Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([NH:33][CH3:34])[CH:30]([CH3:32])[CH3:31]>C1COCC1>[CH2:29]([N:33]([CH3:34])[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(O)c1cccc(-c2cc(-c3ccc(Cl)nc3)on2)c1
Reactant: CNCC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(C)c1ccc(-c2cc(-c3cccc(C(=O)O)c3)no2)cn1
Temperature: 120 °C
Reaction time: 60 h

Procedure:
In a pressure tube, 200 mg (0.64 mmol) of 3-[5-(6-chloro-pyridin-3-yl)-isoxazol-3-yl]-benzoic acid, 97 mg (0.96 mmol, 1.5 eq.) of triethyl amine and 166 mg (1.9 mmol, 3.0 eq.) of isobutyl-methyl-amine are dissolved in 3 ml of THF. The reaction mixture is heated to 120° C. and after 6 h to 150° C. After 60 h, the mixture is cooled to room temperature and the solvent is removed. After addition of 10 ml of water, the pH is adjusted to 2 and the precipitate filtered off. The solid is then dissolved in 10 ml of methanol and 5 ml of dichloroethane, precipitated through addition of 10 ml of hexane and filtered. Recrystallisation from 15 ml of dichloromethane and 1 ml of methanol yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 352.2
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:20][NH2:21])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:34]=[C:33]([CH:35]3[CH2:37][CH2:36]3)[NH:32][N:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:35]1([C:33]2[NH:32][N:31]=[C:30]([NH:29][C:27]3[CH:26]=[CH:25][N:24]=[C:23]([NH:21][CH2:20][C:15]4[C:14]5[CH:13]=[N:12][N:11]([S:1]([C:4]6[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=6)(=[O:3])=[O:2])[C:19]=5[CH:18]=[CH:17][N:16]=4)[N:28]=3)[CH:34]=2)[CH2:37][CH2:36]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(CN)nccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of (1-tosyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanamine (300 mg, 1.3 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (258 mg, 1.05 mmol), and DIPEA (0.5 mL) in IPA (2 mL) was heated at 120° C. overnight. The reaction mixture was concentrated under reduced pressure to afford 400 mg (61%) of crude N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine as yellow oil. MS (ESI): m/z=502.3 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]2[N:4]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:31])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]2[N:4]=1)=[O:31]
Reactant: CSc1ncc2ccc(CNc3ccccc3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(CNc3ccccc3)n2n1
Yield: 27.9 %

Procedure:
(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine (0.280 g, 1.04 mmol) was dissolved in Methylene chloride (5 mL, 80 mmol) and the solution was treated with m-Chloroperbenzoic acid (0.313 g, 1.40 mmol) at room temperature. The reaction was allowed to stir until HPLC showed consumption of starting materials. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 83 mg of (2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. (M+H)=287.0. 1H NMR (400 MHz, DMSO, d6) δ 9.24 (s, 1H), 7.25 (m, 1H), 7.10 (m, 3H), 6.64 (d, 2H, J=8.08 Hz), 6.55 (t, 1H, J=7.12 Hz), 6.22 (m, 1H), 4.68 (m, 2H), 2.92 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:29]([O:33][C:34]([NH:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50](O)=[O:51])=[O:35])([CH3:32])([CH3:31])[CH3:30].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>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:50]([C:38]3[N:39]=[C:40]([C:42]4[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=4[F:49])[S:41][C:37]=3[NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:51])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (20 mg, 0.051 mmol), (5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6, 22 mg, 0.062 mmol), HATU (49 mg, 0.13 mmol), DMF (0.12 mL) and DIPEA (20 mg, 0.15 mmol) were mixed together and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 0-100% EtOAc in hexanes) to give the sub-title compound as a colorless gum (30 mg, 80%). LCMS calc. for C35H43F2N6O7S (M+H)+: m/z=729.3. Found: 729.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[K+].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1>C(#N)C>[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][N:46]([CH2:6][CH2:7][CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Reactant: COc1cncnc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Yield: 57.6 %

Procedure:
To a solution of crude 3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (18.3 mmol, 1.0 equiv.) in 225 mL of anhydrous acetonitrile was added 3.03 g (18.3 mmol, 1.0 equiv.) of potassium iodide, 3.81 mL (21.9 mmol, 1.2 equiv.) of N,N-diisopropylethylamine and 3.89 g (20.1 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 500 mL of chloroform. The organic layer was washed with 100 mL portions of 10% potassium carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide followed by chromatography on silica gel using 20% methanol in ethyl acetate to obtain 4.83 g (58%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from hot methanol gave 4.05 g (68%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine hydrochloride, m.p. 170° C. (d). Elemental analysis calculated for C22H30N6O3S/3 HCl: C, 46.52; H, 5.86; N, 14.80; found: C, 46.14; H, 6.22; N, 14.51.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36]Br)=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C>O1CCCC1>[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCN1
Reactant: CC[C@H](NC(=O)c1c(CBr)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)c1c(CN2CCCC2=O)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 2-pyrrolidinone (0.1 ml) in tetrahydrofurane (2 ml) sodium hydride (20 mg, 60% dispersion in mineral oil) was added. The reaction mixture was stirred at ambient temperature until the gas evolution ceased then 3-bromomethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (30 mg) was added. After 30 min acetic acid (0.05 ml) was added and volatiles were removed in vacuo. The product was purified by flash chromatography on SiO2 (5 g, 1,2-dichloroethane then gradient 50% to 100% ethyl acetate in heptane) to give 17 mg of white solid. Yield 56%. LC-MS (m/z) 480.5 (MH+); tR=1.21.
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C@@H:22]4[CH2:26][CH2:25][O:24][CH2:23]4)=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[O:24]1[CH2:25][CH2:26][C@@H:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([C@@H:11]3[O:12][CH2:13][CH2:14][NH:9][CH2:10]3)=[CH:20][CH:19]=2)[CH2:23]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N[C@@H]3CCOC3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1cc([C@H]2CNCCO2)ccc1N[C@@H]1CCOC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 4-((1R)-1-phenylethyl)-(2S)-2-(4-[N-{(3R)-tetrahydrofuran-3-yl}amino]phenyl)morpholine (0.40 g, 1.09 mmol) and ammonium formate (0.69 g, 10.9 mmol) in mixture of tetrahydrofuran (50 ml), methanol (100 ml) and water (16 ml) was added 10% palladium on carbon (wet, 150 mg) and stirred at 95° C. for one hour. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (2S)-2-[4-{N-((3R)-tetrahydrofuran-3-yl)amino}phenyl]morpholine (0.28 g, quant.) as a colorless oil.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:26]O)[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:9][CH:8]=1.N1C(C)=CC(C)=CC=1C.[O:40]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[NH:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl.CO.O>[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:26][N:43]4[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[O:40][CH2:41][CH2:42]4)[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:9][CH:8]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: c1ccc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.8 %

Procedure:
Methanesulfonyl chloride (0.10 mL) is added to a cold (0° C.) solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.41 g) from Preparation No. 10, DMAP (0.030 g), and 2,4,6-collidine (0.19 mL) in anhydrous DMF (15 mL). The mixture is stirred at room temperature for 12 h and then benzomorpholine (1.60 g) from above is added. The reaction mixture is stirred at room temperature for 2 h and is then heated to 65° C. overnight. The mixture is cooled to room temperature and poured water. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by column chromatography (eluent CH2Cl2 (1 L), 1% MeOH/CH2Cl2 (2 L)) and then recrystallization from CH2Cl2/hexanes affords 0.56 g (100%) of the title compound as a pale gold solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.O>C(#N)C>[NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Solvent: CO
Solvent: CC#N
Product: N[C@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Example 1 was repeated with the difference that the sample to be tested was a tyrosine of unknown enantiomer composition, the comparison samples were (RS)-, (R)-, and (S)-tyrosine, and the mobile phase was a mixture of methanol, water, and acetonitrile in a 1:1:0.6 ratio by volume. In this case, the (R)-tyrosine gave a spot with an Rf -value of 0.34 and the (S)-tyrosine gave a spot with an Rf value of 0.26.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[C:35](=[O:37])[CH3:36])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCN(C(C)=O)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 232.1 mg, 5.80 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (25 ml). To this suspension was added under an argon atmosphere 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (537.9 mg, 1.18 mmol) and the reaction mixture was stirred at 60° C. for 20 minutes. Then, acetyl chloride (0.5 ml, 7.03 mmol) was added into the reaction mixture and stirred at the same temperature for 1 hour. After the reaction solution was cooled down to room temperature, an aqueous saturated solution of sodium hydrogen carbonate was added to the reaction mixture and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 3:1) to obtain the rotamer 1 (Rf=0.38; hexane-ethyl acetate 3:1) of the title compound (46% yield). Melting point: 134-136° C. (Ethyl acetate-hexane)
Reaction SMILES: [C:1](=[O:10])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])N>CN(C)C1C=CN=CC=1>[C:1](=[O:10])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCOC(N)=O
Agent: CN(C)c1ccncc1
Product: CCCCCCOC(=O)OCCCCCC
Yield: 98 %

Procedure:
The procedure described in Example 1 is followed, but additionally 5 parts of p-dimethylaminopyridine are introduced into the reaction mixture. Analysis by gas chromatography shows that over the same period 44.8% of n-hexyl carbamate have been converted and 101 parts of di-n-hexyl carbonate (98.0% of theory, based on converted n-hexyl carbamate) are formed; the product is isolated by subsequent fractional distillation at 121°-23° C./4 mbar.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][Br:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccccc2)c1

Procedure:
3-Phenylbenzyl bromide (melting point 54°-56° C.) was prepared by illumination of a solution of 3-phenyltoluene and N-bromosuccinimide in carbon tetrachloride in the presence of azobisisobutyronitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][S:8][CH3:9].[Br:17]Br>CO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][S:8][CH3:9]
Reactant: BrBr
Reactant: CSC[C@H](NCc1ccccc1N)C(=O)O
Solvent: CO
Product: CSC[C@H](NCc1cc(Br)ccc1N)C(=O)O
Reaction time: 2 h

Procedure:
To a stirred suspension of 2.40 gm of N-(2-amino-benzyl)-S-methyl-cysteine in 50 cm3 anhydrous methanol a solution of 0.52 cc of bromine in 20 cc of methanol was added dropwise. After the addition of bromine was finished, stirring was continued for 2 hours. The solvent was evaporated in vacuo on a water bath, and residue was dissolved in 50 cc of distilled water. The aqueous solution was decolored by refluxing for 1 hour in the presence of a small quantity of charcoal. The coal was removed by filtration, and the pH of the filtrate was adjusted to 5 by addition of dilute ammonia. The desired product precipitated out. The mixture was allowed to stand for several hours, whereupon the precipitate was centrifuged off, washed with water and dried in a drying chamber. Melting point: 228° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].CI.[C:14](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH3:14][O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (60% dispersion, 3.0 g, 77 mmol) was added in three portions to a solution of 2-chloro-5-methylphenol (10.0 g, 70.1 mmol) in DMF (100 mL) at 0° C. under nitrogen. Methyl iodide (5.0 mL, 77 mmol) was added and the solution was warmed to RT. After 1 h, 10% aqueous citric acid (200 mL) and EtOAc (1.0 L) were added. The layers were separated and the aqueuos layer was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (12 g, 100%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20]C)=O)[CH:12]=1.C[O-].[Na+]>CO>[OH:3][NH:2][C:18](=[O:20])[CH2:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: COC(=O)Cc1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Cc1cccnc1)NO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 13.8 g. (200 mmole) of hydroxylamine hydrochloride and 27.8 ml. (200 mmole) of triethylamine in 500 ml. of methyl alcohol was cooled to a temperature of -5° C. and 30.2 g. (200 mmole) of methyl 3-pyridineacetate were added. The mixture was stirred for 6 hours at room temperature and then 10.8 g. (200 mmole) of sodium methylate were added causing a slight exotherm to occur. The reaction mixture was then stirred for 27.5 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The crude residue of product was sonicated with 50 ml. of chloroform and filtered. The insoluble crude product (25.10 g) was crystallized from 50 ml. of water. There were obtained 15.54 g. of product melting with decomposition at about 163° C. to about 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:24][CH2:23][C:21]1[CH:20]=[CH:19][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:18])=[C:2]([Cl:1])[CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(CO)cc3Cl)c2n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(COCc4ccccc4)cc3Cl)c2n1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
To a suspension of methyl 3-(2-chloro-4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg) in dimethylformamide (8.0 ml) were added sodium hydride (51 mg) and benzyl bromide (277 mg) under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Chloroform and sodium hydrogencarbonate were added to the residue, and the mixture was partitioned. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column (eluent: chloroform:methanol=50:1) to give the objective compound (322 mg) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH2:3][OH:4]>C(O)C.[Pt]>[NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH2:3][OH:4]
Reactant: N[C@@H](/C=C/c1cccc(Cl)c1)CO
Agent: [Pt]
Solvent: CCO
Product: N[C@H](CO)CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
To a stirred solution of (E)-(S)-2-amino-4-(3-chloro-phenyl)-but-3-en-1-ol (155 mg) at r.t. in ethanol (5 ml) under an argon atmosphere was added 5% Pt/C (16 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 20 hrs. The catalyst was filtered off and the filtrate was concentrated to give (S)-2-amino-4-(3-chloro-phenyl)-butan-1-ol (102 mg, 65%) as light yellow oil. MS (ISP): 202.2 ([{37Cl}M+H]+), 200.2 ([{35Cl}M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([NH:11][C:12]([N:14]1[C:18]2[CH2:19][CH2:20][O:21][CH2:22][C:17]=2C(C2C=CC(F)=C(F)C=2)=[N:15]1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=O)=[C:35]([F:42])[CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]2[C:19]3[CH2:20][O:21][CH2:22][CH2:17][C:18]=3[N:14]([C:12]([NH:11][C@@H:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:31])=[O:13])[N:15]=2)=[C:35]([F:42])[CH:34]=1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(Cl)cc2F)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 88 was prepared according to the procedure for the synthesis of compound 36 by replacing 3,4-difluorobenzoyl chloride with 4-chloro-2-fluorobenzoyl chloride. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.16-7.24 (m, 2H), 6.45 (br, 1H), 4.65 (s, 2H), 4.18 (d, J=9.1 Hz, 1H), 3.94 (t, J=5.6 Hz, 2H), 3.73 (br, 2H), 3.45 (br, 2H), 3.17 (br, 2H), 1.10 (s, 9H). Purity: 98%.