Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[N:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1nncc2ccccc12
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1ccc(N2CCN(c3nncc4ccccc34)CC2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 15.9 %

Procedure:
A mixture of 5.11 g (15 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 2.48 g (15 mmol) of 1-chlorophthalazine, 2.08 g (15 mmol) of powdered K2CO3 and 55 ml of absolute DMF was warmed to 85° C., and 346 mg of powdered K2CO3 were added at 85° C. with stirring in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (a total of 1.038 g, 7.51 mmol of K2CO3), and the mixture was stirred for a further 2 hours at 90° C. and 3 hours at 105° C. The DMF was then removed by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after through mixing, and the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue remaining (4.75 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.6 cm, height 43 cm) by elution with CH2Cl2 /C2H5OH mixtures with increasing C2H5OH content (1-10% by volume). The fractions in which, according to TLC, the required compound was concentrated were combined and evaporated. The crystalline residue produced (2.04 g) was boiled briefly with 15 ml of CH2Cl2, cooled in an ice bath, and filtered off under suction. 0.73 g of pure 1-(4-hydroxyphenyl)-4-(1-phthalazinyl)piperazine, melting point 244°-45° C., were thus obtained. The mother liquor was again purified by chromatography in analogous fashion to the first column chromatography on a silica gel/CH2Cl2 column (diameter 2.0 cm, height 22 cm). The concentrated product produced from this procedure was, like the first part, boiled briefly with 7 ml of CH2Cl2 and filtered off under suction when cool. A further 0.28 g of pure compound, melting point 244°-45° C., was obtained from this procedure. The total yield was 1.01 g=22% of theory;
Reaction SMILES: [CH2:1]([N:3]([CH3:18])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][C:12]=1[CH3:13])(=[O:6])=[O:5])[CH3:2].[NH2:19][C:20]1[C:25]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[NH:31][CH2:30][CH2:29]3)=[CH:24][C:23](Br)=[CH:22][N:21]=1>>[NH2:19][C:20]1[N:21]=[CH:22][C:23]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:18])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:24][C:25]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][CH2:30][CH2:29]2
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Reactant: CCN(C)S(=O)(=O)c1cnc([Sn](C)(C)C)cc1C
Product: CCN(C)S(=O)(=O)c1cnc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1C
Yield: 15.1 %

Procedure:
General method D was applied to N-ethyl-N,4-dimethyl-6-(trimethylstannyl)pyridine-3-sulfonamide (226 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N,4-dimethyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (41 mg, 33% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84-8.88 (m, 2H), 8.56 (s, 1H), 8.23 (s, 1H), 8.06 (br. s., 1H), 8.00 (d, J=7.8 Hz, 1H), 7.49-7.56 (m, 2H), 3.38-3.48 (m, 2H), 3.23 (q, J=7.0 Hz, 2H), 3.00 (t, J=6.3 Hz, 2H), 2.81 (s, 3H), 2.61 (s, 3H), 1.09 (t, J=7.0 Hz, 3H); MS (EI) m/z=452.5 [M+1]+.
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[OH:27]/[CH:28]=[C:29](/[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[N:39][CH:40]=1)\[C:30](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:29]([CH2:34][C:35]4[CH:40]=[N:39][CH:38]=[N:37][CH:36]=4)[C:28](=[O:27])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 27 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (450 mg, 0.826 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (321 mg, 1.652 mmol) and K2CO3 (228 mg, 1.652 mmol) in NMP (5 mL) was heated with a microwave reactor at 160° C. for 1.5 h. Purification via MDAP then afforded the title compound (120 mg, 22.25% yield). LCMS: rt=3.46 min, [M+H+]=539
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH2:34][CH2:35][Cl:36].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]([CH2:33][CH2:34][CH2:35][Cl:36])[C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)[nH]c2c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)n(CCCCl)c2c1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxylate (140 mg, 0.331 mmol) and 1-bromo-3-chloropropane (156 mg, 0.994 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydride (17 mg, 0.430 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl-1H-indole-6-carboxylate (167 mg, yield 100%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][C:54]1[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:51][CH2:52][CH2:53][C:54]2[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=2)=[O:27])=[CH:18]1
Reactant: Cn1cccc1CCN
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cccc1CCNC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (4 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.139 g, 1.03 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.199 g, 1.40 mmol). This mixture was stirred 2 hours and 0.16 g (1.3 mmole) of 2-(2-aminoethyl)-1-methylpyrrole was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, saturated aqueous sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4 and purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 67% ethyl acetate/hexane eluant). Concentration followed by drying under vacuum for 48 hours at 60° C. provided 0.301 g (59%) at product; 1H NMR (CDCl3) δ 1.49-1.60 (2H, m), 1.56 (3H, s), 1.70-2.00 (12H, m), 2.61 (2H, t, J 7 Hz), 3.23-3.55 (4H, m), 3.50 (3H, s), 4.82 (1H, br s), 5.20 (1H, br s), 5.76 (1H, br s), 6.00 (1H, t, J 3Hz), 6.34 (1H, br s), 6.53 (1H, br s), 6.97 (1H, br s), 7.09-7.19 (2H, m), 7.36 (1H, d, J 8 Hz), 7.59 (1H, d, J 8 Hz), 8.16 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 27.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.061 g, 0.14 mmol) obtained in step 2 and ethanesulfonamide (0.073 g, 0.70 mmol), the title compound (0.021 g, 27%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:37]([C:30]3[C:29]([NH2:28])=[CH:34][C:33]([C:35]#[N:36])=[CH:32][N:31]=3)=[O:38])[N:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)n2)CO[C@@]1(C)C(F)(F)F
Reactant: N#Cc1cnc(C(=O)O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@]1(C)C(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of [(2R,5R)-5-(6-amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (80 mg, 0.206 mmol), 3-amino-5-cyano-pyridine-2-carboxylic acid (40.3 mg, 0.247 mmol, Acid-4, HOAt (50.5 mg, 0.371 mmol) in DMF (1 ml) and EDC.HCl (59.2 mg, 0,309 mmol) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 and brine, and dried with MgSO4.H2O. The title compound was obtained after chromatography on silica gel (toluene/1-3% EtOAc) to give 71 mg of the title compound as a pale yellow solid slightly contaminated with some starting material. HPLC: RtH1=3.608 min; ESIMS: 534 [(M+H)+]; 1H-NMR (600 MHz, CDCl3): 10.92 (s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.82 (t, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 6.33 (br, 1H), 4.39 (d, 1H), 4.12 (d, 1H), 1.66 (s, 3H), 1.60 (s, 9H), 1.59 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH:6]([CH2:21][CH:22]=[NH:23])[S:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.N[C:25]1[CH:30]=CC=[CH:27][CH:26]=1>C(O)C>[OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH:6]([CH:21]2[CH:27]=[CH:26][CH:25]=[CH:30][C:22]2=[NH:23])[S:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3
Reactant: COc1cc2c(cc1OC)C1C(CO)CSC(CC=N)N1CC2
Reactant: Nc1ccccc1
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)CSC(C3C=CC=CC3=N)N1CC2
Yield: 62 %

Procedure:
3.4 g (0.01 mole) of 1-(hydroxymethyl)-4-(iminoethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H-[1,3]thiazino[4,3-a]isoquinoline are refluxed with 1.86 g (0.02 mole) of aniline in 30 ml of ethanol for 5 hours. The excess of ethanol and aniline is distilled off and crystallized from ethanol to yield the desired compound, melting at 187° to 189° C. Yield: 62%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:47]([NH:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)Nc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg, 0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL), triethylamine (19.3 μL, 0.138 mmol) and phenyl isocyanate (9.5 μL, 0.087 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (27.3 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][CH:14]([OH:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(O)CC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 3-bromo-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (1 g, 3.4 mmol, 1 equiv) in THF (30 mL) and DCM (20 mL) at 0° C. was added Dess-Martin reagent (2.9 g, 6.8 mmol, 2 equiv). The resulting mixture was stirred at rt for 3 h. After that, 60 mL of aq. Na2S2O3 was added. The mixture was extracted with ethyl acetate (3×100 mL), dried over Na2SO4. After filtration and concentration, 700 mg of the desired product was obtained, which was directly used for the next step without further purification. MS (ESI): 293, 295 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](Cl)=[N:6][N:7]=1.[C:18]([NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[C:18]([NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:5]2[N:4]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:3]3[C:2]([Cl:1])=[N:7][N:6]=2)[CH:31]=1)(=[O:25])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1nnc(Cl)n2ccc(-c3ccccc3)c12
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Temperature: 100 °C
Yield: 31.9 %

Procedure:
To a solution of 1,4-dichloro-8-phenylpyrrolo[1,2-d][1,2,4]triazine (0.150 g, 0.568 mmol) in 1,4-dioxane (15 mL) and water (4 mL) was added N-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (prepared according to WO 2011/028741) (0.232 g, 0.682 mmol) followed by potassium carbonate (0.235 g, 1.70 mmol) The reaction mixture was purged with N2 for 30 min. Bis(triphenylphosphine)palladium(II) chloride (20.0 mg, 0.0280 mmol) was added to the reaction mixture and heated at 100° C. in a sealed tube for 12 h. The reaction mixture was allowed to cool and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure to give a residue which was suspended in water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 30% EtOAc/hexanes) to yield N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (80.0 mg, 32.0%) as a pale yellow liquid. LCMS Method B-3: retention time 2.07 min, [M+1]=442.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.19 (s, 9H), 7.23 (d, J=3.2 Hz, 1H), 7.42-7.55 (m, 5H), 7.90 (d, J=3.2 Hz, 1H), 8.00 (br s, 1H), 8.73 (t, J=2.0 Hz, 1H), 9.17 (d, J=2.0 Hz, 1H), 9.22 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:39])=[C:7]([CH:38]=1)[CH2:8][N:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:23]([CH3:29])=[N:24][CH:25]=[N:26][C:27]=2[CH3:28])=[O:21])[CH2:12][CH2:11]1)#[N:2].Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:9]([CH2:8][C:7]2[CH:38]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[F:39])[CH:10]2[CH2:11][CH2:12][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24][C:23]=3[CH3:29])=[O:21])[CH2:14][CH2:15]2)=[CH:36][CH:35]=1
Reactant: COC(=O)CBr
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cc(C#N)ccc2F)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
A mixture of COMPOUND 233 (91 mg, 0.17 mmol), methyl bromoacetate (29 mg, 0.19 mmol) and K2CO3 (47 mg, 0.34 mmol) in DMF (1.7 mL) were heated at 80° C. for 25 h to give COMPOUND 237 as a yellow foam (90 mg, 87%) after work-up and purification. 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.9 Hz), 1.58 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.68-2.88 (m, 3H), 3.31-3.53 (m, 2H), 3.78 (s, 3H), 3.82 (m, 1H), 3.93 (s, 2H), 4.54 (s, 2H), 6.57 (m, 2H), 6.76 (m, 2H), 7.17 (m, 1H), 7.52 (m, 2H), 8.28 (m, 1H), 8.83 (s, 1H). ES-MS m/z 603 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[Cl:24][S:25]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([F:1])=[CH:3][C:4](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:6]=2[F:15])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccccc2)c(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1

Procedure:
To a solution of (E)-ethyl 3-(3,5-difluoro-4-phenoxyphenyl)-2-methylacrylate (intermediate 41.2) (1 g, 3.14 mmol) in DCM (3.14 mL) under N2 was added chlorosulfonic acid (0.419 mL, 6.28 mmol) dropwise. After 1 hour an additional 0.209 mL chlorosulfonic acid was added. After an additional hour the reaction mixture was quenched with ice-water and extracted into EtOAc (2×200 mL). The combined organic layers were dried briefly (<10 min) over Na2SO4 and concentrated to recover 1.283 g of the title compound (98%) as a yellow oil.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[CH2:22][CH2:23][S:24][C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=6)=[CH:28][C:26]=5[CH:27]=4)=[O:20])=[CH:14][CH:13]=3)[CH3:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][C:25]3[S:24][CH2:23][CH2:22][C:21]([C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:9]([CH3:10])[CH:6]5[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]5)=[CH:13][CH:14]=4)=[O:20])=[CH:27][C:26]=3[CH:28]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCS3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCS3)cc1
Reaction time: 66 h
Yield: 65.3 %

Procedure:
To a solution of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (130 mg) in THF (15 ml) was added at room temperature 6N hydrochloric acid (1 ml), and the mixture was stirred for 66 hours. To the mixture was added sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting solid was recrystallized from ethyl acetate/hexane to give pale yellow crystals of 7-(4-methoxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl) aminomethyl]phenyl]-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 284) (78.3 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29].[CH3:30]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:30])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3n(C)c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)COc1cccc(C=CC(=O)c2c(OC)c3ccccc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.55 g of 1-methyl-4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone and 5 ml of hexamethylphosphoramide was added 67 mg of sodium hydride (60% oily) under ice-cooling. After stirred at room temperature for 1 hour, 0.2 ml of dimethyl sulfate was added, and this was stirred at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. After dried over anhydrous sodium sulfate, the extract was concentrated under reduced pressure, and the resulting residue was subjected to silica column gel chromatography to obtain 0.21 g of 1-methyl-4-methoxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (60e)] as a yellow crystal.