Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=1.B([C:25]1[CH:36]=[CH:35][C:28]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])=[CH:27][CH:26]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:31][CH:30]([CH2:29][C:28]1[CH:35]=[CH:36][C:25]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=2)=[CH:26][CH:27]=1)[C:32]([OH:34])=[O:33]
Reactant: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(Oc2cc(-c3ccc(CC(N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
A microwave vial was charged with 4-chloro-2-amino-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1N) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 14.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-methylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24 Hz, 4H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, 1H), 6.75 (m, 1H), 4.30 (t, 1H), 3.21-3.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1.N[C:18]1[CH:19]=C(C(Br)=CN=1)C(OC)=O.N(C(CC)C)=C=O.N>>[Br:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH:15]([CH2:18][CH3:19])[CH3:16])=[O:13])=[N:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Reactant: COC(=O)c1cc(N)ncc1Br
Agent: CCC(C)N=C=O
Agent: N
Product: CCC(C)NC(=O)Nc1cc(C(N)=O)c(Br)cn1

Procedure:
The compound was synthesized by a method analogous to the synthesis of Intermediate 43 starting with methyl 2-amino-5-bromoisonicotinate, 2-isocyanatobutane and ammonia solution (7N, MeOH). MS (ESP): 303 (M+1) for C10H13BrN4O2
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]CCCC.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:42][CH:43]=1)=O>O.C(OCC)(=O)C.CN(C)C=O>[CH3:47][CH:46]([CH3:48])[C:45]([NH:44][C:41]1[S:42][CH:43]=[C:39](/[CH:37]=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:40]=1)=[O:49]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Agent: CCCC[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.4 %

Procedure:
A mixture of 4-nitrobenzyl bromide (381 mg), triphenylphosphine (463 mg) and N,N-dimethylformamide (3 ml) was stirred for 5 hours at room temperature. To the mixture were added potassium butoxide (238 mg) and then N-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (350 mg), and the mixture was stirred for 13 hours at the same temperature. The reaction mixture was poured into ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed to give 2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide (36.0 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([CH2:13][O:14][CH3:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32][Cl:33])=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:33].[CH3:15][O:14][CH2:13][C:7]1([CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH3:2])[CH:4]=2)[CH2:12][CH2:11][N:10]([CH2:32][C:31]2[N:27]([CH2:26][C:25]3[CH:34]=[CH:35][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:28]=[N:29][CH:30]=2)[CH2:9][CH2:8]1
Reactant: COCC1(Cc2cccc(C)c2)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of 4-(3-methylbenzyl)-4-methoxymethylpiperidine hydrochloride salt (1.57 g, 5.8 mmol), 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydrochloride salt (1.57 g, 5.8 mmol), and diisopropylethyl-amine (5.1 mL, 29 mmol) in anhydrous acetonitrile (75 mL) was heated at 60° C. overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as free base. The free base obtained was dissolved in anhydrous diethyl ether (50 mL), cooled to 0° C., and bubbled with anhydrous hydrogen chloride gas for 20 second. The resultant mixture was concentrated, and the residue solid recrystallized from a mixture of methanol and diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[CH2:11][O:12][CH3:13]>CN(C=O)C>[CH3:11][O:12][CH2:13][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccnc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Pyridin-3-ol (25 g, 260 mmol) was added to a stirring mixture of NaH (11 g of a 60 wt % dispersion with mineral oil, 260 mmol) and DMF (350 mL) at 0° C. After 30 min, the reaction mixture was allowed to warm to RT, stirred for 90 min, and then chloromethoxymethane (20 mL, 260 mmol) was added. After 18 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The layers were separated, the organic material was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was dissolved with CH2Cl2, the solution was filtered through a plug of silica gel (sequential elution; 9:1→1:1 hexane-ethyl acetate), and the second filtrate was concentrated to give 10 g (27%) of 3-(methoxymethoxy)pyridine as a clear yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:36]([F:39])=[N:37][CH:38]=1.C([O-])(=O)C.[K+]>O>[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[CH:34]=[C:35]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)[C:36]([F:39])=[N:37][CH:38]=1
Reactant: CC1(C)OB(c2cc(C3OCCO3)cnc2F)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4OCCO4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51; (2.102 g, 5.462 mmol), 5-(1,3-dioxolan-2-yl)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Example 234; 1.901 g, 6.442 mmol), Am-Phos (200.6 mg, 0.2833 mmol), and potassium acetate (1.51 g, 15.4 mmol) were suspended in water (4 mL) and 1,4-dioxane (20 mL) and nitrogen was bubbled through the suspension for 30 s. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred under nitrogen for 4 h. Then, the reaction was cooled to room temperature, treated with water (40 mL), and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered through a Celite® (diatomaceous earth) pad, and concentrated. The crude material was purified on a silica gel filter (600 mL fritted funnel with about 3 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH) to give 4-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.175 g). 1H NMR (CDCl3, 400 MHz) δ 8.65 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.42 (d, J=1.37 Hz, 1H), 7.23 (dd, J=8.41 Hz, 5.87 Hz, 4H), 6.87 (dd, J=10.27 Hz, 8.71 Hz, 4H), 5.93 (s, 1H), 4.83 (s, 2H), 4.81 (s, 2H), 4.17-4.04 (m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 2.55 (s, 3H). m/z (ESI, +ve ion) 518 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][CH:36]=[CH:37][C:30]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:35]1[C:31]2=[N:32][CH:33]=[CH:34][C:29]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=4)[C:13](=[O:26])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:27])[N:6]=3)[CH2:3][CH3:4])=[C:30]2[CH:37]=[CH:36]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 9A).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[CH3:10][N:11]1[C:20]2[C:15](=[CH:16][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:30].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:11]([CH3:10])[C:12](=[O:30])[CH2:13][CH2:14]3)[CH:7]=[N:6][CH:5]=1
Reactant: OCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(-c3cncc(CO)c3)ccc21
Temperature: 120 °C
Yield: 36.9 %

Procedure:
A microwave vial was charged with (5-bromo-pyridin-3-yl)-methanol (376 mg, 2.0 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) (574 mg, 2.0 mmol) and DMF (4 mL). After purging the reaction mixture with argon, bis(triphenylphosphine)palladium(II)chloride (140 mg, 0.2 mmol) and 2 N aq. Na2CO3 solution (2.0 mL, 4 mmol) were added and the reaction was heated in the microwave at 120° C. for 50 min. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2×20 mL). The resulting filtrate was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (198 mg, 74%) as a white solid. MS: 269.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([O:49][C:50]([NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([C:60](O)=[O:61])[CH2:56][CH2:55]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:2][C:3]1[C:4]([CH2:9][NH:10][C:60]([C@H:57]2[CH2:56][CH2:55][C@H:54]([CH2:53][NH:52][C:50](=[O:51])[O:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:59][CH2:58]2)=[O:61])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), 1-hydroxybenzotriazole (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(C)(C)CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(Cc1ccccc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenyl-4-methylpentane (1.0 g--see Preparation 12) in 90% sulphuric acid (10 ml) was heated at 90° for 1 hour. The mixture was poured onto ice (100 g), basified to a pH of about 12 by the addition of 40% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.6 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2.[CH3:26]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:13]([NH:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]([C:17]([F:20])([F:19])[F:18])[O:8]2)=[CH:3][C:2]=1[CH3:26])[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(NCC(C)C)cc2OC1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1=Cc2cc(C)c(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 25 %

Procedure:
A mixture of ethyl 6-chloro-7-(isobutylamino)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 608b, Step 1 (2.10 g, 5.57 mmole), trimethylboroxine (1.58 mL, 12.66 mmole), [(tBu3P)PdBr]2 (0.04 g), and Cs2CO3 (3.17 g, 9.74 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil which was subject to flash chromatography (silica gel) and eluted with 0-15% EtOAc/hexanes to give yellow oil (0.5 g, 25%). No further purification was performed. GCMS m/z 357.0 (M+). LCMS m/z 358.0 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].[Cl:7][C:8]([Cl:12])([Cl:11])[C:9]#[N:10]>CCOCC>[Cl:7][C:8]([Cl:12])([Cl:11])[C:9](=[NH:10])[O:6][CH2:3][CH:4]=[CH2:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 80% sodium hydride (945 mg., 31.5 mmol.; washed twice with 25 ml. of hexane) in dry. ether (30 ml.) was treated dropwise with a solution of 2-propen-1-ol (21.4 ml., 18.3 g., 315 mmol.), in dry ether (45 ml.), stirred for 20 minutes at room temperature under argon and then cooled to 0° C. (ice-salt bath). Trichloroacetonitrile (30 ml. or 42.3 g., 0.30 mole) was added over a period of 15 minutes and the brownish solution was stirred at 0° C. for 40 minutes, at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to a syrup, treated with a solution of methanol (1.2 ml.) in pentane (30 ml.) and stirred vigorously for 5.0 minutes. The light brown precipitates were filtered off, washed with pentane (2×30 ml.) and the combined flitrates concentrated down to a light brown liquid. The liquid was redissolved in pentane (30 ml.), stirred for a few minutes, and the resulting suspension filtered, and the precipitates obtained washed with pentane (30 ml.), repeating the procedure at least one more time. The clear filtrate was concentrated and dried in vacuo to give 54.0 g. of title compound as a light red-colored liquid. This material was stored as a solution in hexane at 10° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([O:35]C)=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1.ClC1C=CC(C2C=CC=C(COC3C=C4C(CCN(C5CCCC5)C4=O)=CC=3)C=2)=CC=1C(O)=O>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:16][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:17])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:15][CH2:14]4)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Reactant: O=C1c2ccc(O)cc2CCN1C1CCCC1
Agent: O=C(O)c1cc(-c2cccc(COc3ccc4c(c3)C(=O)N(C3CCCC3)CC4)c2)ccc1Cl
Product: O=C(O)c1cc(-c2cccc(COc3ccc4c(c3)CCN(C3CCCC3)C4=O)c2)ccc1Cl
Yield: 68.1 %

Procedure:
2-Cyclopentyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.106 g, 0.5 mmol) and methyl 3′-(bromomethyl)-4-chlorobiphenyl-3-carboxylate (0.208 g, 0.6 mmol) were processed according to the general procedure described for 4-chloro-3′-((2-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)biphenyl-3-carboxylic acid, to provide 4-chloro-3′-((2-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)methyl)biphenyl-3-carboxylic acid (0.162 g, 69% over 2 steps) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.87-7.75 (m, 3H), 7.65-7.57 (m, 2H), 7.49-7.41 (m, 2H), 6.95-6.90 (overlapping doublets and singlet, 2H), 5.20 (s, 2H), 4.97-4.93 (m, 1H), 3.34 (t, 2H, J=6.1 Hz), 2.84 (t, 2H, J=6.1 Hz), 1.69-1.46 (m, 8H). LC-MS (ESI) Calcd for C28H26ClNO4 [M+H]+: 476.16. Found: 476.00. HRMS (ESI) calcd for C28H26ClNO4 [M+H]+: 476.1623. Found: 476.1623.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][CH:14]=[N:15][C:16]=3[CH3:17])[C:9](=[O:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[NH:13][CH:14]=[N:15][C:16]=4[CH3:17])[C:9](=[O:18])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Yield: 23 %

Procedure:
The title compound (23% yield) was prepared from 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to the HCl salt. 1H NMR (360 MHz, DMSO-d6) δ 13.45 (br s, 1H, NH), 11.76 (br s, 1H, NH), 9.19 (s, 1H), 8.31 (s, 1H, H-vinyl), 7.92 (s, 1H), 7.73 (m, 1H), 7.45 (m, 2H), 7.36 (m, 1H), 2.33 (s, 3H7CH3). MS 371.4 [M++1].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([CH3:18])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxobutanoate as a yellow solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[I:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:14])[CH3:15])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(I)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(I)cc1CO)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A solution of Intermediate 61a (2.88 g, 6.60 mmol) in DCM (50 mL) at 0° C. under N2 was treated dropwise with diisobutyl aluminium hydride (1.0M in THF, 16.6 mL, 16.6 mmol) and the mixture was stirred at RT overnight. The mixture was cooled to 0° C., then treated dropwise with another portion of diisobutyl aluminium hydride (1.0M in THF, 8.3 mL, 8.30 mmol) and stirred at RT for 1 h. The mixture was cooled to 0° C. and quenched by dropwise addition of water to give a gel that was partitioned between EtOAc/ether and brine/water/aqueous potassium sodium tartrate solution. The insoluble salts were filtered off and the phases separated. The aqueous phase was extracted with EtOAc (2×) and the combined organic layers were washed with a 10% aqueous citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was pre-adsorbed onto diatomaceous earth and purified by FCC, using 0-15% EtOAc in cyclohexane, to give the title compound as a colorless oil (1.04 g, 39%). LCMS (Method 3): Rt 5.29 min, m/z 405 [MH+].