Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.CCOC(C)=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>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E) (40 mg, 0.077 mmol), phenylboronic acid (11 mg, 0.093 mmol, 1.2 eq), K2CO3 (27 mg, 0.19 mmol), tetrabutylammonium bromide (2.5 mg, 0.0077 mmol), and dichlorobis(triphenylphosphine)palladium(II) (2.2 mg, 0.003 mmol) in 1,4-dioxane (0.5 mL) and water (0.25 mL) was heated to 90° C. for 75 minutes, cooled to rt, diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 88:12-82:18, to provide the desired product tert-butyl 7-(6-(methoxycarbonyl)-5-phenylpyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29G): 1H NMR (300 MHz, CDCl3) δ 8.41 (1H, d), 7.88 (1H, d), 7.80 (1H, d), 7.71 (1H, dd), 7.48-7.37 (5H, m), 7.19 (1H, d), 3.80-3.70 (5H, m), 2.82 (2H, t), 1.96 (2H, m), 1.57 (9H, s).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH3:13].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:25]2([CH3:27])[CH2:26][O:6]2)=[O:28])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(CC)c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: CCc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-Chloroperoxybenzoic acid (14.71 g, 0.08524 mol) was added in portions to the refluxing solution of N-(3-ethyl-4-nitrophenyl)-2-methylacrylamide (6.68 g, 0.02852 mol) and 2,6-di-tert-butyl-4-methylphenol (149 mg) in dichloromethane (180 ml). After refluxing for 5 h the reaction mixture was allowed to cool to room temperature. The precipitated 3-chlorobenzoic acid was filtered, and the filtrate was extracted three times with 1M Na2CO3 and water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using dichloromethane as an eluent. 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, 3J=7.4 Hz), 1.55 (3H, s), 2.84 (2H, q, 3J=7.4 Hz), 2.99 (1H, d, 2Jgem=5.1 Hz), 3.06 (1H, d, 2Jgem=5.1 Hz), 7.81 (1H, dd, 3J=9.0 Hz, 4J=2.3 Hz), 7.85 (1H, d, 4J=2.2 Hz), 7.97 (1H, d, 3J=9.0 Hz), 9.88 (1H, s, —NHCO—).
Reaction SMILES: [CH3:1][Si:2]([NH:5][Si](C)(C)C)([CH3:4])[CH3:3].[NH:10]1[CH:14]=[CH:13]N=[CH:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:4])([CH3:3])[N:5]1[CH:13]=[CH:14][N:10]=[CH:11]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)n1ccnc1

Procedure:
HMDS (11.46 mL, 0.055 mol, 1.5 eq) was added dropwise over 20 min to a solution of imidazole (5.0 g, 0.074 mol, 2 eq) in 150 ml of toluene under argon, then the reaction mixture heated to reflux for 3 h. The reaction mixture was then concentrated to dryness under reduced pressure. Distillation of the residue gave AA2-2 as a colorless oil in 85%. For best results, this product should be stored at 0° C. under argon.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[S:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.I[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([S:22][CH3:31])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:28])([F:27])[F:29])[CH:3]=1
Reactant: CI
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodomethane following General Procedure B.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cccs2)n1
Product: c1csc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)c1
Yield: 61 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(2-thienyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)oxazole. The yield was 61%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH2:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:19][C:20]#[CH:21])[CH2:23][CH2:24]3)[C:8]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reactant: C#CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(C2Cc3cc(C)ccc3Sc3ccc(F)cc32)CC1

Procedure:
7 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin are heated under reflux for 20 hours with 7.8 g. of N-(2-propynyl)-piperazine and 40 ml. of chloroform. The chloroform is removed by evaporation and the residue is treated with ether and aqueous sodium hydroxide solution and mixed well. The ether phase is acidified with ethanolic hydrochloric acid. The precipitate which forms is removed by filtration, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulfate, evaporated, and there is obtained 1-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl]-4-(2-propynyl)-piperazine which is converted into the dihydrochloride by reaction with ethanolic hydrogen chloride. The dihydrochloride melts at 230°-231° C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([CH3:20])=[C:7]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[N:8]=1)([CH3:3])[CH3:2].Cl.[NH:22]1[CH2:25][CH:24]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]([C:4]1[NH:5][C:6]([CH3:20])=[C:7]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([N:22]2[CH2:25][CH:24]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[CH2:23]2)=[O:16])[N:8]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2nc(C(C)C)[nH]c2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc(C(C)C)[nH]c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
The mixture of 5-(2-isopropyl-5-methyl-1H-imidazol-4-yl)-2,4-dimethylbenzoic acid (compound 159.3, 250 mg, 0.92 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 195 mg, 1.0 mmol), EDCI (264 mg, 1.4 mmol), HOBt (170 mg, 1.0 mmol) and DIEA (640 μL, 3.7 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with saturated NaHCO3 and extracted with EtOAc (60 mL). The organic phase was washed with brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane and lyophilized to give 85 mg (22%) of the title compound as a white solid. m/z (ES+) 413 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
14.6 g (30.0 mmol) of (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester and 7.74 g (35.0 mmol) of 2-bromomethyl-naphthalene were dissolved in 110 ml of dimethylformamide under argon and then 1.77 g (40.0 mmol) of sodium hydride dispersion (55% in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice-water, the resulting product was extracted 3 times with dichloromethane, the organic phases were washed twice with distilled water, then dried over magnesium sulfate, filtered and concentrated in a water-jet vacuum. The resulting crude product was chromatographed on silica gel with dichloromethane and methanol to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester as colorless oil; MS: 626.5(M+H+).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[CH:12]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]([O:21]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[CH:19]=[O:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: Cc1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1C=O
Reaction time: 4 h
Yield: 36 %

Procedure:
This compound was prepared from 412 (615 mg, 2.24 mmol) in a manner similar to that for 409a except for after the drop-wise addition of substituted indole, the solution was stirred for 4 h to provide an orange precipitate. The precipitate was further purified by chromatography (isocratic 5% MeOH/DCM) to yield a white solid (250 mg, 36%): mp 201-203° C. TLC Rf 0.33 (75% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 9.70 (s, 1H), 8.08 (s, 1H), 7.26-7.24 (m, 2H), 2.69 (s, 3H), 1.52 (s, 9H). 13C NMR (150 MHz, d6-DMSO) δ 184.4, 153.4, 149.4, 134.5, 131.6, 125.9, 115.6, 113.9, 111.4, 110.3, 79.0, 28.5, 11.7. Elemental analysis calculated for C15H18N2O3.0.125H2O: C, 65.14; H, 6.65; N, 10.13. Found: C, 64.82; H, 6.81; N, 10.14. HRMS ESI calculated for C15H18N2O3 (M+H)+ 275.1390; (M+Na)+ 297.1210. Found (M+H)+ 275.1393; (M+Na)+ 297.1210.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester 1.03 g (65%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in THF (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](Cl)=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].[C:31]([NH:41][NH2:42])(=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([N:41]([C:31](=[O:40])[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[NH2:42])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: COc1cccc(C(=O)NN)c1
Reactant: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(c(N(N)C(=O)c3cccc(OC)c3)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
The compound of step 6 (100 mg, 0.237 mmol) was taken in 2 ml EtOH and treated successively with m-anisic hydrazide (99.6 mg, 0.6 mmol) and TEA (Triethylamine) (35 microl, 0.25 mmol) at room temperature and stirred at 60° C. for 72 h.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]([O:25]CC)=[CH2:24])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:28])[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH3:29].C([O-])(O)=O.[Na+]>CO>[F:2][C:3]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:28])[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH3:29]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
2 mL of 3N HCl solution was added to a solution of 3-[1-(4,6-Difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-(1-ethoxy-vinyl)-imidazo[1,2-b]pyridazine in 10 ml MeOH. The reaction solution was stirred at room temperature for 3 hours and then neutralized with sat. NaHCO3 solution. Solvent was evaporated and the residue was purified on chromatography (CH2Cl2:MeOH 10:1) to give the title compound as a yellow solid (30 mg, 41%). LCMS (method C): [MH]+=355.9, tR=3.75 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH:44]=[N:43][CH:42]=[CH:41]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:44]1[C:45]2[C:40](=[CH:39][C:38]([NH:37][C:11](=[O:13])[CH:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:30])[CH3:31])=[CH:18][CH:19]=3)[CH2:9][N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:47][CH:46]=2)[CH:41]=[CH:42][N:43]=1
Reactant: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonyl(methyl)amino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E204) in pyridine was added was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205).
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:16][C:17]2([CH3:21])[CH2:20][NH:19][CH2:18]2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=3)=[N:5][NH:4][C:3]1=[O:28].C=O.[BH3-][C:32]#N.[Na+]>CO.CC(O)=O>[CH3:32][N:19]1[CH2:20][C:17]([NH:16][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][CH2:7][C:6]2[N:15]3[CH:2]([CH3:1])[C:3](=[O:28])[NH:4][N:5]=2)([CH3:21])[CH2:18]1
Reactant: [BH3-]C#N
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CNC4)cc3N21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CN(C)C4)cc3N21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
A solution of 4-methyl-6-(3-methyl-azetidin-3-ylamino)-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.095 g, 57% purity, 0.15 mmol) and paraformaldehyde (0.015 g, 0.45 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated at 80° C. for 2 h. NaBH3CN (0.019 g, 0.30 mmol) was added and the reaction mixture was stirred at 80° C. for 0.5 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was washed with aqueous saturated Na2CO3 solution (2 mL). The aqueous phase was extracted with EtOAc (4×20 mL). The combined organic layer was dried, filtered and concentrated in vacuo to give crude 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 78% over two steps), which was used in the next step directly. LC/MS (Table 1, Method 2) Rt=0.924 min; MS m/z: 392 [M+H]+. A solution of 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 0.15 mmol) in ammonium hydroxide (25%, 5 mL) and dioxane (5 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 16) to give 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.022 g, 27%). LC/MS (Table 1, Method 4) Rt=1.722 min; MS m/z: 392 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-5-bromobenzothiazole (32.0 g), N-bromosuccinimide (25.1 g), carbon tetrachloride (700 ml) and a catalytic amount of benzoyl peroxide (0.2 g) was refluxed under irradiation by an UV lamp for 14 hours. The reaction mixture was cooled to room temperature, filtered to remove the precipitated succinimide and the filtrate was evaporated to dryness. The resulting solid was chromatographed over silica gel to obtain the product (7.8 g; m.p. 107° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])=[O:25]
Reactant: CCCCCCCC(=O)NCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCCOS(C)(=O)=O
Yield: 105.7 %

Procedure:
To a solution of 2.00 g (8.22 mmol) of N-(4-hydroxybutyl)caprylamide and 1.37 ml (9.86 mmol) of triethylamine in 50 ml of methylene chloride was added 0.76 ml (9.86 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.55 g of the desired compound (96.5% colorless powder), mp: 59.0°-60.0° C.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.CS(O[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[N:28]([C:31]2[S:32][C:33]([C:37](=[O:46])[NH:38][CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[C:34]([CH3:36])[N:35]=2)[CH:27]=[N:26]1)(=O)=O>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:32][C:33]([C:37]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:46])=[C:34]([CH3:36])[N:35]=3)[CH:27]=[N:26]2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 47, making variations as required to replace (4-fluorophenyl)methanamine with 4-fluoroaniline to react with 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate, the title compound was obtained as a colorless solid in 66% yield: mp 163-164° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.56 (br s, 1H), 8.51-8.41 (m, 1H), 8.22 (s, 1H), 7.71-7.62 (m, 1H), 7.23-7.19 (m, 1H), 691-6.75 (m, 3H), 6.54-6.47 (m, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-3.92 (m, 3H), 3.53-3.39 (m, 2H), 2.61 (s, 3H); MS (ES+) m/z 454.1 (M+1).