Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC1N=CC=C(NC)C=1.[CH3:11][P:12](Cl)(Cl)=[O:13].[CH3:16][CH:17]([CH2:19][CH2:20][CH2:21][C@H:22]([C@@H:24]1[C@:42]2([CH3:43])[C@H:27]([C@H:28]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[C:31]([CH2:32][C@H:33]([CH2:35][CH2:36]2)[OH:34])=[CH:30][CH2:29]3)[CH2:26][CH2:25]1)[CH3:23])[CH3:18].[NH2:44][CH2:45][CH2:46][N:47]([CH2:51][CH2:52][NH2:53])[CH2:48][CH2:49][NH2:50].[NH4+:54].[OH-:55]>ClCCl.CO.ClCCl>[CH3:18][CH:17]([CH2:19][CH2:20][CH2:21][C@H:22]([C@@H:24]1[C@:42]2([CH3:43])[C@H:27]([C@H:28]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[C:31]([CH2:32][C@H:33]([CH2:35][CH2:36]2)[OH:34])=[CH:30][CH2:29]3)[CH2:26][CH2:25]1)[CH3:23])[CH3:16].[CH2:45]([NH2:44])[CH2:46][N:47]([CH2:51][CH2:52][NH2:53])[CH2:48][CH2:49][NH2:50].[CH3:11][P:12]([NH2:54])(=[O:13])[O-:55]
Reactant: [OH-]
Reactant: [NH4+]
Reactant: CP(=O)(Cl)Cl
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CNc1ccnc(NC)c1
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: CO
Product: CP(N)(=O)[O-]
Temperature: 25 °C

Procedure:
Refering to FIG. 6, 4-Dimethylaminopyridine (DMAP) (0.31 g, 2.5 mmol) was added to a solution of methylphosphonic dichloride (0.332 g, 2.5 mmol, 31P NMR s, 43.93 ppm) stirring at room temperature under positive pressure argon gas. The resulting clear, colorless solution was cooled to −70° C. and a solution of cholesterol (0.97 g, 2.5 mmol) in anhydrous dichloromethane (20 ml) was added via syringe with vigorous stirring over a period of one hour. The reaction mixture was allowed to warm to room temperature and was maintained for 18 hours at which time 31P NMR analysis of a small aliquot of the reaction mixture indicated complete reaction (d, 39.08 ppm). Crude (13) was treated with additional DMAP (0.31 g, 2.5 mmol) and the reaction mixture cooled to −70° C. while stirring under positive pressure argon. Tris(2-aminoethyl)amine (TREN) (0.37 ml, 2.5 mmol) in anhydrous dichloromethane (20 ml) was added dropwise via syringe over a period of two hours. The reaction mixture was warmed to room temperature and stirred for an additional 18 hours (reaction complete by 31P NMR). Direct loading onto flash silica followed by a gradient of 10 to 20% MeOH/dichloromethane with 1 to 4% NH4OH gave 0.442 g of (18) as a white foam: (yield,28% over two steps), 31P NMR (d, 32.57 ppm), mass spec. calcd=592.89, found=593.49.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>CO>[CH2:15]([O:14][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[CH:13][N:5]2[CH2:4][C:3]([OH:22])=[O:2])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cnc2c(OCc3ccccc3)ncnc21

Procedure:
Methyl(6-(Benzyloxy)purin-9-yl)acetate (2.10 g; 7.0 mmol) was dissolved in methanol (70 ml) and 0.1 M NaOH (85 ml) is added. After 15 min. the pH of the reaction mixture was lowered by addition of 0.1 M HCl (˜80 ml) to pH 3. The precipitate was separated from the mixture by filtration and washed with water and ether. Yield: 1.80 g (90.2%). 1H-NMR (DMSO-d6): 8.55 (1H, s); 8.37 (1H, s); 7.55-7.30 (5H, m); 5.64 (2H, s); 5.09 (2H, s).
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][NH:16][NH2:17])=[CH:13][CH:12]=1>C(O)C>[NH2:8][C:7]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][C:11]([Br:10])=[CH:12][CH:13]=2)[C:5](=[O:4])[CH:6]=1
Reactant: CCOC(=O)CC#N
Reactant: NNCc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)cc2)[nH]1
Temperature: 60 °C

Procedure:
9.2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of p-bromobenzylhydrazine in 50 ml of ethanol is then added at room temperature. The mixture is warmed to 60° C for 2 hours, the substance which was precipitated is filtered off and the filtrate is evaporated. The residue is taken up with water, the mixture is shaken with ether and the aqueous phase is acidified with dilute acetic acid. The crude product is purified by twice recrystallising it from alcohol.
Reaction SMILES: C(O)(C)C.[F:5][C:6]1[CH:7]=[C:8]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]3[CH2:24][CH2:23][Si:22](OC(C)C)(OC(C)C)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[F:12].C(C1C=CC=CC=1)(=O)C>C(N(CC)CC)C>[F:5][C:6]1[CH:7]=[C:8]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]3[CH2:24][CH2:23][SiH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(C)O[Si]1(OC(C)C)CCC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: Fc1ccc([C@H]2CC[C@H](C3CC[SiH2]CC3)CC2)cc1F

Procedure:
A solution, in 100 ml of dichloromethane, of 42.0 g of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 1 was added to 250 ml of a dichloromethane solution of 1.0 mol/liter of iodine monochloride at room temperature, followed by agitation for 1 hour to obtain 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-dichloro-1-silacyclohexane. Subsequently, a mixture of 50.0 g of isopropyl alcohol and 300 g of triethylamine was added to the solution at room temperature, followed by agitation under reflux for 1 hour. The resultant solution was concentrated, after which 200 ml of hexane was added thereby permitting secondarily produced hydrochloride to be settled down. The hydrochloride was removed by filtration and the resultant filtrate was concentrated to obtain a mixture of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1,1-diisopropoxy-1-silacyclohexane and acetophenone. This mixture was subjected to distillation under reduced pressure to remove the acetophenone therefrom, and the residue was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour, after which the mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The resultant extract was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 26.2 g of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1-silacyclohexane. The results of IR analysis of the product are shown below.
Reaction SMILES: O1CCCC1.[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)Cc1ccc(Sc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Sc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a tetrahydrofuran (4 mL) solution of the (6-phenylsulfanyl-pyridin-3-yl)acetohydroximoyl chloride (100 mg, 0.359 mmol) described in Manufacturing Example 97-1-4 and 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.13 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (55 μL, 0.40 mmol), which was stirred under nitrogen atmosphere for 1 hour at 50° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (25 mg, 58%).
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22]Cl.[H-].[Na+].Cl>CN(C)C=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:22]=1[C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)=[O:24]
Reactant: O=C(CCl)Nc1ccccn1
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of 590 mg. (3 mmole) of N-methylsaccharin and 1.02 g. (6 mmole) of N-(2-pyridyl)chloroacetamide in 3 ml. of dimethylformamide at 40° C. was added 250 mg. (10.3 mmole) of 99% sodium hydride portionwise over a period of one hour. The reaction mixture was allowed to stir at 40° C. for 2.5 hours and was then added to 100 ml. of 5% hydrochloric acid solution and 300 ml. of ice. The precipitate was filtered and dried to give 24 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15](OCC)=O.[C:24]1(OC)[CH:29]=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl.CN1CCNCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]3[C:15]([N:1]4[CH2:24][CH2:29][N:4]([CH3:5])[CH2:3][CH2:2]4)=[N:1][C:2]4[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=4[NH:4][C:5]=3[S:9][C:8]=2[CH:10]=1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12
Reactant: COc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN1CCNCC1
Product: Cc1ccc2c3c(sc2c1)Nc1ccccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate (3.7 g), 1-methylpiperazine (80 ml), anisole (16 ml) and titanium tetrachloride (3 ml), 3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.4 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].CI.[C:17](=O)([O-])[O-].[K+].[K+].O.CN([CH:27]=[O:28])C>>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([O:28][CH3:27])=[O:6]
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(OC)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Hydroxy-5-trifluoromethylbenzoic acid (2 g) was initially charged at RT in DMF (15 ml) while stirring, and admixed dropwise with methyl iodide (3.0 ml). After adding potassium carbonate (5.6 g), the mixture was stirred for 5 h and left to stand overnight. It was then admixed with water and extracted three times with MtB ether. The combined MTB ether phases were dried over sodium sulfate, filtered and concentrated. 2.29 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c2ncccc12
Yield: 79.5 %

Procedure:
10.0 mmol of 5-chloro-8-hydroxyquinoline (ALDRICH) are dissolved, with stirring, in 20 ml of dry DMF, in a 50 ml round-bottomed flask provided with stirring and a thermometer. Then 11 mmol of potassium carbonate and 10% by weight of potassium iodide are added. A solution of 11 mmol of benzyl chloride (JANSSEN) in 5 ml of DMF is added dropwise over 5 minutes, at room temperature and with stirring. After 18 hours of reaction at 50° C., the reaction mixture, supplemented with 100 ml of water is extracted with 4×50 ml of tert-butyl methyl ether. The organic phases are combined, then washed with 3×50 ml of 1N HCl. The aqueous phases are combined, alkalized to pH=9 and extracted with 2×50 ml of ethyl acetate. After drying the organic phase over MgSO4, the solvent is evaporated under reduced pressure. The desired product is obtained after recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[S:8]1[C:4]2[CH:3]=[C:2]([N:1]=[C:11]=[O:12])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc2ncsc2c1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc2ncsc2c1

Procedure:
A mixture of 6-aminobenzothiazole (600 mg; 4 mmol) in toluene (40 ml) and phosgene (20 ml 20% in toluene; 40 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 6-benzothiazolylisocyanate. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (500 mg; 2.0 mmol) in toluene (20 ml) and refluxed for 16 h. The precipitate was isolated and recrystallized from methanol/ether to give 440 mg of the title compound. M.p. 210°-213° C. MS (70 eV): m/z 430 (13%, M+), 254 (32), 209 (77), 176 (100), 121 (38), 70 (83).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A mixture of 1-(4-trifluoromethylphenyl)piperazine (5.2 g, 22.59 mmol), N-(2-bromoethyl)phthalimide (5.22 g, 20.53 mmol) and potassium carbonate (3.36 g, 24.28 mmol) in DMF (30 ml) was stirred at 100° C. for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=50/1), and the resulting solid was washed with methanol, and then dried in vacuo to afford N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}phthalimide (4.85 g, yield 53%) as a white powder.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](C#N)#[N:19].N1C=CC=CC=1.Cl>O.CN1CCCC1=O>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)=[CH:12][N:11]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#CC#N
Reactant: CCCCCc1ccc(-c2ccc(Cl)s2)cn1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCCCCc1ccc(-c2ccc(C#N)s2)cn1
Temperature: 70 °C

Procedure:
A mixture of 26.6 g of 5-chloro-2-(2-pentyl-5-pyridyl)-thiophene, 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 150° for 2 hours. It is cooled, a solution of 120 g of FeCl3.6 H2O in 600 ml of 20% strength hydrochloric acid is added and the mixture is warmed at 70° C. for 1.5 hours, with stirring, and worked up in the customary manner to give 2-(2-pentyl-5-pyridyl)-thiophene-5-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:33])[CH2:22][S:23][C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:34][N:35](C)[CH:36]=O>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:22][C@H:21]([NH:20][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=[C:2]([N:35]([CH3:36])[CH3:34])[N:3]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH3:33]
Reactant: CN(C)C=O
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(N(C)C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 12 %

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine (1.02 g, 2.0 mmol) (Example 5) in dimethylformamide (10 ml) to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(dimethylamino)adenosine (0.12 g, 12%) as a foam (following column chromatography), 1H NMR (DMSO6) δ1.38 (3H, d, --CHCH3), 2.92 (6H, s, --N(CH3)2), 3.40-3.72 (4H, m, H-5'a and H-5'b and --CH2 --), 3.88 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.65 (1H, q, H-2'), 4.72-4.85 (1H, m, --CH--), 4.89 (1H, t, 5'-OH), 5.14, 5.36 (2H, 2d, 2'- and 3'-OH), 5.75 (1H, d, H-1'), 7.35, 7.46 (2H, 2 t, Ar--H), 7.50 (1H, d, N--H), 7.84, 7.99 (2H, 2d, Ar--H), 7.94 (1H, s, H-8). HPLC retention time 16.8 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[Cl:22])[CH2:6][CH2:5]1)(=O)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C.Cl[SiH](Cl)Cl>C(Cl)Cl>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH:1]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:2])[CH2:5][CH2:6]1)=[O:23]
Reactant: Nc1ccccc1
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: Cl[SiH](Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Nc1ccccc1)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Trans-N-(4-acetylcyclohexyl)-2-chloro-5-(trifluoromethyl)-benzamide (200 mg, 0.57 mmol) and aniline (54 mg, 0.57 mmol) in DCM (10 mL) is added DMF (0.1 mL) followed by trichlorosilane (78 mg, 0.57 mmol). After stirring at room temperature for 1 hour, further trichlorosilane (5×78 mg, 5×0.57 mmol) is added at 1 hour intervals for the next 5 hours. Further DMF (0.1 mL) was then added and the mixture is stirred at room temperature overnight. The colourless solid that is formed is recovered by filtration, washed successively with water and then EtOAc and dried. [MH+425.38]. The racemic mixture was separated by supercritical fluid chromatography on chiral stationary phase analogously to that reported for Example 1.37.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:16])[CH:14]=[CH2:15]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:14]=[CH2:15])[O:10][CH2:11][Cl:12]
Reactant: O=C(Cl)OCCl
Reactant: C=CC(=O)OCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)OCCl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (0.98 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.82 (4H, m, CH2 --CH2), 4.27 (4H, m, 2×CH2 --O), 5.77 (2H, s, Cl--CH2 --O), 5.8-6.7 (3H, m, CH=CH2)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[C:15]([C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Yield: 61.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzonitrile (350 mg, 1.45 mmol) and potassium carbonate (263 mg, 1.9 mmol) in anhydrous DCM (3 ml) was added dropwise phenyl chloroformate (0.91 ml, 7.3 mmol) as a solution in DCM (1.5 ml). The crude was purified by silica gel chromatography (DCM/EtOAc 6-50%) to afford phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (320 mg, 61%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 6.45 (s, 1H), 7.26-7.28 (m, 3H), 7.31-7.38 (m, 2H), 7.75-7.82 (m, 4H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:23])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:23][C@H:22]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a suspension of sodium hydride (oil, 60%, 1.61 g) in DMF (50 mL) was added 4-hydroxypyridine (3.83 g) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, and (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (13.3 g) was added thereto in small portions under ice-cooling. The reaction mixture was stirred for 2 hr under ice-cooling, and at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43]>ClCCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[Cl:43])[CH3:34])=[O:8])=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22]
Reactant: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)O)ccc1Cl
Reactant: CNc1cccc(F)c1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)N(C)c2cccc(F)c2Cl)ccc1Cl
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
To a stirred solution of 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid (50 mg, 0.151 mmol) in anhydrous 1,2-dichloroethane (0.5 mL) at room temperature was added oxalyl chloride (23 mg, 0.181 mmol) followed by a catalytic amount of DMF. After stirring for 40 mins, a solution of N-methyl-2-chloro-3-fluoroaniline 29-1 (30 mg, 0.188 mmol) in 1,2-dichloroethane (0.5 mL), followed by 4-(dimethylamino)pyridine (22 mg, 0.179 mmol) were added and the mixture was stirred for 12 h. Direct purification via reverse phase preparative LCMS gave 4-chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide 30-1 (18 mg, 25%) as a colorless solid. MS: 350.5, tR=8.75 min (method 3); 1H NMR (CDCl3) δ 7.50 (1H, m), 7.44 (1H, dd, J=8.4, 1.8 Hz), 7.31 (1H, m), 7.26 (1H, s), 6.95 (1H, dd, J=9, 2.1 Hz), 6.79 (1H, m), 6.55 (1H, s), 3.46 (3H, s), 1.93 (3H, s).