Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([NH:27][CH2:28][CH2:29][OH:30])[N:19]=2)[CH2:14][CH2:13]1>ClCCl>[C:1]([O:30][CH2:29][CH2:28][NH:27][C:20]1[N:19]=[C:18]([N:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=1)(=[O:3])[CH3:2]
Reactant: CCCc1nc(NCCO)nc(N2CCOCC2)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(NCCOC(C)=O)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
4 3 g (0.055 mole) of acetyl chloride, dissolved in 50 ml of dichloromethane, and 5.5 g (0.055 mole) of triethylamine, dissolved in 50 ml of dichloromethane, are simultaneously introduced, between 0° and 5° C., into a solution of 13.4 g (0.05 mole) of 2-[(4-morpholino-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol (compound 1 prepared in Example 1) in 200 ml of dichloromethane. The addition of these two reagents is regulated in a manner such that the acid chloride is always present in the reaction mixture in excess with respect to the triethylamine. The mixture is stirred for one hour at 5° C. and then for 12 hours at room temperature. The reaction mixture is washed successively with an aqueous solution of sodium bicarbonate and with water. It is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue crystallizes in a mixture of toluene-hexane 1:2. The product obtained is first purified by chromatography on silica (eluent: 95:5 (v/v) dichloromethane-ethanol) and is then firstly recrystallized from a mixture of toluene-hexane 1:1. 9.3 g of 2-[[2-(acetoxy)ethyl]amino]-4-morpholino-6-propyl-1,3,5-triazine are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:16])[C:11]=1[O:12][CH2:13][C:14]#[CH:15])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:16])[C:11]=1[O:12][CH2:13][C:14]#[CH:15])[C:5]([OH:7])=[O:6]
Reactant: C#CCOc1c(F)cc(C(=O)OC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To 30 ml of ethanol were added 5.5 g of methyl 3,5-difluoro-4-(2-propynyloxy)benzoate and 10 ml of a 15% aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue to make the mixture acidic, and the precipitated solids were collected by filtration, and 5.0 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[ClH:9].[OH2:10]>>[ClH:9].[NH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[CH2:3][C:4]([OH:10])=[O:7]
Reactant: CC1(C)CNC(=O)C1
Reactant: O
Agent: Cl
Product: CC(C)(CN)CC(=O)O
Temperature: 120 °C
Yield: 92 %

Procedure:
4,4-Dimethyl-2-pyrrolidinone (2.52 grams, 22.3 mmol) was added to a mixture of concentrated HCl (50 ml) and water (50 ml) and the resulting mixture refluxed at 120° C. for 20 hours. After cooling to room temperature the mixture was washed twice with dichloromethane. The aqueous layer was evaporated to give 4-amino-3,3-dimethyl-butyric acid hydrochloride (3.425 grams, 92% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>>[CH3:27][C:21]1[C:20]([Cl:19])=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)c1cccnc1Cl
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Product: Cc1c(Cl)cccc1Nc1ncccc1C(=O)OCOC(=O)C(C)(C)C
Temperature: 140 °C

Procedure:
Into a suitable flask, pivaloyloxymethyl 2-chloro-3-pyridinecarboxylate prepared according to Example 2, supra (21.7 g) and 3-chloro-2-methylaniline (28.4 g) are charged. To begin the reaction the mixture is heated to 140° C. During the reaction the temperature of the reaction mixture rises to 190° C. When reaction is completed, the temperature diminishes. The reaction mixture is then cooled to room temperature. Diluted hydrochloric acid is added to the cooled mixture and the precipitated compound ground into small particles and suspended in the reaction mixture. The solid is separated by filtration and the cake washed with water. Then the washed solid is dissolved in hot methanol and recrystallized by cooling the methanolic solution. The crystallized product is separated and dried under vacuum, at a temperature of 40° C. Pivaloyloxymethyl 2-(2'-methyl-3'-chloro-anilino)-3-pyridinecarboxylate (m.p. 90°-91° C.) is so obtained, with a yield of 22.5 g (77.6% of theory).
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:3][CH2:4]1)=[O:26]
Reactant: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCNCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cl)c1)N1CCN(C(=O)c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 Gram of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride, 0.72 g of m-chlorobenzoylchloride and 1.4 ml of triethylamine were suspended in 15 ml of dichloromethane and the suspension was stirred at a room temperature for 2 hours. Crystals formed in the reaction mixture were collected by filtration and recrystallized from dimethylformamide to obtain 1.07 g of 6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-carbostyril. Colorless powdery crystals. Melting point: over 300° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: CN(C)C(=O)Cl
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using dimethylcarbamyl chloride. The final product was obtained in 11% yield.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:36])[C@@H:20]([NH:28]C(=O)OC(C)(C)C)[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCO>[NH2:28][C@@H:20]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@H:19]([OH:36])[CH2:18][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:38][CH:37]=1)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN(Cc1ccc(C#N)cc1)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N(Cc1ccc(C#N)cc1)C[C@@H](O)[C@@H](N)CC1CCCCC1
Temperature: 65 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl (2S,3R)-4-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (921 mg, 1.68 mmol) was dissolved in EtOH (10 mL) and treated with toluenesulfonic acid monohydrate (337 mg, 1.77 mmol, 1.05 equiv). The mixture was allowed to stir at 65° C. for 40 min. LC-MS analysis showed that the starting material had been consumed and converted to the desired product. The solvent was removed and the residue was dissolved in CH2Cl2 (20 mL). The solution was treated with 1.0 M aq NaOH (20 mL) and the biphasic mixture was stirred for 0.5 h. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated to afford (2R,3S)-3-amino-1-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)-4-cyclohexylbutan-2-ol.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:27]([C:29](OCC)=[O:30])[NH2:28]>CCOC(C)=O>[O:30]=[C:29]1[NH:27][N:28]=[C:1]([C:3]2[N:4]=[C:5]([NH:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(C#N)cc2ccccc12
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate (0.561 g) was added ethyl hydrazinecarboxylate (0.663 g, 6.36 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl. The aqueous and organic layers were separated. The organic layer was concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[C:4]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:3]1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([CH3:21])[C:19]([C:4]1[C:5](=[O:18])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[CH:7][N:2]([CH3:1])[CH:3]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: ClC(Cl)Cl
Product: CC(Cl)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 2.7 g. portion of 1-methyl-3-propionyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was dissolved in 125 ml. of chloroform, and 2.3 g. of N-chlorosuccinimide was added. The mixture was stirred under reflux overnight, and was then cooled and washed, first with 1 N sodium hydroxide, and then with saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate and evaporated under vacuum to obtain 2.2 g. of a partially crystalline solid. The product was crystallized from diisopropyl ether to obtain 1.2 g. of the desired product, m.p. 129°, dec., showing the following nmr peaks in DMSOd6 : δ7.5-8.4 (m, 6H, aromatic); 5.8-6.2 (q, 1H, CHCl); 1.5-1.6 (d, 3H, CHClCH3); 3.8 (s, 3H, N--CH3).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][SiH:10]([CH3:12])[CH3:11]>[Pt]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C[SiH](C)C
Reactant: C=CCOCC1CO1
Agent: [Pt]
Product: C[Si](C)(C)CCCOCC1CO1
Temperature: 130 °C

Procedure:
Allyl glycidyl ether (30.3 g, 0.266 moles) and 3 mg of platinum catalyst are weighed into a 300 mL laboratory autoclave. The autoclave, together with its contents, is cooled in an acetone/dry ice bath in an atmosphere of argon and 19.7 g of trimethylsilane (0.266 moles with a boiling point of 6.7° C.) are siphoned over from the condensed phase. The autoclave is closed and heated to 130° C. At the same time, the internal pressure increases to 7.6 bar and then drops again to 3.2 bar, indicating a reaction.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([NH:8][CH2:7][C:6]([OH:21])=[O:5])[S:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reaction time: 3 h

Procedure:
780 mg (2.53 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 3 h. The mixture was concentrated and lyophilized. Yield: 859 mg.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:21]1[C:22]([Cl:34])=[C:23]2[N:32]=[CH:31][N:30]([CH3:33])[C:24]2=[N:25][C:26]=1[C:27]([OH:29])=[O:28]>C1COCC1>[Cl:34][C:22]1[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[C:26]([C:27]([OH:29])=[O:28])[N:25]=[C:24]2[N:30]([CH3:33])[CH:31]=[N:32][C:23]=12
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1cnc2c(Cl)c(Br)c(C(=O)O)nc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)c(Nc3ccc(I)cc3F)c(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-4-iodo-aniline (2.9 g, 22.1 mmol) in THF (20 ml) at −78° C. is added LiHMDS (33.3 ml, 1 M in THF, 33.3 mmol) dropwise. The reaction mixture is stirred for 10 min and a solution of 6-bromo-7-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (WO 2005/051906) (5.63 g, 10.1 mmol) in THF (30 ml) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at this temperature for 16 h. The mixture is concentrated, quenched with 10% HCl solution (70 ml), and extracted with EtOAc (2×200 ml). The combined organic solution is dried over MgSO4 and concentrated to dryness. Purification by trituration with boiling CH2Cl2 gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][C:10](OCC)=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1>[O:15]=[C:8]1[C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[O:16][CH:10]=[CH:9]1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 36 h
Yield: 122.6 %

Procedure:
The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added to trifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassium carbonate (44 g, 318 mmol) and toluene (400 mL). This suspension was stirred at room temperature for 36 hours, then heated to reflux for 4 hours. After cooling to room temperature, the suspension was poured over rapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCl (12 N, 50 mL). The resulting organic phase was separated from the clear mixture, was washed with water (5×500 mL), brine (1×500 mL), dried over MgSO4, filtered and concentrated in vacuo yielding tan solid which was dried under high vacuum. This sample was partially dissolved in heptane (100 mL) and ethyl acetate (12 mL) with heating on a steam bath, was filtered to remove insoluble material. The filtrate was allowed to cool to room temperature yielding the desired 4-oxo-4H-1-benzopyran as a fluffy tan solid (14.17 g, 56%): mp 106.7-108.6° C. This material was of suitable purity to use in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[CH3:22][CH:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:25]([CH:23]([CH3:24])[CH3:22])(=[O:27])=[O:26])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(C#N)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added propane-2-sulfonyl chloride (201 μL, 1.8 mmol) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give propane-2-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 384.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:42][OH:43])[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:43][N:42]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 23 (162 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellowish oil. LC/MS (method B): 555.5 (M+H)+. HPLC (Method A) Rt 4.98 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].[OH-].[K+]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Ic1ccc2nccn2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-iodoimidazo[1,2-α]pyridine (Intermediate 6, 448 mg, 1.84 mmol) in concentrated sulfuric acid (1.8 mL) at 15° C. was added concentrated nitric acid (0.54 mL) dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for one hour and was poured onto 10 g of ice. The pH of the mixture was adjusted to 4 with aqueous potassium hydroxide solution and the resultant solids were collected by filtration, washed with water and dried. The crude product was recrystallized from dichloromethane/hexanes to afford the title compound. LC/MS 289.8 (M+1).
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[NH2:10][CH2:11][C@@H:12]1[C@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@H:15]2[C@H:14]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH2:31])[O:13]1.[BH3-]C#N.[Na+]>CO>[NH2:31][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[C:28]=1[N:29]=[CH:30][N:22]2[C@H:14]1[C@@H:15]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][C@@H:16]2[C@@H:12]([CH2:11][NH:10][C@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]2)[O:13]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: COC(=O)C1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (4.60 g, 35.94 mmol), 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (11.0 g, 35.94 mmol) and Ti(iPrO)4 (4.0 g, 14.08 mmol) in MeOH (80 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (4.5 g, 71.87 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL) and filtered, extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to obtain the title compound (6.2 g, Yield 41%). 1H NMR (500 MHz, CDCl3): δH 8.38-8.34 (m, 1H), 7.90 (s, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.75 (br s, 2H), 5.48-5.46 (m, 1H), 5.03-5.01 (m, 1H), 4.35-4.33 (m, 1H), 3.69-3.66 (m, 3H), 3.50-3.17 (m, 1H), 3.05-2.73 (m, 3H), 2.48-2.44 (m, 2H), 1.95-1.91 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 419.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Oc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Oc1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a stirred solution of 25 g of 4fluorophenol in 40 cc of pyridine and 30 cc of toluene was added dropwise 40.9 g of 2-chlorobenzoylchloride at room temperature. And the resulting mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction mixture and extracted with ethyl acetate. The ethylacetate layer was washed 4 times with 1N HCl , dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was recrystallized from hexane to obtain 49.1 g of compound A. Yield: 87.8%.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])=[CH:3][CH:4]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: OCc1ccc(S)cc1
Product: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Yield: 49.5 %

Procedure:
Using the method of Preparation 153 using (4-mercaptophenyl)methanol (4.42 g, 31.5 mmol) and 5-bromonicotinonitrile (5.49 g, 30.0 mmol) affords the title compound (3.60 g, 50%): 1H NMR (CDCl3) δ 1.92 (t, J=5.9 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 7.48 (q, J=8.2 Hz, 4H), 7.58 (t, J=2.0 Hz, 1H), 8.61 (dd, J=2.0, 3.1 Hz, 2H).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:8]=1[CH2:7][S:6][C:5]2=[O:9].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:32][C:11]([F:10])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[C:7]2/[C:8]3[N:4]([CH2:3][CH2:2][N:1]=3)[C:5](=[O:9])[S:6]/2)[CH2:17][CH2:16]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1SCC2=NCCN12
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=c1s/c(=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)c2n1CCN=2
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a solution of 2,7-dihydro-3H-imidazo[1,2-c][1,3]thiazol-5-one (260 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (620 mg) in 2-propanol (5 mL) was added piperidinium acetate (292 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from heptane to give the title compound (140 mg).