Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:23])[C:20]=1[CH2:21]O)[CH2:6][CH2:7][CH3:8].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:5]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:23])[C:20]=1[CH2:21][Cl:3])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCn1ccnc1Sc1cncc(Cl)c1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1ccnc1Sc1cncc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SOCl2 (27 μL, 0.37 mmol) was added dropwise to a stirred solution of [3-(1-butyl-1H-imidazol-2-ylsulfanyl)-5-chloro-pyridin-4-yl]-methanol (22 mg, 0.74 mmol) in DCM (4 mL). After stirring for 1 h at room temperature, saturated aqueous Na2CO3 solution (5 mL) and DCM (5 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 316.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 2,3-dimethylphenol (1.0 g, 8.19 mmol), ethyl bromoacetate (1.0 mL, 9.0 mmol) and cesium carbonate (2.67 g, 8.19 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. After this time, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried and concentrated in vacuo to afford the title compound (1.7 g, 100% yield). LCMS, [M+Na]+=231.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH:36]1[CH:35]=[C:32]([CH2:33][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:18]2[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)[CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:16][CH:17]=2)=[O:20])[C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(NCCCCNCc1ccccc1C(F)(F)F)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethylbenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0260 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (57.1 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(N(CC)CC)C.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.O>[CH2:15]([O:22][C:23]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To azetidine-3-carboxylic acid (49.5 mmol, 5 g) in dioxane (150 ml), water (150 ml) and triethylamine (54.4 mmol, 7.58 ml) was added N-(benzyloxycarbonyloxy)succinimide (51.9 mmol, 12.94 g) and stirred at room temperature for half an hour. The reaction mixture was quenched with water and 30 ml of 2N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, filtered through a phase separation filter and concentrated in vacuo. The residue was dissolved in dichloromethane and extracted three times with aqueous saturated sodium hydrogencarbonate solution. The aqueous layers were combined, acidified with 2N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, washed with brine, filtered through a phase separation filter and concentrated in vacuo to give 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid (10.27 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 5 °C

Procedure:
A mixture of 6.08 g (25 mmol) of 5-amino-4-cyano-3-(4-methoxy-benzylamino)-pyrazole, 5.14 ml (30 mmol) of N,N-dimethylformamide diethyl acetal and 90 ml of toluene is heated under reflux for 3 hours. The reaction mixture is then cooled to approx. 5° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 147-148° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[N:16][C:17](S(C)(=O)=O)=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1.[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40]>>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:17]2[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[C:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:38])[F:37])[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=4)[CH2:8][CH2:9][NH:10][C:11]=3[N:18]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCN2
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCN3)CC1
Yield: 48.1 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-2-(methylsulfonyl)-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (Compound of Reference Example 20; 83.8 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (43.8 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[C:15]([F:22])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[NH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH2:23][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[F:22])[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[N:12]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1

Procedure:
5-Chloro-N-[1-[(3-cyanophenyl)methyl]-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 45) (600 mg, 1.26 mmol) was dissolved in THF (13 mL) and stirred in an ice bath. The solution was then treated dropwise with lithium aluminium hydride (1M in diethyl ether) (0.881 mL, 0.881 mmol) and stirred under nitrogen overnight. Further six portions of lithium aluminium hydride (1M in diethyl ether, 0.126 mL at a time) were added dropwise to the reaction and stirred for another day. The reaction was quenched with 2M NaOH solution (4 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) before being dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was dissolved in methanol and loaded onto a methanol conditioned sulfonic acid cartridge (SCX-2) 50 g. The cartridge was washed with methanol and eluted with 2M ammonia in methanol. Ammoniacal fractions were evaporated to give a brown gum (100 mg). The aqueous layer was back extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous magnesium sulphate before being evaporated in vacuo to give a brown gum (60 mg). The aqueous layer was back extracted with chloroform-isopropanol 3:1 (100 mL). The organic layer was dried over anhydrous magnesium sulphate before being evaporated in vacuo to a further 40 mg. The solids in the aqueous layer were collected by filtration. The solid was dissolved in methanol and filtered to remove any insoluble material. The filtrate was evaporated in vacuo to a further batch of 300 mg. The combined batches were dissolved in methanol and loaded onto a methanol pre-conditioned 50 g sulfonic acid (SCX-2) cartridge. The cartridge was washed with methanol and then eluted with 2M ammonia in methanol. Ammoniacal fractions were evaporated in vacuo to give the title compound as a brown gum (220 mg) LCMS (System A) RT=0.81 min, ES+ve m/z 481/483 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:8]=[CH:9][C:10](I)=[N:11][CH:12]=1.[CH:14]1([C:17]([CH:25]2[CH2:27][CH2:26]2)=[N:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:15]1.[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]([CH:25]2[CH2:27][CH2:26]2)([CH:14]2[CH2:15][CH2:16]2)[NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])=[N:11][CH:12]=1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Reactant: Brc1ccc(I)nc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC(c1ccc(Br)cn1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (2 M in THF, 1.843 mL, 3.69 mmol) was added dropwise over 5 minutes to a cooled solution of 5-bromo-2-iodopyridine (0.999 g, 3.52 mmol) in THF (7.00 mL) under Ar(g) at 0° C. and then the reaction mixture was stirred for 1 hour. A solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.715 g, 3.35 mmol) in THF (3.00 mL) was added via syringe over 4 min at 0° C. to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour and was warmed to room temperature. Saturated aqueous NH4Cl (15.0 mL) was added to the reaction and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0.5-3% methanol in dichloromethane) to yield (R)—N-[(5-bromopyridin-2-yl)(dicyclopropyl)methyl]-2-methylpropane-2-sulfinamide as a yellow oil. MS APCI calc'd for C16H24BrN2OS [M+H]+ 371 and 373. found 371 and 373.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.N1C=CC=CC=1.[C:18]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[N:29]=[CH:28][C:27]=1[NH2:36])(=[O:20])[CH3:19]>C1(C)C=CC=CC=1.ClCCl>[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[C:26]2[C:35]3[N:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:29]=[CH:28][C:27]=2[N:36]=[CH:1]1)(=[O:20])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OCCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OCCCn1cnc2cnc3cccnc3c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
Triethyl orthoformate (1.86 mL, 17.0 mmol) and pyridine hydrochloride (0.164 g, 1.42 mrnmol) were added to a stirred suspension of 3-[(3-amino[1,5]naphthyridin-4-yl)amino]propyl acetate (prepared as described in Part C of Examples 127-135, 3.70 g, 14.2 mmol) in toluene (70 mL). The mixture was heated at reflux with a Dean-Stark trap. After 2.5 hours, additional triethyl orthoformate (1 mL) was added and heating was continued for another 2 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford a dark oil that was dissolved in dichloromethane (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3.50 g of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl acetate as an orange oil that was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of 4.46 g (20.0 mmol) of 6-bromo-2-naphthalenol (obtained from Aldrich Chemical Company (#B7,340-6) and used without purification), in 20 mL of DMF at room temperature under argon was added 480 mg (20 mmol) of 95% sodium hydride over the course of 15 min. The resulting light yellow solution was stirred 30 min and 3.5 mL (22 mmol) of 1-bromohexane was added. The reaction was heated to 50° C. and stirred for 60 min. The reaction was quenched with ice water, the resultings solids filtered, washed with water and dried in vacuo at 60° C. Purification of the residue by chromatography on silica gel (5×20 cm column, hexanes as elutant) gave 5.00 g, 81% yield, of title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][CH:4]2[CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]([OH:8])[CH2:3]1
Reactant: NCc1ccccc1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Solvent: OCCO
Product: CN1CCC(NCc2ccccc2)(c2ccccc2)C(O)C1

Procedure:
A mixture comprising 3.7 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine, 2.5 g. of benzylamine and 10 ml. of ethylene glycol was heated at 150° C. on an oil bath overnight. After work-up by the method described in Example 1, 5.45 g. of residue were obtained from which 4.11 g. of the desired free base 1-methyl-4-phenyl-4-(N-benzylamino)-3-hydroxy piperidine were isolated, this compound having a melting point of 162°-4° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C@@H:10]([CH2:15][N:16](C(OCC1C=CC=CC=1)=O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[S:22]1(=[O:32])=[O:31])[CH2:9][CH2:8]2)(=O)C.[ClH:43]>[Pd].C(O)(=O)C>[ClH:43].[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C@@H:10]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[S:22]1(=[O:32])=[O:31])[CH2:9][CH2:8]2
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@H](CN(CCCCN1C(=O)c3ccccc3S1(=O)=O)C(=O)OCc1ccccc1)O2
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCNC[C@H]1CCc2cc(O)ccc2O1
Reaction time: 4 h

Procedure:
2 g of 10% palladium on carbon are added to 11.2 g (19 mmol) of (2R)-2-({[(benzyloxy)carbonyl][4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-butyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl acetate in 200 ml of glacial acetic acid and 67 ml of concentrated hydrochloric acid, and the mixture is hydrogenated at 3 bar and room temperature for 4 hours. The catalyst is filtered off, and 5 ml of 25% strength aqueous ammonia are then added and the mixture is concentrated. The residue is purified by chromatography (silica gel, mobile phase dichloromethane/ethanol, gradient 1:0 to 5:1). The resulting product fractions are freed from the solvent by concentration and taken up in ethanol, and 10 ml of a 4 N solution of HCl gas in ethanol are added carefully. After cooling in ice, the resulting solid is filtered off with suction, dissolved in 550 ml of hot ethanol and treated with activated carbon. After filtration, the mixture is concentrated to about 100 ml. The precipitated crystals are filtered off with suction and dried under reduced pressure. This give 3.15 g (37% of theory) of 2-[4-({[(2R)-6-hydroxy-3,4-dihydro-2H-chromen-2-yl]methyl}amino)butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide hydrochloride as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O.O>[NH:26]1[CH2:25][CH2:24][CH2:23][N:22]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:6]([OH:39])=[O:5])=[CH:14][CH:13]=1)=[O:27]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
240 mg of (2S)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-2-(toluene-4-sulfonylamino)-propionic acid tert-butyl ester were dissolved in 5 ml of methylene chloride and 1.6 ml of trifluoroacetic acid/water (95/5). The mixture was stirred for 2 hours at ambient temperature. The solvents were removed in vacuo. The residue was triturated with diethyl ether, filtered and dried in vacuo. Yield 196 mg. MS (ES+): m/e=503.1 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:19]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.I[CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH3:13][C:14]1[C:19]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH2:38][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[N:24]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(C)(=O)=O)cc1
Reactant: C[Si](C)(C)CI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to −78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 44) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at −78° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1 N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155–157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: C, 53.77; H, 4.94; N, 8.75; S, 6.98.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.[C:17](#[N:21])[CH:18]([CH3:20])[CH3:19].C(#N)C.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([C:18]([CH3:20])([CH3:19])[C:17]#[N:21])=[CH:7][C:2]=2[F:1])=[N:14]1
Reactant: Cc1cc(F)cc(F)c1C1=NC(C)(C)CO1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C#N)cc(F)c1C1=NC(C)(C)CO1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A flask containing a solution of 2-(2,4-difluoro-6-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole (14.84 g, 65.9 mmol) and isobutyronitrile (9.11 g, 132 mmol) in dry tetrahydrofuran (130 ml) was cooled to −15 to −20° C. (acetonitrile/dry ice bath) under an argon atmosphere. A solution of potassium bis(trimethylsily) amide (171 ml, 0.5M in toluene) was added via slow drop-wise addition. The mixture was stirred for 30 minutes at −15° C. and then gradually warmed to 15° C. over about 1.5 hours. The material was quenched via the addition of a saturated solution of aqueous ammonium chloride (100 ml). Water (80 ml) and diethyl ether (50 ml) were added and the material was transferred to a reparatory funnel and the organic phase was collected. This was washed with an equal volume of water and the organic phase was collected. The aqueous phases were back extracted with ether (2×100 ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by chromatography on silica gel eluting with 60% ethyl acetate/hexane to provide semi-pure product as a golden yellow oil (18 g, 75% pure). This material was used “as is” in subsequent steps. (M+H)+=275 m/e.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]([CH3:19])=[CH:18][C:9]1=2.[C:39](Cl)([Cl:41])=[O:40].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:39]([Cl:41])=[O:40])[C:10]2[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)Cl)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.91 mmol) in toluene (5 mL), add phosgene (0.91 mmol) as a 1.93 M solution in toluene. Next, add diisopropylethylamine (0.96 mmol) dropwise at room temperature. After stirring at room temperature for 1 h, dilute the reaction with ethyl acetate (10 mL) and wash with water (5 mL). Dry the organic phase over sodium sulfate, filter, and remove solvent under a stream of nitrogen. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-25%), to afford the title compound as a colorless foam. MS (ES+): 615 (M+H).