Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:12]=1[C:13]#[N:14]>CN(C=O)C.CCOC(C)=O>[CH:19]([C:16]1[CH:17]=[CH:18][C:11]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[C:12]([CH:15]=1)[C:13]#[N:14])=[O:20]
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C=O)cc1C#N)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
To a solution of 0.50 g (4.38 mmol) of 1,1,1-trifluoro-2-propanol in 15 mL of DMF at 0° C. was added 0.13 g (5.26 mmol) of sodium hydride (60% dispersion in mineral oil). After stirring for 10 min, 0.65 g (4.38 mmol) of 2-fluoro-5-formylbenzonitrile was added. The reaction mixture was gradually warmed up to rt and stirred overnight. The mixture was diluted with 20 mL of EtOAc and washed with brine (10 mL), H2O (3×10 mL), and brine (10 mL L). The organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/EtOAc as the eluant gave 0.44 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.67 (d, J=6.4, 3H), 4.95 (m, 1H), 7.22 (d, J=8.9, 1H), 8.12 (dd, J=2.0, 6.7, 1H), 8.16 (s, 1H), 9.96 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][CH:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1[CH2:28][C@@H:27]([C:29]2C=CC=[CH:31][CH:30]=2)NC[C@@H]1C)=O)(C)(C)C>>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[C:15]1[CH:31]=[CH:30][CH:29]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)C(C)CN1
Reactant: C[C@H]1CN[C@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](c2ccccc2)CN1

Procedure:
trans-1-Benzyl-5-methyl-2-phenyl-piperazine was prepared in analogy to the preparation of benzyl-2,5-dimethyl-piperazine (see above) starting form trans-2-Methyl-5-phenyl-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [S:1]1[C:5]2([CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[S:1]1[C:5]2([CH2:9][C@@H:8]([C:10]([O:12][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:11])[NH:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1CC2(CN1)SCCS2
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1)SCCS2
Reaction time: 0.17 h

Procedure:
To a solution of (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, p-toluenesulfonate (6.0 g.) in 30 ml. of anhydrous dimethylformamide at 50 ° under argon is added a dimethylformamide solution of diphenyldiazomethane (3.6) portionwise. After 10 minutes at 50°, the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and precipitated with ether. The solvent is then decanted and the residue triturated with ethyl acetate/ether to give (S)-1,4-dithia-7-azaspiro [4.4]nonane-8-carboxylic acid, diphenylmethyl ester, p-toluenesulfonate.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=O)=O)=CC=1.[I-:29].[Na+]>CC(=O)CC>[I:29][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1
Reactant: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCC(=O)c1ccc(CCI)cc1
Yield: 99.6 %

Procedure:
2-(4-Octanoyl phenyl)ethyl p-toluene sulfonate (1.23 g) prepared in the above-described procedure was dissolved in 2-butanone (18 ml) to obtain a solution. Sodium iodide (550 mg) was added to the solution, and the solution was heated to reflux for 40 minutes. The reaction solution was concentrated, and the solution was partitioned with water-dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 4′-(2-iodoethyl)octanophenone (1.09 g) in the form of white crystal.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>CO.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]carbamate (4.3 g, 11.3 mmole) in MeOH (100 mL) at RT was added 4M HCl in dioxane (50 mL). After stirring for 3 h at RT, the reaction solution was concentrated to a white solid (quant.): LCMS (ES) m/z 281 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[S:8]2)=[O:4].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:25](=[O:26])[C:24]1[CH:23]=[C:22]([O:21][CH3:20])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=1)[S:8]2)=[O:4]
Reactant: COC(=O)c1cn2cc(-c3ccccc3N)sc2n1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COC(=O)c1cn2cc(-c3ccccc3NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2n1
Temperature: 25 °C
Yield: 243.2 %

Procedure:
2-(2-Amino-phenyl)-imidazo[2,1-b]thiazole-6-carboxylic acid methyl ester (27 mg, 0.095 mmol) was mixed with 1 mL of pyridine along with 22 mg of 3,4,5-trimethoxybenzoyl chloride. The reaction mixture was reacted in a microwave reactor at 160° C. for 10 minutes. It was then cooled to room temperature and concentrated. The resulting crude product was purified by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA to afford 108 mg of 2-[2-(3,4,5-trimethoxybenzoylamino)-phenyl]-imidazo[2,1-b]thiazole-6-carboxylic acid methyl ester (MS, M++H=468).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[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:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([O:50][CH2:51][CH2:52][NH:53][CH2:54][CH2:55][O:56][CH:57]([CH3:59])[CH3:58])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:53]([CH2:52][CH2:51][O:50][CH:47]([CH3:49])[CH3:48])[CH2:54][CH2:55][O:56][CH:57]([CH3:58])[CH3:59])=[O:42])[CH2:36][CH2:35]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:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)OCCNCCOC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC(C)C)CCOC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(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]-piperidin-4-yl}-acetic acid was coupled with bis-(isopropoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C46H63Cl2N5O5 [(M+H)+] 836.4279, observed 836.4274.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][CH3:10])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: CSc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(Cl)c(C=O)c(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred solution of (3,5-dichlorophenyl)(methyl)sulfane (1.0 g, 5.1 mmol) in THF (15 mL), n-BuLi (1.6 M in THF, 4.8 mL, 7.7 mmol) was added dropwise at −78° C. and stirred for 1 h at the same temperature. A solution of DMF (0.6 mL, 7.7 mmol) in THF (3 mL) was added slowly at −78° C. and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl aq. (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A57-1 (1.4 g, 99%) as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C1C=CC=CC=1>[O:15]=[C:11]([CH3:10])[CH2:12][C:13]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:14]
Reactant: CC(C)(C)OC(=O)CN
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
3.93 g (50 mmol) of t-butyl 2-aminoacetate was dissolved in 65 ml of benzene. To the above mixture, 4.41 g (52.5 mmol) of diketene was added dropwise and the reaction mixture was stirred for one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled away from the reaction mixture under reduced pressure, whereby 9.821 g (91.2%) of the captioned compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:15])[CH:6]=1)[CH3:2]>C1COCC1.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:13])[CH3:14])[N:8]=[C:7]([CH3:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)nc(C=C(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
2-Methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g, 45.2 mmol) is dissolved in THF (100 mL) and methanol (100 mL), Pd/C (800 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 5 h. The catalyst is filtered off and the filtrate is evaporated. The crude product is purified by CC on silica gel eluting with hexane:EA 1:1 to give 2-methyl-6-(2-methyl-propyl)-isonicotinic acid ethyl ester (9.78 g) as a colourless oil; LC-MS: tR=0.71 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:26]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][N:26]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncccc1N)C(=O)O

Procedure:
(2S)2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)propionic acid was prepared by a similar method to (2S)2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[Si](C)(C)CNCCc1ccc(Cl)cc1
Yield: 49.9 %

Procedure:
The compound of formula (P11), wherein n=2 and R″ is chloro, was prepared from a mixture of chloromethyltrimethylsilane (3.7 mL, 42.8 mmol), 2-(4-chlorophenyl)ethylamine (10 g, 64.25 mmol), and K2CO3 (4 g, 28.9 mmol) in acetonitrile (80 mL). The reaction mixture was refluxed for 13 h and after cooling, the precipitate was filtered off and the filtrate concentrated under vacuum. The resulting oil was chromatographed over silica gel (CH2Cl2/MeOH/Et3N: 97/2/1) to yield the above-referenced compound as a colorless oil (5.17 g). 1H NMR (CDCl3): 7.25 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz), 2.7-2.9 (4H, m), 2.08 (3H, s), 0.95 (1H, br s), 0.02 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl.C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][S:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1nnc(S)s1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(=O)CSc1nnc(C)s1
Yield: 91.3 %

Procedure:
A solution of 5-methyl-1, 3,4-thiadiazole-2-thiol (264 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (10 mL) and acetonitrile (10 mL) was stirred at 20° C. for 3 hours under nitrogen. The precipitates were filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (450 mg, yield 69%) as a solid. 1H-NMR (300 Hz, D3COD and d6-DMSO) δ (ppm): 4.22 (q, J=7.1 Hz, 2H), 3.78 (d, J=14.1 Hz, 1H), 3.71 (d, J=14.1 Hz, 1H), 2.74 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[C:36]2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=[C:32]([NH2:39])[C:31]=2[N:30]=[C:29]1[CH3:40]>>[NH2:39][C:32]1[C:31]2[N:30]=[C:29]([CH3:40])[N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12]([N:11]=[N:10][C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:36]=2[C:35]([CH3:37])=[C:34]([CH3:38])[N:33]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)c3ccc(N=Nc4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 34-50, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 551.2551.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([OH:14])(=[O:13])[CH:11]=O>CO>[NH2:4][C:3]1[C:5]([CH3:9])=[CH:6][C:7]([CH:11]([C:7]2[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[C:10]([OH:14])=[O:13])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: O=CC(=O)O
Solvent: CO
Product: Cc1cc(C(C(=O)O)c2cc(C)c(N)c(C)c2)cc(C)c1N
Temperature: 25 °C

Procedure:
A mixture of 2,6-dimethylaniline (40 parts) and methanol (150 parts) was stirred at ambient temperature. Glyoxylic acid 50% w/v (24.5 parts) was added and the mixture was stirred for 24 hours at ambient temperature. The precipitated product was isolated by filtration, washed with methanol (30 parts) and dried to yield di(4-amino-3,5-dimethylphenyl)acetic acid (44.3 parts).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Yield: 68.4 %

Procedure:
To a solution of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (490 mg, 1.07 mmol, 1.00 equiv), EDCI (250 mg, 1.31 mmol, 1.22 equiv), HOBt (180 mg, 1.33 mmol, 1.24 equiv), triethylamine (330 mg, 3.27 mmol, 3.04 equiv) and pyridin-3-ylmethanamine (330 mg, 3.06 mmol, 2.84 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition of 60 mL ice/water. The solid was collected by filtration and washed with water (1×20 mL) and dried in an oven under reduced pressure to give 0.40 g (68%) of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 547 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.86 (d, J=7.6 Hz, 2H), 7.74-7.72 (m, 3H), 7.53 (d, J=7.6 Hz, 2H), 7.36 (s, 1H), 4.67 (s, 2H), 4.51 (d, J=4.0 Hz, 2H), 3.55 (s, 6H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The compound (67.0 mg) obtained in Example 79-3 was dissolved in anhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride (20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 2 days. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(=O)OC(C)(C)C)CC2)C1=O

Procedure:
The title compound was prepared from (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C) and tert-butyl piperazine-1-carboxylate according to the procedure described in Example 91 Step D.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(COC)OC.O>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][O:11][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC1(C)[C@H]2CC=C(CCOCC(=O)O)[C@@H]1C2
Temperature: 45 °C
Yield: 52609 %

Procedure:
To a solution of (−)-nopol (Aldrich) (100 g, 0.60 mmol) in dimethoxy ethane (350 mL) was added NaH (60% oil dispersion, 31.1 g, 0.81 mmol). The mixture was refluxed for 2.5 hours, cooled to 45° C., and 2-chloroacetic acid (23.5 g 0.25 mmol) in dimethoxy ethane (180 mL) was added drop wise over a period of 1.5 hours. The reaction mixture was refluxed for 1 hour. After cooling at room temperature, water (75 mL) was added slowly, followed by 10% aqueous NaOH. The mixture was extracted with ether (1 L) (discarded), the aqueous phase was acidified and extracted with ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was distilled under reduced pressure to yield the title compound (29.5 g, 135-137° C. at 1.0 mm of Hg). n25D 1.4914, mp 78-80° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH2:9]1)=O)(C)(C)C.[ClH:40].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:40].[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:27]([C@H:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:39])=[CH:35][CH:34]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of the compound (973 mg) obtained in Step 2 in ethyl acetate (10 ml) was added, with stirring at room temperature, 4N hydrogen chloride/ethyl acetate solution (4.73 ml). After stirring at room temperature for 4 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in a mixed solvent of ethyl acetate and diisopropyl ether, collected by filtration and dried to give the title compound (742 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1cccc(Br)c1)S(C)(=O)=O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m).