Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[O:9][C:8]([C:10]([Cl:12])=[O:11])=[N:7][N:6]=1)([CH3:3])[CH3:2].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>>[ClH:12].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:10]([C:8]3[O:9][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6][N:7]=3)=[O:11])[CH2:30][CH2:29]2)[N:15]=1
Reactant: CC(C)Sc1nnc(C(=O)Cl)o1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)c4nnc(SC(C)C)o4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from 5-isopropylthio-1,3,4-oxadiazole-2-carbonyl chloride (1.54 g., 7.5 mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.1 g., 7.5 mmole) following the procedure of Example 1. The product had a M.P. of 260°-263° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]#[CH:20])[CH:18]=1)[CH3:11].C(N(C(C)C)CC)(C)C.[C:31]1([CH:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:38]2[CH2:41][CH:40]([N:42]=[N+:43]=[N-:44])[CH2:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.[Cu](I)I>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]2[N:44]=[N:43][N:42]([CH:40]3[CH2:41][N:38]([CH:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:39]3)[CH:20]=2)[CH:18]=1)[CH3:11]
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C#Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Agent: I[Cu]I
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1cc(-c2cn(C3CN(C(c4ccccc4)c4ccccc4)C3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-ethynyl-2-aminopyridine (4.2 g, 12.62 mmol) was dissolved in methanol (40 mL), and diisopropylethylamine (8.36 g, 64.78 mmol), copper iodide (62 mg, 0.33 mmol) and 1-(diphenylmethyl)-3-azidoazetidine (3.34 g, 12.62 mmol) were added successively. The reaction was stirred overnight at room temperature. TLC test showed that the raw materials were completely reacted. The resultant mixture was concentrated under reduced pressure;
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.[OH-].[Na+]>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (50 g, 114.5 mmol, 1 equiv) and methanol (750 mL, 15 volumes) was slowly added 1 N sodium hydroxide (220 mL, 4.4 volumes). After stirring at room temperature for 2 hours, the reaction was concentrated in vacuo. Water (750 mL) was added to the residue and the pH was adjusted to 5.0 using 1 N hydrochloric acid (250 mL). The resulting slurry was stirred for 30 minutes and the precipitated solids were collected by filtration and dried in vacuo and then dissolved in methanol (75 mL) and ethyl acetate (675 mL). The solution was dried over sodium sulfate and filtered, and concentrated in vacuo. The residue was slurried in ethyl acetate (250 mL). The solids were collected by filtration to give 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (28.1 g, 60%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([CH:10]=O)[CH2:7]1.[CH3:22][NH:23][C:24]1[CH2:28][S:27][C:26](=[O:29])[N:25]=1.CC(C)([O-])C.[K+].O>C(O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8](/[CH:10]=[C:28]2/[C:24]([NH:23][CH3:22])=[N:25][C:26](=[O:29])[S:27]/2)[CH2:7]1
Reactant: O=CC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Reactant: CNC1=NC(=O)SC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CNC1=NC(=O)S/C1=C\C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Yield: 9.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azetidine-3-carbaldehyde (90 mg) and 4-(methylamino)-1,3-thiazol-2(5H)-one (38 mg) in ethanol (3 mL) was added potassium tert-butoxide (32 mg) at room temperature, and the mixture was stirred with heating under reflux for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:71]([S:73][CH2:74][CH2:75][NH2:76])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:76][CH2:75][CH2:74][S:73][CH2:71][CH3:72])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCSCCN
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(ethylthio)ethyl]amine hydrochloride (14.2 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (7 mg, 23%). LC-MS m/z 607 (M+H)+.
Reaction SMILES: CO[C:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].Cl.[CH:18]([NH:21][NH2:22])([CH3:20])[CH3:19].C(N(CC)CC)C>C(O)C>[NH2:6][C:5]1[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: COC(Cc1cccc(Br)c1)=C(C#N)C#N
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nc(Cc2cccc(Br)c2)c(C#N)c1N
Yield: 87.3 %

Procedure:
Compound 33 (3.124 g, 11.3 mmol), isopropylhydrazine hydrochloride (1.27 g, 11.5 mmol) (purchased from Ryan Scientific) and triethylamine (6.40 mL, 46.0 mmol) were allowed to react in ethanol (75 mL) at room temperature for 1 hr. After concentrating the reaction mixture, it was purified by silica chromatography using a chloroform/methanol solvent system (methanol gradient increased with time from 0-10%). The relevant fractions were concentrated in vacuo to yield a yellow powder (3.15 g, 87% yield): 1H NMR (400 MHz, DMSO) δ 7.41 (m, 2H), 7.26 (td, J=7.7, 1.2, 1H), 7.21 (dt, J=7.7, 1.3, 1H), 6.50 (s, 2H), 4.38 (hept, J=6.5, 1H), 3.81 (s, 2H), 1.27 (d, J=6.5, 6H); 13C NMR (100 MHz, DMSO) δ 151.01, 150.15, 141.24, 131.05, 130.53, 129.16, 127.45, 121.55, 115.16, 71.77, 47.24, 32.88, 21.35; [M+H]+ calculated for C14H15BrN4 319.0, 321.0 found 318.9: 321.0.
Reaction SMILES: [CH:1]12[CH2:8][N:7]([C:9](OC(C)(C)C)=O)[CH2:6][CH:5]1[CH2:4][CH2:3][NH:2]2.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[N:34]=[C:24]2[N:25]=[C:26](S(C)(=O)=O)[N:27]=[C:28]([NH2:29])[N:23]2[N:22]=1.CCN(CC)CC.[Cl:42][C:43]1[CH:50]=[CH:49][C:46](CCl)=[CH:45][CH:44]=1>CC#N>[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:9][N:7]2[CH2:6][CH:5]3[CH:1]([N:2]([C:26]4[N:27]=[C:28]([NH2:29])[N:23]5[N:22]=[C:21]([C:17]6[O:16][CH:20]=[CH:19][CH:18]=6)[N:34]=[C:24]5[N:25]=4)[CH2:3][CH2:4]3)[CH2:8]2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCC3CN(Cc4ccc(Cl)cc4)CC32)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate (0.5 mmol; see U.S. Pat. No. 5,071,999) was added to a mixture of 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.5 mmol, 1 eq.; see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and Et3N (0.6 mmol) in 5 mL of CH3CN. The reaction mixture was stirred at reflux for 2 hours. It was then cooled to room temperature and concentrated. The resulting residue was taken up in EtOAc, washed with brine, dried with Na2SO4, and concentrated under reduced pressure. This material (1-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid tert-butyl ester) was dissolved in 2 mL of 25% TFA in CH2Cl2 and allowed to stand at room temperature for 2 hours. It was then concentrated and the resulting residue was dissolved in 3 mL of CH3CN along with 0.5 mmol of 4-chlorobenzyl chloride and 0.8 mmol of Et3N. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 8.20 (brs, 1H), 7.70 (d, J=1.0 Hz, 1H), 7.10 (d, J=3.6 Hz, 1H), 7.0-7.30 (m, 4H) 6.60 (dd, J=3.6, 1.0 Hz, 1H), 4.80 (brs, 2H), 2.30-3.8 (m, 10H). MS m/z: 438 [M+H]+.
Reaction SMILES: [N+]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].Cl>C(O)C.O>[C:11]1([OH:14])[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.9 %

Procedure:
To a slurry of 2.88 g (15 mmol) of 7-nitro-1-tetralone in 60 mL absolute ethanol was added 0.58 g (15 mmol) of sodium borohydride. The reaction mixture was then stirred at room temperature for 2 hours. The resulting mixture was then rotaevaporated to dryness and the residue obtained was suspended in 100 mL of water. 3 N hydrochloric acid was added dropwise until the reaction mixture had pH 7. The suspension obtained was then extracted with five 50 mL portions of ethyl ether and the combined ether layer was washed once with 100 mL water. The ether layer was dried over anhydrous sodium sulfate, filtered and rotaevaporated to give an off-white residue which was recrystallized from a 1:1 mixture of absolute ethanol and water to yield 2.68 g (92%) of the napthalenol; mp 112-113° C.; IR (KBr): 3300; 1H NMR: δ1.73-2.26 (4H, m), 2.29 (1H, s), 2.78-2.91 (2H, m), 4.83(1H, m), 7.24 (1H, d, J=8.1), 8.00-8.04 (1H, dd, J=8.1, 2.4), 8.35(1H, d, J=2.4),; 13C NMR: δ19.2, 29.9, 32.5, 68.3, 122.7, 124.1, 130.3, 140.9, 145.4.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]COC)=[CH:9][C:8]([I:15])=[C:7]2[C:3]=1[CH:4](O)[N:5]([C:17]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:6]2=[O:16].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.O>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:15])=[C:7]2[C:3]=1[CH2:4][N:5]([C:17]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:6]2=[O:16]
Reactant: COCOc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(c1ccccc1)N1Cc2c(Cl)c(O)cc(I)c2C1=O
Yield: 108 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-5-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (100 mg, 0.21 mmol) was dissolved in nitromethane (4 mL), and the solution was treated with trifluoroacetic acid (0.097 mL, 1.26 mmol) and triethylsilane (0.200 mL, 1.25 mmol). The mixture was added with water and saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-5-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (97.0 mg, yield 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][C:21](=O)[CH2:20]3)[C:15](S)=[N:14][N:13]=1.[CH3:28][NH:29][CH3:30].[BH-](OC(C)=O)(OC(C)=O)[O:32]C(C)=O.[Na+].O>C1COCC1.CC(O)=O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[C:12]1[N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH:21]([N:29]([CH3:30])[CH3:28])[CH2:20]3)[C:15](=[O:32])[NH:14][N:13]=1
Reactant: CC(C)c1cc(-c2nnc(S)n2-c2ccc3c(c2)CC(=O)C3)c(O)cc1O
Reactant: CNC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc3c(c2)CC(N(C)C)C3)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Compound 11 (340 mg, 0.9 mmol) was dissolved in THF (4 mL). AcOH (2 drops, cat. amount) was added followed by dimethylamine in THF (1N solution, 0.7 mL, 1.35 mmol). NaBH(OAc)3 (286 mg, 1.35 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 30 min. Water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (MeOH:CH2Cl2=2:8) afforded the title product as a pale yellow solid (80 mg, 25%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 50 °C
Yield: 78.4 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile [164 mg, 1.0 mmol, prepared as described in Yasubiro Imakura et. al. Chem. Pharm. Bull. 40 (7), 1691-1696 (1992)] in anhydrous DMF (2 mL) was added allyl bromide (0.11 mL, 1.3 mmol), followed by K2CO3 (166 mg, 1.2 mmol). The resulting suspension was heated to 50° C. under Argon for 4 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 30% to 60% EtOAc/hexane to furnish the title compound (160 mg, 80% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:41][CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COCCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-methoxyethylamine according to conditions described in general procedure C. Mp: 95-97° C.; 1H NMR (400 MHz, CDCl3) δ 3.25 (t, J=4.7 Hz, 4H), 3.29 (s, 3 H), 3.43 (bs, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 5.32 (s, 1 H), 6.10 (s, 1 H), 6.77 (d, J=12.3 Hz, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 7.28-7.32 (m, 2 H), 7.50-7.59 (m, 2 H), 7.89-7.98 (m, 3 H), 8.13 (s, 2 H).
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)(O)=[O:2].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.O>[S:38]1[CH2:39][CH2:40][N:35]([C:1]([CH2:4][O:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)[CH2:9][CH2:8][CH2:7]2)=[O:2])[CH2:36][CH2:37]1
Reactant: C1CSCCN1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3ccccc32)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCSCC3)c3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 5-carboxymethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.50 g) in dimethylformamide (60 ml) are added successively thiomorpholine (0.66 ml), diethyl cyanophosphate (0.89 g) and triethylamine (1.37 ml) with stirring under ice-cooling. The mixture is stirred for 30 minutes under ice-cooling, and at room temperature for 20 minutes. Water (60 ml) is added to the reaction solution, and extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:2→3:1), and recrystallized from ethyl acetate/n-hexane to give 5-(thiomorpholinocarbonylmethoxy)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) as white powder, m.p. 235°-237° C.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2)(=O)C.CO.[ClH:27].CCOCC>C(O)C>[ClH:27].[NH2:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2
Reactant: COCCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: COCCCC1CC(N)c2cc(S(N)(=O)=O)sc2S1(=O)=O

Procedure:
A solution of 4-acetamido-5,6-dihydro-6-(3-methoxypropyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (7.3 g), (prepared employing substantially the same procedures as described in Example 10, Steps A through I), methanol (70 ml.) and 6N HCl (70 ml.) was heated at reflux for 18 hours then evaporated at reduced pressure to a volume of 20 ml. The reaction mixture was made basic with aqueous NaHCO3 and extracted wth ethyl acetate (2×80 ml.). The organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was crystallized from ethanol (20 ml.) to remove the cis isomer and the product thus obtained was redissolved in hot ethanol, treated with an excess of ethanolic HCl and ether to provide 1.0 g of the title compound which melts at 262° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19].Cl.[CH2:25]([O:32][P:33]([CH2:42][C@H:43]([OH:46])[CH2:44][NH2:45])([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][P:33]([CH2:42][C@H:43]([OH:46])[CH2:44][NH:45][C:21](=[O:23])[C@@H:17]([NH:16][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[CH:18]([CH3:20])[CH3:19])([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Example 12 Method B using N-Boc-L-valine-L-valine and ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl phosphinic acid benzyl ester hydrochloride. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a RediSep disposable column. 1H NMR (CD3Cl, 300 MHz): δ 7.45-7.30 (m, 5H), 6.50 (d, 1H), 5.15-4.98 (m, 3H), 4.55 (br.s, 1H), 4.33-4.22 (m, 1H), 4.20-4.05 (m, 1H), 3.95-3.84 (m, 1H), 3.56-3.40 (m, 1H), 3.38-3.26 (m, 1H), 2.35-2.12 (m, 2H), 1.98-1.79 (m, 4H), 1.78-1.63 (m, 4H), 1.49 (s, 9H), 1.38-1.15 (m, 3H), 1.13-0.85 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 59.46, 58.33. LCMS m/z: [M+H]+=624.85.
Reaction SMILES: [CH3:1][CH:2]([OH:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][CH:6]=1.[H-].[Na+].[Na].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[CH3:1][CH:2]([O:16][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: CCC(C)Sc1ccc(OCC(C)O)cc1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCC(C)Sc1ccc(OCC(C)Oc2nccs2)cc1

Procedure:
Following the procedure of Example 6, 1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethanol (1.60 g, 6.7 mmol) is treated with sodium hydride (0.48 g, 10.0 mmol), and the resulting sodium salt is reacted with 2-bromo-1,3-thiazole (800 1, 8.7 mmol) to give 2-{1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethoxy}-1,3-thiazole.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=[O:30])OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.O.Cl.[NH:49]1[CH2:54][CH2:53][C:52](=[O:55])[CH2:51][CH2:50]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:49]4[CH2:54][CH2:53][C:52](=[O:55])[CH2:51][CH2:50]4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: O=C1CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 59 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (440 mg, 0.841 mmol) synthesized in Production example 5-2 was dissolved in N,N-dimethylformamide (5 ml); triethylamine (0.543 ml, 3.90 mmol) and 4-piperidone hydrochloride monohydrate (0.530 g, 3.93 mmol) were added thereto; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the title compound (0.202 g, 0.496 mmol, 59%) as a colorless amorphous solid.