Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1)[CH3:31]
Reactant: CCOC(=O)CCCCBr
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCn1nc(C(=O)OCC)cc1C(=O)OCC
Yield: 93.8 %

Procedure:
Diethyl 3,5-pyrazoledicarboxylate (50 g, 0.236 mol) was dissolved in acetonitrile (500 ml) under a nitrogen atmosphere. Potassium carbonate (33 g, 0.236 mol) was added followed by ethyl 5-bromovalerate (37.7 ml, 0.235 mol) and the mixture heated under reflux for 2 hours. The solvent was removed in vacuo leaving a clear oil which was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase further extracted with ethyl acetate (×2). The organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give 75 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])OC2C=CC=CC=2)=[CH:33][CH:32]=1>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:46])[NH:37][C:34]4[CH:33]=[CH:32][N:31]=[CH:36][CH:35]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 3.9 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:11]=1)([O-])=O>CC(O)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnccc1C1=CC(N2C(=O)c3ccccc3C2=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-(3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1.0 equiv.) in AcOH (0.38 M) was added Fe (6.0 equiv.) and the reaction was stirred at room temperature for 2 h. Filtered, then washed with methanol and concentrated the filtrate. To the crude was added ethyl acetate and saturated NaHCO3, the organics were dried with Na2SO4, and concentrated to give 2-(3-(3-aminopyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione as a yellow thick gum in 96% yield. LC/MS=320.0 (M+H), LC=2.410 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)[CH3:38]
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-[5-aminobenzimidazol-1-yl]phenyl]-3-(4-chloro-3-(trifluoro-methyl)phenyl)urea hydrochloride and ethyl chloroformate by the same method as in Example 41.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CCCCBr
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Yield: 91 %

Procedure:
50.0 g of 2-aminobiphenyl, 38.2 g of ethyldiisopropylamine and 61.9 g of ethyl 5-bromovalerate are reacted analogously to Example 47a) to obtain 80.0 g of ethyl 5-(biphenyl-2-yl)aminovalerate as a non-crystallizing oil.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:35][C:22]1[C:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH2:36][O:37][CH2:38][C:39]#[CH:40])[CH:21]=1
Reactant: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((prop-2-ynyloxy)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (prepared using methods analogous to those in Example 1 and Example 5 above, 251 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6.0 mL) at 15° C., was added LiOH—H2O (19.7 mg, 0.47 mmol). After stirring for 12 h at room temperature, the reaction was complete, as indicated by HPLC. The reaction mixture was concentrated and the residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed with brine (20 mL), 5% KHSO4 in brine (20 mL), dried over anhydrous sodium sulfate, evaporated, and the residue was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.45) to obtain 156 mg of title compound as a white solid (yield 84%; purity 99.2%, as determined by HPLC). 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (s, 4H), 4.86 (d, J=12.4 Hz, 1H), 4.60 (d, J=12.4 Hz, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.20 (s, 2H), 4.12 (d, J=14.8 Hz, 1H), 4.06 (d, J=14.8 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 3.86 (d, J=12.4 Hz, 1H), 3.70-3.66 (m, 1H), 3.52-3.41 (m, 4H), 2.63 (s, 1H), 1.36 (t, J=6.8 Hz, 3H); LC-MS (m/z) 477 [(M+1)+], 521 [(M+45)−].
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]CC(C1N=CC2CCCCC=2C=1)=O>>[Br:15][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1cc2c(cn1)CCCC2
Reactant: CC(=O)c1ccc2c(c1)CN(C)CC2
Product: CN1CCc2ccc(C(=O)CBr)cc2C1

Procedure:
*7-bromoacetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 7-acetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (P.Charpentier et al., Tetrahedron, 1996, 52, 10441) according to the procedure for preparing 3-bromoacetyl-5,6,7,8-tetrahydroisoquinoline described in Example 1.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[S:37](=O)(=[O:40])([OH:39])[OH:38]>>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][S:37]([OH:40])(=[O:39])=[O:38])[C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COS(=O)(=O)O)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
10 mL of concentrated sulfuric acid was added to 1.00 g (1.98 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4) and the mixture was stirred at 50° C. for 20 minutes. The reaction solution was cooled on ice, ice water was added and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=9:1-chloroform:methanol:aqueous ammonia=40:10:1) and triturated with ethanol to give 293 mg of Compound 119 (yield: 36%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 61.6 (0.12 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to afford 61 (47 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 7.28 (d, 1H), 7.20 (d, 2H), 7.09 (d, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.19 (s, 2H), 4.56 (t, 1H), 3.36 (dd, 1H), 2.99 (dd, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:37][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)O)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[H-].[Na+].C(OC(=O)C)(=O)C.[NH3:55]>CN(C=O)C>[CH2:1]([C:8]1[C:9]([O:37][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[NH2:55])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: N
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2ccc(C(N)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of (3-benzyl-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (446 mg, 0.830 mmol, Example 110) and DMF (15 mL) was added NaH (60% in mineral oil, 90 mg, 2.3 mmol) at room temperature. After stirring for 15 minutes, acetic anhydride (0.16 mL, 1.7 mmol) was added. After stirring for 1 hour, NH3 (7.0 M in MeOH, 1.0 mL, 7.0 mmol) was added. The mixture was stirred overnight and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layers were washed with water, and the aqueous layer was back extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to afford the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 8.97 (s, 1H), 8.77 (d, J=2.02 Hz, 1H), 8.11 (d, J=2.02 Hz, 1H), 8.00 (dd, J=2.27, 8.34 Hz, 1H), 7.94 (d, J=9.09 Hz, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.62 (dd, J=2.27, 8.84 Hz, 1H), 7.20-7.24 (m, 4H), 7.12-7.18 (m, 1H), 6.94 (d, J=1.52 Hz, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.72 (s, 3H); MS m/e 538.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl>C1COCC1.CO.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([S:9][CH:10]2[CH2:11][CH2:12][CH:13]([NH2:16])[CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
tert-Butyl (4-{[4-(trifluoromethyl)phenyl]thio}cyclohexyl)carbamate (0.38 g, 1.01 mmol) was dissolved in THF:MeOH 8:2 (10 ml) and HCl in 1,4-dioxane (4M, 2 ml) was added. The reaction mixture was stirred at rt for 15 h, and then evaporated. The crude product was diluted with EtOAc (100 ml), washed with a mixture of saturated aqueous Na2CO3 and water (1:2, 100 ml) and water (2×100 ml). The organic layer was dried over Na2SO4, filtrated and evaporated to yield the title compound (0.27 g, 97%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.56-7.48 (m, 4H), 7.46-7.39 (m, 4H), 3.59-3.52 (m, 1H), 3.17-3.07 (m, 1H), 2.90-2.79 (m, 1H), 2.78-2.68 (m, 1H), 2.13-2.03 (m, 2H), 1.99-1.14 (m, 18H); 13C-NMR (CDCl3, 125 MHz): δ 141.6, 141.0, 130.2, 129.7, 125.9, 125.9, 50.0, 48.9, 45.0, 44.0, 36.6, 32.3, 32.1, 30.5, 29.2, 29.0, 28.6.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:6])[CH:2]=[CH2:3].[Li]CCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:9][CH:8]=1)[CH3:6])[CH:2]=[CH2:3]
Reactant: CC(C)=O
Reactant: C=CCN(CC=C)[C@H](C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCN(CC=C)[C@H](C)c1ccc(C(C)(C)O)cc1
Temperature: -78 °C
Yield: 64 %

Procedure:
2.76 g (9.9 mmol) (R)-diallyl-[1-(4-bromo-phenyl)-ethyl]-amine was dissolved in 30 ml THF (dry) under N2 atmosphere. The mixture was then cooled to −78° C. and 5.0 ml (12 mmol) of 2.5M n-BuLi in hexanes was added drop-wise. The mixture was then cooled to −90° C. and acetone was added, while stirring continued at −90° C. for 10 m. The mixture was then allowed to warm to room temperature and the reaction was thereafter quenched with MeOH. Water was then added and the resulting mixture was extracted with ether. The ether extracts were combined; washed with water and brine; dried over MgSO4; and filtered and concentrated in vacuo. Chromatography on silica gel using 15% ethyl acetate/hexanes yielded 1.6 g (64%) of the desired final product.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C([O-])([O-])=O.[K+].[K+].C[N:36]([CH:38]=O)C>>[NH:36]1[C:38]2[C:10](=[C:5]([C:7]3[N:8]=[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:10]4[S:11][C:3]([CH2:2][NH:19][C:20]5[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=5)[C:23]([NH2:25])=[O:24])=[CH:4][C:5]=4[N:6]=3)[CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:8]1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cccc(N)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cccc(NCc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 3-aminobenzamide (35 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 303 after reverse phase HPLC purification (28 mg). MS (Q1) 486 (M)+
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)Cl>>[F:32][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:15]2[C:14]([CH3:34])=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C@H:7]([CH3:8])[CH2:6][N:39]2[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]2)[C:10]3=[O:35])=[O:33])[CH:27]=[CH:26][C:25]=1[C:28]([F:30])([F:31])[F:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n([C@H](C)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), tert-butyl 1-piperazinecarboxylate (100 mg, 0.0006 mol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product as a light yellow oil (100 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C#N)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(-c2ccc(N(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc2)cc1
Temperature: 75 °C

Procedure:
A 2 L flat bottomed flask fitted with an argon inlet and condenser was charged with (4-(bis(4-chlorophenyl)amino)phenyl)boronic acid (39.3 g), 2-(4-iodophenyl)-2-methylpropanenitrile, compound from Example 5 (c) (27.1 g) and tetrahydrofuran (591 mL). Sodium carbonate (33.9 g) was dissolved in water (393 mL) and this was added to the tetrahydrofuran mixture. The reaction mixture was then heated to 75° C. for 16 hours. Ethyl acetate (200 mL) and water (200 mL) were added and the mixture filtered through a celite pad. The layers were split, the organic layers washed with brine (600 mL), dried over MgSO4 and concentrated. The resulting material was purified by flash column chromatography eluting with ethyl acetate/heptane mixtures. The fractions were concentrated to a thick slurry and the solid filtered off, washed with heptane and dried under vacuum to give an off-white solid. Yield: 27 g. 1H NMR (400 MHz, CDCl3): δ 7.56-7.42 (6H, m, Ar—H), 7.21 (4H, m, Ar—H), 7.15-7.02 (6H, m, Ar—H), 1.77 (6H, s, CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2CC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.92, m/z=458.1-459.1 [M+H]+, m/z=456.2-457.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.81-1.91 (m, 1H) 2.53 (s, 3H) 2.67 (d, J=10.27 Hz, 1H) 3.00-3.08 (m, 2H) 3.18-3.28 (m, 1H) 4.16-4.21 (m, 1H) 4.83 (d, J=3.42 Hz, 1H) 6.93 (d, J=9.05 Hz, 1H) 7.30-7.36 (m, 3H) 7.68 (dd, J=7.95, 2.32 Hz, 1H) 7.77 (d, J=2.20 Hz, 1H) 7.84-7.92 (m, 3H) 8.48 (d, J=1.96 Hz, 1H) 10.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3].[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1.Cl>C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=2[CH3:11])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(C)[nH]c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (0.295 g, 1.93 mmol) in anhydrous DCM (5 mL) was added dropwise to a stirred suspension of aluminum trichloride (0.714 g, 5.35 mmol) in anhydrous DCM (10 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 2-(3-bromophenyl)acetyl chloride (48) (0.500 g, 2.14 mmol) in anhydrous DCM (5 mL) was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction mixture was poured onto ice (50 mL) and conc HCl (2 mL). The layers were separated and the aqueous layer extracted with DCM (2×50 mL). The combined organics were washed sequentially with 2M HCl (2×75 mL), water (50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product, which was used directly in the next stage; m/z (LC-MS, ESI−), RT=2.46 min (M−H=350.00).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:11][OH:12]>>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: CO
Reactant: Nc1ncc(Br)nc1Br
Agent: Cl
Product: COc1ncc(Br)nc1Br
Temperature: 60 °C
Yield: 47 %

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromopyrazin-2-amine (1.0 g, 4.0 mmol), methanol (10 mL), methanolic HCl (2.5 M, 0.32 mL, 0.80 mmol) and isoamylnitrile (1.6 mL, 12 mmol). The resulting mixture was heated at 60° C. for 2 h. TLC indicated a complete conversion. Work-up: the solvent was evaporated. The residue was re-dissolved in dichloromethane, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:20 EtOAc/petroleum ether, to afford 0.50 g (47%) of the product as a white crystal. MS m/z: 267 (M+H+).