Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[C:12]([O:11][C:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:19][CH:16]2[CH2:18][CH2:17]2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1C[C@H](CNC2CC2)[C@H](F)C1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
(3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCN(S(C)(=O)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Methanesulfonyl chloride 335 (41 mg, 0.3665 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H pyrrolo[2,3-b]pyridine 336. 1H NMR (400 MHz, DMSO) δ: 12.05 (s, 1H), 8.55 (d, 1H), 8.30 (s, 1H), 8.19 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.24 (m, 2H), 4.33 (m, 1H), 3.65 (d, 2H), 3.60 (s, 3H), 2.94, (m, 2H), 2.92 (s, 3H), 2.03 (m, 2H), 1.98 (m, 2H) and MS ES+488.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[C:39]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-(methylsulfonyl)phenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O5S, 410.1; m/z found, 411.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.99 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.31-8.27 (m, 3H), 8.18 (d, J=8.5 Hz, 1H), 7.97 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 3.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)ccc1F

Procedure:
Example 109 was prepared from bis(4-methylphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.30–8.13 (m, 1H), 8.08–7.92 (br, 1H), 7.43–6.89 (m, 9H), 6.76–6.61 (br, 1H), 4.98–4.79 (br, 1H), 4.70 (s, 1H), 3.39–3.16 (m, 4H), 2.83–2.63 (m, 2H), 2.63–2.47 (m, 1H), 2.45–2.12 (m, 4H), 2.27 (s, 6H), 2.02–1.64 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 544.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([C:21]#[N:22])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncc(OCc2ccccc2)cc1Br
Temperature: 100 °C

Procedure:
To a solution of 53-(benzyloxy)-5-bromopyridine 1-oxide (from step 2) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give a mixture of two benzoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 16 h
Yield: 44 %

Procedure:
(R)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride salt (387 mg) (amine free base prepared in U.S. Pat. No. 5,545,735) was added to a mixture of tetrahydrofuran (40 mL), 5-chloroindole-2-carboxylic acid (356 mg), 1-hydroxy-7-azabenzotriazole (272 mg), and 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (382 mg) at room temperature. Diisopropylethylamine (202 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was redissolved in ethyl acetate (100 mL). This was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with 20% methanol in diethyl ether (20 mL four times). Drying under vacuum provided pure title compound (283 mg). HPLC/MS [M+H]+, 354.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][O:14]S(C)(=O)=O)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([N:40](C2C=CC(F)=CC=2)[C:41]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)=[O:42])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33](O)=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[C:1]([O:9][C:10]1([CH2:13][O:14][C:33]2[CH:32]=[C:31]3[C:36]([C:27]([O:26][C:25]4[CH:24]=[CH:23][C:22]([NH:40][C:41]([C:43]5([C:46](=[O:47])[NH2:48])[CH2:45][CH2:44]5)=[O:42])=[CH:21][C:20]=4[F:19])=[CH:28][CH:29]=[N:30]3)=[CH:35][C:34]=2[O:37][CH3:38])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(OC(=O)c2ccccc2)CC1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(N)=O)CC4)cc3F)ccnc2cc1OCC1(OC(=O)c2ccccc2)CC1
Temperature: 45 °C
Yield: 69 %

Procedure:
To a mixture of 1-((methylsulfonyloxy)methyl)cyclopropyl benzoate (801 mg, 2.97 mmol) and N-(3-fluoro-4-(7-hydroxy-6-methoxy quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1 g, 1.98 mmol) in DMA (5 mL) were added Cs2CO3 (1.93 g, 5.94 mmol, Aladdin). The reaction was heated at 45° C. overnight. The solvent was then removed in vacuo, and the residual was diluted with CHCl3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residual was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a light yellow solid (800 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:19](O)(=[O:21])[CH3:20].[OH-].[Na+]>C(OC(=O)C)(=O)C>[C:19]([O:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5])(=[O:21])[CH3:20]
Reactant: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(OC(C)=O)c(C(=O)c2ccc(Cl)cc2)c1

Procedure:
2-Hydroxy-5-ethyl-4'-chlorobenzophenone (3 g), in acetic anhydride (10 ml) and acetic acid (1 ml) were refluxed for 3.5 hours, and allowed to cool. The mixture was poured into dilute NaOH solution and extracted with chloroform. The chloroform was washed with 10% NaHCO3 solution (50 ml), dried (MgSO4) and evaporated to leave an oil which was distilled, b.p. 160°-165° C. at 3.5 mm/Hg (2.3 g) to give the desired product.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([P:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>CC(C)=O>[CH2:17]([P:12]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:13][CH2:14][CH2:15][CH3:16])=[C:2]1[CH2:3][C:4](=[O:5])[O:6][C:1]1=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Product: CCCCP(CCCC)(CCCC)=C1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Maleic anhydride (9.81 g; 0.1 mole) in 25 ml acetone and tri-n-butylphosphine (20.23 g; 0.1 mole) in acetone were blended at 0°-5° C. under a blanket of dry nitrogen. The resulting red solution was stirred for 1 hour at room temperature and then placed under vacuum to remove the bulk of the acetone solvent. The resulting red viscous liquid gave 15 g of yellow-brown crystalline product. This solid was separated by filtration and washed with cold acetone giving a yellow crystalline product which melts at 70° C., resolidifies and melts again at 85° C. with gassing. The infrared (IR) and nuclear magnetic resonance (NMR) spectra and elemental analysis of the product were consistent with a compound represented by the structure ##STR7##
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)=[O:13].O>CS(C)=O>[C:1]1([S:7]([C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH3:11])=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 87.3 %

Procedure:
Preparation 1 of WO 96/262,196 described the reaction of sodium benzenesulfinate (43 g, 0.26 mol) and 4-fluoroaceto phenone (30 g, 0.22 mol) at 130° C. in dimethyl sulfoxide (200 mL) for 48 hours. The mixture is then poured into 1000 mL of water. The solid formed is colled and dried to give 50 g of 1-(4-phenylsulfonyl-phenyl)-ethanone. This solid is suspended in ethanol (350 mL), heated to 60° C. and treated as described in J. Med. Chem., 34, 3295 (1991) to give 4-phenylsulfonyl benzoic acid melting at 269–271° C. A suspension of 4-phenyl sulfonylbenzoic acid (15 g, 0.57 mol) in toluene (50 mL) is treated with thionyl chloride (25 mL). A few drops of N,N-dimethylformamide are added and the suspension is heated to 70° C. for three hours. The solution is concentrated to give the title intermediate compound which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:16][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])[CH3:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][NH:16][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CN[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)NC)cc2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
[(1R)-1-(4-Bromophenyl)-2-(4-morpholinyl)ethyl]methylamine (100 mg, 0.29 mmol) was dissolved in EtOH (5 mL) at room temperature with magnetic stirring. The resulting solution was treated with {4-[(ethyloxy)carbonyl]phenyl}boronic acid (62.9 mg, 0.32 mmol) followed by K2CO3 (122.3 mg, 0.88 mmol) and PdCl2(dppf)2.CH2Cl2 (12.0 mg, 0.015 mmol). The reaction mixture was maintained at 80° C. for 16 h. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated and then partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered and then concentrated. The residue was purified by silica gel chromatography (40 g Redisep column, silica, 40 um, 60 Å, 40 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 2% for 20 min, 5% for 20 min, detection at 254 nm) to give the title compound as a yellow oil (59.7 mg, 48% yield). MS (ES) m/e 369 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2]1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH:30]([CH2:33][OH:34])[O:31][CH3:32]>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH:30]([O:31][CH3:32])[CH2:33][O:34][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(CO)COC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 58.7 %

Procedure:
The above epoxide (17) (4.75 g, 16 mmoles) was reacted with 6.1 g (32 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 4.57 g of the desired compound as a colorless wax.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8](/[C:9](=[C:15](/[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)\[C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)/[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.O>C(O)C>[C:3]([C:5]1[CH:13]=[C:12]2[C:8](/[C:9](=[C:15](/[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[CH:29][CH:28]=3)\[C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)/[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C)CC2)cc1)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4cc(C(=O)O)ccc43)c3ccc4c(c3)OCCO4)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.36 g of 6-methoxycarbonyl-3-(Z)-{1-[4-(1-methylpiperazin-4-yl-methyl)-phenylamino]-1-(3,4-ethylenedioxyphenyl)-methylene}-2-indolinone (Example 1.57) in 5 ml of ethanol are combined at 80° C. with 1.6 ml of 1 molar sodium hydroxide solution and stirred for 2 hours at 80° C. After the addition of 1.6 ml of 1 molar hydrochloric acid and 2 ml of water the mixture is stirred overnight without any heating. The precipitate formed is suction filtered, washed successively with water, a little ethanol and finally diethyl ether and then dried at 80° C.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9])([O:3][CH3:4])=[O:2].OO.C(=O)(O)[O-:14].[Na+]>>[CH3:4][O:3][C:1](=[O:2])[CH2:5][CH2:6][CH:7]1[O:10][CH:8]1[CH:9]=[O:14]
Reactant: COC(=O)CCCC(C)=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: COC(=O)CCC1OC1C=O

Procedure:
Mono-methyl succinate (1), wherein alk is methyl, was chlorinated with oxalyl chloride in dimethyl formamide and methylene chloride to afford 3-carbomethoxypropionyl chloride (2). Compound (2) was catalytically hydrogenated over palladium-charcoal catalyst in the presence of 2,6-lutidine to yield 3-carbomethoxypropionaldehyde (3) which was reacted with formylmethylene triphenylphosphorane under Wittig reaction conditions to obtain 5-carbomethoxy-2-pentanal (4). Compound 4 was epoxidized with aqueous hydrogen peroxide in the presence of 1N sodium bicarbonate to afford methyl-4,5-epoxy-6-oxohexanoate (5). Compound (5) was reacted with tridecyltriphenylphosphonium ylid to give methyl-4,5-epoxy-6(Z)-nonadecenoate (6).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2]
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2C#N)ccn1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4cccnn4)cn3)cc2C#N)ccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetic acid 111-10 (50 mg, 0.2 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 181 as white solid. MS m/z 407.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.13 (s, 1H), 9.22 (dd, 1H), 9.13 (d, 1H), 8.59 (d, 1H), 8.56 (dd, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.83-7.79 (m, 2H), 7.67 (d, 1H), 7.48 9s, 1H), 7.42 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][C:18](O)([CH3:20])[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][CH3:23])[N:7]=1.C([N:32](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C1COCC1>[NH2:32][C:18]1([CH3:20])[CH2:19][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:22][CH3:23])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:2]=3[F:1])[N:11]=2)(=[O:15])=[O:14])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC(C)(O)C2)nc(SCc2cccc(F)c2F)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CC(C)(N)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
A solution of N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-3-hydroxy-3-methylazetidine-1-sulfonamide (the product from example 129, 0.2 g) in THF (5 ml) was treated with diisopropylethylamine (0.45 ml) and methanesulfonylchloride (0.11 ml) under nitrogen.
Reaction SMILES: C(O)(=[S:3])C.[H-].[Na+].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:34][CH2:33]2)=[O:31])[CH2:13]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[SH:3][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:36][CH2:37]2)=[O:31])[CH2:13]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(O)=S
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
51 μl of thioacetic acid were added, whilst ice-cooling, to a suspension of 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 1.4 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 340 mg of (2S,4R)-4-methanesulfonyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step 90(c)(i) above] in 2 ml of dry N,N-dimethylformamide was then added to the mixture, and the mixture was stirred at between 80° C. and 90° C. for 4 hours. At the end of this time, the temperature of the reaction mixture was allowed to reduce to room temperature, after which the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was worked up and purified according to the procedure described in step 90(b)(i) above, to give 166 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(ii) above.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[NH2:28][C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1ccccc1N
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (26.76 g; 151 mmol), obtained as described above for Intermediate 7 step 1, in anhydrous DCM (270 ml) was treated dropwise over 25 minutes with a solution of o-toluidine (13.6 ml; 126.0 mmol) and DIEA (43.4 ml; 252 mmol) in anhydrous DCM (100 mL). At the end of addition, the reaction mixture was washed with water then brine, dried over MgSO4, filtered and dried under vacuum to afford the title compound used without further purification as a brown solid.