Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:40])[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].Cl>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:27]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:40])[CH2:28][CH2:29]4)(=[O:37])=[O:38])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
1-(4-Fluorophenyl)piperazine (185 mg, 1.0 mmol) and pyridine (1 mL) were dissolved in dichloromethane (60 mL) under argon. The solution was chilled in ice-water bath and XW2-004 1-(4-methoxy-4-oxobutanoyl)indoline-5-sulfonyl chloride (333 mg, 1.0 mmol) was added. The reaction solution was then warmed to room temperature and stirred for 3 hours. After the reaction, water [(50 mL with 37% HCl (1 L)] was added to the solution. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. Removal of dichloromethane afforded light green solid product which was then triturated with methanol (10 mL). The white solid product was filtered off to give methyl 4-(5-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)indolin-1-yl)-4-oxobutanoate, the methyl ester of XW2-011B, (320 mg, yield 67%); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.62 (dd, 1H, J=8.3, 2.0 Hz), 7.58 (d, 1H, J=2.0 Hz), 6.95 (t, J=9.0 Hz, 2H), 6.84 (m, 2H), 4.21 (t, J=8.6 Hz, 2H), 3.72 (s, 3H), 3.30 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.77 (s, 4H). The white solid obtained from the above reaction (289 mg, 0.63 mmol) was mixed with methanol (10 mL) and lithium hydroxide (1 mL of a 1.0 M aq. solution) in a 20 mL microwave reaction tube. The tube was capped and irradiated in the microwave reactor (Biotage Initiator I) at 90° C. for 10 minutes. The reaction solution was concentrated under vacuum and the residue was diluted with 20 mL of water treated with NaOH solution (1.0 M) till pH>10. The aqueous solution was extracted with ethyl acetate (2×10 mL). Then the aqueous layer was acidified to pH˜4, extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulted solid was washed with dichloromethane to afford XW2-011B (180 mg, 69%) as a light orange solid product. Mp=213-215° C.; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.58-7.65 (m, 2H), 6.95 (t, J=9.0 Hz, 2H), 6.82 (dd, J=4.5, 4.5 Hz, 2H), 4.20 (t, J=8.6 Hz, 2H), 3.31 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.80 (s, 4H); HPLC 98% (Rt=3.30, 90% methanol in acetonitrile); HRMS (ESI-ve) m/z calculated for C22H23FN3O5S (M−H)−460.13479. found 460.13475.
Reaction SMILES: [OH-].[K+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15].[C:18](=[S:20])=[S:19].[CH3:21]I>C(O)C.O>[S:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:18](=[S:20])[S:19][CH3:21])([OH:17])(=[O:15])=[O:16]
Reactant: CI
Reactant: S=C=S
Reactant: NCCCCCCCCCCS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=S)NCCCCCCCCCCS(=O)(=O)O
Reaction time: 12 h

Procedure:
A suspension of 56 g. (1.0 mol.) of potassium hydroxide and 118.7 g. (0.5 mol.) of 10-aminodecanesulfonic acid in 170 ml. of water is stirred for 30 minutes at 25°, then 40 g. (0.52 mol.) of carbon disulfide and 80 ml. of ethanol are added and the reaction mixture is stirred at 25° for 12 hours. The mixture is refluxed gently for 2 hours and cooled. Methyl iodide (71 g., 0.3 mol.) and 130 ml. of ethanol are added to the mixture and it is stirred at 25° for 12 hours. The mixture is evaporated to remove the ethanol and the solid residue is collected by filtration to give methyl 10-sulfodecyldithiocarbamate.
Reaction SMILES: COC(OC)[N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.C([Li])CCC.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:8]2[CH:7]=[CH:6][NH:5][N:4]=2)[OH:22])=[CH:19][CH:18]=1
Reactant: COC(OC)n1cccn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc[nH]n1
Reaction time: 48 h
Yield: 29.8 %

Procedure:
A solution of 14.2 g of 1-(dimethoxymethyl)-pyrazole in 125 ml of tetrahydrofuran at -40° C. was treated with 79 ml of a 1.27M solution of n-butyllithium in hexane under a nitrogen atmosphere. When this addition was complete, 25.2 g of 4,4'-dichlorobenzophenone were added. The reaction was stirred for 48 hours allowing the temperature to come to room temperature. The reaction mixture was added to 200 ml of water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and evaporated. The semi-solid residue was triturated with toluene. The toluene filtrate was collected and evaporated and the residue therefrom was purified by high pressure liquid chromatography over silica gel. The appropriate fractions were combined and evaporated to provide 9.5 g of the desired title product. Crystallization from 15% ethyl acetate in hexane provided material with a melting point of 138°-140° C. A second recrystallization provided material with the following analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4cccc5ccccc45)nc3n2)CC1
Yield: 70.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.378 g of 1-naphthyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.97 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-naphthalen-1-yl-urea, ESMS (20/80 MeOH/CH3 CN+0.1% AcOH): M+ +H=615 (Base), 446; mp 186.5°-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](O)=[O:30])=[N:4][C:5]([Cl:28])=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[N:14][O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[N:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][N:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([Cl:28])=[N:4][C:3]([CH2:29][OH:30])=[C:2]([Cl:1])[N:7]=3)[CH2:9][CH2:10]2)[CH2:21][CH2:20]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(C(=O)O)nc3Cl)CC2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)nc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 56c obtained in the previous step was combined with triethylamine (50 μL, 0.36 mmol) in 2 mL of THF and treated at 0° C. with ethyl chloroformate (30 μL, 0.31 mmol). The mixture was stirred at room temperature for 4 h then it was added to a stirred suspension of sodium borohydride (32 mg, 0.84 mmol) in water and the stirring was continued for 3 h. The mixture was quenched with aqueous NaHCO3 (5 mL) and water (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were dried and concentrated and the residue was purified by reparative TLC(eluent: EtOAc) to afford 56-1: LC-MS 442.0 (MH+-18), tR=7.43 (Method 2). EC50: 35 nM.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H]([N:55](C)C)[C@H]2O)[C@@](OC)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@]1(O)C.[OH-].[Na+]>>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:55][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=C1CCCCC1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCCCC1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A mixture of polyphosphoric acid (150 g) and 2-(phenylmethyl)cyclohexanone, oxime (9 g, 45 mmol), which had been prepared as described by W. G. Kofron et al., J. Org. Chem., 41, 439 (1976), was heated with manual stirring to 120° C. for 20 minutes and then at 130° C. for ten minutes. The hot solution was poured onto 1000 g of ice, the pH adjusted to 4 with solid NaOH, and extracted 3× with EtOAc. After washing with brine, drying over Na2SO4, and concentration, the residue was chromatographed on silica gel using 1:1 EtOAc/hexane to elute a 1:1 mixture of the two isomeric lactams. The mixture was separated by prep HPLC using a C18 reverse phase YMC S15 column with 68% solvent B as eluant to yield 2.3 g (26%) of the title compound and 1.8 g of the isomeric hexahydro-3-(phenylmethyl)-2H-azepin-2-one.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1[C:19]2[N:20]3[C:24]([C:25](=O)[C:17]4[C:18]=2[C:13]([CH:14]=[CH:15][N:16]=4)=[CH:12][CH:11]=1)=[CH:23][CH:22]=[CH:21]3>O.C(O)C.N1C=CC=CC=1>[CH2:8]([O:7][C:5]([CH2:4][O:3][N:2]=[C:25]1[C:17]2[C:18]3[C:13]([CH:14]=[CH:15][N:16]=2)=[CH:12][CH:11]=[CH:10][C:19]=3[N:20]2[C:24]1=[CH:23][CH:22]=[CH:21]2)=[O:6])[CH3:9]
Reactant: CCOC(=O)CON
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 56.1 %

Procedure:
A solution of ethyl aminooxyacetate hydrochloride (18.0 g.) in water (64 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (16.0 g.) in ethanol (320 cc.) and pyridine (9.1 g.). Boiling is maintained for 3 hours 30 minutes. After cooling, water (640 cc.) is added. The greenish yellow crystals thus obtained are filtered off and washed with 25% ethanol and then with water. After drying, crude 7-ethoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij isoquinoline (21.6 g.) is obtained and is recrystallised from a mixture of ethyl acetate (110 cc.) and cyclohexane (165 cc.). 7-Ethoxycarbonylmethoxyimino- 7H-indolizino[5,6,7-ij]isoquinoline (13.1 g.), melting at 134° C., is thus obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH3:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][CH2:20][NH2:21].[CH3:22][N:23]1[CH:28]=[C:27]([CH2:29]Cl)[C:26]([C:31](OC)=[O:32])=[C:25]([Cl:35])[C:24]1=[O:36]>CO.CC#N>[Cl:35][C:25]1[C:24](=[O:36])[N:23]([CH3:22])[CH:28]=[C:27]2[CH2:29][N:21]([CH2:20][CH2:19][C:11]3[N:10]([CH3:9])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]=3)[C:31](=[O:32])[C:26]=12
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Reactant: Cn1c(CCN)nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Temperature: 90 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
K2CO3 (8.35 g, 60.4 mmol) was added rapidly to a suspension of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (5 g, 20.15 mmol) in MeOH (50 ml) and the reaction was stirred for about 5 h. The mixture was filtered and the filtrate was concentrated. The residue and TEA (28.1 ml, 201 mmol) were added to a solution of 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (5.04 g, 20.15 mmol, see compound (6) of Example b1)) in MeCN (100 ml). The mixture was heated at about 90° C. overnight. The reaction was cooled to r.t. and the mixture was filtered through a sintered glass funnel. The solid was washed with water and dried to afford the title compound (3.9 g, 10.93 mmol, 54.2% yield).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:61][CH2:62][CH2:63][NH2:64])=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[CH2:61][CH2:62][CH2:63][NH:64][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])=[O:14])=[CH:56][CH:55]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid (0.300 g, 1.24 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.647 mL, 3.71 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.470 g, 1.24 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.369 g, 1.24 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 25 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.50 g (81%) of the pure titled compound as a white foam; mp 50-60° C. APCI-MS m/z 500.3 (MH+).
Reaction SMILES: [CH2:1]=O.[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5](O)=O.[CH3:12][NH:13][CH3:14]>O>[CH3:12][N:13]([CH2:5][C:4](=[CH2:1])[C:3]([O:9][CH2:10][CH3:11])=[O:8])[CH3:14]
Reactant: CCOC(=O)CC(=O)O
Reactant: C=O
Reactant: CNC
Solvent: O
Product: C=C(CN(C)C)C(=O)OCC
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Aqueous formaldehyde (161 ml, 37%) was added slowly to a solution of ethyl hydrogen malonate (132g) and dimethylamine (350 ml, 26% aqueous) in water (150 ml) at 15° C. The mixture was stirred at 15° C for 30 minutes, heated slowly to 40° C and stirred for a further 30 minutes. Decarboxylation commenced at 26° C. After cooling, the organic material which had separated as a colourless oil was extracted with ether (3 × 250 ml). The ether extracted was dried over anhydrous sodium sulphate and evaporated at atmospheric pressure. The residue was shown to be a mixture by the appearance of two carbonyl peaks (1740 cm-1 and 1720 cm-1) in the infrared spectrum. The mixture was distilled under vacuum to give ethyl 2-dimethylaminomethylacrylate (50g, 32% boiling point 34° C/0.7mm; νc=o 1722cm-1) and ethyl 1,3-bis (dimethylamino) propane-2-carboxylate (87g, 43%, boiling point 58° C/0. 8mm;νc=o 1740 cm-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]([C:13]1[C:18]([F:19])=[C:17]([Cl:20])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.CCN(C(C)C)C(C)C.[O:32](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1.CO>[Cl:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH:11]=[O:32])[C:18]=1[F:19]
Reactant: C=CC[C@@H](c1nccc(Cl)c1F)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC=O)c1nccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
(S)-tert-Butyl(1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)(methyl)carbamate: A solution of Intermediate 30A (0.11 g, 0.345 mmol), 4 N HCl in dioxane (3 mL), and MeOH (3.00 mL) was stirred at rt for 1 h. The reaction mixture was concentrated. The residue was re-dissolved in acetonitrile (3.00 mL) and added DIEA (0.241 mL, 1.380 mmol) followed by BOC2O (0.104 mL, 0.449 mmol). The reaction was stirred at rt for 2 h and concentrated. The residue was purified by silica gel chromatography to yield the desired product (0.11 g, 101%). MS (ESI) m/z: 314.9 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH3:31])[CH2:20][C:21]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:22]=3[CH3:30])=[O:18])[CH:13]=[N:14][C:8]=2[NH:7][C:6]1=[O:32].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH3:31][N:19]([CH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[CH3:30])[C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[N:14][C:8]2[NH:7][C:6](=[O:32])[N:5]([CH2:4][CH:3]=[O:2])[CH2:10][C:9]=2[CH:11]=1
Reactant: COC(CN1Cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2NC1=O)OC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC=O)C(=O)N3)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
A suspension of (E)-3-[3-(2,2-dimethoxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]-N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (450 mg, 0.937 mmol) in CH2Cl2 (20 mL) was treated with TFA (1 mL) and H2O (1 mL). The reaction was allowed to stir overnight at room temperature. The solution was washed with saturated NaHCO3 (2×15 mL). The aqueous solutions were extracted with CH2Cl2 (40 mL). The combined CH2Cl2 solutions were washed with brine, dried over Na2SO4, and concentrated to give the title compound (440 mg, 99%) as a white solid and as amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.54 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.53-7.31 (m, 4H), 5.11-4.88 (m, 2H), 4.51 (s, 2H), 4.18 (s, 2H), 3.15-2.93 (m, 3H), 2.42 (s, 3H); MS (ESI) m/e 435 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14]>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 2-amino-5-chloro-benzoic acid methyl ester (5.55 g, 30 mmol) and 3-nitro-benzaldehyde (4.99 g, 33 mmol) in ethanol (100 mL) was heated to reflux for 2 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-chloro-2-[(3-nitro-benzylidene)-amino]-benzoic acid methyl ester (7.2 g, 75%) as a white solid: LC/MS m/e calcd for C15H11ClN2O4 (M+H)+: 319.72, observed: 319.0.
Reaction SMILES: CO[C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2C)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:18][C:19]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([OH:33])=[CH:22][C:23]([C:30]([OH:32])=[O:31])=[CH:24]2.Cl.Cl.N[C:37]1C=C(S(O)(=O)=O)C2C([C:46]=1N)=C(O)C=CC=2>>[CH2:37]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]3[NH:29][C:28]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:33])[CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=5)[C:19]=4[N:18]=3)[CH:3]=2)=[CH:16][CH:15]=1)[CH3:46]
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(O)c2c1N
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: COc1c(C=O)cccc1-c1ccccc1C
Agent: Cl
Product: CCc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1

Procedure:
Follow the procedure of example 1c) except substituting 4′-ethylbiphenyl-3-carbaldehyde for 2-methoxy-3-(2′-methyl phenyl) benzaldehyde and 5,6-diamino-4-hydroxynaphthalene-2-carboxylic acid for 3,4-diamino-5-hydroxy-1-naphthalene sulfonic acid dihydrochloride, the title compound was prepared as a solid (0.046 g, 99%). MS(ES) m/z 409 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:21][CH:20]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCOc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H2O (1:9 mL) at room temperature was added concentrated HCl (0.1 mL). The mixture was heated at reflux for 1 h, cooled to room temperature, and made basic with 2 N NaOH (2 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude black solid was purified by chromatography (4:1 hexanes/EtOAc) to afford 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g, 80%) as a brown oil: 1H NMR (300 MHz, CDCl3), δ 8.01 (d, J=2.7 Hz, 1H), 7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5 Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:15]([F:14])([F:24])[F:25])[NH:8][C:9]2=[N:10][NH:11][CH:12]=[C:13]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1cccs1

Procedure:
The title compound was prepared from thiophene-2-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][C:17](=O)[CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21]([OH:27])(=[O:26])[CH2:22]C(O)=O.C([O-])(=O)C.[NH4+:32].C(O)C.CO>>[NH2:32][C:17]1([CH2:22][C:21]([OH:27])=[O:26])[CH2:18][CH2:19][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)[CH2:16]1
Reactant: CCCCCCCCc1ccc(C2CCC(=O)C2)cc1
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCc1ccc(C2CCC(N)(CC(=O)O)C2)cc1
Temperature: 80 °C

Procedure:
3-(4-Octyl-phenyl)-cyclopentanone, malonic acid (0.076 g, 0.734 mmol), ammonium acetate (0.057 g, 0.734 mmol) were suspended in the mixture of ethanol (1.50 mL, 25.7 mmol) and methanol (0.50 mL, 12.36 mmol) in a 15-mL, 2-necked round-bottomed flask equipped with a condenser. The heterogeneous mixture was heated to reflux at 80° C. for about 24 hours. Heating was removed. The crude mixture was taken up in dichloromethane/water mixture (20 mL/20 mL). The resulting fine suspension was filtered, washed several times with water and dichloromethane, and vacuum-dried to yield 2-(1-amino-3-(4-octylphenyl)cyclopentyl)acetic acid (0.020 g, 0.060 mmol) as off-white solid.