Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (870 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (6 ml), and tetrahydrofuran (4 ml) was stirred at room temperature for one hour. The reaction mixture was poured into water, then 1 N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (730 mg, yield: 89%) was obtained. This was recrystallized from acetone-isopropyl ether. Melting point: 165–166° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CCOC(=O)C1CC(O)CC1CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C1CC(OCc2ccc(OC)cc2)CC1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a mixture of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (37.78 g, 203 mmol, Preparation #P.1) in DCM (100 mL) and cyclohexane (200 mL) at about 0° C. was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (93.58 g, 331 mmol) followed by dropwise addition of trifluoromethanesulfonic acid (1.6 mL, 18.0 mmol) over about 35 min. The reaction mixture was stirred at about 0° C. for about 30 min. The ice bath was removed and the reaction mixture was stirred at ambient temperature for about 16 h. The suspension was poured into ice-water (500 mL) and stirred for about 30 min. The solid was removed by filtration while washing with DCM (100 mL). The layers in the filtrate were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with water (200 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified using silica gel chromatography eluting with a gradient of 0-100% DCM:EtOAc (95:5) in DCM to give ethyl 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.80 g, 64%): LC/MS (Table 1, Method b) Rt=2.90 min; MS m/z: 307 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:4]=1[C:5]([NH:7][CH:8]1[C:30](=[O:31])[N:10]2[CH:11]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])[C:12]3([S:19][C@H:9]12)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[O:6]>[Pd].C(O)C>[CH3:37][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][CH:8]1[C:30](=[O:31])[N:10]2[CH:11]([C:20]([OH:22])=[O:21])[C:12]3([S:19][C@H:9]12)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[O:6]
Reactant: COc1cccc(OC)c1C(=O)NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(C)CC3)S[C@H]12
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(OC)c1C(=O)NC1C(=O)N2C(C(=O)O)C3(CCN(C)CC3)S[C@H]12
Yield: 72.5 %

Procedure:
Under a hydrogen pressure of 3.2 kg/cm2 and in the presence of 1.5 g of palladium on carbon (10% Pd), a solution of 2 g (0.0038 mole) of benzyl 6-(2,6-dimethoxybenzamido)-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylate (prepared in II.1.a) in 700 ml of ethanol is hydrogenolyzed in a Parr's apparatus for 1 hour. This is followed by filtration, the filtrate being evaporated to dryness and the residue washed with a little ethanol. 1.2 g of 6-(2,6-dimethoxybenzamido)-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylic acid is thus obtained; yield: 60.4%; M.P. 193°-194° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([N:28]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[S:54](=[O:57])(=[O:56])[NH2:55])=[CH:44][CH:43]=1)[C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:55][S:54]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[C:45]1[CH:44]=[CH:43][C:42]([CH2:41][N:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:47][CH:46]=1)(=[O:57])=[O:56])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (2.0 equivalents), CDI (2.0 equiv), 1-[N-pentyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step B) (1.0 equiv), and DBU (2.0 equiv), according to the procedure of Example 3, Step C, to give a 78% yield of the desired material after flash chromatography as an off-white solid, mp 71°-74° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; FAB-MS m/e 630 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Fc1cccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)c1
Product: Fc1cccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3-fluorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and piperazine.
Reaction SMILES: [CH2:1](OC(C1SCCSC=1CCC)=O)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][S:22](=[O:29])(=[O:28])[C:21]=1[CH2:30][CH2:31][CH3:32])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[S:25](=[O:26])(=[O:27])[CH2:24][CH2:23][S:22](=[O:28])(=[O:29])[C:21]=1[CH2:30][CH2:31][CH3:32])=[O:19])[CH2:16][CH2:1][CH3:2]
Reactant: CCCC1=C(C(=O)OCC)S(=O)(=O)CCS1(=O)=O
Reactant: CCCC1=C(C(=O)OCC)SCCS1
Product: CCCCOC(=O)C1=C(CCC)S(=O)(=O)CCS1(=O)=O

Procedure:
By following substantially the procedure of Example 1, Step C, 3-ethoxycarbonyl-2-n-propyl-5,6-dihydro-1,4-dithiin (9.0 g.) yields 8.15 g. of 3-ethoxycarbonyl-2-n-propyl-5,6-dihydro-1,4-dithiin-1,1,4,4-tetroxide 73.5°-74.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)(=[O:9])=[O:8]>C(O)(=O)C.[Fe]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([NH:6][CH2:5][C:4]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 92.7 %

Procedure:
A mixture of N-(3,4-dichlorobenzyl)-2-nitrobenzenesulfonamide (4 g) and iron (2 g) in acetic acid (30 ml) was stirred at 100° C. for 45 minutes. After cooling, the iron was filtered off. The filtrate was made alkaline with a diluted aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. Recrystallization from ethyl ether gave 2-amino-N-(3,4-dichlorobenzyl)benzenesulfonamide (3.40 g).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([NH:15][C:16](=[NH:19])[NH:17][CH3:18])=[O:14])[CH3:3].[CH3:20]N(C(OC)OC)C.Cl.CO>CC#N.O>[ClH:1].[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[N:12]1[CH:18]=[N:17][C:16]([NH:19][CH3:20])=[N:15][C:13]1=[O:14])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 46.6 %

Procedure:
To a suspension of 22.8 g (80.0 mmol) of 1-(2,6-diethylphenyl)-3-methylamidinourea hydrochloride in CH3CN (100 ml) were added 19.1 g (160.0 mmol) of DMF-DMA and the reaction mixture was heated at reflux for 3 hours. The CH3CN was removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer extracted with CHCl3 (1×100). The combined CHCl3 extracts were washed with H2O (1×100 ml), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirmed the desired free base. The solution was dissolved in H2O and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which was crystallized from CH3CN to give after vacuum drying over the weekend (105° C., house vacuum) 16.7 g (71%) of crude product. The material was recrystallized from CH3CN (a hot filtration was necessary to remove some undissolved solid) to give 11.0 g (47%) of desired product as a white crystalline solid:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][C:9]2[N:13]=[CH:14][C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[CH:16][C:8]1=2.[N:32]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH:37]2[CH2:42][CH2:41][N:40]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([C:15]4[CH:14]=[N:13][C:9]5[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]6[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=6[O:3][C:2]([F:30])([F:31])[F:1])[C:8]=5[CH:16]=4)=[CH:18][CH:19]=3)=[O:23])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2OC(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2ccccc2OC(F)(F)F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 65 %

Procedure:
4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid (98 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (65% yield). LCMS: m/z=565.98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, bs), 2.88 (7H, m), 2.27 (1H, m), 2.57 (4H, s), 2.98 (2H, m), 3.46 (2H, m), 3.63 (2H, m), 3.81 (1H, bs), 4.55 (2H, s), 5.21 (1H, s), 6.71 (1H, s), 7.33 (8H, m), 7.71 (1H, s).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:29])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=[CH:19][CH:18]=3.Cl.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1COCC1.CO.C(O)C.CC(C)=O.CCCCCCC>[F:29][C:8]1[CH:7]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH:5]=[C:4]([F:3])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)N1CC(C)(C)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
7.5M Sodium hydroxide (32.9 ml, 247.10 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (11.28 g, 24.71 mmol) in THF (143 ml) and methanol (71.4 m). The reaction was stirred at room temperature for 4 h. The pH of the aqueous was adjusted to ˜6.5 by addition of 2N HCl solution, then the solution was extracted with diethyl ether (3×150 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% methanol in DCM which afforded a yellow solid. Attempted trituration with acetone/heptane failed due to higher than expected solubility. The solvents were removed to give a yellow solid which was triturated in isohexane (50 ml) with a few drops of diethyl ether, the resulting solid was filtered off and dried to give crude product (11.14 g) as a yellow powder. The solid was dissolved in ethanol (100 ml), under nitrogen and in the dark. The solution was then evaporated to 5 mBar using a vacuum pump at 62° C. in the dark. This procedure was repeated twice and the resulting resulting yellow glass scratched with a spatula into a fine powder and subjected to 5 mBar using a vacuum pump at 62° C. for 60 min, to afford a yellow powder. The powder was then left in a vacuum oven over P2O5 at 62° C. at 300 mBar overnight to afford the title product (9.77 g, 89%) as a pale yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 1.07-1.16 (3H, m) 1.18-1.29 (6H, m), 2.39 (1H, dd), 2.62 (1H, dd), 2.92 (2H, dd), 3.56 (1H, d), 5.26 (1H, s), 6.70 (1H, d), 7.02 (2H, dd), 7.22 (1H, d), 7.47 (3H, dd), 7.58 (1H, d), 10.60 (1H, s), 12.60 (1H, s). m/z: ES+ (ElectroSpray+) [M+H]+ 443.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[C:34]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:13]([C:3]3[CH:4]=[N:5][C:6]4[C:11]([C:2]=3[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=4)=[O:15])[CH2:27][CH2:28]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)c1cnc2cccc(O)c2c1O
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cnc2cccc(O)c2c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.2 g) is added to a solution of 4,5-dihydroxyquinoline-3-carboxylic acid (0.7 g), which is prepared according to the method described in Japanese Patent First Publication No. 65874/1981, in dry dimethyl sulfoxide (30 ml) and the mixture is stirred at room temperature for 30 minutes. 4-(4-Diphenylmethyl-1-piperazinyl)butylamine (2.2 g) is added to the reaction mixture and the mixture is stirred at room temperature for 6 hours, and thereto is added water (about 200 ml), and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is subjected to silica gel column chromatography, followed by elution with chloroform - methanol (30 : 1). The obtained crystals are recrystallized from isopropyl alcohol to give the desired compound (0.72 g). m.p. 215° to 218° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35]/[CH:36]=[CH:37]/[CH:38]=[O:39])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.C(O)C.[OH-].[OH-].[Pd+2]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:17])=[O:18])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCN([C@@H](C/C=C/C=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCN([C@@H](CCCC=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of the material from Step 4 (7.2 g, 12.04 mmol) in (1:1) EtOAc-ethanol (232 mL) was degassed with nitrogen, and 20% palladium hydroxide on carbon (0.72 g, 1.03 mmol) was added. The reaction mixture was stirred under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 4 g of the title compound. 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 7.79 (d, J=7.96 Hz, 2H), 7.50 (d, J=7.99 Hz, 2H), 4.79 (s, 2H), 3.68-3.60 (m, 1H), 3.45 (t, J=20.48 Hz, 2H), 3.23-3.09 (m, 1H), 3.08-2.98 (m, 1H), 2.37 (d, J=7.09 Hz, 2H), 1.62-1.06 (m, 10H), 0.91 (s, 9H), 0.84 (t, J=6.94 Hz, 3H), 0.80 (s, 9H), 0.09 (s, 6H), −0.06 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH2:9][CH:8]=2)[S:5][CH:6]=1>[Pt].C(O)C.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(Cl)cs2)n1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3c2nc(Cl)cs2)n1
Reaction time: 168 h

Procedure:
A suspension of 10-(4-chlorothiazol-2-yl)-1,3-dimethyl-5-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (25 mg, 0.058 mmol) and 10% platinum on carbon (12 mg, 6.15 μmol) in ethanol (2.2 ml) and THF (6.6 ml) was stirred under an atmosphere of hydrogen for 7 days. The mixture was filtered and the residue rinsed thoroughly with ethanol and the combined filtrates evaporated under vacuum. Purification by chromatography on silica, eluting with 80% EtOAc/hexane afforded a crude material which was triturated with diethyl ether to afford the title compound.
Reaction SMILES: CN(C=O)C.[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([C:32]1[NH:36][C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=1)[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:36]3[C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=[C:32]3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a DMF (75 mL) solution of 4′-bromomethylbiphenyl-2-sulfonic acid t-butylamide (4.7 g, 12.2 mmol), was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (2.3 g, 12.2 mmol) and potassium carbonate (1.7 g, 12.2 mmol). The mixture was stirred at room temperature overnight. EtOAc (400 mL) was added and the organic was washed 3 times with a sodium bicarbonate solution (200 mL) followed by saturated aqueous NaCl (200 mL). The solvent was removed and purification was achieved by silica gel chromatography (50/50 hexanes/EtOAc) using an isocratic gradient yielding intermediate (1a) as an off-white solid (5.0 g). Anal. HPLC: retention time=5.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C25H30ClN3O3S, 488.18; found 488.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C>>[OH:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:13](=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: Nc1cnc2cccnc2c1O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1cnc2cccnc2c1O
Yield: 46.3 %

Procedure:
Using the general method of Example 57 Part B, 3-amino[1,5]naphthyridin-4-ol (1.8 g, 11.2 mmol) was reacted with butyryl chloride (1.3 g, 12.3 mmol) to provide 1.2 g of N-(4-hydroxy[1,5]naphthyridin-3-yl)butanamide as a charcoal gray solid, m.p. >360° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][C:36]=2[O:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([F:33])[CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][C:36]=2[O:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(OCC(C)C)c(Cn3nc(C(C)(C)C)cc3C(C)(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1Cn1nc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a mixture of ethyl 3-[4-({3-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]-4-isobutoxybenzyl}amino)-2-fluorophenyl]propanoate (0.62 g, 1.16 mmol), methanol (6 mL) and tetrahydrofuran (12 mL) was added 1 M aqueous sodium hydroxide solution (2.32 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid, and diluted with ethyl acetate, and the organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/4) to give the title compound (0.52 g, yield 83%) as colorless crystals.