Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:18](=[O:16])[NH:19][C:4]2=[O:5]
Reactant: N#CO[Na]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2[nH]1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-amino-5-chlorobenzoic acid (10 g, 58.48 mmol, 1.00 equiv) in water (100 mL), acetic acid (8 g, 133.33 mmol, 2.24 equiv). This was followed by the addition of NaOCN (8.2 g, 126.15 mmol, 2.13 equiv). The mixture was stirred for 30 mins at 30° C. To this was added sodium hydroxide (86 g, 2.15 mol, 37.00 equiv). The resulting solution was stirred overnight at 30° C. The solids were collected by filtration. The residue was dissolved in water. The pH value of the solution was adjusted to 7 with hydrogen chloride (12 mol/L). The solids were collected by filtration. This resulted in 5 g (44%) of 6-chloroquinazoline-2,4(1H,3H)-dione as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:5]1[N:1]=[C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1

Procedure:
A solution of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (20.04 g, 79.74 mmol) in THF (450 mL) was cooled to −46 C (bath) before the flask was charged with NBS (14.27 g) in equal portions (10-min apart). LCMS data indicated complete reaction after 15 min, so the contents were concentrated to a yellow, solid foam that was further dried under vacuum overnight. The crude material (monobromide:dibromide=40:27) was purified by chromatography to give pure white solid (8.08 g, 24.47 mmol, 31%) as the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:21]2[CH:22]=[N:18][NH:19][CH:20]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cn[nH]c2)CC1
Yield: 66.9 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), 1H-pyrazole-4-boronic acid pinacol ester (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%), LC-MS (ESI, 3.5 min) Rt 1.06 min, m/z 306 (100%, [M+H]+); m/z (ESI) C14H17ClN5O requires 306.1116 found [M+H]+ 306.1114.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Reaction time: 4 h
Yield: 85 %

Procedure:
1.25 g (3.05 mmol) of 2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in 4.50 mL of phosphorus oxychloride, then stirred for 4 hours is at 120° C. Then excess phosphorus oxychloride is distilled off, the residue is combined with water. The precipitate formed is suction filtered, washed with plenty of water, and dried, then stirred with methanol. 0.960 g of product III (85%) is obtained.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([OH:27])=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.CCN(CC)CC>C(Cl)Cl.O>[Br:19][C:20]1[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:27]
Reactant: COc1ncc(Br)cc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
T3P (8.2 g, 25.8 mmol) was added to a solution of 5-bromo-2-methoxynicotinic acid (3 g, 12.9 mmol), (4-fluorophenyl)methanamine (1.6 g, 12.9 mmol) and Et3N (3.9 g, 38.7 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at RT for 1 h. Water (50 mL) was added and the mixture was extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=4:1) to give the product of 5-bromo-N-(4-fluorobenzyl)-2-methoxynicotinamide (4.0 g, yield: 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.64 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 7.32 (dd, J=5.2, 8.4 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 4.63 (d, J=6.0 Hz, 2H), 4.05 (s, 3H). MS (M+H)+: 339/341
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (0.8 g, 2.1 mmol) was dissolved in ethanol (10 ml) and 2N sodium hydroxide (3.1 ml) was added. The mixture was stirred at ambient temperature overnight. Excess concentrated hydrochloric acid was added followed by dichloromethane. The mixture was concentrated in vacuo and water and dichloromethane was added. The phases were separated and the organic phase was dried (MgSO4). The solvent was evaporated in vacuo to give a foamy residue which was re-evaporated with dichloromethane to give 0.65 g of the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(F)ccc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(F)ccc4Br)oc23)[C@@H]1CO

Procedure:
Compound of example 29 (3.9 g, 7.92 mmol) was subjected to demethylation using pyridine hydrochloride (39 g, 337.6 mmol) as described in example 17, to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[C:23]#[N:24])=[CH:18][CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(C#N)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a stirred mixture of 68 parts of 1-chloro-2-methoxy-4-nitrobenzene, 230 parts of a sodium hydroxide solution 50%, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 360 parts of tetrahydrofuran is added dropwise, during a 5 minutes period, a solution of 43.2 parts of 4-chlorobenzeneacetonitrile in 90 parts of tetrahydrofuran. Upon completion, stirring is continued for 4 hours at 60° C. The reaction mixture is poured into 2000 parts of crushed ice. The whole is acidified with concentrated hydrochloric acid. The layers are separated. The aqueous phase is extracted with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding α-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=O)(C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][NH:8][C@H:9]([C:24]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: COCCN
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Product: COCCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, and 2-methoxyethylamine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z=322.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([CH:17]=[O:18])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([Mg]Br)#[CH:20]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([CH:17]([OH:18])[C:19]#[CH:20])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1c(-c2cccc(Cl)c2)nn2cnccc12
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde (1.5 g, 5.82 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium bromide (17 mL, 0.5 M in tetrahydrofuran, 8.73 mmol). The reaction mixture was stirred 4 hours at room temperature then quenched with water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 1-[2-(3-chlorophenyl)pyrazolo[1.5-c]pyrimidin-3-yl]-2-propyn-1-ol (1.41 g, 85%). Rf 0.17 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 9.27 (s, 1H), 7.93–7.90 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H), 7.50–7.41 (m, 2H), 5.78 (s, 1H), 2.99 (br, 1H), 2.71 (s, 1H); MS m/z 284 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17]>>[CH2:1]([O:19][C:18](=[O:20])[C@H:16]([CH3:17])[NH:15][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH:2]([CH3:11])[CH3:3]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: C[C@H](N)C(=O)O
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc2ccccc2c1

Procedure:
Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine is iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128°-129° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C:11]3([NH2:10])[CH2:12][CH2:13]3)=[CH:19][CH:18]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C(NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 3 h

Procedure:
{1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-carbamic acid benzyl ester (1.08 g, 2.65 mmol) is dissolved in ethanol (50 mL), and 10% Pd/C is added (200 mg). The mixture was stirred under a balloon on hydrogen for 3 hours. The reaction mixture was stirred through a plug of silica gel to give the desired compound. HRMS 275.2123 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:13][Mg]Br>CCOCC>[OH:5][C:4]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:1][CH2:2][CH2:3]1
Reactant: O=C1CCCCc2ccccc21
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CCCCc2ccccc21
Yield: 93.3 %

Procedure:
Following the procedure of Example 1, step 1, 26.02 g (0.162 mol) of 1-benzosuberone in 250 ml of anhydrous ether was reacted with 68.0 ml (0.204 mol) of 3.0M methyl magnesium bromide in ether to afford 26.65 g (93%) of the title product as a yellow oil. NMR δ(CDCl3) 1.59 (3H, s), 1.77-1.97 (6H, m), 2.83-2.96 (2H, m), 7.06-7.24 (3H, m), 7.67 (1H, d of d, J=7.6 and 1.5 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327 g, 1 mmol, Example 14b) in chloroform (12 ml). The reaction mixture was stirred for 10 min then diluted with dichloromethane (50 ml). This was washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (350 mg, 86% yield, m.p. 153-156° C.).
Reaction SMILES: [C:1]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.Cl.Cl.CC1C=C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)N(C2C=CC=CC=2)N=1.Cl.[C:54]([NH:58][NH2:59])([CH3:57])([CH3:56])[CH3:55]>C(O)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[N:58]([C:54]([CH3:57])([CH3:56])[CH3:55])[N:59]=[C:3]([CH3:5])[CH:2]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)NN
Agent: Cc1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n(C(C)(C)C)n1
Reaction time: 15 h
Yield: 18.9 %

Procedure:
1-Acetoacetyl-4-tert-butoxycarbonylpiperazine [product of Example 222 (1), 3.92 g] was dissolved in ethanol (300 mL), and tert-butylhydrazine hydrochloride (1.81 g) and molecular sieves 3A (10 g) were added thereto at room temperature. The mixture was stirred for 15 hr. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was dissolved in pyridine (200 mL), and phosphorus oxychloride (3.0 mL) was added thereto at room temperature. The mixture was stirred for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with dilute hydrochloric acid to pH 3. The mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 1-tert-butoxycarbonyl-4-(1-tert-butyl-3-methyl-5-pyrazolyl)piperazine (886 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C=C(C)C)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution of methyl 2-methoxy-4-(2-methyl-1propenyl)benzoate (178 mg) in methanol (3 ml) and 1,4-dioxane (3 ml) was added 1N aqueous solution of sodium hydroxide (2 ml). The mixture was stirred at 50° C. for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate. Evaporation of the solvent gave 2-methoxy-4-(2-methyl-1propenyl)benzoic acid (142 mg) as solid.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].[Si]([O:15][CH2:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)O)(C(C)(C)C)(C)C.[OH-].[Na+]>C(#N)C.O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:23][C:19]2[S:20][CH:21]=[CH:22][C:18]=2[CH2:17][CH2:16][OH:15])=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccsc1C(O)c1ccc(F)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OCCc1ccsc1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
Chlorotrimethylsilane (5.56 g, 51.2 mmol) was added slowly to a solution of sodium iodide (7.7 g, 51.2 mmol) in acetonitrile (80 mL) at rt. After stirring for 15 min the mixture was cooled to 0° C. and a solution of (3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)(4-fluorophenyl)methanol (3.75 g, 10.2 mmol) in acetonitrile (10 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h and then at rt for 2 h. After cooling down to 0° C., 2 N sodium hydroxide (30 mL) was added slowly and the mixture stirred for 30 min. 100 mL of water was added and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:20) to afford the title compound as a solid (1.8 g, 75%). MS (M+H)+ 237.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15](O)[CH:16]=[CH2:17]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH:16]=[CH2:15])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1C(F)(F)F
Yield: 59 %

Procedure:
In a manner analogous to Example l(a) starting with 2 g (9.7 mmoles) of 4-hydroxy-2-trifluoromethylbenzoic acid treated at 100° C. for 12 hours with 20 ml of allyl alcohol and 260 μl of concentrated sulfuric acid, give 1.4 g (59% yield) of the expected ester having a melting point of 82°-83°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:24])[N:20]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OCC(C)C)c1
Reactant: COCCN
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC(C)C)n1
Yield: 62 %

Procedure:
2-{2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-N-(2-methoxy-ethyl)-acetamide (130 mg, 62%) was prepared from {2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (181 mg, 0.5 mmol) and 2-methoxyethylamine following the general procedure K.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
Part A: To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (3.12 g, 15 mmol, J. Chem. Soc 3832 (1954); ibid 677 (1944)) and 2-(trifluoromethyl)phenylboronic acid (3.42 g, 18 mmol) in benzene (50 ml) was added 1M aqueous sodium carbonate (20 ml) and 500 mg of tetrakis(triphenylphosphine)palladium. This mixture was refluxed for 4.5 hours, then was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (10% then 20% ethylacetate in hexanes) afforded 4-Chloro-2-methyl-5-nitro-6-(2-(trifluoromethyl)phenyl)-pyrimidine (1.90 g) as a pale yellow solid. CI Mass Spec. (M+H)+ =318.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and dimethylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 3.35-3.8 (m, 12H), 2.98 (s, 6H); MS (DCI) m/z 380 (M+H)+;