Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(OB(O)O)cc1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g), 4-methylphenylboric acid (3.9 g), a 2 M aqueous solution of potassium carbonate (40 ml) and ethanol (40 ml) was added toluene (100 ml), and the resulting mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Thereto was added tetrakis(triphenylphosphine)palladium (1.26 g), and the resulting mixture was refluxed under an argon atmosphere for 4.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, methanol (200 ml) and a 2 M aqueous solution of potassium carbonate (50 ml) were added to the residue, and the resulting mixture was stirred overnight at room temperature. After concentration, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and was then back-extracted with 1 N hydrochloric acid. The aqueous layer was made alkaline with a 1 N aqueous solution of sodium hydroxide, was then saturated with sodium chloride and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g) as colorless crystals.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C1C=CC=CC=1.[OH-]>C(O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (1.08 g, 2.64 mmol) and palladium [ll] hydroxide on carbon (0.6 g) in absolute ethanol (25 mL) was shaken under a hydrogen atmosphere (3 atm) at 40° C. for 4 hours. The resulting mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to afford the title compound (0.60 g, 2.62 mmol, 99%) as a white foam: 1H NMR (DMSO-d6) δ10.65 (br s, NH), 7.14 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.60 (dd, J=2.0 and 8.6 Hz, 1H), 3.63-2.83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H); [α]25 =+9° (MeOH, c=1.0); HRMS calculated for C14H19N3 : 229.1575; found: 229.1593.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:23][NH:24][CH2:25][CH2:26][CH2:27][OH:28].ClC1C(C(O)=O)=C(C2C=CC=CC=2)C=CN=1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCCO>>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:23][N:24]([CH2:25][CH2:26][CH2:27][OH:28])[C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:17])=[CH:5][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1cc(-c2ccccc2)c(C(=O)O)c(Cl)n1
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Agent: OCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc(-c2ccccc2)c(C(=O)N(CCCO)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Cl)n1

Procedure:
The same process as in Step 2 in Reference Example 12 was repeated, except that 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid was reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine in place of reacting 2-chloro-4-phenyl-3-pyridinecarboxylic acid with N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, to obtain the entitled compound as a pale-yellow, oily substance. NMR(200 MHz, CDCl3) ppm: 1.15-1.65(2H,m), 2.59(3H,s), 2.75-3.20(2H,m), 4.06(1H×2/5,d,J=15.4 Hz), 4.31(1H×2/5,d,J=15.4 Hz), 4.65(1H×3/5,d,J=15.2 Hz), 4.74(1H×3/5,d,J=15.2 Hz), 7.16(1H,s), 7.20-7.60(5H,m), 7.72(2H,s), 7.78(1H,s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][CH:20]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Yield: 70.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.35 g, 0.5 mmol) in TFA (2 mL) and dichloromethane (2 mL) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1N Na2CO3 aq. (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.21 g, 70%).
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.CN.[CH3:34][N:35]1CCCC1>O1CCOCC1>[CH3:34][NH:35][C:24](=[O:25])[NH:23][C:19]1[CH:18]=[C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4])=[O:30])=[N:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CN1CCCC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 130.7 %

Procedure:
A mixture of Example C2 (0.163 g, 0.394 mmol), methylamine hydrochloride (0.053 g, 0.789 mmol) and N-methylpyrrolidine (0.070 g, 0.828 mmol) in dioxane (3 mL) was heated at 80° C. overnight, cooled to RT, and concentrated to dryness. The residue was suspended in MeCN and the mixture was sonicated for a few minutes. The light beige solid was collected by filtration and washed with MeCN. This solid was partitioned with DCM and water with stirring for 15 min. The aqueous layer was separated and extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated to dryness. The residue was suspended in MeCN/water, frozen and lyophilized to afford N-((5-((2-(3-methylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide as a white solid (0.199 g, 125%). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 10.50 (s, 1H), 9.20 s, (1H), 8.22 (d, J=2.9 Hz, 1H), 8.09-8.03 (m, 2H), 7.97-7.87 (m, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.00 (s, 1H), 6.55 (dd, J=5.8, 2.4 Hz, 1H), 2.64 (d, J=4.6 Hz, 3H), 1.21 (s, 9H); MS (ESI) m/z: 387.2 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH:8](=[N:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nn1nnnc1S
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Sc1nnnn1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 689.4 %

Procedure:
7.0 g of 1-amino-5-mercapto-1H-tetrazole and 0.6 g of benzaldehyde were dissolved in 120 ml of ethanol, and the solution was stirred at room temperature for 4 hours. After the reaction, the solution was evaporated to remove solvent. The residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate solution was washed with water, dried and evaporated to remove solvent. Then, isopropyl ether was added to the residue obtained, and the crystalline precipitates were collected by filtration. 8.0 g of 1-benzylideneamino-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[NH:5][C:4](=[S:15])[N:3]=1.I[CH2:17][CH3:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:5]=[C:4]([S:15][CH2:17][CH3:18])[N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(-c2ccc(Br)cc2)[nH]c(=S)n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Yield: 81.8 %

Procedure:
To a solution of 4-amino-6-(4-bromophenyl)pyrimidine-2(1H)-thione (53.90 g, 191.0 mmol) and iodoethane (16.96 mL, 210.1 mmol) in 200 mL of DMSO was slowly added 200 mL of aqueous saturated sodium bicarbonate at ambient temperature with stirring. The reaction was allowed to stir for 1 hour before iodoethane (8.0 mL, 99.1 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 500 mL of water and stirred for 20 minutes. The solid was collected by means of vacuum filtration and was dried under high vacuum overnight to afford 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (51.0 g, 156.2 mmol, 81.76% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[C:19]([OH:21])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.[NH2:43][CH2:44][C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18]([C:19]([NH:43][CH2:44][C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[O:21])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CCNC(=O)C(=O)O)cc1OC1CCCC1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Product: COc1ccc(CCNC(=O)C(=O)NCc2ccncc2)cc1OC1CCCC1

Procedure:
Using a solution of N-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]oxamic acid (284 mg, 0.92 mmol), EDAC (220 mg, 1.16 mmol) and dimethylaminopyridine (140, 1.25 mmol) and 4-aminomethyl pyridine in an analogous method to that of Example 12 above provided the title compound yielding (126 mg, 34%): m.p. 129°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added 3-cyanophenylisocyanate (14 mg, 0.095 mmol) in DCM (0.1 mL) drop-wise. The reaction was slowly warmed to ambient temperature and stirred for 1 hour. The reaction was diluted with DCM (2 mL), washed with water, and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5 to 85% acetonitrile/water to yield the pure final product as a solid (3.2 mg, 37% yield). MS (apci) m/z=460.2 (M+H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[C:15]([CH3:16])=[C:14]([NH:17][S:18]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)(=[O:20])=[O:19])[O:13][N:12]=1.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[S:18]([NH:17][C:14]1[O:13][N:12]=[C:11]([CH3:10])[C:15]=1[CH3:16])(=[O:19])=[O:20]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2)c1C
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
N,N-diisoproplyethylamine (222 μl, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 2-(trimethysilyl)ethoxy methyl chloride (SEM chloride) (226 μl, 1.28 mmol) was added dropwise via syringe, and the resultant yellow solution was stirred at room temperature for 5 hours. Evaporation of solvents left an oil which was extracted into ethyl acetate, washed with water and brine solution and dried over magnesium sulfate. Flash chromatography of the residue using 10% ethyl acetate/hexanes yielded 321 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide as a clear colorless oil which solidified into a white solid upon standing (71% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCCN
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Ethyl 4-aminobutanoate hydrochloride (1.77 g) and 2,4-dimethoxybenzaldehyde (1.75 g) were dissolved in ethanol (50 ml), and the solution was heated under reflux for 1 hr. The mixture was allowed to be cooled to room temperature, sodium triacetoxyborohydride (2.2 g) was added thereto, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (40 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.77 g) as a yellow oil.
Reaction SMILES: C(N)CN.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[C:15]([NH:17][C:18](=[N:21][CH3:22])SC)#[N:16]>>[C:15]([NH:17][C:18]([NH:21][CH3:22])=[N:14][CH2:13][CH2:12][NH:11][CH2:10][C:6]1[S:5][CH:9]=[CH:8][N:7]=1)#[N:16]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1nccs1
Solvent: NCCN
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylenediamine with 2-chloromethylthizaole by the procedure of Example 34, then reacting the resulting N-(2-thiazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N' -[2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38]
Reactant: Cc1cc(CCl)c(F)cc1F
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c(F)cc1F
Temperature: 60 °C
Yield: 39 %

Procedure:
To a solution of Intermediate 1 (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-chloromethyl-2,4-difluoro-5-methyl-benzene from Step C (23 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol) and 18-crown-6 (3 mg). The slurry was heated at 60° C. for five hours. After cooling to room temperature the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil. (27 mg, 39% yield). MS (M+H): 527; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 5.47-5.56 (m, 2H), 6.80-6.84 (m, 1H) 7.34-7.38 (m, 1H), 7.55-7.59 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=7.05 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: C([O:5][NH:6][C:7]([C@:9]1([CH3:40])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:38]=[O:39])[CH2:10]1)=[O:8])(C)(C)C.FC(F)(F)C(O)=O>>[CH:38]([N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@@:9]([CH3:40])([C:7]([NH:6][OH:5])=[O:8])[CH2:10]1)=[O:39]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NO)cc2)c2ccccc2n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To 0.092 g of (3S,4R)-N-tert-butoxy-1-formyl-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide was added 3 mL of trifluoroacetic acid, and the resulting mixture was stirred at 45° C. for 8 h, and then concentrated. The residue was purified by silica chromatography (silica pre-washed with MeOH), eluting with a gradient of 5-20% MeOH/CH2Cl2 to afford (3S,4R)-1-formyl -N-hydroxy-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (0.05 g, 60%) as a colorless solid. MS: 513.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=3)=[CH:10][N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:14]1[N:13]=[C:12]([C:11]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]([CH:22]([CH3:24])[CH3:23])[CH:10]=2)[CH:17]=[CH:16][N:15]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(-c2ccc(Cl)s2)n1
Reactant: NCc1ccccc1
Product: CC(C)n1cc(-c2ccnc(NCc3ccccc3)n2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine (1 eq, 5.2 mmol) in 25 mL benzylamine was stirred overnight at room temperature. The solvent was evaporated and the residue was diluted in dichloromethane and washed three times with HCl 1M. The organic layer was then dried over MgSO4 and evaporated to afford 2.3 g of N-benzyl-4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine (96% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][N:21]=[C:20]2[N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCCCCC(C)Nc1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: CCCCCCC(C)Nc1ccc2c(c1)CCN2c1ncnc2cc(OC)c(OC)cc12
Yield: 96 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 96% yield from [2,3-dihydro-1H-indol-5-yl]-(1-methyl-heptyl)-amine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 61°-63° C.; GC-MS: 434 (M+); anal. RP18-HPLC RT: 6.91 min.).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.C(N(CC)CC)C.[C:34]1([CH:40]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:41][N:42]([CH3:60])[C:43](=[O:59])[CH:44]([NH:51][CH2:52][CH2:53][C:54]2[N:55]=[CH:56][NH:57][CH:58]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:51]([CH:44]([C:43](=[O:59])[N:42]([CH2:41][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[CH3:60])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:52][CH2:53][C:54]1[N:55]=[CH:56][NH:57][CH:58]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(c1ccccc1)N(CCc1c[nH]cn1)C(=O)c1ccccc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-Benzoylbenzoic acid (0.341 g, 1.51 mmol) was taken up in a 2M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). One drop of N,N-dimethylfornamide was added and the frothy mixture was stirred overnight and concentrated. A solution of the crude 2-benzoylbenzoyl chloride in methylene chloride (4 mL) followed by triethylamine (0.25 mL, 1.8 mmol) was added to the product of step 2 (0.220 g, 0.502 mmol). The mixture was heated at reflux for 2 hours and concentrated. The residue was taken up in 5:1 methanol/1 N aqueous lithium hydroxide (12 mL) and stirred for 1 hour. The reaction was again concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a foamy amber solid. Flash chromatography over silica (methylene chloride/methanol) provided 0.229 g (71%) of product as a foamy pale amber solid: 1H NMR (CDCl3) δ 7.91-6.92 (m, 26H), 6.54-6.39 (m, 1H), 6.34-6.06 (m, 1H), 4.83-4.31 (m, 2H), 3.97-2.82 (m, 3H), 2.70-2.39 (m, 3H), 2.35-2.09 (m, 2H) ppm. MS (ESI) m/z 648 (M+H+).