Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]#[N:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:13]([NH:16][OH:17])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: N#Cc1sc(N)nc1-c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1sc(N)nc1-c1ccccc1

Procedure:
2-Amino-4-phenyl-thiazole-5-carbonitrile (0.13 g, 0.6 mmol) was suspended in 1:1 water/ethanol (v/v) (24 mL) and added hydroxylamine hydrochloride (1.47 g, 21 mmol) and potassium carbonate (1.86 g, 13 mmol). The reaction mixture was heated at reflux for 3 days, then the solvent was reduced and the aqueous phase was extracted with dichloromethane. The organic layer was washed with water and brine, and was dried over sodium sulfate. The solvent was evaporated to yield a yellow solid. Yield: 0.1 g, 66%.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=[O:13])[CH:5]=[CH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C1(C)C=CC=CC=1>[N:15]1([CH:5]([CH2:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[C:4](=[O:13])[C:2]([CH3:14])([CH3:1])[CH3:3])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)C=CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC(C(=O)C(C)(C)C)n1cncn1
Temperature: 25 °C

Procedure:
2,2,7,7-tetramethyl-oct-4-en-3,6-dione (0.01 mol) and 1,2,4-triazole (0.01 mol), suspended in toluene (100 ml), were refluxed for 24 hours. On cooling to room temperature, the organic layer was washed with water (4×100 ml) and dried over sodium sulphate. Removal of the solvent gave 4-(1,2,4-triazol-1-yl)-2,2,7,7-tetramethyl-octan-3,6-dione, m.p. 66°-69°.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:25][C@@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)[N:19]=[N:20][C:21]=3[C:22]([NH2:24])=[O:23])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:40]([Cl:44])(=[O:43])[CH:41]=[CH2:42]>CN1C(=O)CCC1>[C:40]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:18]2[N:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[N:17]=2)[CH2:27]1)(=[O:43])[CH:41]=[CH2:42].[ClH:44]
Reactant: NC(=O)c1nnc(N[C@@H]2CCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide (83) HCl salt (60 mg, 0.13 mmol) in NMP (4 mL) was added DIEA (160 μL, 0.90 mmol) and then acryloyl chloride (25 μL, 0.30 mmol). The mixture was stirred at RT for 30 min, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to afford the title compound (84) as an HCl salt. MS found for C22H26N8O4 as (M+H)+ 467.1, (M−H)− 465.2. UV: λ=242 nm.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(CC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C1CCC(Cc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 1-((6-((4-(tert-butyl)cyclohexyl)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (150 mg, 0.33 mmol) in MeOH (5 mL) was added NaOH (68 mg, 1.7 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 80° C. for 4 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was purified by prep-HPLC (CH3CN: H2O/0.05% TFA=0-95%) to afford the desired product 1-((6-((4-(tert-butyl)cyclohexyl)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (120 mg, 85%). ESI-MS (M+1)+: 422.3. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H), 7.84˜7.81 (m, 1H), 7.77-7.74 (m, 1H), 7.58 (d, J=10 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35˜7.32 (m, 1H), 4.36 (s, 2H), 3.50˜3.46 (m, 2H), 3.22-3.20 (m, 2H), 2.77-2.75 (m, 1H), 2.58-2.56 (m, 2H), 2.15-2.11 (m, 2H), 1.91 (br, 1H), 1.75-1.66 (m, 3H), 1.56-1.25 (m, 6H), 1.00-0.88 (m, 2H), 0.81 (s, 9H). HPLC: 96.20%
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.O=[C:10]1[CH2:17]C(C)(C)C[C:12](C)=[CH:11]1>>[CH3:17][C:10]1[CH2:11][CH2:12][CH:7]2[C:2]([CH:1]=1)=[CH:3][C:4](=[O:8])[CH2:5][CH2:6]2
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC1=CC(=O)CCC1
Product: CC1=CC2=CC(=O)CCC2CC1

Procedure:
This material is prepared according to the procedure for Preparation 1 wherein 3-methyl-2-cyclohexenone is substituted for isophorone.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.CCCCCC>[CH3:8][C:7]1[S:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:36][CH:37]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.4 %

Procedure:
A mixture of 4-(chloromethyl)-5-methyl-2-phenylthiazol (394 mg), methy E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylormamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was subjected to silica gel chromatography to obtain methy E-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino]-4-phenylbutyrate (570 mg, yield 71%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([Si](C)(C)C)[N:15]=[N:14]1.[I:22]I>O1CCCC1.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([I:22])[N:15]=[N:14]1
Reactant: C[Si](C)(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc(I)nn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl- 1,2,3-triazole (EP-400842-A1; 1.00 g) in tetrahydrofuran (20 ml) was added silver trifluoroacetate (623 mg) and iodine (716 mg) at −78° C. under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature over 1 hour and then left to stir for a further 16 hours. The reaction was filtered and the filtrate diluted with water (100 ml) and extracted with ether (100 ml), the organic fraction was separarted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica, 100 g) eluted with dichloromethane:hexane (2:1) to give the title compound as a pale yellow crystalline material, m.p. 194-195° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CCOCC.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[F:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][NH:6][CH2:7][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1

Procedure:
A mixture of 3.44 g of trans-1-ethoxycarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine of Example 47, 50 ml of absolute ethanol and 26 ml of 20% aqueous NaOH solution is refluxed 18 hours under a nitrogen atmosphere. The ethanol is removed in vacuo, and the aqueous residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil which quickly crystallizes to a solid. The solid is triturated with hexane and filtered to afford a solid, m.p. 99°-101° C. This material is dissolved in 100 ml of ether and treated dropwise with a solution of 1.05 g of fumaric acid in a mixture of 60 ml of ether and 15 ml of absolute ethanol. The resultant solid is filtered, washed with ether and dried to afford a salt of trans-4-(4-fluorophenoxy)-3-phenylpiperidine fumarate, m.p. s 142.5°, 143° C. dec.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30](O)=[O:31])=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@H:73]([CH2:81][CH2:82][CH3:83])[C:74]([N:76]1[CH2:79][CH:78]([F:80])[CH2:77]1)=[O:75]>CN(C=O)C>[F:80][CH:78]1[CH2:77][N:76]([C:74]([C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[CH:28]=2)=[O:31])[CH2:81][CH2:82][CH3:83])=[O:75])[CH2:79]1
Reactant: CCC[C@@H](N)C(=O)N1CC(F)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In a round-bottomed flask, (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-pentan-1-one trifluoroacetate (crude from Step 2) was dissolved in DMF (1.5 ml) and N,N-diisopropylethylamine (0.60 ml, 3.44 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and HATU (104 mg, 0.27 mmol) were added. The yellow reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 128 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide as an off-white powder.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[NH3:12].[CH3:13][OH:14]>>[C:13]([C:5]1([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C:2]2=[O:3])[CH2:6][CH2:11][NH:1][CH2:2][CH2:4]1)(=[O:14])[NH2:12]
Reactant: O=C1CCc2ccccc2N1
Reactant: N
Reactant: CO
Product: NC(=O)C1(N2C(=O)CCc3ccccc32)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(1-Ethoxy-1-iminomethyl)benzoyl]-4piperidinyl{-3,4-dihydrocarbostyril (1 g) is dissolved in methanol (10 ml) and thereto is added aqueous ammonia (10 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue. The mixture is extracted with chloroform, dried with sodium carbonate, concentrated and then purified by silica gel column chromatography (solvent: chloroform: methanol=10:1) and recrystallized from ethanol/n-hexane to give 1-[1-(4-carbamoyl-4-piperidinyl]-3,4-dihydrocarbostyril (0.2 g) as white powder, m.p.: 101°-104° C.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:12]([C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1)[CH2:13][CH3:14]
Reactant: CCCc1nc(C=NNC(=S)SC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1ncc2cn[nH]c(=S)n12

Procedure:
A 102.2 gm. portion of 3-(2-n-propyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in 500 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product as a white solid, m.p. 201.5°-203.5° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12].[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:18][CH2:17][O:16][CH2:15][CH2:14][Cl:13]
Reactant: ClCCOCCCl
Reactant: COc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCCCl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of 50% sodium hydride in 250 ml. of dry dimethylformamide was added in portions 31.6 g. of 2-chloro-4-methoxyphenol. To this mixture was added 143 g. of bis(2-chloroethyl) ether, and the reaction mixture was heated at reflux with stirring for 8 hours. The volatile solvent was removed, the residue partitioned between water and methylene dichloride, and the organic solution washed with water and dried over anhydrous magnesium sulfate. The product was twice distilled to give 2-[2-(2-chloro-4-methoxyphenoxy)ethoxy]ethyl chloride, b.p. 139°-140° C. (0.05 mm.).
Reaction SMILES: C[Si](C)(C)CCO[CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.[CH3:16][Si:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][O:20][CH2:21]N1C(C#N)=CN=C1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][C:8]1[N:7]([CH2:6][CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:30])([CH3:29])[CH3:16])[CH:11]=[C:10]([C:12]#[N:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Reactant: C[Si](C)(C)CCOCn1cncc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCCn1cc(C#N)nc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and a condenser with a nitrogen inlet was charged with a mixture of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and 3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g, 2.69 mol, as prepared in the previous step) and carbon tetrachloride (1.8 L). Agitation was initiated and the mixture was heated to 60° C. At this point N-bromosuccinimide (502 g, 2.82 mol) was added in several portions over 30 min, which resulted in an exotherm to 74° C. The reaction was allowed to cool to 60° C. and further stirred at 60° C. for 1 h. The reaction was allowed to cool slowly to ambient temperature and the resulting slurry was filtered and the filtrate washed with satd NaHCO3 solution (4.0 L). The organics were passed through a plug of silica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate (6.0 L) as eluent. The fractions containing the product (based on TLC analysis) were combined and concentrated under reduced pressure to give a crystalline light yellow solid, which was then filtered and washed with heptane (500 mL) to give the title compound as a crystalline white solid [593 g, 73%). The 1H and 13C NMR spectra were consistent with the assigned structure and showed no evidence of the minor regioisomer.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Lithium hydroxide (160 mg, 6.8 mmol) in water (10 mL) was added to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate in methanol (30 mL). The reaction was stirred for 24 h., and was concentrated under reduced pressure to remove the methanol. The remaining water layer was adjusted to pH=3 using 1 N HCl aqueous solution, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-isopropoxyphenyl)propanoic acid (1 g, 90%). Analytical LCMS (M+H-Boc)+: m/z=223.9.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[CH3:11][O:12][CH:13](Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:12][C:13]1[C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[CH:7][C:8]=1[CH:3]=[O:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc(C)cc1C=O
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of 1-methoxy-2,4-dimethylbenzene (8.00 g, 58.7 mmol) and 1,1-dichloromethyl methyl ether (7.40 g, 64.7 mmol) in methylene chloride (30 mL) was added titanium tetrachloride (20.0 g, 105 mmol) at 0° C. and the mixture was stirred at that temperature for 20 minutes. This reaction mixture was poured into iced water and the organic layer was taken, washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.40 g of the title compound. Yield 98%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([C:31]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[C:17]([F:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(N)n1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylpyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (13 mg, 0.1 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C(Cl)Cl>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)nc1F
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)nc1F
Temperature: 25 °C

Procedure:
2,6 difluoronicotinic acid, (0.479 g, 3.012 mmol) was suspended in 30 mL dry methylene chloride and treated with thionyl chloride (2.5 mL, 34.27 mmol), under reflux for 90 minutes. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure on a rotary evaporator, the residue obtained was further dried under high vacuum to give 2,6 difluoronicotinoyl chloride. 2,6 difluoronicotinoyl chloride was suspended in 30 mL acetonitrile, to this was added 2-fluoro-5-chlorobenzamidine (0.52 g, 3.012 mmol) and di-isopropylehylamine (1.04 mL, 6/024 mmol). The reaction mixture was allowed to stir at room temperature for one hour, at this time the formation of the acyl amidine intermediate was confirmed by LCMS as set forth below. The reaction mixture was then heated to reflux for three hours and cooled to room temperature. The reaction mixture was concentrated to dryness on a rotary evaporator and the residue was taken up in water. The suspension obtained was placed in an ice bath and acidified with 10% aq. hydrochloric acid to pH 4. The solid precipitate that formed was filtered and washed with water and anhydrous ether and dried to give 0.611 g of 2-(2-fluoro, 5-chloro) phenyl-7-fluoro-pyrido-8-pyrimidone. ESIMS M+obsd. 294.3 M+cald. 293.66. 1H NMR d6 DMSO. δ13.15, bs, 1H; δ8.7, t, 1H; δ7.9, m, 1H; δ7.75, m, 1H; δ7.5, t, 1H; δ7.4, dd, 1H;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Yield: 48.7 %

Procedure:
A mixture of 2-chloro-5-nitro-toluene (2.0 g, 12 mmol), of 4-methylimidazole (1.0 g, 12 mmol) and of cesium carbonate (5.7 g, 17.5 mmol) in acetonitrile (20 mL) was refluxed for 15 h. The reaction mixture was cooled, quenched by addition of water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure and the crude material was purified by column chromatography on silica gel using ethyl acetate as eluent to yield the title compound (1.27 g, 50%) as a slightly brownish solid. MS ISP (m/e): 218.3 (100) [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=1)=[CH:10][C:9]([Cl:27])=[CH:8][CH:7]=2.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:28]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:27])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:49])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 73 %

Procedure:
The methyl 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate from above and 2-chloro-benzenesulfonyl chloride were reacted according to the procedure in Example 1 Step 7 to generate the desired product in 73% yield.