Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:14]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][S:12][CH2:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C2=CCSCC2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196 ml), pyridine (6.23 g, 79.1 mM) added, and the mixture stirred under nitrogen at −20°. A solution of benzyl chloroformate (9.54 g, 53.9 mM) dissolved in dry dichloromethane (25 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of isohexane (300 ml) precipitated the desired product (15.5 g).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:13]=2)=[C:7]([CH3:30])[CH:6]=1.CO.Cl.CO>C(COC)OC>[OH:4][C:5]1[CH:6]=[C:7]([CH3:30])[C:8]([C:12]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:13]=2)=[C:9]([CH3:11])[CH:10]=1
Reactant: COCOc1cc(C)c(-c2cc(C(=O)OC)ccc2COc2ccccc2)c(C)c1
Agent: Cl
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(COc2ccccc2)c(-c2c(C)cc(O)cc2C)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4′-(methoxymethoxy)-2′,6′-dimethyl-6-(phenoxymethyl)biphenyl-3-carboxylate (1.77 g, 4.35 mmol) in a mixed solvent of methanol (10 mL) and dimethoxyethane (5 mL) was added 10% hydrogen chloride-methanol solution (1 mL), and the mixture was stirred at 45° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-25:75) to give the title compound (1.47 g, yield 93%) as a colorless amorphous powder.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1>N[C@@H](CO)C>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][S:14][C:4]1[N:3]=[C:2]([NH:10][C@H:9]([CH3:12])[CH2:8][OH:13])[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=1
Reactant: Cc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Agent: C[C@@H](N)CO
Product: Cc1nc2c(N[C@H](C)CO)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The titled compound was prepared from the product of example 35, step (b) (200 mg) and D-alaninol (120 μl) using the method of Example 2, step (f).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])C)([CH3:4])([CH3:3])C.[CH:12](N)([CH3:14])[CH3:13].C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>>[CH:1]([NH:5][C:6](=[O:11])[C:7]1[CH:9]=[CH:14][CH:12]=[CH:13][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)N
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccccc1
Yield: 92 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with benzoyl chloride (11.72 mL, 100 mmol) afforded LPh,iPrH as white crystalline solid (15.02 g, 92%) upon crystallization of the crude product from Et2O at −20° C. followed by sublimation at 70° C./0.05 Torr: mp 101-103° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
A mixture of 3,6-dichloropyridazine (20.1 g, 135 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (25.46 g, 122 mmol) and potassium carbonate (50.7 g, 367 mmol) in 1,4-dioxane (500 mL) and water (200 mL) under nitrogen was degassed by bubbling in nitrogen for 15 min. Dichlorobis(triphenylphosphine)palladium (II) (1.2%, 1 g, 1.4 mmol) was than added and nitrogen was bubbled in the mixture for another 10 min. The reaction mixture was stirred at 90° C. for 3 h, then cooled to room temperature and concentrated in vacuo to remove the majority of the 1,4-dioxane. The residue was partitioned between 1 N aqueous potassium carbonate (400 mL) and ethyl acetate (400 mL) and the phases separated. The aqueous layer was extracted with ethyl acetate (2×300 mL) and dichloromethane (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The residue was stirred in diethyl ether (150 mL) and the orange precipitate was filtered and dried to return the title compound (12.76 g, 65.6 mmol, 54% yield). The filtrate was concentrated onto silica gel and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate/hexane to return starting 3,6-dichloropyridazine as a white solid (9.9 g, 66.4 mmol, 49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Br
Reactant: O=S(Cl)Cl
Product: Fc1c(N=C(Cl)c2c(Cl)cccc2Br)ccnc1Cl
Temperature: 25 °C
Yield: 83 %

Procedure:
A stirred solution of 2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzamide (4.8 g, 13.2 mmol) in thionyl chloride (100 mL) was heated at 100° C. for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 30% diethyl ether in pentane to afford the title compound as a pale yellow solid (4.2 g, 83% yield). LCMS (Method D): RT=4.47 min, m/z: 383 [M+H+].
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([O:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33]
Reactant: COc1cccc2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCNCC
Product: COc1cccc2c1c1c(n2CCO)CCCC1C(=O)O
Yield: 75.9 %

Procedure:
9-(2-Benzyloxy-ethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (10) (1.0 g, 2.1 mmol) in methanol (50 ml) was shaken with 10% palladium on charcoal (300 mg), and hydrogen gas excess for 18 h at 55° C. The reaction was then filtered through a pad of celite and the filtrate concentrated in vacuo to give 578 mg (100%) 9-(2-hydroxyethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (11) as a foam. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.0, 14.4, 20.0, 22.0, 28.0, 36.4, 40.6, 42.0, 54.7, 60.6, 99.2, 102.6, 107.0, 116.7, 121.1, 136.1, 137.5, 138.0 153.5, and 175.7.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40].O>CN(C)C=O>[C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])#[N:2]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
72 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 9) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 31 mg of anhydrous potassium carbonate, and 31 mg of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 1 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 80 mg of methyl 2-[3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 5-7 of the present invention].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH2:16][CH2:17][CH:13]([N:12]([CH3:18])[CH3:11])[CH2:14]1)[C:5]#[N:6]
Reactant: CN(C)C1CCNC1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(c2ccc(C#N)cc2Cl)C1

Procedure:
0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231 mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with stirring and under an argon atmosphere. After stirring at ambient temperature for 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate after thorough mixing. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][C:12]([C@@H:9]3[CH2:10][CH2:11][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 97.2 %

Procedure:
2.00 g 1-Tert.butoxycarbonyl-azetidin-2(S)-carboxylic acid, 1.70 g 1-amino-6-aminomethyl-isoquinolin, 3.50 g TBTU were dissolved in 40 mL DMF. 3.55 mL N-methylmorpholine was added slowly with stirring. The solution was applied to a reversed-phase chromatography column (lenght 100 mm, diameter 14 mm, Merck Lichroprep RP-18, 15-25 μ). Elution was started with 25 mL of methanol/water containing 0.3% acetic acid (10 90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fraktions of 5 mL each were sampled. The solvent was evaporated to give 3.4 g of the tile compound. MS: 357
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]2[CH:9]1[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)(O)[O-].[Na+].IC>CN(C)C=O>[CH3:25][O:18][C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH3:24])[C:10]=12)=[O:19]
Reactant: CC1c2c(C(=O)O)nc(C(F)(F)F)n2CCN1C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nc(C(F)(F)F)n2c1C(C)N(C(=O)OC(C)(C)C)CC2
Yield: 137.6 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 39a (0.349 g, 1 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and sodium bicarbonate (0.84 g, 10 mmol) was added to the solution under stirring. Iodomethane (0.43 g, 3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 40 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 39b (0.5 g, yield 100%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1.Cl[CH2:33][C:34]1[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:33][C:34]4[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(O)cc2n1Cc1c(F)cc(Br)cc1F
Reactant: Cc1cnc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(Br)cc1F
Temperature: 100 °C

Procedure:
To a mixture of racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (110 mg, 0.22 mmol), 2-(chloromethyl)-3-fluoro-5-methylpyridine (35 mg, 0.22 mmol) in acetonitrile (5 mL) was added Cs2CO3 (79 mg, 0.24 mmol) and heated at 100° Celsius. After 1 hr the mixture was concentrated to dryness and the residue was purified by FCC to provide racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester was added MeOH (2 mL), and NaOH (1 mL, 1 N). The mixture was heated to 110° Celsius. After 1 h the mixture was concentrated to dryness and purified by FCC to provide the title compound and the trans-isomer see Example 124. MS (ESI): mass calcd. for C28H25BrF3N3O3, 587.10; m/z found, 588.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.22 (s, 1H), 7.52-7.45 (m, 2H), 7.28 (d, J=7.6, 2H), 6.99 (d, J=2.0, 1H), 6.88 (dd, J=8.7, 2.3, 1H), 5.54 (two d, J=16.4, 2H), 5.18 (s, 2H), 3.79 (d, J=4.6, 1H), 2.78-2.63 (m, 1H), 2.40 (s, 3H), 2.36-2.20 (m, 1H), 2.12-1.86 (m, 3H), 1.86-1.67 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C)C=O.C(Cl)(C([Cl:20])=O)=O>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([Cl:20])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)cn1
Yield: 94 %

Procedure:
5-chloropyrazine-2-carboxylic acid (1.00 gram, 6.31 mmol) in dichloromethane (30 ml) was treated with catalytic amount of dimethylformamide, followed by (COCl)2 (0.85 ml, 9.46 mmol). The resulting mixture was stirred over night. The reaction was concentrated in vacuo, and dried under vacuum to give desired 5-chloropyrazine-2-carbonyl chloride as solid (1.05 g, 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9]N1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:9][CH2:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CSc1ccncc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClCSc1ccncc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A solution of 4-methylthiopyridine (2.28 g, 18.2 mmol), N-chlorosuccinimide (3.0 g, 23 mmol) and pyridine (2.9 mL, 3.0 mmol) in benzene (40 mL) was heated at 50°-60° C. for 3 h. The mixture was allowed to cool to room temperature. The solvent was decanted and the residue was rinsed with benzene (2×10 mL). The organic phases were combined and evaporated. The residue was passed through a pad of silica gel (40 g) to give the title material (1.35 g) contaminated with the starting material. The impure product was repurified on silica gel preparative plates (eluted with CH2Cl2 /CH3CN: 1/1) to give the pure title material (926 mg, 32%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@:7]([NH2:25])([CH2:21][C:22](=[O:24])[OH:23])[N:8]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])C(OC(C)(C)C)=O.C(OCC)C.[ClH:40].O1CCOCC1>>[ClH:40].[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@:7]([NH2:25])([CH2:21][C:22](=[O:23])[OH:24])[NH:8][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)N(C(=O)OC(C)(C)C)C(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Reaction time: 1 h

Procedure:
N-t-Butoxycarbonyl-α-aminoisobutyryl-α-L-aspartyl-L-phenylalanine methyl ester (2.3 g) was dissolved under ice cooling in 4N-HCl/dioxane (20 ml), and the mixture was stirred for one hour. Ethyl ether (150 ml) was added, and the crystals which separated out were collected by filtration. Yield: 1.8 g.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CC(C)=O>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH2:27][C:28]#[N:29])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: N#CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCSc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.3 g), chloroacetonitrile (1.4 g), triethylamine (0.61 g), and dry acetone (20 ml) is refluxed for 20 hours. After cooling the triethylamine hydrochloride formed is removed by filtration, and the filtrate is evaporated in vacuo. To the residue, water (35 ml) and ethylacetate (75 ml) are added, and the pH of the aqueous layer is adjusted to pH 7.5 by addition of 4 N hydrochloric acid. The organic layer is then separated, washed with diluted sodium hydrogen carbonate, dried and evaporated in vacuo. The residue is crystallized from chloroform petroleum ether to yield cyanomethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate with a melting point of 134°-135° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Cl[CH2:42][C:43]1[C:44]([CH:51]2[CH2:53][CH:52]2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>C1COCC1.O>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([CH:51]3[CH2:53][CH:52]3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: ClCc1c(C2CC2c2ccccc2)noc1C1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c(C3CC3c3ccccc3)noc1C1CC1)C2
Reaction time: 0.17 h

Procedure:
A solution of N-Boc-nortropine (80 mg, 0.35 mmol) and 18-crown-6 (125 mg, 0.5 mmol) in THF (2.5 mL) was cooled to 0° C., treated with potassium tert-butoxide (59 mg, 0.53 mmol) and stirred for 10 min. A solution of 4-(chloromethyl)-5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole (80 mg, 0.29 mmol) in THF (0.5 mL) was added and the resulting mixture stirred at rt for 2 h and then poured into water and extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, concentrated to yield tert-butyl 3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS m/z 409.1 (M−56+1).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CN(C)C(=O)C.[C:21](Cl)(=O)[CH2:22][CH3:23]>O>[CH2:22]([C:23]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[N:14]=1)[CH3:21]
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)=NO
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc(Cc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a mixture of N′-hydroxy-2-(4-nitrophenyl)ethanimidamide (6.17 g) and N,N-dimethylacetamide (50 mL) was added propionyl chloride (3.22 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue and xylene (200 mL) was heated under reflux for 15 hrs. with azeotropic dehydration. The reaction mixture was concentrated and the obtained residue was subjected to silica gel column chromatography to give 5-ethyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole as brown crystals (4.40 g, yield 60%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 69-70° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1ccc2oc(=O)n(C)c2c1
Yield: 74.2 %

Procedure:
5-Acetylbenzo[d]oxazol-2(3H)-one (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol), and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 5-acetyl-3-methylbenzo[d]oxazol-2(3H)-one (0.4 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 3.48 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: BrCC1C=CNN=1.C(N)CN.[NH:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][NH2:21])=[N:13]1.[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:14]1[CH:15]=[CH:16][NH:12][N:13]=1)#[N:23]
Reactant: NCCNCc1cc[nH]n1
Reactant: CN=C(NC#N)SC
Agent: BrCc1cc[nH]n1
Solvent: NCCN
Product: CNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
Reacting 3-bromomethylpyrazole with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyrazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedue of Example 3(d) gives N-cyano-N'-methyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-guanidine trihyrochloride.