Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C(OCC)C>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: NC1CC1
Solvent: CCOCC
Product: CCOC(=O)CNC1CC1
Reaction time: 3 h

Procedure:
Ethyl bromoacetate in diethyl ether was added dropwise to a solution cooled to +5° C. of cyclopropylamine in diethyl ether. A white solid formed. The mixture was stirred for 3 hours while maintaining the cooling. The precipitate was filtered off and extracted with ether and the filtrate was evaporated. The residue was triturated with benzene/cyclohexane and the solid was filtered off. The filtrate was evaporated and the residue was distilled and fractionated to give ethyl cyclopropylaminoacetate of boiling point 32°-33° C./0.7 mmHg: nD19 =1.4384.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[C:7](=[O:23])[N:6]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4].[OH-].[Na+]>>[O:23]=[C:7]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][N:8]1[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:21])([F:22])[F:20])(=[O:12])=[O:11]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1

Procedure:
Steps 4 and 5: In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid. Finally, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 586.8 ([M+H]+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH:14]([CH:15]=[N:16][O:17][CH3:18])[CH:13]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)=[CH:5][CH:4]=1.CCCCCC>C(Cl)Cl>[ClH:2].[CH3:18][O:17][N:16]=[CH:15][CH:14]1[C:9]2([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH:13]1[CH2:12][NH:11][CH2:10]2
Reactant: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CON=CC1C2CNCC12c1ccc(Cl)cc1
Yield: 186.8 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 1-(4-chlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (210 mg, 0.598 mmol) obtained in step-1 of example 5 in dry DCM (10 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde O-methyl oxime (140 mg, 81%) as white solid as mixture of isomers.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=1>>[C:14]([C:13]1[CH:16]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:30]=3)=[O:32])[N:5]=2)[CH:10]=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])#[N:15]
Reactant: N#Cc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]1
Product: N#Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.10 g) and 3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.077 g) using the method of Example 34(d). Yield 0.21 g. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (t, 2H), 4.41 (t, 2H), 7.09 (s, 1H), 7.24-7.39 (m, 2H), 7.82-7.91 (m, 3H), 8.37-8.70 (m, 5H), 13.84 (br s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>O1CCOCC1.O>[CH3:13][O:12][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1COc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methoxy-2′-phenoxymethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.24 mmol) in 1,4-dioxane and H2O was added lithium hydroxide (a spatula tip), and the reaction was stirred at 55° C. overnight. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[NH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]([CH2:24][C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:31][CH2:32]2)=[O:26])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(-c2cccs2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2cccs2)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-Thiophen-2-yl-2H-pyrazole-5-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1: Rf=0.62) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.06-7.36 (m, 1H), 6.96-7.2 (m, 3H), 6.84-6.92 (m, 3H), 54.46 (s, 2H), 4.3-4.4 (q, 2H), 3.6-3.82 (m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1O.[C:10](=O)([O-])[O-:11].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Cl)ccc1C
Yield: 77.5 %

Procedure:
Commercially available 2-chloro-5-methylphenol (19.8 g, 70 mmol) was dissolved in 450 ml acetone. Potassium carbonate (28.9 g, 209 mmol) was added, followed by iodomethane (29.7 g, 209 mmol), and the mixture was refluxed overnight with vigorous stirring. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with sodium sulfate, and concentrated giving 8.5 g 4-Chloro-2-methoxy-1-methyl-benzene (100%). 1H NMR (300 MHz, CDCl3) •2.28 (s, CH3, 3H), 3.92 (s, —OCH3, 3H), 6.91 (d, Ar, 1H, J=2.0 Hz), 6.95 (dd, Ar, 1H, J=8.0, 2.0 Hz), 7.14 (m, Ar, 1H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CON(C)[C:16]([C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:17]>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:16]([C:18]2[S:22][CH:21]=[N:20][CH:19]=2)=[O:17])[CH:8]=1
Reactant: CON(C)C(=O)c1cncs1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cccnc1)c1cncs1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A n-BuLi solution (2.37 mL, 3.80 mmol, 1.6 M solution in hexane) was slowly added to a −78° C. to a solution of 3-bromopyridine (0.600 g, 3.80 mmol) in Et2O (10 mL). After addition, stirring was continued for an additional 40 minutes and N-methoxy-N-methylthiazole-5-carboxamide (0.752 g, 4.37 mmol, Intermediate 11: step a) dissolved in Et2O (10 mL) was slowly added. The mixture was stirred at −78° C. for 10 minutes then warmed to 0° C. and stirred for 1 hour. The cold solution was quenched with saturated aqueous NH4Cl and warmed to room temperature. H2O was added and layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (CH2Cl2/EtOAc) to provide the title compound as a yellow solid (precipitated from Et2O and dried under reduced pressure).
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[O:26][CH:27]=1)[C:10]([C:12]1[N:13]=[CH:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:34]=[C:32]([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][C:25]1[O:26][CH:27]=[C:23]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[N:24]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccccc2)co1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)CCCCc1nc(NC(=O)c2ncoc2-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-(5-phenyl-oxazole-4-carbonyl)-carbamic acid tert-butyl ester (31 mg, 0.06 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.05 mL, 0.64 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a light brown solid. TLC: rf (1:1 hept-EA)=0.35. LC-MS-conditions 02: tR=1.02 min, [M+H]+=354.25.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12].[Li]CCCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[Br:10][C:6]1[C:5]2[S:11](=[O:13])(=[O:12])[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:26]([OH:27])[C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1c(Br)cccc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(O)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
To sodium hydride (0.52 g, 12.9 mmol) in tetrahydrofuran (20 mL) at 0° C. was added 2,6-dibromo-N-(1,1-dimethylethyl) benzenesulfonamide (4.0 g, 10.8 mmol). The resulting mixture was stirred at ambient temperature for 2-3 h, cooled to −780° C. and treated with n-BuLi (1.6 M in hexanes, 7.4 mL, 11.9 mmol) over a period of 20 min. The reaction was continued to stir for 40 min and treated with N,N-dimethyl formamide (0.9 mL, 11.9 mL). The cooling bath was removed and the mixture continued to stir over a period of 20 min. The work-up consisted of slowly quenching the reaction with 1N NaCl, dilution with water and extraction with ethyl acetate. Drying over sodium sulfate and concentrating under reduced pressure provided the crude product that was purified by the flash chromatography (ethyl acetate/hexane, 1:4) to afford the 7-bromo-2-(1,1-dimethylethyl)-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide (2.1 g, 55 %). 1H NMR (CD3OD): δ1.61 (s, 9H), 6.02 (s, 1H), 7.61 (m, 2H), 7.77 (m, 1H).
Reaction SMILES: ClC1C=CC2OC(NC[C@@H]3[C@H](C)CCCN3C(OCC=C)=O)=NC=2C=1.[NH2:26][CH2:27][C@@H:28]1[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[N:48]=[CH:47][CH:46]=[N:45]1)=[O:36].Cl[C:50]1[O:51][C:52]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:53]=2[N:54]=1>>[F:59][C:56]1[CH:57]=[CH:58][C:52]2[O:51][C:50]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[N:48]=[CH:47][CH:46]=[N:45]3)=[O:36])=[N:54][C:53]=2[CH:55]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc2oc(Cl)nc2c1
Agent: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(F)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. ESI-MS (m/z): 449 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2OCCOCP(OCC)(OCC)=O.C[O-].[Na+].[C:30](O)(=[O:32])C>CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][CH:5]=[N:6]2)=[C:2]([O:32][CH3:30])[N:10]=1
Reactant: CC(=O)O
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2nc[nH]c12
Temperature: 50 °C

Procedure:
To a solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]-2-formamidopurine (0.25 g, 0.61 mmol) in methanol (5 ml), was added sodium methoxide solution (30 wt % in methanol; 0.5 ml, 2.62 mmol). The mixture was stirred and heated at 50° C. for 4 hours. After cooling to ambient temperature, 80% aqueous acetic acid (0.5 ml) was added to give a solution of pH6. The solution was evaporated to dryness and the residue partitioned between dichloromethane (10 ml) and aqueous sodium bicarbonate solution (10 ml). The aqueous phase was washed with dichloromethane (2×10 ml), the combined organic extracts dried (magnesium sulphate), and evaporated to dryness under reduced pressure. The residue obtained was chromatographed on silica gel (eluant dichloromethane: methanol 90:10) to give a 2-amino-6-methoxypurine derivative (0.20 g) which was used without any further purification. The chromatographed material (0.20 g) was dissolved in dichloromethane (2 ml), trimethylsilyl bromide (0.7 ml, 5.3 mmol) added, and the solution left at ambient temperature for 2 days. The solvent was evaporated under reduced pressure and the residue obtained co-evaporated with methanol (×2) to leave a white solid which crystallised from hot water giving the title compound as a white solid (0.105 g, 56%) m.p. 275°-278° C., identical in all respects with the compound obtained in Method A.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][CH2:30][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-:32].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][CH2:30][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([C:25]([NH2:26])=[O:32])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1nn(-c2ncccc2C#N)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(-c2ncccc2C(N)=O)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
To a solution of 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (0.71 mmol, 0.30 g) in dimethylsulfoxide (7.5 mL), potassium carbonate (0.049 g, 0.35 mmol) is added and the mixture is cooled to 0-5° C. before adding 33% hydrogen peroxide solution in water (0.39 mL, 3.78 mmol). The mixture is stirred at room temperature for 2 h. Then, water is added carefully and the reaction mixture is extracted with ethyl acetate. Organic layer is decanted, dried over magnesium sulfate and solvent is evaporated under reduced pressure. Crude is purified by normal phase Isco chromatography using as eluent dichloromethane/methanol mixtures to give 0.252 g that are further purified by reverse phase HPLC to yield 0.198 g of 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carboxamide. MS (m/z): 442 (M+1).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-]>CO>[CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:3])[CH3:4]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Solvent: CO
Product: C[N+](C)(C)CC(O)CC(=O)[O-]
Yield: 98.9 %

Procedure:
In 700 ml of methanol are dissolved under heat 35.0 g (0.177 mole) of DL-carnitine hydrochloride, and the solution is passed through OH type strongly basic resin (DOWEX-1X8). The methanol solution is concentrated to obtain 28.3 g (0.175 mole) of DL-carnitine. To DL-carnitine are added 62.6 g (0.175 mole) of dibenzoyl-L(+)tartaric acid and 93 ml of methanol, and the mixture is dissolved under heat to form dibenzoyl-L( +)tartarates of D-carnitine and L-carnitine. The tartarates are cooled at a temperature of below -10° C. with stirring to fractionally crystallize L-carnitine dibenzoyl-L(+)tartarate. The tartarare is filtered and washed to give L-carnitine dibenzoyl-L(+)tartarate (yield 30.5 g, purity 93.0%). Recrystallization of the tartarate from 100 ml of methanol gives 23.9 g of L-carnitine dibenzoyl-L(+)tartarate as white crystal. [α]D25 =-96.0° (c=1, MeOH), m.p. 154° C. (dec.), purity 99.5%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[C:12]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([NH:32][C:33]2[C:42]([CH3:43])=[CH:41][C:36]([C:37](OC)=[O:38])=[C:35]([CH3:44])[CH:34]=2)=[O:31])[CH2:24][CH2:23]1)=[O:20].[OH-].[Na+]>ClCCl.O>[OH:38][CH2:37][C:36]1[C:35]([CH3:44])=[CH:34][C:33]([NH:32][C:30]([CH2:29][CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:19](=[O:20])[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:27][CH2:26]2)=[O:31])=[C:42]([CH3:43])[CH:41]=1
Reactant: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1M lithium aluminum hydride in THF (1.52 mL, 1.52 mmol) at 0° C. was added methyl 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoate (400 mg, 0.76 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and then a 1:1 mixture of 1M aqueous sodium hydroxide (5 mL) and water (5 mL) was added and stirring was continued for 2 hours. Dichloromethane was added and the organic layer was separated, dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane containing 5% methanol to provide biphenyl-2-ylcarbamic acid 1-[2-(4-hydroxymethyl-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester. LCMS (10-70) Rt=3.94; [M+H+] found 502.5.
Reaction SMILES: [CH3:1][C:2](=[N:4][O:5][CH2:6][C:7]([OH:9])=O)[CH3:3].S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2](=[N:4][O:5][CH2:6][C:7]([Cl:12])=[O:9])[CH3:3]
Reactant: CC(C)=NOCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=NOCC(=O)Cl

Procedure:
To {[(1-methylethylidene)amino]oxy}acetic acid (286 g, 2.18 mol) was added 600 ml of toluene. Thionyl chloride (364 g, 3.06 mol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was heated to reflux for 10 hours. Toluene and thionyl chloride were evaporated under vacuum and the residue was distilled to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:35][CH3:36])=[C:17]([O:20][C@H:21]4[CH2:26][CH2:25][C@@H:24]([NH:27]C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:35][CH3:36])=[C:17]([O:20][C@H:21]4[CH2:22][CH2:23][C@@H:24]([NH2:27])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CC[C@@H](N)CC1

Procedure:
Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline with trifluoroacetic acid in methylene chloride at ambient temperature.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1[N:17]2[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[CH2:20][CH2:21][C@@H:22]([NH2:23])[C:16]2=[N:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](O)=[O:57])[CH2:55][CH2:54]2)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](=[O:57])[NH:23][C@@H:22]3[CH2:21][CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[N:17]4[CH:13]=[CH:14][N:15]=[C:16]34)[CH2:54][CH2:55]2)=[O:51])=[CH:48][CH:47]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 g, 151 mmol) to a 10° C. slurry of (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (30 g, 151 mmol), 1-hydroxybenzotriazole (20 g, 151 mmol), triethylamine (41.97 mL, 301 mmol), and 1-[(4-chlorobenzoyl)amino]cyclopropanecarboxylic acid (40 g, 166 mmol) in THF (300 mL). Remove the ice bath, warm the mixture to ambient temperature, and stir it for 4 hours. Pour the mixture into water (1.0 L) and extract with ethyl acetate (1.0 L). Wash the organic phase with saturated sodium bicarbonate (500 mL), dry over magnesium sulfate, filter, and concentrate under reduced pressure. Slurry the residue in ethyl acetate (300 mL) and heat to 71° C. Cool to ambient temperature, filter the precipitate, and wash with ethyl acetate (100 mL) to give the title compound (38.8 g, 61%): MS (m/z): 421 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][O:22][C:20]1[CH:19]=[C:18]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]2)[CH:21]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1cc(Oc2ccc(C#N)cc2)cc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 88.1 %

Procedure:
Using 0.63 g (1.39 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanoic acid ethyl ester (0.29 g, 1.39 mmol) and following the procedure of Example 42(b) afforded 0.71 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.25 (2H, m), 1.4 (9H, s), 1.75 (9H, m), 2.35 (2H, m) 3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.75 (1H, d), 6.9 (1H, s), 7.15 (3H, d), 7.35 (1H, s), 7.85 (2H, d), 8.25 (1H, d).