Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].[B-:10]([F:14])([F:13])([F:12])[F:11].[CH3:15]C[O+](CC)CC>ClCCl>[F:11][B-:10]([F:14])([F:13])[F:12].[CH:1]([C@H:4]1[CH2:8][O:7][C:6]([CH3:9])=[N+:5]1[CH3:15])([CH3:3])[CH3:2]
Reactant: CC1=N[C@@H](C(C)C)CO1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1=[N+](C)[C@@H](C(C)C)CO1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
15 g (0.12 mol) 4-(S)-isopropyl-2-methyloxazoline are dissolved in 50 ml dichloromethane and cooled to −20° C. 18 g (0.122 mol) Meerwein's reagent are added portionwise. The reaction mixture is stirred for 2 h at room temperature after addition is completed. The solvent is removed under vacuum and the residue is washed with diethyl ether. The yield of 4-(S)-isopropyl-2,3-dimethyl-oxazoliniumtetrafluoroborate is 27 g. The enantiomer excess in the product is >95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([C:12](O)=[O:13])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][O:7][C:6]=2[CH:19]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([C:12]([NH:25][C:24]3[C:26]([CH:30]([CH3:31])[CH3:32])=[CH:27][CH:28]=[CH:29][C:23]=3[CH:20]([CH3:22])[CH3:21])=[O:13])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)C1c2ccccc2COc2cc(Br)ccc21
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2cc(Br)ccc21
Yield: 73.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound K in place of Compound A and 0.78 g of 2,6-diisopropylaniline in place of aniline to obtain 1.54 g of Compound 29.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].C(Cl)(Cl)=[S:18]>CC(C)=O>[N-:11]=[C:7]=[S:18].[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1
Product: [N-]=C=S

Procedure:
To 3-(tert-butyl)phenylamine in acetone at 0° C. was added sodium bicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought to ambient temperature and concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium bicarbonate and sodium sulfate and concentrated to yield 3-(tert-butyl)benzenisothiocyanate. MS: MH+=192.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:3]=1[C:4](OCC)=[O:5].Cl.[CH:24](N)=[NH:25]>C(N)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:1]=[CH:24][NH:25][C:4]2=[O:5]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: Cl
Solvent: NC=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Temperature: 130 °C
Yield: 55.9 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (7.15 g, 22.8 mmol) and formamidine hydrochloride (2.012 g, 25 mmol) in formamide (20 mL) was heated at 130° C. for 12 hours, to afford 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (3.75 g, 56%). 1H NMR (300 MHz, CDCl3) δ 10.89 (br, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 4.29 (t, 4H), 3.86 (t, 4H), 3.48 (s, 6H); LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCOCC3)cc2)n1
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
The AlCl3 (5 g, 38 mmol) was stirred in 100 mL of DCE at 0° C., ethanethiol (4 mL, 54 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(4-morpholinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (2.2 g, 5.4 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 50 mL THF at 0° C., followed by 50 mL 1N HCl and worked up. The crude product was triturated with Et2O/ pet. ether, filtered, and dried in vacuo to give 1.9 g (90 % yield) of white solid: mp 75-80 ° C.; 1H NMR (CDCl3) d 2.59-2.62 (comp, 7H, morpholine and pyr-CH3), 2.79-2.83 (t, 2H, J=5 Hz, CH2N), 3.74-3.77 (m, 4H, morpholine), 4.07-4.11 (t, 2H, J=5 Hz, OCH2), 6.63-6.71 (m, 4H, ArH), 6.94-6.97 (d, 2H, J=8 Hz, ArH), 7.11-7.13 (d, 1H, J=8 Hz, ArH), 7.24-7.27 (d, 2H, J=8 Hz, ArH), 7.53-7.56 (d, 1H, J=8 Hz, ArH); MS(FD) 390 (M+). Anal. Calcd for C24H26N3O3 : C, 73.82; H, 6.71; N, 7.17. Found: C, 73.75; H, 6.71; N, 7.05.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](=O)[CH3:8])[CH2:3][CH2:2]1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>O1CCCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:10][C:11]([S@:14](/[N:16]=[C:7](/[CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)\[CH3:8])=[O:15])([CH3:13])[CH3:12]
Reactant: CC(=O)C1CCOCC1
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)C1CCOCC1
Yield: 43.8 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-4-yl)ethanone (1.9 g, 14.8 mmol) in tetrahydrofuran (30 mL) was added (R)-2-methylpropane-2-sulfinamide (2.15 g, 17.8 mmol) and tetraethoxytitanium (5.06 g, 22.2 mmol) at 25° C. under N2. The reaction was refluxed for 7 hrs. Then the mixture was quenched by water, extracted with ethyl acetate and filtered. The crude product was purified by column chromatography on silica gel eluted with dichloromethane: methanol=200:1 to give (R,E)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide (1.5 g, 44.1%) as a yellow oil.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:35]=[CH:34][C:16]2[C:17](=O)[C:18](=[CH:29]N(C)C)[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:29][C:18]2[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:35]=[CH:34][C:16]=3[C:17]=2[N:5]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20 ml (82 mmole) of 4.12M methanol solution of sodium methoxide was added over 90 min to a solution of 3.6 g (10 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 100 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with methylene chloride gave a white solid, mp 240°-241° C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles, mp 240°-241° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[CH:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and cyclopropanamine (18.29 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (43.0 mg, 0.096 mmol, 45.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.46-0.59 (m, 2 H) 0.59-0.71 (m, 2 H) 1.82-2.02 (m, 3 H) 2.10-2.25 (m, 1 H) 2.46 (br. s., 4 H) 2.74-2.83 (m, 1 H) 3.21 (br. s., 4 H) 3.34-3.46 (m, 3 H) 3.53-3.64 (m, 1 H) 3.94-4.02 (m, 1 H) 6.91 (d, J=8.84 Hz, 2 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.26 Hz, 1 H) 7.68 (d, J=8.84 Hz, 2 H) 8.13 (d, J=4.04 Hz, 1 H) 10.44 (s, 1H); [M+H] calc'd for C25H30N6O2, 447; found, 447. melting point 265-268° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:13]C1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C=O)C>[ClH:13].[CH3:8][C:7]1[C:2]([NH2:1])=[CH:3][C:4]([NH:9][C:10]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1
Reactant: Clc1ncccn1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ncccn2)cc1N
Product: Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of N-(3-amino-4-methyl-phenyl)acetamide (5 g, 25 mmol) in DMF (5 mL) was added 2-chloropyrimidine (3.8 g, 33 mmol) and KI (0.5 g). The reaction was stirred at 100° C. overnight, cooled to 10° C. (100 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in conc. HCl (10 mL), stirred at 80° C. for 2 h and concentrated under vacuum to yield 6-methyl-N′-(pyrimidin-2-yl)benzene-1,3-diamine hydrochloride (3.75 g, 75% yield). 1H NMR (400 MHz, CDCl3): 8.36 (dd, J=15.2, 4.8 Hz, 2H), 7.46 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 6.67 (t, J=4.8 Hz, 1H), 6.39 (dd, J=8.0, 2.4, Hz, 1H), 2.20 (s, 3H); MS (ESI) m/e: 201 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 16A (2.8 g) in THF (20 mL) was added lithium hydroxide monohydrate (500 mg) in water (5 mL). The mixture stirred at ambient temperature overnight and partitioned between ethyl acetate and 0.5 M hydrochloric acid. The extract was washed with water, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 61.8 %

Procedure:
A mixture of 3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic Acid (12.5 g, 120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at 150° C. for 1 h. The reaction was poured onto 3N HC1 (200 mL) and the precipitate was removed via filtration. The product was purified by recrystallization (100 mL hot EtOH) to afford 3-(3,5-dichlorophenyl)-acrylic Acid (11.5 g). 1H NMR (250 MHz, DMSO-d6) δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6,72 (d, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])[CH2:2][CH2:3][CH3:4].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH3:22])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 55 °C
Yield: 42.4 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (900 mg, 3.04 mmol) and K2CO3 (1.38 mg, 10 mmol) in DMF (10 mL) was stirred at RT for 10 minutes. Methyl iodide (647 mg, 4.5 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate (100 mL, 2 times), dried over Na2SO4, concentrated and purified with column chromatography to obtain 400 mg of methyl 2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]([C:8]#[C:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=2)=[O:26])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 4-chloro-3-(trifluoromethyl)benzoic acid are converted to the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1>I.C(OC(=O)C)(=O)C.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: O=C1CCCC1
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c(C2CCCC2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (0.548 g) was dissolved in a mixture of hydriodic acid (10 ml), acetic anhydride (10 ml) and hypophosphorous acid (2 ml). The solution was stirred at 40° while cyclopentanone (1.5 ml) was added in three portions over 3/4 hr. After stirring an additional 1/2 hr., the solution was poured into ice water (125 ml) and the pale yellow product (95%), m.p. 161.5°-163.5° after changing to prisms at ca 140°, separated. For analysis it was recrystallized successively from hexane, from aqueous methanol and again from n-hexane as pale pink prisms m.p. 167.5°-168° (lit20), 164.5°-165.5°). Anal. Calc. for C13H19NO: C, 76.05, H, 9.33; N, 6.82. Found: C, 76.12; H, 9.21; N, 6.65.
Reaction SMILES: [C:1]([N:3]([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4](=[NH:7])SC)#[N:2].[CH3:22][NH2:23]>C(O)C>[C:1]([N:3]([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4]([NH:23][CH3:22])=[NH:7])#[N:2]
Reactant: CN
Reactant: CSC(=N)N(C#N)C(c1ccccn1)c1ccccc1C
Solvent: CCO
Product: CNC(=N)N(C#N)C(c1ccccn1)c1ccccc1C
Yield: 85 %

Procedure:
A mixture consisting of 5.9 g (0.02 mol) of N-cyano-S-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]isothiourea prepared in (a), 30 ml of 20% solution of methylamine in ethanol and 70 ml of ethanol was prepared and reacted at room temperature overnight. The reaction solution was concentrated under a reduced pressure. The residue was recrystallized from ethyl acetate to produce 4.7 g of the subject material, N-cyano-N'-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]guanidine (yield: 85.0%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: COCCOCC(=O)O
Product: COCCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use (2-methoxyethoxy)acetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (72% yield). 1H NMR (300 MHz, CDCl3) δ 9.53, 8.34, 7.74, 7.63, 7.56, 7.34, 7.02, 4.16, 4.04-3.89, 3.80-3.77, 3.69-3.65, 3.63-3.61, 3.59-3.56, 3.46, 3.34-3.32. MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].Cl.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([Cl:24])[CH:23]=1.[CH2:31](O)C>>[ClH:17].[Cl:24][C:22]1[CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31]/[CH:2]=[CH:1]/[C:4]3[CH:5]=[N:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])[CH2:27][CH2:26]2)[CH:19]=[C:18]([Cl:17])[CH:23]=1
Reactant: CCO
Reactant: CC(=O)c1cnn(-c2ccccn2)c1C
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Agent: Cl
Product: Cc1c(/C=C/CN2CCN(c3cc(Cl)cc(Cl)c3)CC2)cnn1-c1ccccn1
Reaction time: 24 h

Procedure:
In 150 ml of absolute ethanol was dissolved 2.26 g of 4-acetyl-1-(2-pyridyl)-5-methylpyrazole, and 2.94 g of 1-(3,5-dichlorophenyl)piperazine hydrochloride and 0.9 g of p-formaldehyde were added to the solution, followed by refluxing for 6 hours. To the reaction mixture was further added 0.40 g of p-formaldehyde, and the refluxing was continued for an additional 24 hour period. About a half of the ethanol was removed by evaporation, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to column chromatography on silica gel using a mixture of chloroform-methanol (50:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated. A 1N hydrochloric acid/ethanol solution was added to the residue, followed by concentration. The residue was recrystallized from ethanol to yield 2.90 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(O)ccc2c1=O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCCCN3CCOCC3)ccc2c1=O
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
7-Hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (750 mg, 2.7 mmol) was suspended in methylene chloride (40 ml) at 5° C. and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added. The mixture was stirred for 5 minutes and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes at 5° C. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The solution was then purified directly by column flash chromatography eluting with methylene chloride, and then ethyl acetate, acetonitrile/ethyl acetate (20/80), and acetonitrile/ethyl acetate/ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 7-(3-morpholinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (745 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19]([O:23][C:24]([N:26]([CH2:28][C:29](O)=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]([CH2:28][C:29]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: COc1cccc(Cn2cnc(NC(=O)CN(C)C(=O)OC(C)(C)C)c2C(N)=O)c1
Yield: 63 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.97 g (8.00 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 81 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 2.12 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(3-methoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].Cl.[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C1C[O:27]CC1>C1COCC1>[C:10]1([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:27])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CCc1ccccc1
Reactant: C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
16.1 ml (120 mmol) of a 2M solution of lithium diisopropylamide in cyclo-hexane/ethylbenzene/THF are added under nitrogen and at −70° C. to a solution of 24.0 g (110 mmol) of the aromatic compound 24 in 150 ml of THF. After 1.5 hours at the low temperature, 22.1 g (100 mmol) of the aldehyde 23, dissolved in 50 ml of THF, are added to the batch. After 3 hours at −70° C., the batch is warmed to room temperature, hydrolysed and acidified using hydrochloric acid. The aqueous phase is extracted with MTB ether, and the organic phase is washed with sat. sodium chloride solution, dried over sodium sulfate, evaporated and passed through silica gel (MTB ether/n-heptane 1:10), giving 40.2 g (83%) of the diphenyl-methanol 25.