Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:11]([CH3:19])[NH:10][C:9]2[CH2:20][O:21][C:22](=[O:23])[C:8]1=2.[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[C:11]([CH3:19])[N:10]([CH2:26][CH3:27])[C:9]2[CH2:20][O:21][C:22](=[O:23])[C:8]1=2
Reactant: CC1=C(C(=O)OC(C)C)C(c2sccc2Cl)C2=C(COC2=O)N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(C)=C(C(=O)OC(C)C)C(c2sccc2Cl)C2=C1COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of isopropyl 4-(3-chloro-2-thienyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3.4-b]pyridine-3-carboxylate are dissolved in 25 ml of dimethylformamide and deprotonated with NaH, and 20 mmol of ethyl iodide are added. After the mixture has been stirred at room temperature for 1 hour, it is concentrated, water is added to the residue and the product is filtered off with suction and recrystallized from methanol.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C(Cl)(Cl)Cl>[C:1]([Cl:26])(=[O:22])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Cl

Procedure:
To a solution of 2.40 g of 5,8,11,14,17-eicosapentaenic acid in 15 ml of dry chloroform was added 1.04 ml of oxalyl chloride under argon at room temperature. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the ramaining oxalyl chloride by distillation under reduced pressure to give 5,8,11,14,17-eicosapentaenoyl chloride, which was then dissolved in 15 ml of dry chloroform.
Reaction SMILES: [I:1][C:2]1[N:23]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([O:19]COC)[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1.Cl>CO.O1CCCC1>[I:1][C:2]1[N:23]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1
Reactant: COCOC1(c2ncc(-c3ccnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Temperature: 65 °C

Procedure:
To a solution of 5-(2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl) thiazole (Example 107B) (1.273 g, 2.138 mmol) in methanol (10.8 mL) and tetrahydrofuran (10.8 mL) was added 10% aqueous hydrochloric acid solution (6.61 mL, 21.38 mmol). The reaction mixture was heated to 65° C. for 3 hours. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers separated, and the aqueous layer was extracted with additional ethyl acetate (2×50 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound. MS APCI(+) m/z 552.54 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=1.O>CN(C=O)C>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=3)[CH2:4][CH2:5]2)/[S:14]1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 4-(bromomethyl)naphthalene-1-carbonitrile (153 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl is acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (134 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][C:4]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclohexanol (11.2 g) and pyridine (17 ml) in dichloromethane (100 ml) was added p-toluenesulphonyl chloride (19.5 g). The mixture was then stirred at room temperature under an atomosphere of nitrogen for 3 hours before being partitioned between ether (300 ml) and water. The organic layer was washed consecutively with 4N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (500 g silica gel; 20% ethyl acetate in petroleum ether as eluant) to give 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol [E; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
4.0 g (8.22 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.795 (8.22 mmol) (2S)-4-Amino-2-[(tert-butoxycarbonyl)amino]butanoic acid and 1.43 ml (8.22 mmol) N,N-diisopropylethylamine were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 4/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 4/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.02 g (6.54 mmol, 80% of theory) of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 702.3 %

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 10.9 g (0.077 mole) 4-fluoronitrobenzene, 9.95 g (0.0077 mole) 4-chlorophenol, and 11.8 g (0.085 mole) potassium carbonate in 175 mL of dimethylsulfoxide was heated at 70° C. for two days. The reaction mixture was cooled and filtered. The filtrate was diluted with water until a volume of one liter was obtained. This mixture was extracted with three 200 mL portions of diethyl ether. The combined ether extract was washed with water followed by an aqueous saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate under reduced pressure yielded 13.5 g 4-(4-chlorophenoxy)nitrobenzene (mp 67°-70° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[C:9]([CH3:18])([CH3:17])[C:8]=2[CH:19]=1.O.O.O.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[C:23]([N:14]1[C@@H:15]2[C@@H:10]([C:9]([CH3:17])([CH3:18])[C:8]3[CH:19]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=3[CH2:16]2)[CH2:11][CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN[C@H]1C2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN(C(C)=O)[C@H]1C2

Procedure:
A mixture of 0.56 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline hydrochloride, 0.27 g. of sodium acetate trihydrate, and 7 ml. of acetic anhydride was stirred and heated on a steam bath for three hours. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and diethyl ether. The ether layer was washed with 1N-hydrochloric acid and with saturated aqueous sodium bicarbonate solution. After drying the ethereal solution, filtering, and removing the solvent by evaporation under reduced pressure, there was obtained 0.52 g. of a syrup which crystallized from hexane to yield cis-1-acetyl-1,2,3,4,4 a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline, m.p. 81°-85°C; ir (CHCl3), 1630 cm.-1 (C=O); nmr (CDCl3), 80 (s,3), 78 (s,3).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:13])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:14])=[N:4][CH:5]=1)=[O:13])[CH2:29]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1nc(N(C)C)ncc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1nc(N(C)C)ncc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 2-(dimethyl-amino)-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyl-diimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][CH2:18][C@@H:16]([OH:17])[C@@H:14]([OH:15])[C@:12]2([F:20])[OH:13])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:24]>C(O)C(N)(CO)CO.Cl>[F:20][C@:12]1([OH:13])[C@H:14]([OH:15])[C@H:16]([OH:17])[CH2:18][O:19][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:24])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(N)c2ncn([C@@H]3OC[C@@H](O)[C@@H](O)[C@@]3(O)F)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Nc1nc2c(ncn2[C@@H]2OC[C@@H](O)[C@@H](O)[C@@]2(O)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2,6-Diamino-9-(2-fluoro-β-D-arabinosyl)purine (61.2 mg, 0.21 mmol) was dissolved in 50 mM Tris-HCl buffer solution (20 mL, pH 7.0), and adenosine deaminase (71 units) was added to the resultant solution, followed by stirring at room temperature for 1.5 hours. The resultant reaction mixture was subjected to filtration by use of a membrane filter (PTFE, 0.5 μm), and the filtrate was prepared into 60 mL of an aqueous solution. The aqueous solution was purified by means of reverse-phase ODS column chromatography (80 mL, 0 to 2% aqueous acetonitrile), to thereby yield 60.4 mg of the title compound as colorless crystals (yield: 100%).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH2:31]([NH2:34])[CH2:32][CH3:33]>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:5]([NH:34][CH2:31][CH2:32][CH3:33])=[O:4])[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=3[O:14][CH2:13]2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCCN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCNC(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 1-propylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 177-178° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]=[O:15])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: CNCCC=O
Reactant: Cc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CCC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reactions vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-ureido]propionaldehyde.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH2:36]([N:38]([CH2:44][CH3:45])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)[CH3:37]>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:42][CH2:43][CH:39]([N:38]([CH2:44][CH3:45])[CH2:36][CH3:37])[CH2:40]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: CCN(CC)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)C(C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-diethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.19 (m, 3H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (m, 9H). m/z: 505 [M+H]
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol), was combined with 3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.336 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7 H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield. MS m/z 590.6 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:14][OH:15]>[Pd]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:1]([C:2]1[CH:3]=[CH:4][C:14]([OH:15])=[CH:9][CH:10]=1)[NH:7][C:5]2=[O:6]
Reactant: CO
Reactant: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(O)cc3)nc12

Procedure:
3-Methyl-2-nitrobenzamide (1.20 g, 6.7 mmol) was dissolved in methanol and 10% activated palladium on carbon catalyst (150 mg) was added. The reaction vessel was placed under an atmosphere of hydrogen, at ambient temperature and pressure, until no further hydrogen absorption was observed. The catalyst was removed by filtration of the reaction mixture through a pad of Celite™, which was pre-washed with methanol (150 ml). The solvent was removed under vacuum to give the required product in good yield. The product was used for subsequent reactions without further purification. Yield (0.97 g, 6.4 mmol, 97%), m.p. 145-147° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O.C(N(C(C)C)CC)(C)C>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:16][CH3:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOS(=O)(=O)OCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1ccc(C(=O)OC)cc1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A mixture of 25.0 g (0.165 mol) 4-aminobenzoic acid methyl ester, 21.75 mL (0.165 mol) of diethyl sulfate and 30 mL (0.174 mol) of diisopropyl ethyl amine was heated to 120° C. for 1 hour. The reaction was exothermic and the temperature rose to 140° C. The mixture was allowed to cool down to room temperature and 100 mL of water was added. 4-(ethylamino)benzoic acid methyl ester crystallized over night, was isolated by filtration, washed 3 times with water and dried. The crude 4-(ethylamino)benzoic acid methyl ester was recrystallized from methanol. 14.44 g of 4-(ethylamino)benzoic acid methyl ester was isolated (m.p. 132-135° C.).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (170 mg, 0.521 mmol) in chloroform (10 mL) was added triethylamine (0.145 mL, 1.042 mmol) followed by ethyl chloroformate (0.055 mL, 0.573 mmol). The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated to dryness. The oil was partitioned between 3 mL of ethanol and 3 M of 1 M NaOH. After 1 hour, the reaction mixture was concentrated, and 10 mL of ethyl acetate followed by 4 mL of brine were added. The organic layer was separated, dried over MgSO4, filtered and evaporated. The resulting oil was dissolved in 5 mL of 10% AcCN:Et2O and 0.5 mL of 4 M HCl/dioxane was added. The suspension was stirred for 30 min, and then it was filtered. Ethyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (120 mg, 0.336 mmol, 64.6% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.30-7.39 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 4.19 (dd, J=1.26, 13.64 Hz, 2H), 4.13 (q, J=7.16 Hz, 3H), 3.15 (d, J=7.07 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz, 1H), 2.86 (d, J=3.28 Hz, 2H), 2.54 (ddd, J=3.66, 6.69, 10.36 Hz, 1H), 1.99 (ddd, J=4.04, 7.52, 11.18 Hz, 1H), 1.82 (d, J=12.13 Hz, 2H), 1.56 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.42 (q, J=6.82 Hz, 1H), 1.27 (t, J=7.07 Hz, 3H), 1.17-1.33 (m, 1H); LC-MS Rt=0.76 min; MS (ESI): 303.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]#[N:14])=[C:10]([NH2:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[SH2:20]>C(N(CC)CC)C>[C:1]1([C:7]2[S:8][C:9]([C:13](=[S:20])[NH2:14])=[C:10]([NH2:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: N#Cc1sc(-c2ccccc2)nc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=S)c1sc(-c2ccccc2)nc1N
Yield: 89 %

Procedure:
75 parts of 2-phenyl-4-amino-5-cyanothiazole in 300 parts of dimethylformamide and 15 parts of triethylamine are reacted with 13 parts of hydrogen sulfide as described in Example 1(a). 77 parts of 2-phenyl-4-amino-5-thiocarbamoylthiazole (89% of theory) of melting point 164°-167° C. are obtained.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:10])[N:4]=[CH:3]1
Reactant: CC(C)(C(=O)O)c1c[nH]cn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 58 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)-2-methylpropanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 213, (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (93.4 mg, 58%). 1H-NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 7.52-7.46 (m, 3H), 7.37 (d, 1H), 7.33-7.22 (m, 5H), 7.03-6.98 (m, 2H), 6.95-6.88 (m, 4H), 6.82 (s, 1H), 4.73-4.68 (m, 1H), 4.58 (d, 1H), 4.47 (d, 1H), 4.08 (dd, 1H), 3.64 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H). MS (EI) for C29H30FN4O4 found 517 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][OH:7])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: COC(CO)CO
Reactant: CCCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCCOCC(CO)OC
Yield: 45 %

Procedure:
2-Methylglycerol (10.6 g) and 10.7 g of 1-bromoheptadecane were reacted and worked up in accordance with Example 5-(i) to give 5.2 g of the above-identified alcohol compound.