Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH:15]([CH3:16])[CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CC(C)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.3 mmol) in DMF (10 mL) was added sodium hydride (276 mg, 6.9 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (473 mg, 3.5 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether-hexane to yield 2-(pyridin-4-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (DMSO, HCl salt) d (ppm): 8.62 (d, 2H), 8.10 (d, 2H), 7.18 (s, 1H), 6.90 (m, 1H), 6.80 (m, 1H), 4.62 (m, 2H), 4.40 (m, 3H), 4.05 (m, 1H), 3.80 (m, 1H), 3.05 (s, 3H), 2.38 (s, 3H), 1.75 (d, 3H), 1.70-1.50 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:24][CH3:22])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1ccncc1C(=O)O
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 4-aminonicotinic acid (691 mg, 5.0 mmol), methylamine hydrogen chloride (410 mg, 1.2 eq), EDC (1.15 g, 1.2 eq), HOBt (810 mg, 1.2 eq) in DMF (20 mL) was added DIEA (3.0 mL, 3.0 eq). The mixture was stirred at room temperature overnight. It was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. It was concentrated and purified by silica gel with chromatography (0%˜20% MeOH/DCM) to obtain the desired product 4-amino-N-methylnicotinamide.
Reaction SMILES: [CH:1]([C:3]1([C:12](Cl)=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].[CH2:15](OC(=O)CC(O)=O)C.C(O[Mg])C.S(=O)(=O)(O)O>C(OCCCC)CCC>[CH:1]([C:3]1([C:12](=[O:13])[CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2]
Reactant: C=CC1(C(=O)Cl)Cc2ccccc2C1
Reactant: CCOC(=O)CC(=O)O
Agent: CCO[Mg]
Agent: O=S(=O)(O)O
Solvent: CCCCOCCCC
Product: C=CC1(C(C)=O)Cc2ccccc2C1

Procedure:
1-(2,3-Dihydro-2-vinyl-1H-inden-2-yl)-ethanone was prepared by treating 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid chloride with ethoxy magnesium malonic acid ethyl ester in dibutylether and after that with sulfuric acid according to the method of Reynolds, G.A. and Hauser, C.B., Org. Synth. 30 (1957) 70.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[C:3]([O:5][CH3:6])=[O:4].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][C:2]1([C:3]([O:5][CH3:6])=[O:4])[CH2:7][CH2:8][C:9](=[O:10])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(=O)CCC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(Cl)CCC(=O)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.0 g of Compound (10). To the solution were added 911 μl of thionyl chloride and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated. The concentrate was subjected to a flash chromatography using silica gel, followed by elution with hexane-ethyl acetate (1:2) to give 985 mg of the subject Compound (13).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[NH:30][C:29](=[O:31])[C@@H:28]([NH:32]C(OC(C)(C)C)=O)[CH2:27][C:26]2[CH:40]=[C:22]([CH:23]=[CH:24][C:25]=2[OH:41])[C:21]2=[CH:42][C:17](=[C:18]([OH:43])[CH:19]=[CH:20]2)[CH2:16][C@@H:15]([C:44](=[O:83])[NH:45][CH2:46][CH2:47][CH2:48][C@H:49]([NH:75]C(OC(C)(C)C)=O)[CH2:50][C:51](=[O:74])[NH:52][CH2:53][C@@H:54]([NH:66]C(OC(C)(C)C)=O)[CH2:55][CH2:56][CH2:57][NH:58]C(=O)OC(C)(C)C)[NH:14][C:13]1=[O:84])(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH2:32][C@H:28]1[CH2:27][C:26]2[CH:40]=[C:22]([CH:23]=[CH:24][C:25]=2[OH:41])[C:21]2=[CH:42][C:17](=[C:18]([OH:43])[CH:19]=[CH:20]2)[CH2:16][C@@H:15]([C:44]([NH:45][CH2:46][CH2:47][CH2:48][C@H:49]([NH2:75])[CH2:50][C:51]([NH:52][CH2:53][C@@H:54]([NH2:66])[CH2:55][CH2:56][CH2:57][NH2:58])=[O:74])=[O:83])[NH:14][C:13](=[O:84])[C@H:12]([CH2:11][CH2:10][CH2:9][NH2:8])[NH:30][C:29]1=[O:31]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](N)CNC(=O)C[C@@H](N)CCCNC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1
Reaction time: 2 h

Procedure:
0.32 ml of a 4N solution of hydrogen chloride in dioxane are added to a solution of 25 mg (0.021 mmol) of the compound from Example 262A in 1 ml of dioxane at 0° C. After 2 h at RT, the reaction solution is concentrated in vacuo and coevaporated with dichloromethane several times. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([O:34]C)=[O:33])(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=[O:33])(=[O:29])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Prepared using General Procedure 15: To a stirred solution containing (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (11.2 mg, 0.02 mmol) in MeOH (1 mL) was added 6N NaOH (100 uL). After 1 h, the crude reaction was concentrated and the product purified by preparative HPLC to give 5 mg (45%) of (S)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 159 as light yellow solid. LCMS-ESI (m/z) calculated for C24H23N3O5S2: 497.1; found 498.1 [M+H]+, tR=3.44 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([OH:38])=O)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45].Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ccccn1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 1 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and pyridin-2-amine instead of cis-4-(trifluoromethyl)cyclohexanecarboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)=[O:4].[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:27](=[O:28])[C@@H:19]([NH:18][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1csc(N)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
A solution of 2-amino-thiazole-4-carboxylic acid methyl ester (2.4 g, 15.17 mmol), (S)—N-Boc-phenylalanine (4.518 g, 16.69 mmol), 1-hydroxybenzotriazole (2.255 g, 16.69 mmol) and 1,3-diisopropylcarbodiimide (2.127 g, 16.69 mmol) in a mixture of dichloromethane (50 mL) and N,N-dimethylformamide (25 mL) were stirred at ambient temperature for 24 hours. The mixture was diluted with dichloromethane, washed with water, brine and dried with magnesium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using a gradient between 0 and 25% ethyl acetate in dichloromethane gave 2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (4.97 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A mixture of 2-bromo-4-fluorotoluene (37.4 g), N-bromosuccinimide (39 g), tetrachloromethane (120 ml) and benzoyl peroxide (0.25 g) is refluxed for 5 hours. After standing overnight, the separated succinimide is filtered off and the filtrate is taken down under diminished pressure, yielding 52 g (100%) of crude 2-bromo-4-fluorobenzyl bromide which can be used in the next step without purification. In order to characterize the pure compound, a sample can be distilled; b.p. 127° C./20 Torr.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 69 mg of Z-Phe-Arg-OH, 50 mg of H-Leu-Val-Ile-His-NH2, 16 mg of HOBt and 40 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (45 g of silica gel 60, 40-63 μm, eluant system methylene chloride/methanol/water/glacial acetic acid 330:100: 19:2). Rf (S3)=0.16.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH3:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)[CH3:19]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CCOCCOCCO
Product: CCOCCOCCOc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-(2-ethoxy-ethoxy)-ethanol to give {1-[2-(2-ethoxy-ethoxy)-ethoxy]-isoquinolin-3-yl}-(1H-pyrazol-3-yl)-amine. LC-MS m/e 343(MH+).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][C:21](I)=[CH:22][C:5]=3[C:4]=2[CH:3]=1.C([Mg]Cl)(C)C>O1CCCC1>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:6]3[N:19]=[CH:20][CH:21]=[CH:22][C:5]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2cc(I)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2cccnc21
Reaction time: 1.5 h

Procedure:
A solution of 6-bromo-3-iodo-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (3.0 g, 5.95 mmol) in tetrahydrofuran (40 mL) was cooled at −78° C. To this was added isopropylmagnesium chloride (2.0N solution in tetrahydrofuran, 3.12 mL, 6.2 mmol) dropwise over five minutes. The reaction mixture was stirred at this temperature for 1.5 hours and then quenched with saturated aqueous ammonium chloride solution (1 mL). The reaction mixture was then diluted with 25 mL water and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, filtered, and the concentrated in vacuo to afford a yellow oil, which was used in the next step without any further purification (2.2 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[CH2:34](I)[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:34][CH3:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(C)c1
Reactant: CCI
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@@H](SCc2c(C)cc(C)cc2C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (3.0 g, 6.08 mmol) was treated with ethyl iodide according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=3/1) [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (1.20 g, 38%) was obtained.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][O:14]C(=O)C)[CH:7]=1>CO.O>[OH:14][CH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[CH:9]=1)[C:5]([OH:18])=[O:4]
Reactant: COC(=O)c1cc(C)cc(COC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(CO)cc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
In a 5 liter flask were dissolved 380 g (5.77 mole) of 85% KOH in 2.2 liter of methanol and warmed up to 60° C. The methyl-3-acetoxymethyl-5-methylbenzoate from the previous step was added and heated with stirring at 60° C. for 2.5 hrs. The reaction mixture was cooled down to room temperature and the solvent eliminated in the rotavap. The resulting oil was dissolved in 1.5 liter of water and then washed with ethyl ether (1×1 liter). The aqueous layer was made acidic with concentrated hydrochloric acid and the resulting acidic suspension was extracted with ethyl acetate (3×350 ml). The combined organic extracts were then washed with water (2×600 ml) and then brine (2×500 ml), dried over sodium sulfate and concentrated in the rotavap to give 287.6 g of 3-hydroxymethyl-5-methylbenzoic acid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:12]=[CH:11][C:7](C([O-])=O)=[CH:6][CH:5]=1.ClC(OCC)=O.[NH2:20]C1C=CC=CC=1.C1C2CC3(N)CC(C2)CC1C3>>[C:3]([NH2:20])(=[O:2])[C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccccc1
Agent: CCOC(=O)Cl
Agent: NC12CC3CC(CC(C3)C1)C2
Product: NC(=O)c1ccccc1

Procedure:
As shown in the reaction scheme 2, firstly, monomethylterephthalate may be converted to an anhydride by employing ethyl chloroformate. Then, the anhydride may be reacted with aniline or adamantamine, to produce a benzamide compound. The next reactions may be performed by the same procedure described in the reaction scheme 1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+]>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:9]([C:4]5[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][N:5]=5)=[O:11])[CH:42]=[CH:41][CH:40]=4)=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: O=C(O)c1ncccc1C(F)(F)F
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a solution of 3-(trifluoromethyl)pyridine-2-carboxylic acid (47.5 mg, 0.249 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (43.2 μL, 0.498 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylacetamide (6 mL), and the solution was stirred at room temperature. N-[6-(3-Aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (66 mg, 0.214 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (72.5 mg, 70%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:43])([CH3:42])[O:8][CH:9]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][C:32]([CH:34]=O)=[CH:31][CH:30]=3)=[C:25]([CH3:36])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:37])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+].[C:46]([O:49][CH2:50][CH3:51])(=[O:48])[CH3:47]>O1CCCC1>[CH2:50]([O:49][C:46](=[O:48])/[CH:47]=[CH:34]/[C:32]1[O:33][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:43])[CH3:42])[C:38]([CH3:39])([CH3:41])[CH3:40])=[C:13]([CH3:37])[CH:14]=3)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:24][C:25]=2[CH3:36])=[CH:30][CH:31]=1)[CH3:51]
Reactant: CCOC(C)=O
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C=O)o2)c(C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)o1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Sodium hydride (60% in oil, 8.4 mg, 0.209 mmol) was added to tetrahydrofuran (1 mL) at 0° C. Triethyl phosphonoacetate (0.049 mL, 0.244 mmol) and then a solution of 5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde (Example 3-(6); 100 mg, 0.174 mmol) in tetrahydrofuran (0.6 mL) were added at the same temperature, and the mixture was stirred for 20 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane only to hexane/ethyl acetate=9/1) to give the title compound (112 mg, 100%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([CH3:34])[C:28]([C:29](Cl)=[O:30])=[C:27]([CH3:35])[CH:26]=1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:29](=[O:30])[C:28]2[C:27]([CH3:35])=[CH:26][C:25]([F:24])=[CH:33][C:32]=2[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cc(F)cc(C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Yield: 100 %

Procedure:
To {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.904 g; 4.147 mmol) in DCM (45 ml) under argon at room temperature was added triethylamine (0.573 ml; 4.15 mmol), followed by a solution of 4-fluoro-2,6-dimethylbenzoyl chloride (0.773 g: 4.144 mmol) in DCM (5 ml). After 16 h. the reaction was washed with water, dried with MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate-hexane 0 to 100% gradient to give the title compound (1.57 g; 100%). 1H NMR (CDCl3) δ: 0.85-1.00 (1H, m), 1.30-1.60 (3H, m), 1.60-1.75 (2H, m), 1.75-1.90 (2H, m), 2.22 (6H, s), 2.31 (6H, m), 5.18 (1H, d, J=6 Hz), 6.73 (2H, d, J=9.6 Hz overlaps 1H, br s), 7.20-7.35 (3H, m), 7.42 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 369 (MH+). C23H29FN2O requires 368. Ret. time 1.99 min. The free base was dissolved in methanol. 1M HCl/diethylether was added to the stirred solution and stirring continued at room temperature for 5 minutes. The solution was then evaporated under reduced pressure, redissolved in DCM and evaporated at reduced pressure. The resulting foam was dried for 16 hours at reduced pressure. The hydrochloride salt was obtained as a white foam (1.45 g).