Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([CH:14]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[CH2:15][OH:16])[CH2:13]C1.C(N(CC)CC)C>ClCCl.O>[CH:15]([C:14]1([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=2)[CH2:11][CH2:13]1)=[O:16]
Reactant: OCC(COCc1cccc(Oc2ccccc2)c1)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=CC1(COCc2cccc(Oc3ccccc3)c2)CC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
A solution of dry dimethyl sulphoxide (0.87 g) in dichloromethane (12 cm3) was added dropwise to a stirred solution of oxalyl chloride (0.75 g) in dichloromethane (12 cm3) maintained at -70° C. After a period of five minutes had elapsed, a solution of 2-cyclopropyl-3-(3-phenoxybenzyloxy)propane-1-ol (1.45 g) in dichloromethane (6 cm3) was added dropwise, followed by triethylamine (2.3 g) five minutes later. When the addition was complete the mixture was allowed to warm to the ambient temperature over a period of 2 hours. The reaction mixture was poured into water, and extracted with diethyl ether. The extracts were combined, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent. The residual oil (1.5 g) was purified by column chromatography using a silica gel column and eluting with dichloromethane to yield 1-formyl-1-(3-phenoxybenzyloxymethyl)cyclopropane (1 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)C(c1ccc(F)cc1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccc(F)cc1)N1CCCCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
37% Hydrogen chloride (4.18 ml, 50.9 mmol) was added to a solution of methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 1.27 mmol) in dioxane (5 ml). The reaction was stirred under microwave irradiation at 100° C. for 5 hours. The solvent was evaporated and the solid triturated with acetonitrile to obtain 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (255 mg, 73% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:16]1[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](Br)=[CH:19][N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(CCl)=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:16]1[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:18]=[CH:19][N:20]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Cn2c(Br)cnc2[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc2[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
{(S)-1-[5-bromo-1-(4-methoxy-benzyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester: To a solution of 92C (115.0 g, 0.49 mol) in DMF (1400 mL) at 0° C. was added p-methoxybenzyl chloride (100.4 g, 0.64 mol). The reaction mixture was stirred at rt overnight, then poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude was purified by column chromatography to obtain {(S)-1-[1-(4-methoxy-benzyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester as a white solid (120 g, 74%). 1HNMR (CDCl3, 400 MHz) δ: 7.21 (d, 2H), 7.02 (d, 2H), 6.78 (m, 6H), 6.6 (s, 1H), 5.08, 5.04 (2d, 1H), 4.64 (dd, 2H), 3.78 (s, 2H), 3.2 (m, 1H), 1.3 (m, 9H). LCMS m/z 407 (M+H)+. To this intermediate (25 g, 60 mmol) in acetonitrile at −20° C. was added N-bromosuccinimide (8.7 g, 49 mmol) portion wise and the reaction was stirred at −20° C. for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give 92D as a white solid (11 g, 38%). 1HNMR (CDCl3, 400 MHz) δ 7.25 (d, 2H), 7.04 (d, 2H), 6.83 (m, 6H), 5.2 (s, 1H), 5.09 (m, 2H), 4.8 (d, 1H), 3.78 (s, 3H), 3.2 (m, 2H), 1.3 (m, 9H). LCMS m/z 486 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[C:14]=2[C:4]=1[OH:20])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Yield: 76.1 %

Procedure:
Diphenyl ether (20 ml) was heated to 260° C. or above, and a solution of 6.87 g of N-(3-oxo-1-cyclohexen-1-yl)aminomethylenemalonic acid diethyl ester in 5 ml of diphenyl ether was added thereto drop by drop. The resulting reaction mixture was refluxed for 15 minutes. After being allowed to cool, the reaction mixture was poured into 300 ml of n-hexane. The precipitate so formed was separated by filtration and then purified to obtain a yield of 4.37 g of the desired compound in the form of a pale-yellow powder. This compound melted (and decomposed) at 221°-224° C. Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3340, 2960, 1740, 1690, 1635, 1605, 1560, 1510, 1285, 1170, 1150, 1090, 1035, 920 and 815 cm-1, and its n.m.r. spectrum (d6 -DMSO, 60Mc, TMS) had signals at δ values of 1.31 (3H, t, J=7 Hz), 1.9-3.1 (6H, m), 4.27 (2H, q, J=7 Hz), and 8.55 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[CH2:3]1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([CH2:3][CH:2]([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: CC1Cc2ccc(OCCCC=O)nc2NC1=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1Cc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2NC1=O
Reaction time: 0.08 h

Procedure:
To a solution of crude 4-(6-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.5 g, 2.0 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to 0° C. was added 2,3-dichlorophenylpiperazine (1.1 g, 4.0 mmol, 2.0 equiv). The mixture was stirred for 5 min and NaBH(OAc)3 (2.14 g, 10.0 mmol, 5.0 equiv) was added. The reaction mixture was brought to room temperature and stirred overnight. TLC indicated a trace amount of aldehyde was still left. More NaBH(OAc)3 was added and stirring continued for one more hour. TLC indicated the reaction was complete. The reaction mixture was concentrated to dryness. The resultant pale green residue was dissolved in ethyl acetate and washed with 0.5 N HCl (1×10 mL), saturated NaHCO3 solution (1×10 mL) and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 2% MeOH/CH2Cl2) to afford the title compound as a colorless viscous material (0.63 g, 75% over 2 steps). The enantiomers were separated by chiral HPLC (Chiralpak AD, 40:60 Hexane/EtOH) to give the enantiomers D6a and D6b. MS: APCI: M+1: 463.1 (Exact Mass: 462.16).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(CC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of 10 g of 4-(2-trimethylsilylethinyl)-phenylacetic acid methyl ester in 950 ml of tetrahydrofuran is mixed at 0° C. with 45 ml of a 1-molar solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is stirred for 15 minutes at 0° C. and for 2 hours at room temperature and then concentrated by evaporation. The residue is spread between water and ethyl acetate, the organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-7% ethyl acetate. 5.6 g of 4-ethinylphenylacetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [CH2:1]([C:8]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC2C=CC(OC)=CC=2)=[O:25])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(C1C2C(=CC=CC=2)N(CCCC(OCC2C=CC(OC)=CC=2)=O)C=1)(=O)/C=C/CCCCCC>>[CH2:36]([C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=1)=[O:11])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC(=CC(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)CCCCCCC
Agent: CCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Product: CCCCCCCC(=CC(=O)c1cn(CCCC(=O)O)c2ccccc12)CCCCCCC

Procedure:
The procedure of Ex. 45 was repeated except that 4-methoxybenzyl 4-[3-(3-heptyl-2-decenoyl)-1-indolyl]butyrate obtained in Ex. 53 was used in place of (E)-4-methoxybenzyl 4-[3-(2-nonenoyl)-1-indolyl]butyrate to give 4-[3-(3-heptyl-2-decenoyl)-1-indolyl]butyric acid as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:30](=[O:31])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.I[C:67]1[CH:68]=[N:69][N:70]([CH3:72])[CH:71]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:30](=[O:31])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:67]4[CH:68]=[N:69][N:70]([CH3:72])[CH:71]=4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: Cn1cc(I)cn1
Reactant: O=c1c2cn(Cc3ccc(B(O)O)cc3)c3ccccc3c-2nn1-c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(Cn3cc4c(=O)n(-c5ccccc5F)nc-4c4ccccc43)cc2)cn1
Temperature: 25 °C

Procedure:
(4-{[2-(2-Fluorophenyl)-3-oxo-2,3-dihydro-5H-pyrazolo[4,3-c]quinolin-5-yl]methyl}phenyl)boronic acid (Example 370, 60 mg, 0.14 mmol) was dissolved in degassed dimethylsulfoxide (1 mL), treated with 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (10 mg, 0.022 mmol, 0.15 equiv), 4-iodo-1-methyl-1H-pyrazole (33 mg, 0.16 mmol, 1.1 equiv), an aqueous solution (0.2 mL) of potassium carbonate (50 mg, 0.36 mmol, 2.5 equiv) and palladium(II) acetate (1.6 mg, 0.0073 mmol, 0.05 equiv) and placed into a preheated oil bath at 80° C. for 1 hour. The mixture was cooled to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed once with water (10 mL) and brine (10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 95:5; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.42 (1H, br d, 7.1 Hz), 7.74 (1H, s), 7.65 (1H, td, J=7.7, 2.0 Hz), 7.60 (1H, s), 7.54-7.46 (5H, m), 7.38-7.33 (1H, m), 7.29-7.23 (2H, m), 7.20 (2H, d, J=8.2 Hz), 5.46 (2H, s), 3.94 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 450.1739 [(M+H)+; calculated for C27H21FN5O: 450.1725].
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C([P+](CCCC)(CCCC)CCCC)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: CSCC[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. A solution prepared by dissolving 814 mg (2 mmol) of tetrabutylphosphonium methionine salt in 15 mL of acetonitrile was dropped to the solution, and then the mixture was stirred for 30 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-methionine was obtained. An isolation amount and an isolation yield were 430.9 mg and 80%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cn1
Agent: O=S(=O)(O)O
Product: Nc1ncc(Cl)cc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 56 was repeated, except that 25.0 g of 2-amino-5-chloro-pyridine, 100 ml of concentrated sulfuric acid and 12.5 ml of concentrated nitric acid were used, to give 18.5 g of the title compound, melting at 138-139° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].[OH:12]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+].O=O.S([O-])([O-])=O.[Na+].[Na+]>CC#N.O.OO>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[C:6]([OH:12])=[O:7])#[N:2]
Reactant: O=P([O-])(O)O
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 166.9 %

Procedure:
To a solution of 3-cyano-4-fluorobenzaldehyde (45 g, 301 mmol) in CH3CN (450 mL) was added potassium phosphate monobasic (24 g, 176 mmol) in water (225 mL) and 30% hydrogen peroxide in water (30 mL). The reaction mixture was cooled to 0° C. and sodium chlorite (60 g, 663 mmol) in water (450 mL) was added dropwise over 2 h. The resulting yellow suspension was stirred at room temperature until production of oxygen ceased (4 h). Sodium sulfite (30 g, 238 mmol) in water (100 mL) was added and the reaction mixture stirred for 1 h. The reaction was quenched with 2N HCl (500 mL) and the resulting solid was filtered and washed with water. The aqueous phase was extracted with EA (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, concentrated, and combined with the collected solid to produce a total of 48.5 g (97%) of crude 3-cyano-4-fluorobenzoic acid as a white solid. LCMS-ESI (m/z) calculated for C8H4FNO2: 165.0; found 166.1 [M+H]+, tR=2.54 min. 1H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 8.41 (dd, J=6.3, 2.1 Hz, 1H), 8.30 (ddd, J=8.8, 5.3, 2.2 Hz, 1H), 7.66 (t, J=9.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=3)[C:15]([N+:28]([O-])=O)=[CH:14][CH:13]=2)[CH2:9][CH3:10])=[N:6][CH:7]=1.[CH2:31](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([C:19]4[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=4)[CH:31]=[N:28][C:15]3=[CH:14][CH:13]=2)[CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCO
Reactant: CC[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(OC(C)C)[nH]n2)n1)c1ccc(F)cn1
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](Nc1ccc2ncn(-c3cc(OC(C)C)[nH]n3)c2n1)c1ccc(F)cn1
Temperature: 25 °C

Procedure:
N6-[(1S)-1-(5-fluoropyridin-2-yl)propyl]-N2-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 36, 0.45 g) was dissolved into ethanol (20 mL) with Pd—C (150 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.12 g desired product. MS (electrospray): 396 (M+1) for C20H22FN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H) 8.30 (s, 1H) 7.70 (d, 1H) 7.50 (m 2H) 6.70 (d, 1H) 6.10 (s, 1H) 5.00 (m, 1H) 4.40 (m, 1H) 2.00 (m, 2H) 1.40 (d, 6H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([N:16]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(C2CC2)C1=O
Yield: 70.1 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and cyclopropanamine (0.309 mL; 4.36 mmol) in ethanol (3 mL). 1-cyclopropyl-2-oxopyrrolidine-3-carboxylic acid 0.172 g (70%) was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18](O)=[O:19])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18]([N:4]([O:3][CH3:2])[CH3:5])=[O:19])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (2.75 g) in acetonitrile (120 mL) was neutralized with triethylamine (9.83 mL), 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (8.16 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.77 g) and 1-hydroxybenzotriazole (541 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (8.64 g, yield 94%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([CH2:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](Cc1nnn(C)n1)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](Cc2nnn(C)n2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetate (1.0 g, 2.27 mmol) is dissolved in tetrahydrofuran (11.3 mL) and water (11.3 mL). To this solution is added lithium hydroxide hydrate (0.095 g, 2.27 mmol), and the reaction is stirred at room temperature for 2 hours. The reaction is then acidified to pH=~3 using 1N hydrochloric acid, and extracted well with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated to provide 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetic acid (0.96 g).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:13].N([O-])=O.[Na+].[I-:18].[K+]>Cl.O.ClCCl>[I:18][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:13]
Reactant: CNC(=O)c1cc(C)c(N)c(C)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cc(C)c(I)c(C)c1
Temperature: 0 °C

Procedure:
4-Amino-3,5,N-trimethyl-benzamide (850 mg, 4.77 mmol) is suspended in hydrochloric acid (37%, 2 mL), stirred until completely dissolved then cooled to 0° C. Sodium nitrite (494 mg, 7.15 mmol) in water (0.5 mL) is added and the mixture stirred for 1 hour at 0° C. Potassium iodide (2.38 g, 14.31 mmol) in 1.5 mL water is added and the mixture stirred for 15 minutes. The mixture is diluted with dichloromethane then washed with 10% aqueous sodium thosulfate solution, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound. (Yield 850 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14])[NH2:8].[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:16]=[O:17])[CH:9]=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1c(Cl)cc(N)cc1OCCCl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(N=C=O)cc1OCCCl
Temperature: 25 °C

Procedure:
3-(2-Chloroethoxy)-4-ethoxy-5-chloroaniline (2.50 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-(2-chloroethoxy)-4-ethoxy-5-chlorophenyl isocyanate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 1-butyn-3-ol (0.75 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 1-methyl-2-propynyl N-[3-(2-chloroethoxy)-4-ethoxy-5-chlorophenyl]-carbamate (Compound No. 31) (3.27 g) in a yield of 91.6%.