Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:21][CH3:22]
Reactant: CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
Rats receiving intragastric pretreatment with PL solution only had 3 hours after ethanol macroscopic hemorrhagic lesions involving 35.8±2% of glandular mucosal area. Treatment with oleic acid did not change significantly occurrence of mucosal hemorrhagic lesions -29.1±3%. Rats receiving pretreatment with 120 mM and 240 mM LLC had significantly decreased macroscopic hemorrhagic lesions -6.5±1% and 1.3±0.5% respectively (p<0.01) 3 hours after ethanol. Macroscopic protection rat gastric mucosa against ethanol was similar to that afforded by arachidonic acid except for the presence of marked edema in the forestomach (containing squamous, paraepidermoidal epithelium) 3 hours after ethanol in group pretreated with linoleic acid (C).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]2[CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[NH:1][CH2:11][CH:6]2[C:7]([O:9][CH3:10])=[O:8])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2Cl2 chilled to 0° C. was added 9.05 ml (63.4 mmol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0° C. and 0.8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 6.95 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) to give 2.7 g of product as a viscous yellow oil. From a similar 0.5 g run, there was obtained 0.178 g of an oil. Anal. for C18H20N2O5S: Calc'd: C,57.4; H,5.4; N,7.4; S,8.5; Found: C,57.9; H,5.4; N,6.7; S,7.9; Mass spectrum (ES) 377.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:17]3=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]3[N:15]=[C:14]2[CH2:23][CH2:24][CH3:25])=[CH:10][CH:9]=1)#[N:2].C[Sn]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C(C)=CC=CC=1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([C:7]4[CH:6]=[CH:5][O:4][C:3]=4[C:1]4[NH:34][N:33]=[N:32][N:2]=4)=[CH:27][CH:26]=3)[C:14]([CH2:23][CH2:24][CH3:25])=[N:15][C:16]=12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccoc2C#N)cc1
Solvent: Cc1ccccc1C
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccoc2-c2nnn[nH]2)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
A mixture of 3-[4-(2-cyano-3-furyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (540 mg) and trimethyltin azide (1.095 g) in xylene (10 ml) was stirred at 125° C. for 24 hours. The mixture was concentrated in vacuo. The residue was dissolved in methanol (15 ml) and the methanolic solution was treated with 8.9N methanolic hydrogen chloride (1 ml) for one hour at ambient temperature. The mixture was adjusted to pH 5 with aqueous 1N sodium hydroxide solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (elution by dichloromethane/methanol=15/1-8/1) to yield 7-methyl-2-propyl-3-[4-[2-(1H-tetrazol-5-yl)-3-furyl]benzyl]-3H-imidazo[4,5-b]pyridine (525 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH3:30])[C:20]([N:23]2[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Br:16][C:17]1[CH:18]=[C:19]([CH3:30])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)[C@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1
Reactant: Cc1cc(Br)cnc1N1CCN[C@H](C)C1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(Cl)n2)[C@H](C)C1

Procedure:
Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (6.0 g, 24.7 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (7.0 g, 25.9 mmol) and K2CO3 (6.8 g, 49.4 mmol) in DMA at 60° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(OCC)(=O)C>CN(C)C=O>[N:10]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: Brc1ccc(Br)nc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(-n2cncn2)nc1
Yield: 92.6 %

Procedure:
In 20 ml of dimethylformamide, 1 g of 2,5-dibromopyridin was reacted with 0.58 g of 1,2,4-triazole sodium at 80° C. for 10 hours with stirring. Following the addition of ethyl acetate, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 880 mg of 2-(1,2,4-triazol-1-yl)-5-bromopyridine. This compound was dissolved, along with 1.4 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 50 ml of dimethylformamide and then added with 1.2 ml of triethyl amine and 1.1 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was conducted at 100° C. for 3 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. Purification of the concentrate with column chromatography provided the title compound. 320 mg. Yield 23%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2ccccc2Br)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 2-bromobenzoyl chloride (2 g, 9 mmol) in toluene (30 mL) was added N-methylpiperazine (2 mL, 18 mmol, 2 equiv.). The resulting mixture was stirred overnight. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was taken into dichloromethane, washed with water. The organic layer was concentrated under reduced pressure to give 2 g (77% yield) of intermediate 10.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20]C)=[C:15]([O:18]C)[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Agent: Br
Product: Oc1cc2c(cc1O)C(Cc1ccccc1)NCC2
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Treat 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (10 g) with 48% HBr (100 mL) and heat the mixture at reflux under nitrogen for 2 h. Cool the mixture to room temperature and allow crystals to form overnight. Collect the crystals and wash with cold ethanol to give 7.5 g of the title compound as its HBr salt, mp=233°-236° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:12][CH2:13][C:14]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[CH:15][C:16](OCC)=[O:17])[CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]([N:12]1[CH2:13][C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:15][C:16]1=[O:17])[CH2:5][CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)C=C(CNC(CC(C)C(F)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CC(C)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 140 °C
Yield: 58.3 %

Procedure:
A solution of 2-[2-(2-chloro-phenoxy)-3-ethoxycarbonyl-allylamino]-5,5,5-trifluoro-4-methyl-pentanoic acid methyl ester (726 mg, 1.66 mmol) in acetonitrile (5 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 140° C. for 2.5 h. The mixture was then concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (12 g column, 10% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) which afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid methyl ester (379 mg, 58%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].[CH3:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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.O>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:25][O:24][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:38]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:33])[CH:39]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1Br
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: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1ccnc(C)c1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of N-(4-bromo-3-methoxyphenyl)-4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine, TFA (70 mg, 0.13 mmol), 2-methylpyridin-4-ylboronic acid (36 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (7.6 mg, 6.6 μmol) and Cs2CO3 (172 mg, 0.529 mmol) in DME (994 μL)/water (328 μL) was heated at 100° C. for 18 h. The crude reaction products were purified using preparatory HPLC (Solvent A=10% MeOH-90% water-0.1% TFA, Solvent B=90% MeOH-10% water-0.1% TFA. Column: Phenomenex Luna 30×100 mm, S10, flow rate: 40 ml/min, 40-100% B, 40 min) to afford 30 mg (35% yield) of the titled compound as a yellow oil. LC-MS (M+H)+ 428.2.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:35]1[N:36]([C:40]2[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=2[C:42](O)=[O:43])[N:37]=[CH:38][CH:39]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=[CH:18][C:9]=1[N:8]1[C@@H:1]2[C@@H:6]([CH2:5][CH2:4][N:3]([C:42]([C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[N:36]3[N:37]=[CH:38][CH:39]=[N:35]3)=[O:43])[CH2:2]2)[CH2:7]1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C23H21N7O, 411.47; m/z found 412.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:18][C:17]4[C:16](=[O:19])[N:15]([CH:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[C:14](=[O:33])[N:13]([CH2:34][C:35]5[N:36]=[N:37][N:38]([CH2:40][CH3:41])[N:39]=5)[C:12]=4[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:42]>O1CCOCC1>[ClH:42].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:18][C:17]4[C:16](=[O:19])[N:15]([CH:20]5[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]5)[C:14](=[O:33])[N:13]([CH2:34][C:35]5[N:36]=[N:37][N:38]([CH2:40][CH3:41])[N:39]=5)[C:12]=4[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-[6-(1,3-benzodioxol-5-yl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (239 mg; compound B50) in 1,4 dioxane (6 ml) is added a solution of hydrogen chloride in 1,4-dioxane (1.028 ml, 4.0 M). The reaction mixture is stirred for 3 d at RT. All volatiles are evaporated and the residue is treated with DCM and after removal of the solvent under reduced pressure the title compound is obtained as a solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH:30][C@H:31]([CH:36]([CH3:38])[CH3:37])[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1>C1C=CC=CC=1>[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:30]([S:27]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)(=[O:28])=[O:29])[C@H:31]([CH:36]([CH3:38])[CH3:37])[C:32]([O:34][CH3:35])=[O:33])[CH:40]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)[C@H](NS(=O)(=O)N1CCC(c2ccc(Br)cc2)CC1)C(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
Tri-n-butylphosphine (0.37 ml, 1.5 mmol) was added to a solution of methyl 2-(R)-{[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (560 mg, 1.25 mmol), 3-pyridylcarbinol (0.15 ml, 1.5 mmol), and 1,1'-(azodicarbonyl)piperidine (377 mg, 1.5 mmol) in benzene (30 ml). After stirring at RT for 48 h, the reaction mixture was concentrated and the residue was triturated with ether (60 ml). After filtering off the solids, the ether layer was concentrated in vacuo and the residue was chromatographed (SiO2, 40% ethyl acetate/hexane) to give methyl 2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (41%).
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.O>CCCCCC.C1COCC1>[CH2:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([B:28]([OH:29])[OH:27])[CH:10]=2)[O:5]1)[CH2:2][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC(Br)CC1Cc2ccccc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2cc(B(O)O)ccc2O1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Then, 2.00 g (6.43 mM) of b-bromo-2-octylcoumaran and 28 ml of dry THF were placed in a 100 ml-three-necked flask. To the mixture, 4.5 ml (7.20 mM) of a 1.6M solution of butyllithium in hexane was added dropwise under stirring and nitrogen atmosphere on a dry ice-acetone bath at an inner temperature of -70° to -68° C., followed by stirring for 50 minutes at the same temperature. To the resultant mixture a solution of 3.2 ml (13.9 mM) of triisopropylborate in 5.7 ml of dry THF was added dropwise in 10 minutes at an inner temperature of -73° to -68° C., followed by stirring for minutes at the same temperature. Thereafter, the cooling bath was removed and the inner temperature was increased to room temperature, followed by gradual addition of 9.5 ml of 10%-hydrochloric acid. After the reaction, the reaction mixture was poured into water and subjected to extraction with isopropyl ether, followed by washing with water, drying with mirabilite and distilling-off of the solvent to obtain a residue. To the residue, hexane was added and the mixture was left standing in a freezer to precipitate a crystal. The crystal was recovered by filtration to obtain 1.19 g of 2-octylcoumaran-5-boronic acid (Yield: 67.1%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:18])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])#[C-:34].[H-].[Na+].C1COCC1>C1COCC1>[CH2:39]([O:38][C:36]([C:35]1[N:33]=[CH:34][N:6]2[C:7]=1[CH:8]([CH3:18])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:4]1[CH:3]=[C:2]([Br:1])[CH:21]=[CH:20][C:5]2=1)=[O:37])[CH3:40]
Reactant: CC1N=C(c2ccccc2F)c2cc(Br)ccc2NC1=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
7-Bromo-5-(2′-fluorophenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 137 (3.78 g, 10.88 mmol) was suspended in dry THF (150 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.07 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and then warm to rt over 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.65 mL, 17.42 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. During this time, sodium hydride (60% dispersion in mineral oil, 0.61 g, 15.24 mmol) was suspended in dry THF (60 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.43 mL, 13.07 mmol) was added to the NaH/THF suspension and this mixture allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. with a cooling bath and the mixture in the second reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, after which it was cooled to 0° C. with an ice-water bath and slowly quenched with acetic acid (5 mL). Water was then added to the reaction mixture and this was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure the solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1). The ethyl ester 138 was a white solid (1.82 g, 38%). mp 190-192° C.; IR (KBr, cm−1) 3316, 2925, 1693, 1621, 1485, 1448, 1371; 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1H), 4.41 (m, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.29 (d, J=7.2, 3H). MS (EI) m/e (relative intensity) 442 (M+, 5), 428 (7), 381 (58), 355 (100), 303 (37); [α]26D=−10.9 (c 0.54, EtOAc).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([F:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:44])=[CH:17][C:18]=4[F:43])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3F)ncc21
Yield: 94.5 %

Procedure:
A solution of 0.067 g (0.109 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-229) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0533 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-piperidin-4-yl-benzamide (I-230) as a white solid.
Reaction SMILES: I[CH3:2].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>C1COCC1>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1C
Yield: 49.7 %

Procedure:
Iodomethane (4.98 mL, 80 mmol) was added dropwise to a mixture containing ethyl indole-2-carboxylate (1.89 g, 10 mmol) and sodium hydride (1.2 g, 60% dispersion, prewashed by hexane) in anhydrous THF (60 mL) in a flame dried flask under argon at 0° C. After 4 h at RT the reaction was concentrated on the rotavap. The residue was taken into EtOAc and washed sequentially with H2O and saturated NaCl. Drying (MgSO4) and concentration gave the title compound (1.01 g, 50%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20](I)=[CH:21][C:13]1=2)[CH3:11].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)=[CH:21][C:13]1=2)[CH3:11]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(c1c(F)ccc(F)c1Cl)N1CCNc2ncc(I)cc21
Product: CC(c1c(F)ccc(F)c1Cl)N1CCNc2ncc(-c3ccc(N4CCN(C)CC4)nc3)cc21
Yield: 15 %

Procedure:
1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (53 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as an orange solid (15% yield). LCMS: m/z=435.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66 (3H, d, J=7.1 Hz), 2.35 (3H, s), 2.54 (4H, t, J=4.9 Hz), 3.54 (8H, m), 4.89 (1H, bs), 5.31 (1H, m), 6.68 (1H, d, J=8.9 Hz), 6.72 (1H, s), 6.96 (1H, m), 7.05 (1H, m), 7.52 (1H, dd, J=8.8, 2.5 Hz), 7.57 (1H, s), 8.29 (1H, d, J=2.3 Hz).