Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1F>C1COCC1>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1[NH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 37.3 %

Procedure:
The title compound was prepared from 4-[5-(3,4-dichlorophenyl)pentyl]phenylamine (231 mg, 0.75 mmol), LHDMS (6.28 mL, 1 M in THF, 6.28 mmol) and 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (172 g, 0.75 mmol) in THF (5 mL) using the procedure described in Example 13. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 145 mg (0.28 mmol, 37%) of the desired product
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1ccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzoic acid ethyl ester (Ex. 1.11) (1 eq, 0.086 mmol, 35 mg) and ethanol amine (10 eq, 0.86 mmol, 0.05 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.128 mmol, 17.7 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-benzamide as a white solid; [M+H]+=424
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C(Cl)Cl>CCOC(C)=O>[OH:41][C:35]1([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:12]([C:11]3[C:2]([CH3:1])=[N:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)=[O:14])=[CH:34][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: NCc1ccc(C2(O)CCCCC2)cc1
Reactant: Cc1nc2ncccc2cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
144 mg (0.76 mmol) 2-methyl-1,8-naphthyridine-3-carboxylic acid and 136 mg (0.84 mmol) CDI were refluxed in 5 ml EtOAc for 2 h. The solution was cooled to r.t. and 157 mg (0.76 mmol) 1-(4-(aminomethyl)phenyl)cyclohexanol followed by 5 ml CH2Cl2 was added. The mixture was stirred for 2 days at r.t. Concentrated to dryness and purified by flash chromatography (SiO2, CH2Cl2/MeOH 20:1→10:1) to afford 50 mg (13%) of the title compound.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]([CH3:25])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:25][N:22]1[C:21]2[CH:26]=[CH:27][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:28])[C:20]=2[N:24]=[CH:23]1
Reactant: Cc1c(N)ccc2c1ncn2C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (494 mg) and 4-dimethylaminopyridine (0.01 g) in methylene chloride (40 mL) is added dropwise over 30 minutes, a solution of 5-amino-1,4-dimethylbenzimidazole (176 mg) in methylene chloride (20 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexane, to afford 1,4-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl.C(OC(C)C)(C)C>[CH2:33]([NH:35][C:36]([N:15]1[CH2:16][CH2:17][C:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:13][CH2:14]1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (80 mg, 0.20 mmol) obtained in Example 260 and triethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4 ml), followed by the addition of ethyl isocyanate (0.027 ml, 0.34 mmol) at room temperature. After stirring at room temperature for 6 hours, a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure to give a white solid. The resulting solid was washed with diisopropyl ether, whereby the title compound (74 mg, 0.17 mmol, 85%) was obtained as a white powder.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1)#[N:2]
Reactant: BrCCCCBr
Reactant: COC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCCC1
Temperature: 75 °C
Yield: 77094.2 %

Procedure:
To a 22 L flask equipped with a mechanical stirrer, thermometer and condenser containing a nitrogen inlet was added dry DMF (8 L) and methyl cyanoacetate (800 g, 8.07 mol). Stirring was started and K2CO3 (2.67 kg, 19.3 mol) and then 1,4-dibromobutane (1.74 kg, 8.07 mmol) were added. The exothermic reaction mixture (temperature increased to 75° C.) was stirred at room temperature for 16 h followed by heating at 60-75° C. for 3 h. Approximately 2.5 L of solvent were removed under reduced pressure and the residue was diluted with water (8 L). The resultant mixture was extracted with Et2O (2×2 L) and the combined organic phases were washed with 1 N aqueous HCl and brine. Drying (MgSO4), filtering and concentrating afforded an orange liquid. This material was distilled (fraction boiling at 80° C., 0.7 mm Hg collected) to provide methyl 1-cyanocyclopentanecarboxylate as a clear colorless liquid (953 g, 77% yield). 1H-NMR (400 MHz, CDCl3) δ 3.80 (s, 3 H), 2.29-2.22 (m, 4 H), 1.90-1.84 (m, 4 H); 13C NMR (100.6 MHz, CDCl3) δ 169.2, 119.9, 52.6, 46.6, 36.9, 24.3; EI-MS exact mass calcd for C8H11NO2 : 153.0790; found: 153.0785.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:24](=[O:25])([O:26][CH2:27][CH3:28])[O:16][CH2:15][C:13]1[N:14]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:2]=3[CH3:1])=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)OCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Reaction time: 20 h
Yield: 23 %

Procedure:
8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.4 g, 1.3 mmol) and ethyl chloroformate (0.13 ml, 1.3 mmol) were solved in methylene chloride (20 ml) and were refluxed for 3 h. An additional amount of ethyl chloroformate (0.13 ml, 1.3 mmol) was added and the reaction mixture was refuxed 20 h. A sodium bicarbonate solution was added, the organic layer was separated dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether as eluent and crystallization from diethyl ether: petroleum ether (1:2) gave 0.11 g (23%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[C:11](=[O:13])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
[5-Oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (1.02 g, 2.94 mmol) was added to a solution mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in water and neutralized by adding a saturated sodium hydrogen carbonate aqueous solution. The solvent of the mixture was removed under reduced pressure and the obtained residue was purified by NH-silica gel column chromatography (chloroform/methanol) to yield 642 mg (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:15]2[CH2:16][CH:17]=[CH:18][CH:14]2[C:13]2[C:12]([Cl:19])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[NH:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:20][C:10]1[CH:11]=[C:12]([Cl:19])[C:13]2[CH:14]3[CH:18]=[CH:17][CH2:16][CH:15]3[CH:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=2[CH:9]=1
Reactant: CCOC(=O)C1Nc2cc(Cl)cc(Cl)c2C2C=CCC12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Nc2cc(Cl)cc(Cl)c2C2C=CCC12

Procedure:
Compound 1 was saponified with 1.0 ml sodium hydroxide solution (6N, water) in 20.0 ml ethanol. The ethanolic solution was concentrated to small volume on a rotary evaporator, the residue was taken up in water, reacted with 6N HCl and the aqueous solution extracted three times over ether. The organic phase was washed neutral with water, dried over magnesium sulphate and concentrated to a reduced volume on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Cl)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 42.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2d (200 mg, 0.587 mmol), 6-mercaptopurine monohydrate (110 mg, 0.646 mmol), K2CO3 (90 mg, 0.651 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 113 mg of a yellow crystalline solid (42%), mp 237.1-238.2° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.11 (s, 1H); 7.94 (d, J=8.3 Hz, 1H); 7.78 (d, J=8.1 Hz, 2H); 7.66 (d, J=6.7 Hz, 1H); 7.48-7.56 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.8, 156.8, 153.5, 151.5, 149.6, 145.8, 143.6, 135.7, 134.0, 132.2, 132.1, 131.7, 131.5, 130.5, 130.2, 129.8, 128.8, 125.8, 121.9, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.0.1C2H6O.0.6H2O (0.15KCl: C, 50.34; H, 2.89; Cl, 15.82; N, 17.44; S, 6.65. Found: C, 50.02; H, 2.63; Cl, 15.51; N, 17.39; S, 6.81.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)/[CH:11]=C/C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(Cl)Cl.[BH4-].[Na+].C[OH:37]>>[C:1]([O:7][CH2:8][C@@H:9]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@@H:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=1)[CH2:11][OH:37])(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](COC(=O)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](COC(=O)C(C)(C)C)[C@H](CO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2S,3S,E)-2-(tert-Butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enyl pivalate (1.8 g, 4.1 mmol) was taken up in 40 mL of 1:1 MeOH:CH2Cl2 and chilled to −78° C. Ozone was bubbled through the mixture until a blue color persisted. Nitrogen was then bubbled through the mixture for 15 minutes. Sodium borohydride (0.77 g, 20 mmol) was added, and the mixture was warmed to room temperature. The mixture was stirred for 2 hours. The mixture was quenched with 40 mL of aqueous NH4Cl. After 30 minutes, the mixture was diluted with 20 mL of water and extracted three times with 40 mL of CH2Cl2. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded (2S,3S)-2-(tert-butoxycarbonyl)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butyl pivalate (1.8 g, 100% yield) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:26]C(=O)OC(C)(C)C)[C:10]([NH:12][C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:15][C:14]=2[CH3:25])=[O:11])=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:26][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=2)=[N:15][C:14]=1[CH3:25])=[O:11]
Reactant: Cc1cc(-c2nc(C)c(NC(=O)[C@H](Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)s2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc(C)c(NC(=O)[C@@H](N)Cc3ccc(F)cc3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl (S)-3-(4-fluorophenyl)-1-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-ylamino)-1-oxopropan-2-ylcarbamate (0.061 g, 0.13 mmol) in DCM (0.0083 ml, 0.13 mmol) was added TFA (0.01 ml, 0.13 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was purified by HPLC to give 40 mg of (2S)-2-Amino-3-(4-fluorophenyl)-N-(4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-yl)propanamide 22E. 400 MHz 1H NMR (CD3OD) δ: 8.63 (d, J=8.0 Hz, 1H), 8.28 (br s, 1H), 8.22 (dd, J=8.0, 4.0 Hz, 1H), 7.31 (dd, J=8.0, 4.0 Hz, 2H), 7.09 (dd, J=8.0, 8.0 Hz, 2H), 4.51 (dd, J=8.0, 8.0 Hz, 1H), 3.30 (obscured dd, 1H), 3.23 (dd, J=16.0, 8.0 Hz, 1H), 2.80 (s, 3H), 2.43 (s, 3H). LCMS (ES+) m/z 371.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1(O)[C@:24]2([CH3:25])[CH:11]([CH:12]3[C:21](=[CH:22][CH2:23]2)[C@:20]2([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]2)[C@@H:14]([CH3:28])[CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[C:30]([O-])([O-])([O:32]CC)[CH3:31].Cl.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:30]([C@@:1]1([CH3:2])[O:3][C@:8]2([C@:24]3([CH3:25])[CH:11]([CH:12]4[C:21](=[CH:22][CH2:23]3)[C@:20]3([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]3)[C@@H:14]([CH3:28])[CH2:13]4)[CH2:10][CH2:9]2)[C:6](=[O:7])[CH2:5][O:4]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)C1(O)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reactant: CCOC(C)([O-])[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(=O)[C@]1(C)OCC(=O)[C@]2(CCC3C4C[C@H](C)C5=CC(=O)C=C[C@]5(C)C4=CC[C@@]32C)O1

Procedure:
2-((6S,10R,13S)-17-hydroxy-6,10,13-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate is dissolved in toluene and heated with 1.5 equivalents of ethyl orthoacetate and a trace of pyridinium hydrochloride. Ethanol is distilled off the reaction mixture to drive it to completion.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-({4-[2-(4-Iodophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (6.0 g) obtained in Example 144-1 was dissolved in dichloromethane (25 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (60 mL). Thionyl chloride (5.63 g) was added under ice-cooling and the mixture was refluxed for 4 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was 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, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=6:1 to 4:1) to give the title compound (5.2 g) as a colorless oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2ccccc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Dimethyl malonate (14 mL) was added dropwise to 2.9 g of sodium hydride suspended in 50 mL of dimethylsulfoxide. The mixture was heated at 100° C. for 15 minutes and cooled to room temperature. Crude 4-fluoro-2′-methoxy-3-nitrobiphenyl in 60 mL of dimethylsulfoxide was added and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and quenched with 300 mL of saturated sodium chloride solution and extracted twice with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 2′-methoxy-3-nitrobiphenyl-4-malonate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ1.23-1.28 (m, 3 H), 1.38-1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50-4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65-8.13 (series of m, total 12 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:32][CH2:31][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23](F)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].[NH3:33]>CN(C=O)C>[NH2:33][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:5]4([CH2:31][CH2:32][N:3]([CH2:1][CH3:2])[CH2:4]4)[CH2:9]3)=[CH:17][CH:16]=2)=[O:30])=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(F)c([N+](=O)[O-])c4)cc3)C2)C1
Reactant: N
Solvent: CN(C)C=O
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(N)c([N+](=O)[O-])c4)cc3)C2)C1
Reaction time: 8 h

Procedure:
N-{4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-4-fluoro-3-nitro-benzamide from above was dissolved in DMF (15 ml) and the solution was cooled in an ice bath and saturated with ammonia gas for 10 min. The flask was sealed and left at room temperature overnight. The DMF was then evaporated under reduced pressure and the residue partitioned between dichloromethane and 0.1 N KOH. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel using 10% MeOH/CH2Cl2 1% TEA to afford 4-Amino-N-{4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-3-nitro-benzamide (996 mg) as a yellow foam which was used as is in the next step. 1H NMR (300 MHz, d6-DMSO) δ 10.2 (s, 1H), 8.70 (s, 1H), 7.96 (d, 1H), 7.82 (s, 2H), 7.63 (dd, 2H), 7.24 (dd, 2H), 7.10 (d, 1H), 2.65-2.35 (m, 14H), 1.96 (m, 4H), 1.23 (t, 3H).