichloromethane. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate to yield pure product m.p. 214°-218° C. Analysis: Calculated: C, 65.6; H, 6.8; N, 22.5. Found: C, 65.1; H, 6.6; N, 22.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[O:20]1[C:24]2([CH2:29][CH2:28][C:27](B(O)O)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:17]3[S:18][C:11]4[C:12](=[N:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]4[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=4[F:1])[CH:16]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
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: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.461 g, 1.19 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid (0.659 g, 3.58 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.239 mmol), Na2CO3 (2.98 ml, 5.97 mmol) and dioxane (50 mL). The reaction mixture was stirred at 100° C. until the starting material had been consumed (overnight). Then the reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (0.418 g, 87.9%). LRMS (APCI pos): >97% purity, 254 nm, m/e 399 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.34 (s, 1H), 7.01 (t, 1H), 6.42-6.56 (m, 3H), 6.28 (s, 1H), 4.04 (s, 4H), 3.82 (br s, 2H), 2.80 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[C:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.6 mmol, Aldrich) in dichloromethane was treated with dropwise addition of acryloyl chloride (0.3 mL, 3.7 mmol, Pfaltz and Bauer). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. ESIMS (M+H)+=263.
Reaction SMILES: F[B-](F)(F)F.C([O+]([CH2:11][CH3:12])CC)C.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[NH:19][N:18]=[CH:17]2>C(OCC)(=O)C>[Br:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:16](=[CH:17][N:18]([CH2:11][CH3:12])[N:19]=2)[CH:15]=1
Reactant: CC[O+](CC)CC
Reactant: Clc1cc(Br)cc2cn[nH]c12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCn1cc2cc(Br)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyl oxonium tetrafluoroborate (2.5 g) was added to a solution of 5-bromo-7-chloro-1H-indazole (1.38 g) in ethyl acetate (15 mL), and the reaction solution was stirred at room temperature overnight. After dilution with ethyl acetate, the reaction solution was washed successively with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-chloro-2-ethyl-2H-indazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:12]=O)[C:10]=2[CH:11]=1.[CH3:14][C:15]1[N:16]=[C:17]([CH2:20][C:21]([CH3:23])=O)[S:18][CH:19]=1.[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28]>C(O)(C)C>[CH3:29][C:25]1[NH:24][C:21]([CH3:23])=[C:20]([C:17]2[S:18][CH:19]=[C:15]([CH3:14])[N:16]=2)[CH:12]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4]3)[C:26]=1[C:27]#[N:28]
Reactant: C/C(N)=C/C#N
Reactant: Cc1cnc2cccc(C=O)c2c1
Reactant: CC(=O)Cc1nc(C)cs1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3ncc(C)cc23)C(c2nc(C)cs2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.876 mmol) of the compound from example 23A, 135 mg (0.876 mmol) of the compound from example 4A and 71 mg (0.876 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 145 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[H][H].Cl.Cl[CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[ClH:3].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Sc1ccc(Cl)cc1
Reactant: ClC1CCCc2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(SC2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.65 g (55 mmol) of sodium hydride (80%) were added in portions to a stirred solution of 3.62 g (25 mmol) of 4-chloro-benzenethiol in 36 ml of dry dimethylformamide under nitrogen and cooled in ice. After evolution of hydrogen had ceased, 4.80 g (20 mmol) of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride were added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure in a stream of nitrogen below 50° C. and 4N aqueous sodium hydroxide was added. The mixture was extracted with ethyl acetate and the extracts were washed with ice-cold aqueous sodium hydroxide and then with aqueous saturated sodium chloride, dried over MgSO4 and evaporated to dryness under reduced pressure. A solution of the resulting oil in ether was treated with ethereal hydrogen chloride to precipitate 5.13 g (82%) of 8-(4-chlorophenylthio)-5,6,7,8-tetrahydroquinoline hydrochloride as colorless crystals (from ethanol-ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>[Zn+2].[Br-].[Br-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccc(N)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5° C. and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C., and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[CH3:24]/[C:25](=[CH:29]\[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:26](Cl)=[O:27]>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:26](=[O:27])/[C:25](/[CH3:24])=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Reactant: C/C(=C\c1ccccc1)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C/C(=C\c1ccccc1)C(=O)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (705 mg, 3.9 mmol, 1 eq.) was placed in a mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3 (1.1 g, 7.8 mmol, 2 eq.). (E)-2-methyl-3-phenylacryloyl chloride (705 mg, 3.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)-2-methyl-3-phenylacrylamide (500 mg, 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:25][NH2:26].C(=O)(O)[O-].[Na+]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH:26][CH3:25])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CN
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 130 °C
Yield: 52 %

Procedure:
A mixture of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (50 mg, Example 61) and 40% methylamine methanol solution (5.0 ml) was heated in a sealed tube at 130° C. for 18 hours. After standing to cool, an aqueous saturated sodium bicarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column, to give the title compound (28 mg, 52%) as a pale yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[C:45](=[O:46])[C:44]3[S:43][C:42]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=4[C:36]=3[CH:35]=[N:34]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:30]=[C:22]3[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:33]5[C:45](=[O:46])[C:44]6[S:43][C:42]7[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=7[C:36]=6[CH:35]=[N:34]5)[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:30]=[C:22]2[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
A mixture of {4-[5-({5-acetyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridin-3-yl}methyl acetate 247a (100 mg, 0.16 mmol) and lithium hydroxide (96 mg, 4.0 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 min. The mixture was concentrated under reduced pressure. To the residue was added water (5 mL) and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 247 (51 mg, 53%). MS-ESI: [M+H]+ 599.3. 1H NMR (500 MHz, DMSO-d6, T=80° C.) δ 8.54-8.51 (m, 1H), 8.38 (d, J=3.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.48 (d, J=8.5 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 6.00 (s, 1H), 4.64-4.62 (m, 2H), 4.39 (s, 2H), 3.98-3.95 (m, 2H), 3.89-3.86 (m, 2H), 3.58 (s, 3H), 2.95-2.93 (m, 2H), 2.87-2.84 (m, 2H), 2.08 (s, 3H), 1.89-1.87 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC3[O:33][CH2:34][O:35]C=3C=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:52]C1C=CC(N)=CC=1>C(O)(=O)C>[O:33]1[C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:10]4[N:9]=[CH:8][N:7]([C:1]5[CH:6]=[CH:5][C:4]([Cl:52])=[CH:3][CH:2]=5)[C:12](=[O:13])[C:11]=4[S:14][CH:15]=3)=[CH:18][C:19]=2[O:35][CH2:34]1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccc3c(c2)OCO3)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccc4c(c3)OCO4)c2ncn1-c1ccc(Cl)cc1
Yield: 79.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(benzo[d][1,3]dioxol-5-yl)thiophene-2-carboxylate (60 mg, 0.21 mmol), triethyl orthoformate (0.48 ml), 4-chloroaniline (51.0 mg, 0.4 mmol), and acetic acid (0.06 ml) were used to give 47.3 mg (0.17 mmol, 79.5% yield) of the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:7])(C)(C)C.[NH4+].O[N:35]1C2C=CC=CC=2N=N1>>[NH2:35][C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:13]2[CH:31]=[CH:32][C:10]([CH2:9][CH2:8][C:6]([OH:5])=[O:7])=[CH:11][CH:12]=2)[CH:17]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Product: NC(=O)c1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 285 from 3′-[4-(2-tert-butoxycarbonylethyl)phenoxymethyl]biphenyl-2-carboxylic acid and 1-hydroxybenzotriazole ammonium salt. colorless crystals (yield 66%). MS (APCI−): 374 (M−H).