Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:28]=[C:27]([CH3:29])[N:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2[C:51]([O:52]C)=[CH:50][CH:49]=[C:48](S([O-])(=O)=O)[C:47]=2[O:58]C)CCCCC1.[Na+].C(=O)([O-])[O-].[K+].[K+].C(C1OC(B(O)O)=CC=1)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:30][N:26]1[C:27]([CH3:29])=[CH:28][C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([C:47]6[O:58][C:50]([CH:51]=[O:52])=[CH:49][CH:48]=6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH2:31][CH3:32])=[N:17]2)=[N:25]1
Reactant: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5ccc(C=O)o5)ccn34)c12
Temperature: 65 °C
Reaction time: 10 h
Yield: 443.3 %

Procedure:
A round bottom flask was charged with 7-bromo-N-(1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Preparation H; 100 mg, 0.20 mmol), sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (8.3 mg, 0.016 mmol), potassium carbonate (93 mg, 0.67 mmol), palladium acetate (1.8 mg, 0.008 mmol), and 5-formylfuran-2-ylboronic acid (57 mg, 0.4 mmol). To the flask was added a 5:1 dioxane:water mixture (3 mL), the reaction mixture was degassed under nitrogen, and stirred at 65° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was subjected to preparative thin-layer chromatography on silica with 10% MeOH-DCM as eluent to afford the product (36 mg) as a yellow solid.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:13][C:14]([CH:16]=[CH:17]CCC(C)=C)=[CH2:15]>C1CCCCC1>[C:4]1(=[O:11])[C:5]2[CH:10]([CH2:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:12])[CH2:2][CH2:3]1.[CH2:17]=[CH:16][C:14](=[CH2:13])[CH3:15]
Reactant: C=C(C)C=CCCC(=C)C
Agent: O=C1CCC(=O)C2CC=CC=C12
Solvent: C1CCCCC1
Product: C=CC(=C)C

Procedure:
A solution of 101 g (0.623 mole) of tetrahydronaphthoquinone and 110 g (0.81 mole) of 2,7-dimethyl-1,3,7-octatriene in 300 ml cyclohexane was refluxed for 18 hours. After removal of 200 ml solvent, 300 ml of hexane were added. The mixture was then warmed, stirred with powdered charcoal, and filtered. On cooling, 151.3 g of crude product were obtained (81.5% yield). A 3 g analytical sample, after recrystallization from 20 ml hexane, had a mp of 87.5° to 88° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[I-:42].[Na+].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:17][C:13]1[C:12](/[C:18](/[I:42])=[CH:19]/[C:20](=[O:21])[C:22]2[NH:23][CH:24]=[CH:25][CH:26]=2)=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[CH2:10]2
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: [I-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (5.90 g, 10.4 mmol) and sodium iodide (Aldrich, 4.67 g, 31.4 mmol) was added TFA (Aldrich, 35 mL) slowly at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then poured into a mixture of a saturated aqueous sodium bicarbonate solution (400 mL) and ethyl acetate (500 mL). After separation, the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate, filtered, and dried to give (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one as a brown solid which was used in the next step without further purification. (Yield 3.86 g, 93.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][C:21](O)=O>C(OCC)(=O)C>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:21]1[CH2:20][O:19][CH3:18]
Reactant: COCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CCOC(C)=O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 170 °C
Yield: 9.9 %

Procedure:
3-Amino-4-(2-hydroxy-2-methylpropylamino)quinoline (7.5 g, 32 mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heated at about 170° C. for about 3 hours. The resulting solid residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted twice with 0.2N sodium hydroxide, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated to a volume of about 50 mL. Hexane was added to the ethyl acetate and the resulting precipitate was collected and dried to provide 0.9 g of the desired product as a crystalline solid, m.p. 145°-148° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH2:25])[CH:5]=2.C(N(CC)C(C)C)(C)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>ClCCl.O.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH:25][C:37](=[O:38])[CH2:36][Cl:35])[CH:5]=2
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N)ccc32)cc(Br)c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(NC(=O)CCl)ccc32)cc(Br)c1OC
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 2,7-diamino-3-cyano-4-(3-bromo-4,5-dimethoxy phenyl)-4H-chromene (50 mg, 0.124 mmol) in dichloromethane (2 ml) was added N,N-diisopropylethylamine (0.043ml, 0.247 mmol). The flask was cooled in iced water and a solution of chloroacetyl chloride (14 mg, 0.124 mmol) in dichloromethane (1 ml) was added dropwise. The reaction mixture was stirred for 3 h, diluted with ethyl acetate, then washed with water, brine and dried over anhydrous sodium sulfate, and evaporated. The resulting solid was washed with a small amount of dichloromethane to yield the title compound as a white solid in a yield of 24%. 1H NMR (DMSO d6): 10.45 (s, 1H), 7.56 (s, 1H), 7.14-7.12 (m, 1H), 7.07 (s, 1H), 7.05 (s, 2H), 6.97 (s, 1H), 6.89 (d, J=0.9, 1H), 4.74 (s, 1H), 4.24 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1.[CH3:33]I>CN(C=O)C>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:33])[C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:31][CH:32]=2)=[N:6][N:5]=1
Reactant: CI
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCNC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride suspension (0.71 g, 50%) was added to a stirring solution of (S)-(−)-methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3-yl)oxy)benzoate (5.5 g) (Intermediate 15) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.91 mL) was added and stirred till the reaction completion. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vaccuo to get the thick liquid product. The liquid was triturated with EtOAc:hexane to get the white solid product (5.3 g).
Reaction SMILES: IC1C=CC=C(C)C=1C(O)=O.[NH2:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[C:28]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:35])=[O:22].F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[C:28]([C:29]3[N:30]=[CH:31][CH:32]=[CH:33][N:34]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:35])=[O:22])[C@@H:14]1[CH2:13][NH:12][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: Cc1cccc(I)c1C(=O)O
Product: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-6-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: O[Li].O.[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[O:11][C:12]([C:19]([O:21]CC)=[O:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1.Cl>C1COCC1.CO.O.CCOC(C)=O.O>[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[O:11][C:12]([C:19]([OH:21])=[O:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1
Reactant: CCOC(=O)c1oc(N2CCCC2=O)nc1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1oc(N2CCCC2=O)nc1C(F)(F)F
Reaction time: 8 h
Yield: 94.6 %

Procedure:
LiOH.H2O (0.096 g, 2.28 mmol) was added to a solution of ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-30) (0.140 g, 0.48 mmol) in THF/CH3OH/H2O (2/2/0.5 mL) at RT followed by stirring overnight. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 2.5 mL of 1 M HCl. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The residue was dried in vacuo to yield 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (A-31) as a white solid (0.120 g, 95% yield). 1H NMR (500 MHz, CD3OD) δ 5.18 (br s, 1H), 3.41 (t, 2H, J=6.8 Hz), 2.42 (t, 2H, J=7.2 Hz), 1.93 (m, 2H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11](O)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.C(Cl)Cl>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][N:13]1[C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Add potassium hydroxide (1.15 g, 17.5 mmol, fresh powder) to a solution of tert-butyl 2-(2-bromo-4-fluorophenyl)-2-hydroxyethylcarbamate (1.19 g, 3.56 mmol) and p-toluenesulfonyl chloride (0.75 g, 3.88 mmol) in dry THF (50 mL). Stir the mixture overnight at RT. Dilute with DCM, and wash with water and aqueous saturated sodium chloride. Dry over sodium sulfate and concentrate. Purify by column chromatography (hexane to 5% ethyl acetate in hexane) to give the title compound as a colorless oil (0.46 g, 41%). 1H NMR (400 MHz, CD3Cl) δ 1.47 (s, 9H), 2.08 (d, J=3.2 Hz, 1H), 2.67 (d, J=5.6 Hz, 1H), 3.59 (dd, J=3.6 Hz, 6.0 Hz, 1H), 7.00 (m, 1H), 7.28 (m, 1H), 7.35 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:24]>C(N(CC)CC)C>[CH:4]1[C:5]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:6]=2[NH:7][C:8](=[O:9])[C:3]=1[C:1](=[S:24])[NH2:2]
Reactant: N#Cc1cc2c([nH]c1=O)OCc1ccccc1-2
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 4.20 gm of 2-cyano-4,6-dihydro-3H[2]benzopyrano[3,4-b]-pyridin-3-one to 50 gm of pyridine. Add 3.0 ml of triethylamine to the system. Cool the system to 0°-5° and treat the system with hydrogen sulfide gas until the reaction is complete as indicated by thin layer chromatography. Isolate the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:35])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:35][CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CI
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(OC(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)-propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(C#N)cc2c(=O)n1C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution of methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (30 mg, 0.069 mmol) in Ethanol (3.5 mL), saturated with ammonia gas, was treated with Raney 2800 Nickel (0.5 mL, 0.069 mmol), purged and filled with N2 3×, H2 3×, and stirred under H2 at 40 psi overnight. The mixture was filtered through Celite, washed with MeOH, and concentrated. The residue was purified by column chromatography (0-20% MeOH/DCM) to afford methyl [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (23.7 mg, 0.054 mmol, 78% yield) as a colorless oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid-TFA salt (18.8 mg, 0.033 mmol, 76% yield) as off white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.42 (s, 1 H), 7.61 (d, J=8.4 Hz, 1 H), 7.36-7.15 (m, 3 H), 7.11-6.99 (m, 1 H), 5.23 (s, 1 H), 4.23 (s, 2 H), 3.70 (s, 3 H), 2.36 (s, 3 H), 2.31 (s, 3 H), 0.98 (s, 9 H); LCMS (m/z) ES+=423 (M+1).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:45][N:13]2[C:14](=[O:44])[C@@H:15]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([F:35])([F:34])[CH2:22][C@@H:23]3[CH2:28][C@@:24]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:25][C:26](=[O:27])[C@@H:12]2[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+]>C(O)C>[C:40]([O:39][C:37]([NH:36][C@@H:15]1[C:14](=[O:44])[N:13]2[CH2:45][C@@H:10]([OH:9])[CH2:11][C@H:12]2[C:26](=[O:27])[NH:25][C@:24]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][C@H:23]2[CH2:22][C:21]([F:34])([F:35])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:38])([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OC(=O)c3ccccc3)C[C@H]1C(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 115.3 %

Procedure:
To a solution of (2S,6S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1d, 94.75 mg, 0.149 mmol) in ethanol (0.414 ml) at 0° C. was added dropwise a solution of KOH (0.25 ml, 0.250 mmol, 1 N in ethanol). The solution was stirred at 0° C. for 50 min and LC/MS showed completion. The reaction mixture was quenched by dropwise addition of HCl (1 N in dioxane/ethyl acetate, 0.25 ml) at 0° C. Another portion of (2S,6S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (14.36 mg) was reacted under similar condition. Materials from these two reactions were combined and purified by reverse phase HPLC (acetonitrile/water (0.1% TFA)=30/70 to 100/0, 15 min) to provide the title compound (2S,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (91.3 mg) MS (ESI): m/z=532.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])=[CH:3][C:2]=1[Cl:1]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of (3,4-dichlorophenyl)boronic acid (500 mg, 2.62 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (501 mg, 2.88 mmol), K2CO3 (723 mg, 5.24 mmol) and Pd(PPh3)2Cl2 (36 mg, 0.052 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 hours. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with PE to give 1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (400 mg, 63.3% yield) as colorless oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[CH:31]=[C:30]([C:32](=[O:34])[CH3:33])[C:29](=[O:35])[N:28]([CH:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO.C(Cl)Cl>[ClH:1].[C:32]([C:30]1[C:29](=[O:35])[N:28]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Reaction time: 8 h
Yield: 76 %

Procedure:
Anhydrous HCl gas was bubbled through a solution of 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (398 mg, 0.74 mmol, prepared as in Example 32), in MeOH/CH2Cl2 (10 mL/10 mL) at room temperature for ˜5 min. The reaction mixture was stirred overnight and then solvent was removed under reduced pressure. The remaining solid was triturated with hot ethyl acetate and dried to provide 6-acetyl-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (329 mg, 76%). mp >300° C. Anal. Calc'd for C23H27N7O2.4.25 HCl: C, 46.94; H, 5.35; N, 16.66. Found: C, 46.77; H, 5.33; N, 16.30. M++1: Calc'd: 434.2, Found 434.2.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:18][N:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:20]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([N:19]([CH2:18][CH:17]([OH:16])[CH2:28][N:29]([CH3:31])[CH3:30])[CH3:20])=[CH:22][CH:23]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: CN(C)CC(O)CN(C)c1ccc(N)cc1
Product: CN(C)CC(O)CN(C)c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine (Method 13) and 4-{N-[2-hydroxy-3-(N,N-dimethylamino)propyl]-N-methylamino}aniline (Method 116), the product was obtained. MS (MH+): 471, 473; HPLC (RT): 4.53.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[O:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:27][CH2:28]3)[N:4]2[CH3:19])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (935 mg, 2.7 mmol) in DCM (30 mL) was added 4-morpholino-piperidine (505 mg, 2.97 mmol) and DIEA (0.70 mL). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then poured onto water and the layers were separated. The aqueous layer was extracted with three times with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-30% gradient MeOH in DCM) to give the title compound as a white solid (95%). LCMS: M+H+=436.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)[C:11](=[O:28])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:20][CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][C:12]2([C:11](=[O:28])[NH:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC2(CC1)C(=O)NC[C@H]2c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCC2(CC1)C(=O)NC[C@H]2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 130 mg (0.33 mmol) of (S)-tert-butyl 2-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethylcarbamate and 5 mL of DCM was added 1 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight. The solvents were removed under reduced pressure and the residue was used without further purification: LCMS m/z: 292.2 (M+H)+.