Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH:21]=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]([C@H:18]1[CH2:19][CH2:20][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[CH2:23]
Reactant: COC(C)(C)C
Reactant: O=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
A suspension of 0.977 g of methyltriphenylphosphonium bromide in 12 ml of tert.-butyl methyl ether was treated with 0.308 g of potassium tert.-butylate while stirring and gassing with nitrogen and stirred at room temperature for a further 1.5 hours. The yellow suspension was treated dropwise at 2° C. within 15 minutes with a solution of 0.439 g of trans-4-(3',4'-difluoro-4-biphenylyl)cyclohexanecarboxaldehyde in 12 ml of tert.-butyl methyl ether, stirred at room temperature for a further 1.5 hours and concentrated in a vacuum. Purification of the residue by chomatography on silica gel with methylene chloride and subsequent two-fold recrystallization from hexane gave 0.118 g of pure 4-(trans-4-vinylcyclohexyl)-3',4'-difluorobiphenyl; m.p. (C-N) 97.0° C., cl.p. (N-I) 84.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:18](=[O:19])[C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:13])[CH3:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
0.4 mmol 6-chloro-1-isoindolinone (CAS: 58083-59-3) was dissolved in 3 ml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example B1 and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature, then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated. Chromatography (silica gel; ethyl acetate/heptane) gave the title compound as a slightly yellowish solid. Yield=55%. MS (m/e): 408.2 [M+H]+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=2)(=O)=O)=CC=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cn2)cc1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4ccc(F)cn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 46 starting from N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.085 g, 0.31 mmol) (Example 39d) and 2-(5-fluoropyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.092 g, 0.31 mmol). The product was purified by preparative HPLC to give the title compound. Yield: 0.049 g (39%).
Reaction SMILES: Cl.C([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][C:8](=O)[CH2:9][CH2:10]2)[CH2:5]1)C.[CH2:23]([N:25]([CH2:40][CH3:41])[C:26](=[O:39])[C:27](=[N:31]NC1C=CC=CC=1)[C:28](=O)[CH3:29])[CH3:24].[CH3:42]C(O[Na])=O>[Zn].C(O)(=O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[C:26]([C:27]1[NH:31][C:8]2[CH2:9][C@@H:12]3[C@:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)([CH2:10][CH2:42][N:4]([CH3:5])[CH2:13]3)[CH2:6][C:7]=2[C:28]=1[CH3:29])=[O:39])[CH3:41]
Reactant: CC(=O)O[Na]
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CCC(=O)C[C@H]2C1
Reactant: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@]1(c3cccc(OC)c3)CCN(C)C[C@@H]1C2
Yield: 16.8 %

Procedure:
0.9 g (2.9 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-7-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride (J. Med. Chem., 35, 48, 1992), 0.9 g (3.5 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.28 g (3.5 mmol) of CH3COONa, 0.87 g (13.3 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (CH2Cl2 /MeOH/conc. NH4 OH 86: 10:0.6; Rf=0.27), to yield 0.2 g of the title compound.M.p.=153°-155° C. dec.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=[O:17])(=O)=O.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:11]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=[O:17])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=Cc1ccc(OCCc2ccccc2)c(COc2ccccc2)c1
Reaction time: 48 h

Procedure:
Cesium carbonate (226 mg, 0.69 mmol, 1.5 eq) was added to a stirred solution of 3-[[(methylsulfonyl)oxy]methyl]-4-(2-phenylethoxy)benzaldehyde (155 mg, 0.46 mmol, 1 eq) and phenol (175 mg, 1.86 mmol, 4 eq). The reaction mixture was stirred for 48 h, then partitioned between diethyl ether (50 mL) and water (50 mL). The two layers were separated and the organic layer washed with water (2×100 mL), 1M sodium hydroxide (100 mL), brine (100 mL) and then dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel. Elution with dichloromethane gave a gummy solid, which when triturated with ether crystallized to a white powder (105 mg, 68%). RF (petroleum ether:diethyl ether, 1:1) 0.40. 1H NMR (CDCl3) δ 9.90 (s, 1H, O═C—H), 8.04 (s, 1H, ArH), 7.84 (d, 1H, J 8.4 Hz, ArH), 5.08 (s, 2H, CH2OPh), 4.34 (t, 2H, J 6.5 Hz, OCH2CH2Ph), 3.16 (t, 2H, J 6.5 Hz, OCH2CH2Ph).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15]OS(C1C=CC(Br)=CC=1)(=O)=O)[N:11]=[CH:10][CH:9]=[CH:8]3.[C:27]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:38][CH2:39][CH2:40][NH2:41])#[N:28].[CH2:42](N(CC)CC)C>CS(C)=O>[CH3:42][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3][CH:2]([CH2:15][NH:41][CH2:40][CH2:39][CH2:38][C:32]4[C:31]5[C:35](=[CH:36][CH:37]=[C:29]([C:27]#[N:28])[CH:30]=5)[NH:34][CH:33]=4)[O:1][C:6]3=2)[N:11]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2[nH]cc(CCCN)c2c1
Reactant: O=S(=O)(OC[C@H]1COc2ccc3ncccc3c2O1)c1ccc(Br)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCCc1c[nH]c2ccc(C#N)cc12)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (1.13 g, 2.5 mmol), 3-(5-cyano-1H-indol-3-yl)propylamine (0.65 g, 3.2 mmol) and triethylamine (0.7 mL, 5.0 mmol) in dimethylsulfoxide (40 mL) was heated at 90° C. under nitrogen for 16 hours. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.54 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid, m.p. 170-174° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH3:9])[N:5]=[C:4]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[N:3]=1.[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CC#N.C(O)(C(F)(F)F)=O>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6]2[N:7]=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]3)[N:3]=[C:4]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: OCCN1CCNCC1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(Cl)nc(NCCc2ccc(O)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(CCO)CC2)n1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield via the procedure outlined for Example 14 using 4-[2-({4-chloro-6-[[3-(4-chlorophenyl)propyl](methyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]phenol and 1-(2-hydoxyethyl)piperazine to give a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.23 (d, 2H, J=8.0), 7.10 (d, 2H, J=8.0), 7.09 (d, 2H, J=8.0), 6.67 (d, 2H, J=8.0), 4.88(s, br, 1H), 3.80-3.55 (m, 9H), 3.05 (s, br, 3H), 2.77 (t, 2H, J=6.6), 2.57-2.48 (m, 8H), 1.86 (s,br, 2H); low-resolution MS (ES+) m/e 526 (MH+); RP-HPLC (Capcell Pak C-18 25 cm×4.6 mm; 0-95% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=11.20 min, 99% purity.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[O+]=1.[PH3:36]>C(O)CCC>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[P:36]=1
Reactant: P
Reactant: Cc1cc(C)c(-c2cc(-c3ccccc3)cc(-c3cc(C)c(C)cc3C)[o+]2)cc1C
Agent: F[B-](F)(F)F
Solvent: CCCCO
Product: Cc1cc(C)c(-c2cc(-c3ccccc3)cc(-c3cc(C)c(C)cc3C)p2)cc1C

Procedure:
2.1 g (4.4 mmol) of 2,6-bis(2,4,5-trimethylphenyl)-4-phenylpyrylium tetrafluoroborate in 150 ml of n-butanol were used as starting material. The autoclave product obtained after the reaction with PH3 was evaporated to about 50 ml under reduced pressure at about 80° C. The solid which precipitated was filtered off with suction, washed with n-pentane and subsequently dissolved in toluene. The toluene solution was then washed with water until the aqueous phase was neutral. After removing the solvent and washing with a little n-pentane, the residue was dissolved in dichloromethane. The resulting solution was diluted with methanol and then evaporated under reduced pressure at 30° C. until a solid precipitated. The solid was filtered off with suction, washed with a little n-pentane and subsequently dried in a high vacuum. Yield: 0.8 g (45%) of light-yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.Cl.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>O>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[OH:31])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: CS(=O)c1nc2ccc(Cc3cnc4cccnn34)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
A stirred mixture of 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (260 mg, 0.79 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol hydrochloride (360 mg, 2.38 mmol), DIEA (408 mg, 3.16 mmol) and NMP (10 mL), was heated at 140° C. for 48 h. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 10% MeOH in DCM to afford a solid. The solid was further purified by recrystallization from a 10:1 mixture of DCM: MeOH to afford (1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 27%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (dd, J=4.5, 1.5 Hz, 1H), 8.10 (dd, J=9.3, 1.5 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.19 (m, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.32 (s, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 2.04 (m, 1H), 1.88 (m, 1H), 1.59-1.65 (m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: CC(C)=O.[CH2:5]([O:7][C:8]([C:10]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15](Cl)=[C:16]([F:21])[CH:17]=2)[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=1)=[O:9])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([SH:35])[CH3:34]>O.C(OC(=O)C)C>[CH2:5]([O:7][C:8]([C:10]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([S:35][CH2:33][CH3:34])=[C:16]([F:21])[CH:17]=2)[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCS
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(SCC)c(F)cc2c1=O
Yield: 79 %

Procedure:
Acetone (90 mL) was added to a mixture of 1.96 g (6 mmoles) of 6-fluoro-7-chloro-1-(1,1-dimethylethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 2.5 g (18 mmoles) of anhydrous potassium carbonate. To this suspension was added 1.33 mL (18 mmoles) of ethanethiol. After heating to reflux for 2.5 hours, the solvent was eliminated in vacuo. The residue was taken up with ethylacetate and water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The resulting solid was treated with ether to give 1.67 g of titled compound. MP 159°-60° C.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41]S(C2C=CC=CC=2)(=O)=O)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:28]=1)#[N:26]>O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41][C:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]=2[NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]([F:18])[F:3])[CH:6]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:52])=[O:53])[CH:28]=1)#[N:26]
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)F)c2)CCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 106 mg, 2.67 mmol) is added in portions to a mixture of 3-(3-(difluoromethyl)phenylamino)cyclopent-2-enone (intermediate 5, 595 mg, 2.66 mmol) and 2-methyltetrahydrofuran (20 mL). After 2 h tert-butyl (4-cyano-2-(methyl-sulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 1.00 g, 2.20 mmol) is added, and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with 2-methyltetrahydrofuran. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 665 mg; ESI mass spectrum [M+H]+=532; Retention time HPLC: 1.13 min (Z018_S04).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].[N:30]1([C:35]2[CH:36]=[C:37]([C:41]3[O:46]C(C)(C)[O:44][C:43](=O)[CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][N:32]=[CH:31]1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:43](=[O:44])[CH2:42][C:41]([C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH:36]=1)=[O:46])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 69.2 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (196 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (229 mg, 0.85 mmol) according to the general procedure K. Obtained as a yellow solid (209 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C.Cl>CN(C=O)C.ClCCl>[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9]1
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccc(OCCC2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 96.2 %

Procedure:
Oxalyl chloride (8.64 mL, 99.0 mmol) and one drop of DMF were added to a solution of dichloromethane (30 mL) containing 4-(2-cyclopropylethoxy)benzoic acid (9.28 g, 45.0 mmol) prepared in Example 9 (9a) under ice-cooling. The mixture was stirred at room temperature for 1.75 hours, and the solvent was evaporated. Then, the resulting residue was suspended in THF (3 mL). This suspension added dropwise to a 50% THF aqueous solution (120 mL) containing glycine (4.41 g, 58.7 mmol) and triethylamine (15.7 mL, 112 mmol) under ice-cooling. The mixture was stirred at room temperature for 1.5 hours, and then 10% hydrochloric acid (40 mL) was added thereto under ice-cooling. The produced precipitate was collected by filtration, washed with water, and dried by heating under reduced pressure to give 11.4 g of the title compound (powder, yield: 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:40]1[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (9.24 g, 18 mmol), 4-methylphenylboronic acid (2.94 g, 21.6 mmol) and sodium carbonate (2.86 g, 27 mmol) in toluene (50 ml)-methanol (10 ml)-water (10 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.04 g, 1 mmol) and the mixture was refluxed under heating under an argon, atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.91 g, 84.4%) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)#[N:2].C(=O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].[H-].[Na+]>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][CH:35]=1)(=[O:40])=[O:41])=[O:9])#[N:2]
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1ccc(OCc2ccsc2)cc1OC(C(=O)O)c1ccccc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2cc(OCc3ccsc3)ccc2C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 2 (0.73 g) in dry dichloromethane (50 ml) was treated with N,N' carbonyidilmidazole (0.36 g) and stirred at 25° C. for 2 hours, when evolution of carbon dioxide was complete. A solution of 4-isopropylbenzenesulphonamide (0.60 g) in dry dimethylformamide (20 ml) was treated with sodium hydride (0.13 g, 60% dispersion in mineral oil) and stirred at 25° C. for 2 hours. This solution was then treated dropwise with the solution of acylimidazole prepared above and stirring was continued at 25° C. for 8 hours. The reaction mixture was evaporated, the residue diluted with water (50 ml) and extracted twice with ethyl acetate. The extracts were washed with water, dried and evaporated to give an orange oil which was purified by flash chromatography on silica eluting with ether. Fractions homogenous in the required product were combined and evaporated. The residual pale yellow solid (0.35 g) was recrystallized from a mixture of ethyl acetate and pentane affording the title compound (0.20 g) as colourless crystals, m.p. 187-189° C. [Elemental analysis:- C,63.7; H,4.79; N,5.12%. Calculated:- C,63.7; H,5.17; N,5.17%].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[CH3:36][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([CH3:38])([CH3:37])[C:24]([OH:39])=[O:23])[CH:32]=[C:31]([CH3:33])[C:30]=1[C:34]1[NH:21][C:20]2[CH:19]=[CH:18][C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)ccc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide (from Example 6-36) and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-29. 1N NMR (400 MHz, MeOD): δ 9.20 (s, 1H), 8.68 (d, 1H), 8.43 (s, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 7.19 (s, 2H), 3.00 (s, 2H), 2.27 (s, 6H), 1.29 (s, 6H). MS (m/z) 511.2 (M+1); Retention time: 1.20 min (Method 10).