Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:22]([OH:25])[CH2:23][OH:24]>N1C=CC=CC=1>[CH2:1]([NH:19][C:20]([O:24][CH2:23][CH2:22][OH:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCO
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCO
Reaction time: 8 h
Yield: 79.7 %

Procedure:
In 50 ml of pyridine are dissolved 11.8 g (40 mM) of stearyl isocyanate and 12.4 g (200 mM) of ethylene glycol, and the solution is allowed to stand at room temperature overnight. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is recrystallized from 100 ml of methanol to give 11.38 g (yield 79.5%) of the contemplated product. mp. 81°-82° C.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.O>CN(C=O)C>[CH2:11]([NH:18][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(S)nc1
Reactant: NCc1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1)c1ccc(S)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Combine 6-mercapto-nicotinic acid (0.64 g, 4.1 mmol), benzylamine (0.45 mL, 4.1 mmol) and EEDQ (1 g, 4 mmol) in anhydrous DMF (3 mL). Stir at room temperature for 12 h. Dilute the reaction with water and extract with DCM. Dry over MgSO4, filter and concentrate in vacuo to give a yellow solid. Purify by chromatography on silica gel eluting with 2M ammonia in methanol/DCM (2:98 and 10:90) to give the title compound as a yellow solid (440 mg, 44%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C:17]2(O)[CH2:21][CH2:20][CH2:19][CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@:7]([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCC2)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](C2=CCCC2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Intermediate (1b) (650 mg, 2.1 mmol) was dissolved in 6.8 mL anhydrous THF and the solution was cooled to 0° C. Thionyl chloride (436 μL, 6 mmol) was added dropwise, followed by the addition of pyridine (777 μL, 9.6 mmol). The mixture was stirred at 0° C. for 1 hour. Saturated aqueous ammonium chloride (14 mL) was added and the mixture was stirred for 5 minutes while warming to room temperature. The layers were separated, and the aqueous layer was washed (2×100 mL EtOAc.). The organic layers were combined, dried over Na2SO4, filtered and concentrated to yield intermediate (1c) as a light yellow oil (540 mg), which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]/[N:23]=[CH:12]/[C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:10]=1[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)CCN
Reactant: O=Cc1cccc(F)c1NCCN1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-(2-Morpholinoethylamino)-3-fluorobenzaldehyde (495 mg, 1.962 mmol), 3,3-dimethylbutan-1-amine (400 μL, 2.973 mmol), and MgSO4 were added to toluene (15 mL) and the reaction stirred in a 70° C. oil bath overnight. The oil bath temperature was raised to 100° C. for 2.5 hours, then heat was removed, solvent and volatiles removed under high vacuum on a rotary evaporator at 35° C. to give 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-morpholinoethyl)benzenamine. The crude material was carried on to the next reaction. FIA: 336.49 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 50.6 %

Procedure:
2,4-Difluoronitrobenzene (8.0 g) was dissolved in N,N-dimethylformamide (110 ml) and the solution was admixed with 1H-1,2,4-triazole (3.47 g) and potassium carbonate (6.95 g) and the mixture was stirred under a nitrogen atmosphere at 70° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and washed 5 times with water and then with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:1.3). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 1-(3-fluoro-4-nitrophenyl)-1H-1,2,4-triazole (5.29 g) as yellow powdery crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:10]([OH:15])[OH:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
3-Bromobenzonitrile (3.6 g, 20 mmol) in anhydrous THF (100 ml) is treated with triisopropyl borate (13 ml, 56 mmol) followed by 1.6 M butyllithium in hexane (14 ml, 22 mmol) over 15 min. at −78° C. The reaction is stirred at −78° C. for 45 min . then warmed to room temperature over 60 min. The reaction mixture is poured into 40 ml 2 N HCl and the precipitated solid is collected . The filter cake is washed with water (3×) and methylene chloride (3×) to yield 3-cyanophenyl boronic acid (2.3 g, 15.6 mmol). 1H NMR (CDCl3, 300 MHz) δ 8.4 (br, 2H), 8.13 (s, 1H), 8.07 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H). EI MS M+ 147.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](S(C)(=O)=O)=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.O>O1CCCC1>[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13]([C:1]#[N:2])=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C#N)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
An aqueous solution (2 ml) of sodium cyanide (338 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (758 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:32]/[OH:33])/[CH2:9][C@@H:10]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(N3CCOCC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(N3CCOCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-1-(2-methylpyridin-4-yl)-3-(4-morpholino-phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white solid, MS (ESI+): m/z=416.5 ([M+H]+).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=O.[C:33]([BH3-])#[N:34].[Na+]>CO>[C:33]([CH:11]([NH:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)#[N:34]
Reactant: CCOC(=O)c1ccc(CCCN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(CCCN2CCC(C(C#N)N[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol), ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) were heated to reflux for 5 minutes. The reaction was cooled to room temperature and added sodium cyanoborohydride (0.590 g, 9.39 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and DCM was added and washed with water, brine, dried over MgSO4, filtered and rotovapped off solvent. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off ethyl 4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate then 0% to 20% MeOH:DCM to get off ethyl 4-(3-(4-((((1R,2S)-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate 50 g-HP-silica gel column). Obtained 1.18 g of ethyl 4-(3-(4-(4(1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H); [M+H]+ 421.3
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][CH3:4].[Mg].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH3:4][CH:3]([CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=1)[OH:13])[CH:2]=[CH2:1]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC=CCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)C(O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
Crotyl chloride (154.7 g, 1.71 mol) in dry tetrahydrofuran (530 ml) was added to magnesium turnings (46.0 g, 1.89 mol) in dry tetrahydrofuran (130 ml) at such a rate so as to maintain steady reflux. After addition was complete the mixture was heated under reflux for a further hour and then cooled to 0° C. 4-Chlorobenzaldehyde (120.0 g, 0.854 mol) in dry tetrahydrofuran (780 ml) was added over a period of 2 hours. After a further hour the solution was decanted from the excess magnesium into saturated aqueous ammonium chloride solution and the magnesium washed with ether. 2M Hydrochloric acid was added to dissolve the precipitate and the mixture extracted with ether. The combined extracts were washed with water, dried and evaporated in vacuo. Partial purification was achieved by chromatography [SiO2, hexane-ethyl acetate mixtures] to give 3-methyl-4-(4-chlorophenyl)-but-1-en-4-ol (118.45 g, approximately 90% pure, approximately 64%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.ICI.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-6-[1-(ethenyloxy)propyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (170 mg, 0.39 mmol) in dichloromethane (4.0 mL) was added a solution of diethyl zinc id hexane (1.0 M, 2.0 mL, 2.0 mmol) and diiodomethane (0.31 mL, 3.84 mmol) at 0° C. After stirring at 0° C. for 1.5 hr, aqueous ammonium chloride was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (87.7 mg, 0.196 mmol, 50%) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18])[CH2:9][CH2:10][CH3:11].C(CN)O>O.C(O)C>[CH2:8]([N:12]1[C:16](=[O:17])[C:15](=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[NH:14][C:13]1=[O:18])[CH2:9][CH2:10][CH3:11]
Reactant: O=Cc1cccs1
Reactant: CCCCN1C(=O)CNC1=O
Solvent: O
Solvent: CCO
Solvent: NCCO
Product: CCCCN1C(=O)NC(=Cc2cccs2)C1=O
Yield: 51.1 %

Procedure:
A mixture of thiophene-2-carboxaldehyde (5.6 g; 0.05 mole), 3-n-butylhydantoin (7.8 g; 0.05 mole) and ethanolamine (4.6 g; 0.075 mole) in water/ethanol (50 ml/30 ml) was stirred and boiled under reflux for 4 hours. The mixture was cooled in the refrigerator and the resultant brownish yellow crystals filtered off, washed with water, sucked dry and recrystallised from ethyl acetate (with carbon treatment) to give the title compound (6.4 g; 51%) having m.p. 140° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([F:47])[CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][C:42]=1[F:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (44 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (55 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 7.31-6.85 (m, 3H), 5.45-5.18 (m, 1H), 4.90-4.60 (m, 2H), 4.50-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.60 (m, 2H), 3.40 (m, 1H), 3.20-2.70 (m, 2H), 2.24 (m, 1H), 1.70 (m, 1H), 1.42 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +532.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:18]=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CO.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(OCC)(=O)C>[CH:25]1([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=Cc1ccc(OCC2CCCCC2)c(Br)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC2CCCCC2)c(-c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 32.2 %

Procedure:
A solution of 2-naphthaleneboronic acid (535 mg) in methanol (5.0 ml), Intermediate 25 (1.16 g), and 2 M aqueous sodium carbonate (0.9 ml) were added with toluene (10.0 ml) and tetrakistriphenylphosphinepalladium(0) [hereinafter abbreviated as “(Ph3P)4Pd”] (116 mg, Nakarai Tecs), and stirred at 80° C. for 17 hours. The reaction mixture was added with ethyl acetate (100 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (Compound No. C-1, 345 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:16][NH2:17])[N:3]=1.CC(O)=O.[N:22]([O-])=O.[Na+]>O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[N:3]2[N:22]=[N:17][N:16]=[C:4]2[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c2nnnn2c1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A 25 mL round bottom flask was charged with 2-bromo-6-hydrazinyl-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (0.92 g, 3.0 mmol) and CH3COOH (2 mL). To the above was added dropwise a solution of NaNO2 (0.32 g, 4.6 mmol) in water (2 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and then extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4% MeOH in CH2Cl2, to afford 0.72 g (75%) of the product as a white solid. MS m/z: 312 (M+H+).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)[C:4]([O:6]C)=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]([NH2:40])=[NH:39])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:45])([F:44])[F:43]>CN1C(=O)CCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]3[NH:40][CH:1]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:4](=[O:6])[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:43])([F:44])[F:45]
Reactant: COC(=O)C(C=O)Cc1cncnc1
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 200 °C
Yield: 27.4 %

Procedure:
To the mixture of methyl 2-formyl-3-(5-pyrimidinyl)propanoate (67.9 mg, 0.350 mmol) and K2CO3 (149 mg, 1.076 mmol) in NMP (2 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 3 h. Purification via MDAP then afforded the title compound as a white solid (38 mg, 22.4% yield). LCMS: rt=3.02 min, [M+H+]=516.0
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:5])=[O:4].S(OC)(O[CH3:27])(=O)=O.O>CN(C=O)C>[CH3:27][N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2[N+](=O)[O-])cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in 3.0 ml of DMF, 2′-nitro-p-toluenesulfonanilide (1.00 g (3.42 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.4 ml (4.22 mmol)) was added dropwise. After 2 hour's stirring, water was added to bring about separation of crystals. The resulting crystals were filtered, washed with water, dried and subjected to silica gel column chromatography with ethyl acetate-hexane (1:2 to 1:1) as eluent to give 0.93 g (89%) of N-methyl-2′-nitro-p-toluenesulfonanilide (Compound No.38) as pale yellow crystals.