Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C:13]([CH2:16]I)([CH3:15])[S:12][C:11]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([SnH](CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(CI)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of N-((4S)-4-(3-bromo-4-fluorophenyl)-6-(iodomethyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (0.13 g, 0.23 mmoles, 1.0 equiv) in toluene (1.5 mL) is added 2-2′-azo-bis-isobutyronitrile (0.006 g, 0.03 mmoles, 0.15 equiv) and tri-n-butyltin hydride. The reaction mixture is stirred at room temperature for 3 h and concentrated under reduced pressure. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of 5% ethyl acetate:hexanes to 20% ethyl acetate:hexanes to give the title compound (25% yield): MS (m/z): 435, 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenyl}-2-propenoate (128) (0.26 g, 0.57 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 129 was obtained as light yellow foam (0.24 g, 99%). mp 111-114° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.88 (s, 6H), 1.25 (s, 2H), 1.87 (s, 2H), 1.90 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.06 (s, 1H), 7.16 (d, J=7.7 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59 (d, J=7.5 Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 423 (M−H)−. Anal. Calcd for C26H29ClO3: C, 73.48; H, 6.88; Found: C, 73.18; H, 7.06.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23]>>[C:25]([N:24]([CH2:22][CH3:23])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CCNC(C)(C)C
Product: CCN(c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 79 mg, 0.280 mmol) and N-ethyl-2-methylpropan-2-amine (142 mg, 1.399 mmol, TCI International, Portland, Oreg.), heating at 120° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butyl(ethyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=6.94 Hz, 3H) 1.60 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 3.80 (q, J=6.91 Hz, 2H) 6.94 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.41 (t, J=7.73 Hz, 1H) 7.69 (d, J=8.22 Hz, 1H) 7.87 (d, J=7.43 Hz, 1H) 8.71 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O.C1C=CC=CC=1>CN(C)C=O.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC

Procedure:
A solution of diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (10.8 g) in N,N-dimethylformamide (325 ml) was shaken with 10% palladium on carbon (3.6 g) in hydrogen atmosphere at ambient temperature. After the absorption of hydrogen was finished, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give a residue, to which was added benzene. The mixture was concentrated under reduced pressure to give crude crystals of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=4)[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: COc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)n1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)n1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (40.0 mg, 0.125 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-2-(6-methoxy-2-pyridinyl)-3-methyl-4-quinolinamine. 1H NMR (CDCl3) δ ppm 7.78-7.87 (1H, m), 7.77 (1H, dd,), 7.61-7.68 (2H, m), 7.56 (1H, dd, J=7.2, 0.8 Hz), 6.98-7.09 (1H, m), 6.86 (1H, dd, J=8.2, 0.8 Hz), 6.45 (1H, d, J=2.5 Hz), 3.93 (3H, s), 3.86-4.01 (4H, m), 3.71-3.83 (4H, m), 3.09-3.53 (4H, m), 3.02-3.08 (4H, m), 2.26 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4](Cl)=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][C:3]1[C:4]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: Clc1ncncc1Br
Reactant: NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ncncc2Br)CC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g, 0.36 mmol) in DMF (2 mL) was added triethylamine (0.51 mL, 3.6 mmol). After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p. 188-190° C.; umax (CHCl3)/cm−1 3012, 2853, 1682, 1566, 1447, 1359, 1144, 1017, 950; m/z (ESI) C10H14BrN4O requires 285.0346, found [M+H]+ 285.0344.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH:11]=[C:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CN1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN1CCC(=Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification on silica yielded 181. NMR: (CDCl3) 2.37 (3H,s); 2.55 (6H,m); 2.82 (2H,t,J=5.5 Hz); 3.93 (4H,t,J=4.8 Hz); 4.10 (4H,t,J=4.8 Hz); 6.44 (1H,s); 7.33 (1H,s); 7.51 (1H,s); 7.60 (1H,d,J=8.2 Hz); 8.28 (1H,d,J=7.1 Hz); 9.03 (1H,s); 10.25 (br s). M+H(447)
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1.CC(N(C)C)=O>C(CC(C)(C)C)(C)C>[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH2:30])=[CH:26][N:25]=2)=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: CC(C)CC(C)(C)C
Product: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), 6-chloronicotinamide (31.32 g, 200 mmol), DMAC (622 mL) and iso-octane (70 mL) was slowly heated to reflux at 140° C. A water trap filled with iso-octane was used to collect water formed in the reaction, and reflux was maintained for 5.5 h. The mixture was allowed to cool to room temperature, and the solids were filtered and washed with EtOAc. The filtrate was concentrated in vacuo to 88.6 g of solid which was dissolved in EtOAc (500 mL). To this solution was added water (800 mL), 1N HCl (200 mL) and MeOH (50 mL). The pH of this mixture was adjusted to 7.2 with con. HCl, and the aqueous layer was separated and washed with methyl t-butyl ether (500 mL). The product was crystallized by addition of 10N NaOH (20 mL) which raised the pH to 11. This pH was maintained by addition of 10N NaOH as needed during the course of the crystallization (90 min). The product was filtered, washed with water and dried in vacuo at 45° C. to 53.11 g (93%) of white solid which was >98% pure by HPLC analysis: 1H NMR (300 MHz, DMSO-d6) NMR was consistent with the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[NH:30][N:29]=[N:28]2)=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:30]1[C:31](=[O:32])[N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:15])([F:33])[CH:17]([F:19])[F:18])=[CH:26][CH:25]=2)[N:28]=[N:29]1)[CH3:13]
Reactant: O=c1[nH]nnn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 66.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.049 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.17 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]- 5(1H,4H)-tetrazolone, 1.28 g of 1-[(1R, 2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-5 (1H, 4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(=NC(CCC2C=C3C(=CC=2)C2[S:82][C:81]([C:87]4[O:91][N:90]=[C:89]([C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)[C:88]=4[C:98]([F:101])([F:100])[F:99])=[N:80]C=2CC3)C(OCC)=O)C2C=CC=CC=2)C=CC=CC=1>>[C:8]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2[S:82][C:81]([C:87]4[O:91][N:90]=[C:89]([C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)[C:88]=4[C:98]([F:101])([F:100])[F:99])=[N:80][C:28]=2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 93A employing ethyl 2-(diphenylmethyleneamino)-4-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)butanoate (Preparation 119A) as a starting material. The compound had an LC/MS M+1=706.4.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:11][C@H:10]([CH3:12])[CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][C@@H:10]1[CH2:9][O:8][C:6]2[N:7]=[C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[O:11]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@@H]1COc2nc(Cl)nc(N3CCOCC3)c2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCCCO
Product: C[C@@H]1COc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2O1
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of (R)-2-chloro-6-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (65 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (80 mg, 0.36 mmol), Pd(OAc)2 (1 mg, 10 mol %), (S)-phos (4.1, 20 mol %) and potassium phosphate tribasic (106 mg, 0.50 mmol) in n-butanol (2.25 mL) and water (0.25 mL) was degassed and then heated at 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM) affording 102 (23 mg, 29%). LCMS: RT=3.09 min, [M+H]+=331. 1H NMR (400 MHz, DMSO): δ 9.15 (2H, s), 5.73 (2H, s), 4.44 (1H, dd, J=11.44, 2.17 Hz), 4.31-4.24 (1H, m), 4.08 (1H, dd, J=11.45, 8.21 Hz), 3.89-3.73 (8H, m), 1.42 (3H, d, J=6.38 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]C)=O)[N:2]=1.[NH2:15][NH2:16]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:15][NH2:16])=[O:13])[N:2]=1
Reactant: NN
Reactant: COC(=O)c1cc2ccccc2cn1
Solvent: CCO
Product: NNC(=O)c1cc2ccccc2cn1
Yield: 86 %

Procedure:
To a solution of methyl isoquinoline-3-carboxylate (10 g, 53.42 mmol) in ethanol (100 mL) was added hydrazine (17.1 g). The reaction mixture was refluxed for 30 min and concentrated under high vacuum to remove hydrazine. The resulting residue was triturated with ethanol (20 mL) to give isoquinoline-3-carbohydrazide (8.6 g, 86%). LRMS (M+H+) m/z 188.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:66][O:67][C:68](=[O:71])[CH2:69][NH2:70].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:70][CH2:69][C:68]([O:67][CH3:66])=[O:71])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)CCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 233 (28.7 mg, 0.05 mmoles) in anhydrous dimethylformamide (0.5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14 mg, 0.07 mmoles) and 1-hydroxybenzotriazole hydrate (10 mg, 0.07 mmoles) at room temperature for 15 minutes. A mixture of glycine methyl ester hydrochloride (12.6 mg, 0.1 mmole) and N,N-diisopropylethylamine (0.014 ml, 0.1 mmole) in anhydrous dimethylformamide (0.235 ml) was added to the reaction and shaken at room temperature overnight. The reacton mixture was acidified with 1N aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and filtrate concentrated in vacuo. The residue purified by HPLC to provide the titled compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C:31]([NH:33][NH2:34])=[O:32].[F:44][C:45]1[CH:50]=[C:49]([N:51]2[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]2)[C:48]([O:57][CH3:58])=[CH:47][C:46]=1/[CH:59]=[CH:60]/[C:61](O)=[O:62].[Cl-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[F:44][C:45]1[CH:50]=[C:49]([N:51]2[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]2)[C:48]([O:57][CH3:58])=[CH:47][C:46]=1/[CH:59]=[CH:60]/[C:61]([NH:34][NH:33][C:31](=[O:32])[CH:30]([C:35]1[CH:36]=[C:37]([F:43])[C:38]([F:42])=[C:39]([F:41])[CH:40]=1)[CH2:29][CH2:28][CH2:27][Cl:26])=[O:62]
Reactant: COc1cc(/C=C/C(=O)O)c(F)cc1-n1cnc(C)c1
Reactant: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)c(F)cc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
IPEA (0.31 mL) and BOPCl (119 mg) were added to a solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride (114 mg) and (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (99 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 200 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [BH4-].[Na+].Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)=[CH:7][CH:6]=1>CO>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][NH:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Sodium borohydride (0.720 g, 19.0 mmol) was added in small portions to a solution of 1-(4-bromophenyl)-6-methoxy-3,4-dihydroisoquinoline, hydrochloride (3.62 g, 10.2 mmol) in MeOH (30 ml) at 0° C. The reaction mixture was stirred for 30 min, warmed to rt, and stirred at rt for 1 hr, then quenched by the dropwise addition of H2O (10 ml). Acetic acid (10 drops) was added with stirring, and the resulting mixture was basified to pH 10 with 1N NaOH and extracted with EtOAc (3×25 ml). The combined extracts were washed with 1N NaOH followed by saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to give 3.24 g (100% yield) of white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH2:12][C:6]1([O:13][CH3:14])[CH:7]=[CH:8]2)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH2:12][C:6]1([O:13][CH3:14])[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1CC2C=CC1(OC)CC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CC2CCC1(OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100-mL, round-bottomed flask containing a magnetic stir bar were added 5% palladium/carbon catalyst (100 mg) and methanol (20 mL). Neat 1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester (1.96 g, 1.80 mL, 10.0 mmol) was added. A balloon containing H2 gas was attached and the mixture was stirred at room temperature overnight. The catalyst was removed by vacuum filtration through a small plug of silica gel and the solvent was removed under reduced pressure to provide the title compound. NMR (DMSO-d6, 300 MHz) δ 1.40-1.89 (m, 11H), 2.87 (ddd, J=10.5, 6.4, 2.0 Hz, 1H), 3.07 (s, 3H), 3.57 (s, 3H). MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:19][O:20][CH2:21]Cl.O>O1CCCC1>[Cl:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:19][O:20][CH3:21])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cc(Cl)sn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COCOc1cc(Cl)sn1
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of 5-chloro-isothiazol-3-ol (5.00 g) in tetrahydrofuran (50 mL), 1,8-diazabicyclo[5.4.0]undeca-7-ene (8.42 g) was added, and to the resultant reaction mixture, a solution of chloromethyl methyl ether (4.45 g) in tetrahydrofuran (25 mL) was dropped under ice-cooling at an inside temperature of 10° C. or less. After the completion of dropping, the inside temperature was elevated to room temperature and the reaction mixture was stirred for 10 minutes. To the reaction mixture, water was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (6.15 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.FC(F)(F)C(O)=[O:12].OO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:12]
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(Br)nc1
Agent: OO
Solvent: O
Product: [O-][n+]1cc(F)ccc1Br

Procedure:
2-Bromo-5-fluoropyridine (15 g, 85.6 mmol), trifluoroacetic acid (70 mL, 908 mmol) and hydrogen peroxide (35% in water) (9 mL, 105 mmol) were stirred overnight at 70° C. The mixture was poured into water and extracted with dichloromethane. The organic layers were washed with NaHCO3 (aq), dried over MgSO4 and the solvent was removed i.vac.