Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 4-tert-butoxycarbonylamino-benzoic acid (50 g, 0.21 mol) and HOBT (31.33 g, 0.231 mol) in dry THF (0.5 L) was added EDAC (44.44 g, 0.231 mol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (40.4 ml, 0.231 mol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (39.4 ml, 0.231 mol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (600 ml) and the resulting mixture was extracted with EtOAc (3×500 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the solid residue was added diethyl ether (100 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 60.5 g (77%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester as a solid.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CS(C)=O>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][N:17]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
To 5 mL of dry ethanol were added 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.54 g, 6.61 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.25 g, 6.61 mmol). The mixture was heated at the reflux temperature for about 6 hours, and was then cooled and concentrated. The residue was purified by silica gel chromatography with 95/5 chloroform/methanol. The product was isolated as a yellow foam. Yield 1.52 g (55%). mp 200°-202° C. FDMS m/e=421 (M+ of free base). α[D]589 =+4.39 (c=1.00, dimethylsulfoxide)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[CH2:19][CH:18]([C:20]2[S:21][C:22]([Br:26])=[C:23]([Br:25])[CH:24]=2)[CH:17]([C:27]([OH:29])=O)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl.CN(C=O)C>[ClH:33].[CH2:8]([N:15]1[CH2:19][CH:18]([C:20]2[S:21][C:22]([Br:26])=[C:23]([Br:25])[CH:24]=2)[CH:17]([C:27]([Cl:33])=[O:29])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Cl)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
The product from step c) (2.3 g, 5.18 mmol) in CH2Cl2 (26 ml) was treated with oxalyl chloride (2.3 ml, 26.3 mmol) followed by DMF (4 drops) and the mixture was stirred for 1 hour at 22° C. The solvent was evaporated in vacuo to give the crude subtitle compound as pink solid that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH2:64]([O:66][C:67]([C@H:69]1[CH2:74][CH2:73][C@@H:72]([NH2:75])[CH2:71][CH2:70]1)=[O:68])[CH3:65]>ClCCl>[C:1]([O:5][C:6](=[O:33])[CH:7]([CH2:17][N:18]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1([C:14](=[O:15])[NH:75][C@H:72]2[CH2:71][CH2:70][C@@H:69]([C:67]([O:66][CH2:64][CH3:65])=[O:68])[CH2:74][CH2:73]2)[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The t-butyl ester from step (b) above (11.97 g, 26.54 mmole) in dry dichloromethane (200 ml), under nitrogen, was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.19 g, 53 mmole), 1-hydroxybenztriazole (3.94 g, 29 mmole), triethylamine (16.08 g, 22.15 ml, 159 mmole) and cis-4-aminocyclohexane-carboxylic acid ethyl ester hydrochloride (6.04 g, 20 mmole). After stirring overnight at room temperature, the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute hydrochloric acid (2x), dilute aqueous sodium bicarbonate, water, dried (Na2SO4) and evaporated to yield the crude product (15.5 g). This was chromatographed on silica (400 g) eluting with 1 to 10% diethyl ether in dichloromethane. Evaporation of the desired fractions gave 3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)-carbamoyl]cyclopentyl}-2-(dibenzylaminomethyl)propanoic acid t-butyl ester as an oil (11.43 g, 71%). Found: C,73.38; H,8.87; N,4.42. C37H52N2O5 requires: C,73.48; H,8.67; N,4.68%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][S:19](Cl)(=[O:21])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]([Cl:57])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]>CCCCCCC.C(OCC)(=O)C>[Cl:57][C:31]([Cl:30])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46]([S:19]([CH2:18][CH:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:21])=[O:20])[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 71.9 %

Procedure:
Prepared from 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (640 mg) and 3,4-dihydro-1H-β-carboline-2,9-dicarboxylic acid 2-tert-butyl ester 9-(2,2,2-trichloro-ethyl) ester (500 mg) to give, after chromatography (SiO2, 2:1 heptane-ethyl acetate), the title compound (608 mg, 61%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[N:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cn1nnc(-c2ccc(CCc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2ccc(CCc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of ethyl [5-(4-(3-(2-quinolinylmethyloxy)phenethyl)phenyl)tetrazol-3-yl]acetate in 5 ml ethanol and 40 ml of 1N NaOH is stirred at 70° C. for 4 hours. This is cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 5-(4-(3-(2-quinolinylmethyloxy)phenethyl)phenyl)tetrazol-3-yl acetic acid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]([C:23]1([NH2:32])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cc(CO)cc(C(=O)O)c1OC1CCC1
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
Solvent: O
Product: CCOC(=O)C1(NC(=O)c2cc(CO)cc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 2-cyclobutoxy-5-hydroxymethyl-3-methyl-benzoic acid (410 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (425 mg, 1.7 mmol), HATU (760 mg, 2 mmol) in anhydrous DMF (5 mL) is added DIPEA (4354, 2.5 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is poured into the reaction mixture, and then extracted with EtOAc (3×7 mL). The combined organic layers are concentrated in vacuo. The residue is purified by reverse phase chromatography (gradient elution: 20-100% ACN in water) to give product (285) as colorless oil (70 mg, 10%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:5]=[N:4][CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cncc(-c3ccc(CC(N)C(=O)O)cc3)n2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 7.9 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 5.5 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01(m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.0(m, 1H), 4.45(d, 2H), 4.65(m, 1H), 6.90(s, 2H), 6.95(s, 1H), 7.32(d, 2H), 7.60(t, 1H), 7.90(s, 1H), 7.95(d, 2H), 8.25(s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.O1CCOCC1.C(N(CC)CC)C.[C:44](Cl)(Cl)=[O:45].[NH2:48][C:49]1[CH:53]=[CH:52][O:51][N:50]=1>C1(C)C=CC=CC=1>[O:51]1[CH:52]=[CH:53][C:49]([NH:48][C:44]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:45])=[N:50]1
Reactant: Nc1ccon1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccon3)cc2)nc2c1CCN(c1ncccn1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0795 g, 0.000197 mol) in dry 1,4-Dioxane (1.50 mL, 0.0192 mol) was added Triethylamine (0.0302 mL, 0.000217 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.120 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 3-aminoisoxazole (0.0874 mL, 0.00118 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 9.69 (s, 1H), 9.12 (s, 1H), 8.74 (d, J=1.6, 1H), 8.44 (d, J=4.7, 2H), 8.28 (d, J=8.7, 2H), 7.57 (d, J=8.7, 2H), 6.87 (d, J=1.7, 1H), 6.69 (t, J=4.7, 1H), 4.91 (d, J=18.6, 1H), 4.75 (d, J=18.7, 1H), 4.18-4.09 (m, 2H), 3.86 (dd, J=17.0, 9.4, 2H), 3.73-3.69 (m, 1H), 3.66-3.58 (m, 3H), 3.43 (t, J=10.8, 1H), 2.75 (s, 2H), 1.26 (d, J=6.7, 3H). LC/MS-m/z+514.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[NH:13][CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[O:23][CH:22]=[C:21]([C:24]([Cl:26])=[O:25])[CH:20]=1>C1C=CC=CC=1>[ClH:26].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([C:24]([C:21]3[CH:20]=[C:19]([CH3:18])[O:23][CH:22]=3)=[O:25])[CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1
Reactant: Cc1cc(C(=O)Cl)co1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)N2C[C@H](C)N(CCCc3ccccc3)C[C@H]2C)co1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-(3-phenylpropyl)-2,5-dimethylpiperazine, 5-methyl-3-furoyl chloride and benzene.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])C>>[CH:35]([C:18]1[C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:37]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Yield: 65 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 161, the title compound was synthesized in the same manner as in Example 20. Yield: 65%. Melting point: 134-140° C. (hexane-ethyl acetate).
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[CH:39][C:40](Br)=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].CN(C)[CH:45]=[O:46].[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO>[C:35]([N:19]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[C:40]([CH2:45][OH:46])[CH:39]=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CN(C)C=O
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
Add butyl lithium (0.157 mL, 0.252 mmol, 1.6 M in hexanes) dropwise to a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.168 mmol) in tetrahydrofuran (2 mL) under nitrogen at −78° C. and stir for 1 h. Add N,N-dimethylformamide (0.052 mL, 0.672 mmol) dropwise to the cold solution and stir for 40 min at −78° C. then warm to room temperature. Quench the reaction with saturated aqueous ammonium chloride (10 mL) and dilute with ethyl acetate (20 mL). Separate the layers and wash the organic layer with water (2×30 mL) and brine (30 mL), then dry over sodium sulfate, filter and remove solvent under reduced pressure to provide the crude aldehyde. Dissolve the crude aldehyde (0.091 g, 0.167 mmol) in methanol (3 mL) and add sodium borohydride (0.019 g, 0.501 mmol) in one portion at room temperature. After stirring for 3 h, dilute the reaction with ethyl acetate (25 mL) and wash with brine (40 mL), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the crude material by chromatography on silica gel, eluting with acetonitrile to provide the title compound as an off-white solid (0.008 g, 8%): ESI MS 547 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([CH:22]=[CH2:23])[CH:19]=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[B-](F)(F)(F)F.[N:32]#[O+:33].[C:34](#[N:36])[CH3:35]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[N:32]([OH:33])[C:34]([CH3:35])=[N:36][CH:23]=3)[CH:19]=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC#N
Reactant: N#[O+]
Reactant: C=Cc1cc(OCC)cc(C(Nc2ccc(C#N)cc2)C(=O)OCC)c1
Agent: F[B-](F)(F)F
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)n2O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
A solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-vinyl-phenyl)-acetate (300 mg, 0.856 mmol) obtained in Example 236.2 in acetonitrile (2 ml) was slowly added dropwise at −30° C. to a solution of nitrosyl tetrafluoroborate (112 mg, 0.942 mmol) in acetonitrile (3 ml). The mixture was stirred for 2 h. at 0° C. and for 1.5 h. at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2→CH2Cl2/MeOH 4:1). There were obtained 135 mg (38%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)-phenyl]-acetate as a yellowish foam; MS: 421 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:30][N:7]2[C:2]([OH:1])=[C:3]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:4](=[O:16])[N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:8])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 10.1 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 357 mg, 1.03 mmoles), 3,4-dichlorobenzyl bromide (193 uL, 1.13 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (50 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (s, 1 H), 10.11 (t, J=5.68 Hz, 1 H), 7.59 (dd, J=5.18, 3.16 Hz, 2 H), 7.24-7.34 (m, 6 H), 5.01 (s, 2 H), 5.02 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H).
Reaction SMILES: N1C=CC(CNCCN)=N1.C(N=C=S)C.[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)=S)[CH3:17].[N:31]#[C:32][NH2:33].[Pb]>>[C:32]([NH:33][C:19]([NH:18][CH2:16][CH3:17])=[N:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)#[N:31]
Reactant: N#CN
Reactant: CCNC(=S)NCCNCc1cc[nH]n1
Agent: NCCNCc1cc[nH]n1
Agent: [Pb]
Solvent: CCN=C=S
Product: CCNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
By the procedure of Example 3(b), reacting N-(3-pyrazolylmethyl)ethylenediamine with ethyl isothiocyanate, then reacting the resulting N-ethyl-N'-[2-(3-pyrazolylmethylamino)ethyl]thiourea with lead cyanamide gives N-cyano-N'-ethyl-N"-[2-(3-pyrazolylmethylamino)-ethyl]guanidine. By the same procedure, using propyl isothiocyanate the corresponding N'-propyl compound is prepared. Also, by the same procedure, using 2-(dimethylaminoethyl isothiocyanate, the product is N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyrazolylmethylamino)ethyl]-guanidine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[CH:13]1(O)CCCC1>>[CH:4]1([O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:1][CH2:3][CH2:2][CH2:13]1
Reactant: Nc1cc(OCC2CC2)ncn1
Reactant: OC1CCCC1
Product: Nc1cc(OC2CCCC2)ncn1
Yield: 86 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclopentanol was used as the alcohol. 6-(cyclopentyloxy)pyrimidin-4-amine (0.238 g, 1.328 mmol, 86% yield) was obtained as a white solid. m/z (ESI) 180.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.NC(N)=[S:12].CC(CC)=O>O>[SH:12][C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Cl)nn1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccc(S)nn1
Yield: 23.4 %

Procedure:
A mixture of 3-chloro-6-methoxy pyridazine (0.69 mol, 100 g), thiourea (1.38 mol, 105 g) and ethyl methyl ketone (1.8 L) was refluxed for 3 hours. The reaction was cooled and the supernatant was poured into water and extracted with 1 M sodium hydroxide (4×100 mL). The sodium hydroxide solution was washed with EtOAc (2×50 mL), the aqueous extract was acidified with sufficient conc. HCl to lower the pH to 5 and the resulting yellow solid was collected and air-dried to obtain 3-mercapto-6-methoxy pyridazine (24%, 23 g); mp 198° C.-200° C.