Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N+:3]=1[CH2:9][C:10]([O:12]CC)=O.[Br-].C[O-].[Na+]>CO.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH2:9][C:10](=[O:12])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C[n+]1cc(Br)ccc1N
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide (2.86 g, 8.4 mmol) in methanol (30 mL) was added sodium methoxide (25 wt %, 2.5 mL, 10.1 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The crude material was purified by column chromatography eluting with 3, 5, and 10% methanol/dichloromethane. The product was obtained as a brown solid (56 mg, 3%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.67 (dd, J=1.6, 9.5 Hz, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.52 (s, 2H); MS (m/e): 215 (MH+); HRMS: calc'd MH+ for C7H5BrN2O 212.9672; found 212.9664.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21]([O:23][C:24]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[CH:30][CH:31]=2)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCOc1ccc(Oc2cc(C(F)(F)F)nc(C(F)(F)F)c2C(=O)OCC)cc1
Yield: 68.8 %

Procedure:
A 250 ml round bottom flask is charged with 3.54 g (0.011 mol) of product of Example 19, 2.31 g (0.011 mol) of 4-[(1-ethoxycarbonyl)ethoxy]phenol and 1.82 g (0.013 mol) of K2CO3 in 150 ml of methyl isobutyl ketone. This mixture was stirred at reflux for 18 hours, filtered and concentrated. The residue was taken up in ether, washed with 5% NaOH, water, dried (MgSO4) and concentrated in vacuo to afford 3.75 g of an orange oil. Purification by HPLC using 18% ethyl acetate/cyclohexane as eluting solvent gave 2.66 g of an oil which was kugelrohr distilled at 41 Pa, pot temperature 150°-154° C., affording 2.56 g (47.0%) of product as a clear oil, nD25 1.4732.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[OH-:14].[K+]>C(O)(=O)CCCCCCCCCCC.[OH-].[K+].O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:14])[OH:4]
Reactant: CCCCCCCCOCC1CO1
Reactant: [OH-]
Agent: CCCCCCCCCCCC(=O)O
Agent: [K+]
Solvent: O
Product: CCCCCCCCOCC(O)CO
Temperature: 140 °C
Reaction time: 5 h
Yield: 163.6 %

Procedure:
In an autoclave, 208 g of the resulting crude octyl glycidyl ether, 104.8 g of water, 5.82 g of lauric acid and 18.5 g of potassium hydroxide were charged. The resulting mixture was stirred at 140° C. for 5 hours. The reaction mixture was dehydrated at 100° C. under reduced pressure (6.67 kPa), followed by the addition of 9.7 g of lauric acid and 2.72 g of potassium hydroxide. After reaction at 160° C. for 15 hours, the reaction mixture was purified by distillation under reduced pressure (53 to 67 Pa, 120 to 123° C.), whereby 110.2 g of monooctyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting product had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:4][CH:3]1[CH2:5][CH2:6][C:7]([CH3:14])=[C:8]=[CH:9][CH2:10][C:11](=[O:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:15])[CH2:4][CH:3]1[CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH:9]=[CH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CC=C=C(C)CCC1CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)C=CC=C(C)CCC1CC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
8-(2',2'-Dimethylcyclopropyl)-6-methyl-4,5-octadien-2-one, 5 g, is dissolved in a mixture of 6 ml of methanol and 6 ml of toluene, then 200 mg of p-toluenesulphonic acid are added. The mixture is stirred at room temperature for 63/4 hours. It is diluted with ether, washed neutral with saturated bicarbonate and carbonate solution and with saturated sodium chloride solution, dried and concentrated. The crude product (4.5 g) is distilled in a bulb-tube. In this manner there are obtained 4.2 g (84%) of 8-(2',2'-dimethyl-cyclopropyl)-6-methyl-3,5-octadien-2-one. EZ/EE=4/6.
Reaction SMILES: C1(N)CCCCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
Melting point of the cyclohexylamine salt: 174°-176° C. Prepared analogous to Example 40 from methyl 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyrate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:16])[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:16])[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)c1cc(SCC(C)=O)ccc1C
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:30])[CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20]C(OCC3C=CC=CC=3)=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([NH:41][C@H:42]([C:49]([OH:51])=O)[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N[C@@H](C(O)=O)CC1N=CNC=1)([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=O>>[C:35]1([CH2:34][O:33][C:31]([NH:41][C@H:42]([C:49]([N:14]([CH2:15][CH2:16][CH2:21][CH2:20][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:13][C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:30])=[O:51])[CH2:43][C:44]2[N:48]=[CH:47][NH:46][CH:45]=2)=[O:32])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: O=C(CNCc1ccc(OCc2ccccc2)cc1)NCCOCc1ccccc1
Product: O=C(CN(CCCCOCc1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCOCc1ccccc1

Procedure:
According to Example 10, Step 4, by substituting the compound from Step 1 above for N-[2-(phenylmethoxy)ethyl]-N2 -[[4-(phenylmethoxy)phenyl]methyl]glycinamide and CBZ-histidine for CBZ-D-histidine, the title compound was obtained as a white foam; ES-MS 642 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH2:34]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH2:37][CH3:38]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:42]3[CH:41]=[CH:40][C:39]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:44][CH:43]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCCCCc1ccc(B(O)O)cc1
Product: CCCCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-n-pentylbenzene boronic acid (769 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-pentyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:42][CH3:43])[CH2:38][CH2:39]CO)[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:36][CH2:35][N:37]([CH2:42][CH3:43])[CH2:38][CH3:39])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CC)CCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 32.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(diethylamino)-1-propanol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (25 mg, yield 27%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 43 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with t-butyl-1-piperazinecarboxylate as described in Step 2 of Example 29 to afford 4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazine-1-carboxylic acid tert-butyl ester (43% yield) as a yellow solid. ESI/MS 300 (M), 306 [M-CO2C(CH3)3], 350 [M-C(CH3)3], 406 (M+H); RT=3.89 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=9 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.22 (8H, 2 br m); 1.37 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][N:5]2[C:10]=1[C:9]([O:11]C1C=CC=CC=1)=[N:8][CH:7]=[N:6]2.CS(N)(=O)=O>>[OH:11][C:9]1[C:10]2=[C:2]([CH3:1])[C:3]([O:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Agent: CS(N)(=O)=O
Product: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(O)c12
Yield: 64 %

Procedure:
The compound from Step A above was treated with methanesulfonamide by a procedure similar to that described for the preparation of Example 24 to obtain N-[3-(4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propyl]-methanesulfonamide. (64% yield). MS: (M+H)+=301.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Clc1nc(Cl)c2ccsc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Cl)nc3sccc23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (805 mg, 3.94 mmol), TFA (0.91 mL, 11.82 mmol) in TFE (11 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 2 d. Reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC to afford the product as a white solid (43.4 mg, 36%):
Reaction SMILES: [Br:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Br:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3Br)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4Br)c3)S2)CC1

Procedure:
5-[1-(2-bromo-4-chlorobenzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-bromo-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]1>CN(C=O)C>[CH3:24][C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[N:19]=1
Reactant: Cc1cc(C)n(CBr)n1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2nc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.2 g, 8.8 mmol) was dissolved in anhydrous DMF (50 mL), then potassium carbonate (3.6 g, 26.3 mmol) and 1-(bromomethyl)-3,5-dimethyl-1H-pyrazole (3.0 g, 15.8 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 2-{[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (218 mg, 10% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 5.81 (s, 2H), 5.83 (s, 1H), 6.07 (bs, 1H); LRMS (ES+) m/z 251 (50%, M+1).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH:13]([OH:34])[CH2:14][N:15](CC2C=CC=CC=2)[CH:16]([CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:10]=1[NH:37][CH:38]=[O:39])C1C=CC=CC=1.[H][H]>[Pd]>[CH3:26][C@@H:16]([NH:15][CH2:14][C@H:13]([OH:34])[C:12]1[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([NH:37][CH:38]=[O:39])[CH:11]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(NC=O)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1

Procedure:
4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (120 gms, 0.23 M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-30° C. for 3 hrs. The catalyst was removed by filtration and the clear filtrate concentrated under reduced pressure below 40° C. to yield the title compound. (63 gms, 80%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.[CH3:9]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCOC1
Solvent: CO
Product: COC(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5122.6 %

Procedure:
A solution of tetrahydrofuran-3-carboxylic acid (540 mg, 4.65 mmol, 1.00 equiv) and TsOH (10 mg, 0.06 mmol, 0.01 equiv) in methanol (40 mL) was stiffed at 66° C. in an oil bath. After 16 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 10 mL of ether, washed with 1×20 mL of NaHCO3 (aq., sat.) followed by 3×20 mL of brine, and concentrated under reduced pressure to yield 0.40 g (66%) of the title compound as a colorless oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[F:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1.CCCCCC>[F:14][C:15]1[C:20]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C1CCOCC1
Reactant: Fc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of nbuli (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) was first cooled to −78° C. To the cooled solution was added dropwise, 2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bath was then switched to a 0° C. bath. The reaction mixture was stirred for 10 min at 0° C. and then the dry ice bath was switched back to recool the reaction mixture to −78° C. To the cooled solution was added 2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at −78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol) in 0.6 mL of THF was added dropwise. The resulting mixture was allowed to gradually warm to room temperature overnight. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Purification by Biotage (0-100% EtOAc/hexane) produced product.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CCOC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 2 h

Procedure:
At RT a solution of 153 g (0.66 mol) ethyl 4-amino-3-trifluoromethyl-benzoate in 350 mL EtOH was added to a solution of 100 g (2.5 mol) NaOH in 250 mL water and the reaction mixture was stirred for 2 h at 45° C. EtOH was eliminated i. vac., the remaining aqueous solution was acidified with conc. HCl, the precipitated product was suction filtered, washed with water and dried in the air.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])=[C:2]=[S:3].O.[NH2:15][NH2:16]>C1COCC1>[NH2:15][N:16]1[C:6](=[O:7])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:2]1=[S:3]
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Nn1c(=S)[nH]c2ccccc2c1=O
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Methyl 2-isothiocyanatobenzoate (5.00 g, 25.9 mmol) was dissolved in THF (125 mL), followed by addition of hydrazine monohydrate (2.51 mL, 51.8 mmol). The reaction mixture was refluxed for 1 h, cooled to RT and the precipitate was collected by filtration. The precipitate was washed with water and dried in vacuo to give pure title compound (4.78 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[CH3:11].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:12])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(CO)cc1C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of (4-methoxy-3-methylphenyl)methanol (2.31 g, 15.18 mmoles, 1 eq) in anhydrous CH2Cl2 (50 ml, 0.3M) was added hexachloroethane (3.59 g, 15.18 mmoles, 1 eq) and triphenylphosphine (3.98 g, 15.18 mmoles, 1 eq). This mixture was stirred at room temperature overnight at which point the reaction was transferred to a separatory funnel and washed with H2O, brine, dried over Na2SO4, filtered, concentrated in vacuo and filtered through a plug of silica gel (30% EtOAc/Hexanes) to yield 2.59 g (100%) of product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-methoxybenzoic acid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Reaction time: 2 h

Procedure:
A solution of N-tertiary-butyloxycarbonyl-4-iodoaniline (11.5 g, see P G Ciattini et al, Tet. Lett, 1995, 36, 4133-4136 for preparation) in dimethylformamide (70 mL), under nitrogen, was treated portionwise with sodium hydride (1.6 g, 60% dispersion in mineral oil). When effervescence had ceased (after about 5 minutes) the mixture was treated with methyl iodide and stirring was continued at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was dried and then evaporated to give the title compound (11.5 g) as a pink oil.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[CH2:5]([O:7][CH2:8][C:9]([CH2:11][O:12][CH2:13][CH3:14])=[O:10])[CH3:6].[C:15](OC(=O)C)(=[O:17])[CH3:16].[Cl-].[NH4+]>C1COCC1>[CH2:5]([O:7][CH2:8][C:9]([O:10][C:15](=[O:17])[CH3:16])([CH2:11][O:12][CH2:13][CH3:14])[C:1]#[CH:2])[CH3:6]
Reactant: C#C[Mg]Cl
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC(=O)COCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(COCC)(COCC)OC(C)=O
Yield: 97.6 %

Procedure:
A solution (360 mL, 180 mmol) of ethynyl magnesium chloride in 0.5 M THF was stirred under ice-cooling and 1,3-diethoxyacetone (21.93 g, 150 mmol) was added dropwise. The mixture was stirred under ice-cooling for 30 min and acetic anhydride (18.4 mL, 195 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hr. After the completion of the reaction, aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give acetic acid 1,1-bis-ethoxymethyl-2-propynyl ester (31.36 g, 97%).