Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-(trifluoromethyl)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (4-(trifluoromethyl)phenyl)boronic acid (93.8 mg, 135.1 mg theoretical, 69.4%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [OH-].[Li+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]([O:15]CC)=[O:14]>O.CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of lithium hydroxide (20.0 mg, 0.84 mmol) in water (1 mL), ethyl quinoxaline-2-carboxylate (20.0 mg, 0.99 mmol) in methanol (3 mL) was added. The solution was left to stir at room temperature for 2 h. The solution was concentrated in vacuo. This cream solid residue was dissolved in water and made acidic with concentrated hydrochloric acid. The organic material was extracted into ethyl acetate. The organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield quinoxaline-2-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=2[CH3:71])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:72][C@H:56]([C:55]([O:54][CH3:53])=[O:73])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=3[CH3:71])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (150 mg) was taken in 2 mL of anhydrous DCM and EDCl (64 mg), HOBT (47 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (91 mg) and stirred for 5 minutes. Reaction mixture was cooled to 0° C. and DIEA (164 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction is complete, it was purified by silica gel column chromatography (1:3 EtOAc/hexanes to 2% MeOH in 1:1 EtOAc/hexanes) (152 mg). LCMS (m/z): 853.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1C1(N)CCCCC1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][C:12]2[N:1]([CH:2]3[CH2:3][CH2:4][CH2:10][CH2:11][CH2:12]3)[C:20]([C:22]3[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH3:9]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCOC(=O)c1ccc(C2(N)CCCCC2)c(N)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCC(=O)O)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Following the procedure of example 1, ethyl 3-amino-4-(aminocyclohexyl)benzoate (1.077 g, 4.1 mmol) and 4-formylphenoxyacetic acid (0.748 g, 4.15 mmol) were dissolved in a mixture of DMF (8 mL) and water (0.5 mL). Oxone® (0.7 equivalent, 2.87 mmol, 1.764 g) was added and the mixture stirred for 30 min at room temperature (HPLC: complete). Water was added to precipitate the product, which was collected by filtration, washed with water and dried (1.130 g, 65% yield, brown solid).
Reaction SMILES: CC1C=C(C2C=CC(OC(F)(F)[F:15])=CC=2)SC=1CO.F[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([F:31])=[CH:23][C:22]=1[C:32]1[S:36][C:35]([CH2:37][O:38][Si](C(C)C)(C(C)C)C(C)C)=[C:34]([CH3:49])[CH:33]=1>>[F:15][C:23]1[C:24]([F:31])=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[CH:21][C:22]=1[C:32]1[S:36][C:35]([CH2:37][OH:38])=[C:34]([CH3:49])[CH:33]=1
Reactant: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Product: Cc1cc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118) using ({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane (intermediate 121).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:28]>C(Cl)Cl.CCOCC>[ClH:28].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: FC(F)(F)c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(3,5 bis(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (18, 0.891 g, 2.25 mmol) in CH2Cl2 (13.5 mL) in CH2Cl2 (11 mL) was added HCl (2.0 N solution in Et2O, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(3,5-bis(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (19) as a white solid (0.452 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 9.34 (br s, 2H), 8.14-8.09 (m, 2H), 8.08-8.04 (m, 1H), 6.59-6.53 (m, 1H), 3.83-3.74 (m, 2H), 3.38-3.25 (m, 2H), 2.83-2.71 (m, 2H); ESI MS m/z 296 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)=[O:53])[CH2:52][CH2:51]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCN(C(=O)CN2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(4-methylpiperazin-1-yl)-2-piperazin-1-yl-ethanone (Ibscreen-BB) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N7O3 [(M+H)+] 748.3503, observed 748.3504.
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.1 %

Procedure:
To a 1 L round bottom flask was added the resultant compound from Example 1E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 4.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3) δ 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3 ) δ 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Reaction SMILES: C([O-])(C)(C)C.[K+].[CH3:7][O:8][C:9](=[O:20])[C:10](=[N:18][OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].Cl[CH:22]([F:24])[F:23]>COCCOC>[F:23][CH:22]([F:24])[O:19][N:18]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]([O:8][CH3:7])=[O:20]
Reactant: COC(=O)C(=NO)c1ccccc1C
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)C(=NOC(F)F)c1ccccc1C
Reaction time: 5 h

Procedure:
At 10-20° C., 28.4 g of potassium tert-butanolate are introduced into a solution of 19.35 g of 2-tolylglyoxylic acid methyl ester oxime in 250 ml of 1,2-dimethoxyethane. As soon as a fine suspension has formed, chlorodifluoromethane is introduced at 25-30° C. After 5 hours, the reaction mixture is concentrated by evaporation in vacuo, water is added to the residue and the product is weakly acidified with 2N hydrochloric acid and extracted several times with ethyl acetate. After washing and concentrating the combined organic phases by evaporation, purification is carried out by flash chromatography (silica gel, ethyl acetate/hexane 1:5), yielding 2-tolylglyoxylic acid methyl ester O-difluoromethyloxime in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([SH:14])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:18])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Sc1nccc(-c2ccc(Cl)cc2)n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CSc1nccc(-c2ccc(Cl)cc2)n1
Reaction time: 0.5 h

Procedure:
4-(4-Chlorophenyl)pyrimidine-2-thiol (1.2 g, 5.39 mmol) was taken in 10 ml of an aqueous potassium hydroxide (0.453 g, 5.39 mmol) solution. Iodomethane (503 μl, 5.39 mmol) was added at ambient temperature and the reaction mixture was allowed to stir for 30 minutes. The resulting white solid was collected via filtration and washed with minimal water and hexanes to provide the title compound: EI-MS (m/z) 237 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.O>CN(C=O)C>[CH2:19]([O:18][CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=[C:29]2[C:28]([F:27])([F:39])[F:38])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:20]
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)OCC
Temperature: 60 °C

Procedure:
Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (371 mg, 1 mmol) was dissolved in DMF (5 ml) and K2CO3 (552 mg, 4 mmol) was added followed by 2-trifluoromethyl benzimidazole (204 mg, 1.1 mmol). The reaction mixture was heated to 60° C. for 17 hrs. After the completion of the reaction, water was added and the product was extracted with Et2O. The product was purified by column chromatography on silica gel using ethyl acetate and hexanes as solvent (333 mg, 70%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:25][CH3:26])=[C:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[C:5]([O:25][CH3:26])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Product: COc1c(C(C)O)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared according to the procedure of Example 13 step 5, using of tert-butyl 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)piperidine-1-carboxylate and sodium tetrahydroborate as the starting materials. LCMS calculated for C20H30ClNO4Na (M+Na)+: m/z=406.1; Found: 406.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=3[O:34][CH3:35])[CH:21]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:36]1([NH:39][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:20]3[CH:21]=[C:22]4[C:17](=[CH:18][CH:19]=3)[N:16]=[C:15]([NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:24]=[CH:23]4)=[C:26]([O:34][CH3:35])[CH:27]=2)=[O:30])[CH2:38][CH2:37]1
Reactant: COc1cc(C(=O)O)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A mixture of 4-(2-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)amino)quinazolin-6-yl)-3-methoxybenzoic acid (57 mg, 0.12 mmol), cyclopropyl amine (0.012 mL, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIEA (0.052 mL, 0.30 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 30 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield tert-butyl ((1S,2R)-2-((6-(4-(cyclopropylcarbamoyl)-2-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (58 mg, 93%). MS (ES+) C29H35N5O4 requires: 517, found: 518 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:23]=[O:24]>O1CCCC1>[C:25]([NH:22][C:23](=[O:24])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCNC1CCCCC1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N(CCCCCCO[Si](C)(C)C(C)(C)C)C1CCCCC1
Reaction time: 2 h
Yield: 114 %

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)hexyl)cyclohexanamine (330 mg, 1.05 mmol) in tetrahydrofuran (5 mL) at 0° C. was added 2-isocyanato-2-methylpropane (0.14 mL, 1.16 mmol). The mixture was stirred for 2 hours before it was quenched with methanol, and concentrated. Purification on silica gel with ethyl acetate: hexanes from 0:1 to 1:9 provided desired product as a clear oil (494.1 mg, 114%). 1H NMR (300 MHz, CDCl3): δ 4.11 (s, 1H), 3.99-3.84 (m, 1H), 3.56 (t, J=6.4 Hz, 2H), 2.92 (t, J=8.2 Hz, 2H), 1.80-0.94 (m, 18H), 0.85 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[NH:14])[S:10][CH:11]=1)=[O:6])=[N+]=[N-].C(O)C.[ClH:19]>[Pd].O>[ClH:19].[ClH:19].[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[NH:14])[S:10][CH:11]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1nc(C(=O)CN)cs1
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 12.0 g (53 mmol) of 2-azido-1-(2-guanidino-4-thiazolyl)ethanone, 1.0 g of 10% palladium on carbon, 100 ml of ethanol, 50 ml of water, and 20 ml of concentrated hydrochloric acid was hydrogenated at 3 atm. and room temperature for 1 hour. At this point another 50 ml of water and 300 mg of 10% palladium on carbon was added to the mixture and hydrogenation was continued at 3 atm for another 0.75 hour. The mixture was diluted with 200 ml of water, filtered to remove the catalyst, and the filtrate concentrated leaving 13.1 g (92%) of 2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride as a white powder mp>270°. nmr (DMSO-d6) (δ): 8.58 (b, 4H) 8.44 (s, 1H); 4.58 (b, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14](O)([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].CCN(S(F)(F)[F:24])CC.O>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:24])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC#CCOc1cc(OCC(C)(C)O)ncn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC#CCOc1cc(OCC(C)(C)F)ncn1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
First, 0.33 g of 4-(2-butynyloxy)-6-(2-hydroxy-2-methylpropyloxy)pyrimidine was dissolved in 3 ml of chloroform, to which 0.5 ml of a solution containing 0.25 g of DAST in chloroform was added dropwise at 0° C., followed by stirring for 30 minutes. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(2-fluoro-2-methylpropyloxy)pyrimidine (the present compound (28)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]2[O:14][CH2:13]2)=[CH:4][C:3]=1[Cl:15].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][OH:14])=[CH:4][C:3]=1[Cl:15]
Reactant: Nc1c(Cl)cc(C2CO2)cc1C(F)(F)F
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NC(CO)c1cc(Cl)c(N)c(C(F)(F)F)c1
Yield: 20 %

Procedure:
5.2 g (0.022 mol) of (4-amino-3-chloro-5-trifluoromethyl-phenyl)-ethylene oxide was dissolved in 26 ml of anhydrous ethanol and treated with 5.1 ml (0.049 mol) of tert-butylamine. The mixture was refluxed for 13 h, and then evaporated. The residue was extracted with 2N hydrochloric acid for several times. Aqueous layers were combined and extracted with toluene and treated with activated carbon. The pH was adjusted to 10 with 20% sodium hydroxide solution. The precipitate was collected by filtration, 2-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylaminoethanol was obtained. Yield 20–30%; melting point 85–90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)=[O:27]
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(C(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 60 °C

Procedure:
To the solution of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and m-toluic acid (68.8 mg, 0.5 mmol, 1 eq) in anhydrous DCE (4 mL) was added DMAP (12.2 mg, 0.2 eq) and EDC (115.2 mg, 1.2 eq). The reaction mixture was heated at 60° C. for 1.5 hours. It was then cooled to room temperature, diluted with ethyl acetate, washed subsequently with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and lastly dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was treated with EtOAC-Hex(2:1) with stirring. 2-{4-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide was obtained as slightly brown solid upon filtration in amount of 165 mg (89%).
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:1]1[CH2:9][CH:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
A solution of 100 g (0.76 mol) of L-hydroxyproline and 540 ml of water was cooled to 10° and 297 ml (3.7 mol) of pyridine was added. The temperature was lowered to 5° and 151.2 ml (1.6 mol) of acetic anhydride was slowly added. The reaction was stirred at 0°-5° for 45 min and 81 ml (0.97 mol) of pyridine was added followed by 42.7 ml (0.45 mol) of acetic anhydride. The reaction was stirred overnight in an ice bath allowing the bath to come to room temperature. The reaction was evaporated and the residue was dissolved in ethanol and evaporated to an oily residue. This step was repeated a number of times, and the residue was dissolved in acetone, seeded, and cooled. The white crystals were filtered and recrystallized from ethanol-ether and dried under vacuum at 40° to give 84.8 g of N-acetyl-4-hydroxy-L-proline; mp 124°-131°; [α]D23 -117° (cl, water).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15](=[CH2:28])[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])(C)(C)C>ClCCl>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH:16]([CH3:17])[C:15](=[CH2:28])[C:13]([OH:14])=[O:12])=[CH:19][CH:20]=1)=[O:23]
Reactant: C=C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C(=O)O)C(C)c1ccc(C(=O)OC)cc1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (21.7 mL, 283 mmol) was added to a solution of methyl 4-(3-(tert-butoxycarbonyl)but-3-en-2-yl)benzoate (8.7 g, 30 mmol) in anhydrous dichloromethane (85 mL), and the mixture was stirred at 23° C. for 5 h. The solvents were removed under reduced pressure and the residue was triturated with hexane. The solid was collected by filtration and dried under vacuo to give the title compound. MS: m/z=233.0 (M+1).