Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@@H:20]1[CH2:24][CH2:23][C@:22]([CH3:28])([C:25]([OH:27])=O)[C:21]1([CH3:30])[CH3:29])(=[O:3])[NH2:2].CC[N:33](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:25]([C@@:22]1([CH3:28])[CH2:23][CH2:24][C@@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[C:21]1([CH3:30])[CH3:29])(=[O:27])[NH2:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)C(N)=O
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred solution of (1S,3R)-3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylic acid (30 mg, 0.074 mmol) in DMF (492 μl) were added Hunig's base (97 μl, 0.554 mmol) and HATU (42.1 mg, 0.111 mmol). After 15 minutes, ammonium chloride (19.74 mg, 0.369 mmol) was added. The reaction was heated at 75° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed successively with water, (sat.) ammonium chloride and (sat.) sodium chloride. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a yellow oil. The crude product was chromatographed using reverse-phase HPLC (Column: LUNA 5u C18 21×100). The collected fractions were combined and concentrated under reduced pressure. The product was taken up in ethyl acetate and neutralized with (sat.) sodium carbonate. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (12.7 mg, 0.030 mmol, 40.3% yield) as a white solid. LC/MS found [M+H]+=406.2. 1H NMR (400 MHz, MeOD) δ ppm 8.13-8.17 (1 H, m), 7.92-7.96 (1 H, m), 7.64-7.70 (2 H, m), 7.35-7.44 (2 H, m), 7.23-7.30 (1 H, m), 7.15-7.20 (1 H, m), 4.68-4.77 (1 H, m), 2.54-2.67 (1 H, m), 2.41-2.54 (1 H, m), 1.70-1.80 (1 H, m), 1.60-1.69 (1 H, m), 1.35-1.42 (3 H, m), 1.13-1.19 (3 H, m), 1.06-1.13 (3H, m). HPLC Retention Time=3.058 (HPLC conditions: column. Phenominex Synergy, 4.6×50 mm, Mobile phase A: 90:10 water/methanol with 0.2% H3PO4; Mobile Phase B: 90:10 methanol/water with 0.2% H3PO4; Wavelength: 220 nm; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 4 mL/min.)
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]O)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][Cl:3])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Thionyl chloride (38.7 g., 0.376 mole) was added dropwise to a stirring solution of 4-(p-fluorobenzoyl)-1-(3-hydroxypropyl) piperidine (43.1 g., 0.163 mole) in 400 ml. chloroform at room temperature. After the addition was complete the reaction mixture was stirred at room temperature an additional 16 hours. The mixture was then chilled and 125 ml. 6N sodium hydroxide solution was added dropwise. The chloroform solution was separated, washed with water, and dried over magnesium sulfate. Removal of the solvent gave 42.7 g. crude product (92% yield) with crystallized on cooling. Recrystallization from isooctane gave 25.3 g. pure product, m.p. 66.5°-68.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CCN(CCOC)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
3-(2-methoxyethylamino)-N-methyl-propanamide (Intermediate 111; 608 mg, 3.79 mmol) 5-Bromo-2,4-dichloropyrimidine (Aldrich; 950 mg, 4.17 mmol), Triethylamine (555 μL, 3.98 mmol), and DCM (5 mL) were combined and stirred over the weekend at room temperature.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:12]1[C:13]([CH3:15])=[CH:14][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:18]
Reactant: COC(=O)c1cc(I)c(C)cc1C1CCC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (219.3, 3.0 g, 9.1 mmol), Zn(CN)2 (2.3 g, 19.6 mmol) and Pd(PPh3)4 (0.55 g, 0.47 mmol) in DMF (50 ml) was degassed and the flask was filled with argon through a balloon. The mixture was heated at 100° C. under argon overnight. After cooling to ambient temperature, the reaction was quenched with saturated aq. FeSO4 (20 ml) and diluted with EtOAc (200 ml). The mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 2.0 g, 96%. 1H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m, 1H).
Reaction SMILES: [Br-:1].[Li+].CC1C=CC(S(O[C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@H:19]([CH3:22])[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1>CN(C)C=O.O>[Br:1][C@H:14]1[CH2:18][O:17][C@@H:16]2[C@H:19]([CH3:22])[CH2:20][O:21][C@H:15]12
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3C)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Br
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A stirred mixture of lithium bromide (596 mg, 6.85 mmol) and tosylate (91a) (0.68 g, 2.28 mmol) in dimethylformamide (5 mL) was heated at 110° C. for 1 hour, then at 125° C. for 1.5 hours, then at 130° C. for 2 hours under an atmosphere of argon then diluted with water (20 mL). The product was extracted into diethyl ether (4×10 mL) then the combined organic layers washed with water (3×10 mL), brine (10 mL), dried (MgSO4), filtered and reduced in vacuo to leave an orange oil. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 35:65 gave bromide (92) as a colourless oil (292 mg, 62%). TLC (Rf=0.80, EtOAc:heptane 1:2), [α]D20.5+75.2° (c=1.13, CHCl3); δH (500 MHz, CDCl3) 1.10 (3H, d, J=6.80 Hz, CH3CH), 2.24-2.33 (1H, m, CH3CH), 3.30 (1H, dd, J=11.23 and 8.20 Hz, 1×CH2CHCH3), 4.13 (2H, m, CH2CHBr), 4.20 (1H, t, J=7.99 Hz, 1×CH2CHCH3), 4.28-4.30 (1H, m, CHBr), 4.68 and 4.74 (2H total, t, J=3.87 Hz and dd, J=3.55 and 0.92 Hz respectively, BrCHCHCHO); δC (125 MHz, CDCl3) 9.842 (CH3CH), 39.904 (CH3CH), 51.616 (CHBr), 74.993 and 76.118 (CH2CHBr and CH2CHCH3), 84.708 and 89.891 (BrCHCHCHO).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:6]([N+:32]([O-:34])=[O:33])[C:7]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(4-Chloro-5-ethoxycarbonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (XLVII) (1.0 g) was stirred with sulfuric acid (2 ml) at 0° C., then a mixture of nitric acid (1 ml) and sulfuric acid (1 ml) was dropwise added. After stirring at room temperature for 3 hr, it was poured into ice water (50 ml) and yellow crystals formed immediately which was filtered, washed with water and dried in fume hood overnight (0.5 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([O:20][CH3:21])[C:14]=1[N+:22]([O-:24])=[O:23].CCN(CC)CC>C(Cl)Cl>[CH:12]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([O:20][CH3:21])[C:14]=1[N+:22]([O-:24])=[O:23])=[O:11]
Reactant: COc1nc(C)cc(CO)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1nc(C)cc(C=O)c1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a −70° C. solution of oxalyl chloride (2.0 mL, 22 =mol) in 50 mL of DCM was added 3.4 mL (44 mmol) of DMSO in 10 mL of DCM by dropping funnel. After 2 min, the reaction mixture was treated with 3.99 g (20 mmol) of the alcohol from step C in 20 mL of DCM. The solution was stirred for an additional 15 min at −70° C., treated with 14 mL (50 mmol) of Et3N and warned to ambient temperature over 90 min. The reaction was quenched with 100 mL of water and the two phases were separated. The aqueous phase was extracted with 100 mL of DCM and the combined organic extracts were washed with 50 mL of brine and dried over MgSO4. The yellow solution was concentrated and chromatographed (2:3 EtOAc/Hexane) to afford the aldehyde as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH3:10]>>[F:9][C:5]1[C:6]([NH2:10])=[N:7][C:2](=[O:1])[NH:3][CH:4]=1
Reactant: N
Reactant: Oc1ncc(F)c(Cl)n1
Product: Nc1nc(=O)[nH]cc1F

Procedure:
A process for the preparation of 5-fluorocytosine comprising reacting 2,5-difluoro-4-chloropyrimidine with a proton acid in the presence of water to yield 2-hydroxy-4-chloro-5-fluoropyrimidine, and reacting the 2-hydroxy-4-chloro-5-fluoropyrimidine with ammonia to yield 5-fluorocytosine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].[F:27][C:28]1([CH2:33]OS(C(F)(F)F)(=O)=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:33][C:28]1([F:27])[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:2]
Reactant: O=S(=O)(OCC1(F)CCCC1)C(F)(F)F
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1(F)CCCC1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of N-(diphenylmethylene)glycine ethyl ester (1.94 g, 7.26 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added solid potassium t-butoxide (0.89 g, 7.93 mmol) over 10 min and the resulting solution stirred for an additional 15 min. A trifluoro-methanesulfonic acid 1-fluoro-cyclopentylmethyl ester (2 g, 7.99 mmol) solution in N,N-dimethylformamide (2 mL) was added and the resulting mixture allowed to warm to room temperature over 2 h. The resulting mixture was poured into saturated ammonium chloride and extracted with dichloromethane (200 mL). The organic phase was separated, washed with saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by AnaLogix flash chromatography (AnaLogix SuperFlash Flash Column 120 g, 10% to 20% ethyl acetate/hexanes) which afforded 2-(benzhydrylidene-amino)-3-(1-fluoro-cyclopentyl)-propionic acid ethyl ester (1.36 g, 58%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H), 1.39-1.97 (m, 8H), 2.11-2.41 (m, 1H), 2.45-2.76 (m, 1H), 4.01-4.27 (m, 2H), 4.37 (dd, J=7.5, 4.5 Hz, 1H), 7.16-7.25 (m, 2H), 7.29-7.41 (m, 3H), 7.41-7.56 (m, 3H), 7.64 (d, J=7.8 Hz, 2H).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:13]([OH:27])[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:17]=2[N:18]=1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:13]([OH:27])[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:17]=2[N:18]=1
Reactant: COC(=O)c1ccc2oc(C(O)C(Cc3ccccc3)NC(=O)OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2oc(C(O)C(N)Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
To a solution of the objective compound of step (3) (1.65 g, 3.58 mmol) in methanol (25 ml) was added 10% palladium-carbon (378 mg) under a nitrogen atmosphere, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The catalyst was filtered off, followed by washing with methanol, and the filtrate was concentrated under reduced pressure to give 1.14 g (yield 98%) of 2-amino-1-hydroxy-1-[5-(methoxycarbonyl)benzoxazol-2-yl]-3-phenylpropane as a light-brown solid.
Reaction SMILES: C[CH:2]([CH2:17][CH3:18])[CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][C:7]=2[CH:6]=1.[CH2:19](C1C=CC2OCC(=O)COC=2C=1)CCCC.CC(CC)CC1C=CC2OCC(=O)COC=2C=1.CC(C)CCC1C=CC2OCC(=O)COC=2C=1.CC1C2C=C3OCC(=O)COC3=CC=2CC1>>[CH3:19][CH:3]([CH2:2][CH2:17][CH3:18])[CH2:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: CCC(C)CCc1ccc2c(c1)OCC(=O)CO2
Reactant: CCCCCc1ccc2c(c1)OCC(=O)CO2
Agent: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Agent: CC1CCc2cc3c(cc21)OCC(=O)CO3
Agent: CCC(C)Cc1ccc2c(c1)OCC(=O)CO2
Product: CCCC(C)Cc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, floral-aldehyde odor.—IR (film): ν=1501/1434/1460/1580 cm−1 (ν C═C, Ar), 1265/1303/1201 cm−1 (ν ring), 1049 cm−1 (ν C—O—C), 1740 cm−1 (ν C═O),—1H-NMR (CDCl3): δ=0.83 (d, 3H, 2′-Me), 0.88 (t, J=7.0 Hz, 3H, 5′-H3), 1.11–1.40 (m, 4H, 3′-,4′-H2), 1.68 (mc1 1H, 2′-H), 2.26 (dd, J=13.6, 8.4 Hz, 1H, 1′-Hb), 2.54 (dd, J=13.6, 6.0 Hz, 1H, 1′-Ha), 4.69 (d, J=8.4 Hz, 4H, 2-,4-H2), 6.73 (dd, J=8.0, 2.0 Hz, 1H, 8-H), 6.78 (d, J=2.0 Hz, 1H, 6-H), 6.89 (d, J=8.0 Hz, 1H, 9-H).—13C-NMR (CDCl3): δ=14.15 (q, C-5′), 19.17 (q, 2′-Me), 20.02 (t, C-4′), 34.50 (d, C-2′), 38.77 (t, C-3′), 42.61 (t, C-1′), 75.36/75.63 (2t, C-2,-4) 120.30/121.04 (2d, C-6,-9), 124.28 (d, C-8), 137.61 (s, C-7), 146.05/147.70 (2s, C-5a,-9a), 204.77 (s, C-3).—MS (EI): m/z (%)=77 (9) [C6H5+], 91 (6) [C7H7+], 135 (5) [M+-C5H11—C2H2O], 149 (3) [M+-C5H11—CO], 177 (100) [M+-C5H11], 205 (2) [M+-C3H7], 248 (21) [M+].
Reaction SMILES: C([O:5][CH2:6][CH3:7])(=O)CO.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][N:12]=[CH:11][N:10]=1.C>>[OH:5][CH2:6][C:7]1[NH:8][C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:14]=2[N:15]=1
Reactant: CCOC(=O)CO
Reactant: Nc1cncnc1N
Product: OCc1nc2cncnc2[nH]1
Temperature: 140 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
8.58 g of ethyl glycolate were added to 2.27 g of 4,5-diaminopyrimidine, and the resulting mixture was stirred at 140° C. for 2 hours. At the end of this time, the reaction mixture was freed from ethyl glycolate by distillation under reduced pressure. The residue thus obtained was decolorized by activated charcoal and crystallized by trituration with ethanol, to give 1.81 g of the title compound having Rf=0.27 (on silica gel thin layer chromatography using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([SH:13])[CH2:11][CH3:12]>>[CH2:10]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: CCCS
Reactant: N#Cc1ccc(F)cc1
Product: CCCSc1ccc(C#N)cc1

Procedure:
1 g of 4-fluorobenzonitrile was used in Procedure Q with 1-propanethiol to afford 4-(propylthio)benzonitrile. 860 mg of 4-(propylthio)benzonitrile was reacted via Procedure T to give 4-(propylthio)benzoic acid. 700 mg of 4-(propylthio)benzoic acid was reacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(propylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][CH:20]1[CH2:25][N:24]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)nn1-c1ccccc1

Procedure:
68 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 2-methyl-1-m-tolylpiperazine (63 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:65][CH3:66])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH2:53][F:54])[CH2:49][N:48](C(OCC3C=CC=CC=3)=O)[CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]>>[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:65][CH3:66])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH2:53][F:54])[CH2:49][NH:48][CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.15, 1.29, 2.48, 2.70, 2.90, 2.90, 3.15, 3.23, 3.44, 3.85, 4.11, 4.55, 4.66, 5.32, 6.88, 7.02, 7.24.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[O:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[O:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanone was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to give, after purification by reverse HPLC, 292. MS (Q1) 352 (M+)
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]CC)=[O:26])[CH:19]=2)[NH:14]1)(=[O:5])=[O:4])[CH3:2].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[CH2:1]([S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=2)[NH:14]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)CC)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(ethylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-(2-ethanesulfonylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 389.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C:7](=[O:29])[N:8]([C:14]1[S:15][C:16]([Cl:28])=[CH:17][C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[Cl-].[Cl-].[Cl-].[Cs+].[Cs+].[Cs+].[BH4-].[Na+].CC(C)=O>CO>[CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C:7](=[O:29])[N:8]([C:14]1[S:15][C:16]([Cl:28])=[CH:17][C:18]=1[CH:19]([OH:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C=CC(=O)N(CC(C)(C)C)c1sc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)C=CC(=O)N(CC(C)(C)C)c1sc(Cl)cc1C(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103.8 %

Procedure:
To a solution of 3-[N-[5-chloro-3-(2-chlorobenzoyl)-2-thienyl]-N-neopentylcarbamoyl]acrylic acid ethyl ester (2.37 g) and cesium trichloride.heptahydrate (2.98 g) in methanol (100 ml) was gradually added, sodium borohydride (303 mg) at room temperature. The mixture stirred for 20 minutes at room temperature, to which was added acetone, then the solvent was distilled off. To the residue were added 1M potassium hydrogensulfate and acetic acid ethyl ester. The organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography to give a non-crystalline solid (2.47 g).