Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([C:32](Cl)=[O:33])[CH:26]=[CH:25]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O1CCOCC1.N1C=CC=CC=1>O>[C:1]([NH:9][NH:10][C:32]([C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=2)[CH:28]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)NN
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCOc1ccc2cc(C(=O)NNC(=O)CCCCCC)ccc2c1
Temperature: 85 °C
Yield: 96 %

Procedure:
In a 50 ml-three-necked flask, 0.40 g (2.77 mM) of heptanohydrazide, 1.05 g (3.03 mM) of 6-decyloxy-2-naphthoyl chloride and 20 ml of dioxane were placed and heated to about 85° C. under stirring. To the mixture, 1.05 ml (13.0 mM) of pyridine was added, followed by heating to 90°-92° C. and stirring for 40 minutes at 90°-92° C. After the reaction, the reaction mixture was cooled and poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and further washing with acetone to obtain 1.21 g of N-heptanoyl-N'-(6-decyloxy-2-naphthoyl)hydrazine (Yield: 96.0%). ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([N:18]1[C:19]2=[CH:25][S:24][CH:23]=[C:20]2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)c3cscc3n(C(=O)c3ccccc3)c2=O)CC1

Procedure:
The title compound was prepared by the procedure of Example 11 using 2.0 g (5 mmol) of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione and benzoyl chloride (840 mg, 6 mmol). The named compound (481 mg, 19% yield) was obtained after recrystallization from CH2Cl2 /hexane, mp 153.5°-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 4 and N-(4-hydroxyphenyl)benzamide (703 mg) were dissolved in tetrahydrofuran (10 mL), triphenylphosphine (866 mg) and diethyl diazodicarboxylate (575 mg) were added thereto under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.1 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:26])=[C:19]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: N#Cc1cn[nH]c1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)cnn23)ccc1F
Yield: 80.8 %

Procedure:
A mixture of 0.041 g (0.38 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. Dichloromethane (15 mL) and a saturated sodium bicarbonate solution (10 mL) were added to the resulting residue. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 95 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 81%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.Cl[C:12]1[C:21]([C:22]2[CH:27]=[C:26]([S:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)C.N>Cl.CO.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:12]3[C:21]([C:22]4[CH:27]=[C:26]([S:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=4)=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CSc1cc(-c2nc3ccccc3nc2Cl)nc(C)n1
Reactant: Nc1cccc2[nH]ncc12
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CSc1cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)nc(C)n1
Temperature: 160 °C
Yield: 45.4 %

Procedure:
A glass microwave reaction vessel was charged with 1H-indazol-4-amine (220 mg, 1.651 mmol, Key Organics Limited/Bionet Research, United Kingdom), 1 drop of concentrated HCl, 2-chloro-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxaline (250mg, 0.826 mmol), and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 1 h. The mixture was cooled to room temperature, then neutralized by 2 N NH3 in MeOH, diluted with DCM and filterd through a Celite® (diatomaceous earth). The filtrate was concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to10% 2 M NH3.MeOH in DCM to give N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxalin-2-amine (150 mg, 0.375 mmol, 45.5% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.23 (s, 1H); 12.59 (s, 1H); 8.50 (d, J=7.63 Hz, 1H); 8.42 (s, 1H); 8.31 (s, 1H); 8.03 (d, J=8.22 Hz, 1H); 7.74-7.85 (m, 2H); 7.59 (t, J=7.43 Hz, 1H); 7.41 (t, J=7.92 Hz, 1H); 7.27 (d, J=8.22 Hz, 1H); 2.91 (s, 3H); 2.68 (s, 3H). m/z (ESI, +ve ion) 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:44]([S:41]([N:38]1[CH2:37][CH2:36][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:11]4[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:40][CH2:39]1)(=[O:43])=[O:42])[CH3:45]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCOC)c4)cc23)CC1
Yield: 46 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[CH:30]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[NH:27][N:28]=3)=[O:32])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (50 mg) and 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (44 mg) using the method of Example 34(d). Yield 27 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.74 (m, 2H), 4.42 (t, 2H), 7.07 (d, 1H), 7.17-7.28 (m, 1H), 7.50 (m, 1H), 7.90 (s, 1H), 8.05-8.20 (m, 2H), 8.31-8.42 (m, 1H), 8.52-8.59 (m, 1H), 8.69 (d, 1H), 8.92-9.04 (m, 1H), 13.79 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:27])[N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[O:27]=[C:14]([N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1)[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:28])[C:4]([OH:29])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCC(c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 29.9 %

Procedure:
4-[2-Oxo-2-(4-phenyl-1-piperidinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.9 g) in methanol (80 mL) was treated with 1N sodium hydroxide solution (2.6 mL), and the mixture was stirred at room temperature for 25 minutes. After the methanol was evaporated under reduced pressure, water (25 mL) was added and the solution was acidified with 3N hydrochloric acid, then the aqueous layer was extracted with a dichloromethane-tetrahydrofuran mixture (35 mL; 5:2). The organic layer was dried (MgSO4), evaporated and the resulting solid was crystallized from dichloromethane-tetrahydrofuran-hexane and then from dichloromethane-tetrahydrofuran to furnish 0.25 g of 4-[2-oxo-2-(4-phenyl-1-piperidinyl)ethoxy]-alpha-oxobenzeneacetic acid, mp 209°-210° C. An additional 0.16 g of the acid was recovered from the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@H:7]([CH2:19][CH2:20]/[CH:21]=[C:22](/[C:31]([O:33][CH3:34])=[O:32])\[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[H][H].C1(P([C@H]([C@@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C2C=CC=CC=2)C=CC=CC=1.CC=CCC=CC>C(O)(=O)C.C1COCC1.Cl([O-])(=O)(=O)=O.[Rh+]>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@@H:7]([CH2:19][CH2:20][CH2:21][CH:22]([C:31]([O:33][CH3:34])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Agent: [Rh+]
Agent: CC=CCC=CC
Agent: C[C@@H]([C@H](C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Yield: 92.6 %

Procedure:
A solution of 8.5 g of 47c in 25 mL of acetic acid and 250 mL of THF is hydrogenated at 48 psi of hydrogen over 0.5 g of (bicyclo(2.2.1.)hepta-2,5-diene [2S,3S]bis(diphenylphosphino)butane)rhodium(I) perchlorate for 18 h. The reaction is filtered and evaporated to a residue. The residue is chromatographed using variable gradient hexane-ethyl acetate to give 7.9 g of reduced product as a residue. Multiple crystallizations give 2.6 g of diastereomerically pure 40c. NMR(CDCl3) δ 1.40(d,J=6 Hz,3H); 1.43(s,9H); 1.60-1.97(m,6H); 3.73(s,3H); 3.74(s,3H); 4.12-4.37(m,2H); 4.52-4.61(m,1H); 5.12(bs,3H); 5.44-5.55(b s,1H); 6.73(b s,1H); 7.36(b s,5H); 13C--NMR: δ 18.02(CH--CH3); 21.12(CH2 --CH2 --CH2); 28.23(--OC(CH3)3); 31.87(--CH2 --CH2 --); 32.29(--CH2CH2 --); 47.99(--CHCH3); 52.23(--OCH3); 52.38(--OCH3); 52.75(OCCHN); 54.41(OCCHN); 67.01(--OCH2Ar); 79.97(--OC(CH3)3); 127.99 (phenyl ring carbon); 128.09 (phenyl ring carbon); 128.44 (ArCH); 136.13(ArCC); 155.48(OCONH); 156.23(OCONH); 171.10(--CONH--); 173.03(--CO2 --2X); IR(KBr) (cm-1): 3340(s); 1760(s); 1740(s); 1680(s); 1660 (s); 1660 (s); 1520(s); MS(FAB) m/z 546(M+Na)+ ; 524(MH)+ ; 424(MH--C4H8CO2); Anal. Calcd: C, 57.35; H, 7.12; N, 8.03; Found: C, 57.23; H, 7.27; N, 8.03; rotation [α]D25 -9±1; m.p. 120°-121° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:34][CH:35]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 44.5 %

Procedure:
A solution of 0.38 g of diethyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 4.6 mL of 0.5N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Acetic acid (5 mL) was added, and the resulting white precipitate collected by filtration. The filter cake was washed well with water, methanol, and ether and was dried under reduced pressure to yield 0.15 g (44%) of the title compound, which can be alternatively named as 5,10-dideazaaminopterin; mp>250° C.; NMR (TFA-d1) delta 2.2-2.7(m, 2H), 2.28; 2.7-2.95(m, 2H), 5.0-5.2(m, 1H), 7.35 and 7.85(AB q, 4H, J=9 Hz), 8.7(s, 1H), 9.1(s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]([OH:29])=O)=[CH:10]2.[CH2:30]([S:37][CH:38]([CH2:41][N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)[CH2:39][NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:30]([S:37][CH:38]([CH2:41][N:42]1[CH2:43][CH2:44][S:45][CH2:46][CH2:47]1)[CH2:39][NH:40][C:27]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:14]=2[N:16]([CH3:26])[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=[O:18])=[O:19])=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCC(CN1CCSCC1)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A mixture of 5-(3-methoxypropoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (330 mg), 2-(benzylthio)-3-thiomorpholinopropan-1-amine (200 mg), 1H-1,2,3-benzotriazol-1-ol (120 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (180 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:2, volume ratio) to give the title compound (380 mg, yield 78%) as a pale-yellow amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1.C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:29][C:28]([CH:30]=[C:6]2[S:5][C:4](=[S:7])[N:3]([NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11]([OH:13])=[O:12])[C:2]2=[O:1])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: NCCN
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1NN1C(=O)C(=Cc2ccc(-c3ccccc3Cl)o2)SC1=S
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.090 g, 0.34 mmol), 5-(2-chloro-phenyl)-furan-2-carbaldehyde (0.074 g, 0.36 mmol) (purchased from Aldrich Chemical Co.) and ethylenediamine diacetate (0.065 g, 0.036 mmol) in methanol (8 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 15 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (2 mL), water (2×2 mL), ether (2 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 19 h to afford 2-{5-[1-[5-(2-Chloro-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (141 mg, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 6.55 (1H, d, J=8.0 Hz), 6.87 (1H, t, J=7.6 Hz), 7.32 (1H, t, J=7.6 Hz), 7.44-7.51 (3H, m), 7.62 (1H, d, J=8.0 Hz), 7.66 (1H, d, J=8.4 Hz), 7.80 (1H, s), 7.91 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=8.0 Hz). LC/MS: APCI 457.2, HPLC 97.9%
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31](=[O:40])[C:32]([CH3:39])=[CH:33][NH:34]2>>[CH3:39][C:32]1[C:31](=[O:40])[C:30]2[C:35](=[CH:36][CH:37]=[CH:38][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=3)[N:3]=2)[NH:34][CH:33]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Cc1c[nH]c2cccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4[nH]cc(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 5-amino-3-methylquinolin-4(1H)-one (Compound 203A). 1H NMR (DMSO-d6, 400 MHz): δ=1.18 (t, J=7.07 Hz, 6 H), 2.00 (s, 3 H), 3.15-3.25 (m, 2 H), 3.96 (qd, J=7.37, 7.20 Hz, 4 H), 7.16 (d, J=7.83 Hz, 1 H), 7.24 (dd, J=8.59, 2.27 Hz, 2 H), 7.51 (t, J=7.96 Hz, 1 H), 7.61 (d, J=6.82 Hz, 2 H), 7.97 (d, J=5.81 Hz, 1 H), 8.45 (s, 1 H), 8.71 (br. s., 1 H), 9.84 (s, 1 H), 12.01 (d, J=6.06 Hz, 1 H), 14.42 (br. s., 1 H). MS (ES+): m/z 562.13 [MH+] (TOF, polar).
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CN(C)C)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)C[C@@H]1C[C@@H]1c1c[nH]c2ccc(C#N)cc12
Temperature: 70 °C
Yield: 75 %

Procedure:
Water (4 ml) and an aqueous solution of sodium hydroxide (2 ml, 10 N) were sequentially added to a flask charged with a solution of crude cis-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]-1-(N,N-dimethylaminomethyl)cyclo-propane dissolved in anhydrous ethanol (15 ml). The resulting mixture was heated at 70° C. for 1 h. The solvent was evaporated and the residue was taken up in brine (10 ml). The aqueous layer was extracted with 10% methanol/ethyl acetate (3×5 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography and eluted using a step gradient of a solvent mixture [chloroform/(2 M ammonia/methanol), 90/10, 80/20]. The cis-2-[5-cyanoindol-3-yl]-1-(N,N-dimethylaminomethyl)cyclopropane was obtained as a white solid (63 mg, 75% yield over 3 steps): 1H NMR (400 MHz, CDCl3): δ 8.47 (1H, br s), 8.07 (1H, s), 7.41 (2H, apparent q, J=8.0 Hz), 7.03 (1H, s), 2.37 (1H, dd, J=12.6, 4.7 Hz), 2.18 (6H, s), 1.97 (1H, m), 1.69 (1H, dd, J=12.6, 8.6 Hz), 1.34 (1H, m), 1.22 (1H, m), 0.71 (1H, q, J=5.0 Hz); MS m/e 240 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][NH:11][C:12]#[N:13])(=[O:5])[CH3:4].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1C=CC=CC=1>[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]#[N:13])(=[O:5])[CH3:4]
Reactant: CCCCCC(CCCNC#N)OC(C)=O
Reactant: CCOC(=O)C(C)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(C#N)CCCCCC(C)C(=O)OCC)OC(C)=O
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (57% in mineral oil) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformide (75 ml.) is treated, over 30 minutes, with 4-acetoxynonylcyanamide (22.6 g., 0.1 mole) (Example O, Step 5) dissolved in benzene (20 ml.). Stirring is continued for one hour. Then, ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 3.5 hours. The cooled reaction is poured into water (400 ml.) and extracted with ethyl acetate (2 × 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvent is removed in vacuo to give ethyl 7-[N-(4-acetoxynonyl)cyanamido]-2-methylheptanoate as a pale yellow liquid.