Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:11]([NH:12][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(C(=O)OC)c1N

Procedure:
To a solution of methyl 2,3-diaminobenzoate (3.0 g) in THF (50 mL) was added N,N-diisopropylethylamine (4.0 mL). The solution was stirred under ice-cooling, methoxyacetyl chloride (1.81 mL) in THF (10 mL) was added dropwise slowly, and it was stirred for 3 hours at the same temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and THF was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (3.60 g) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[N:5]=[CH:4][NH:3][C:2]=1[CH3:1])#[N:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (17.0 g) and N-cyano-N',S-dimethylisothiourea (11.2 g) in acetonitrile (500 ml) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-142°.
Reaction SMILES: [F:1][C:2]([F:26])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[F:26][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N+:23]([O-:35])=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccncc3)n2)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (1.37 mmol)of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4(4-pyridyl)-2-pyrimidineamine are suspended in 10 ml of methylene chloride; 430 mg (1.37 mmol) of m-chloroperbenzoic acid are added and the reaction mixture is stirred for 4 h at RT. After extraction with water and 2N aqueous sodium hydroxide solution, the organic phase is dried and concentrated using a rotovapor. Chromatography (methylene chloride/methanol=19:1 to 9:1) and subsequent crystallisation (methylene chloride/diethyl ether) give N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineamine in the form of lemon-yellow crystals; FAB-MS: 381 (M+ +H), m.p. 191°-192°.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:27][CH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Reactant: OCc1ccc(B(O)O)cn1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(-c2ccc(CO)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=459.2 [M+H]+, m/z=456.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.84 (m, 4H) 3.05-3.21 (m, 4H) 4.62 (br. s, 2H) 5.50 (br. s, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.54 (d, J=8.03 Hz, 1H) 7.81 (dd, J=8.03, 2.26 Hz, 1H) 7.83-7.89 (m, 2H) 8.01 (d, J=2.38 Hz, 1H) 8.51-8.55 (m, 1H) 8.76 (d, J=2.38 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][C:11]#[CH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([NH2:24])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].Cl>CO>[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([NH:24][C:5]2[N:4]=[C:3]([O:9][CH2:10][C:11]#[CH:12])[C:2]([Br:1])=[CH:7][N:6]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(N)cc(N)c1
Reactant: C#CCOc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CO
Product: C#CCOc1nc(Nc2cc(N)cc(C(=O)OC)c2)ncc1Br
Temperature: 65 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 5-bromo-2-chloro-4-(prop-2-ynyloxy)pyrimidine (15 g), methyl 3,5-diaminobenzoate (45 g) and concentrated hydrochloric acid (15 ml) in methanol (600 ml) was stirred at 65° C. for 8 h. After concentration to half the volume water was added and the precipitate collected by filtration. The precipitate then was treated with sodium hydroxide solution (1 n) and dichloromethane. The organic phase then was washed with water and brine, dried (Na2SO4) and evaporated to dryness to give the title compound (13.8 g).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]C(C)([O-])C.[K+].CI>C(O)(C)(C)C>[CH:1]1([C:6]2([CH3:21])[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc2c(c(C)c1C)C(=O)C(C1CCCC1)CC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Product: COc1cc2c(c(C)c1C)C(=O)C(C)(C1CCCC1)CC2
Temperature: 20 °C

Procedure:
2-Cyclopentyl-6-methoxy-7,8-dimethyl-1-tetralone (Example V, Step 4) (12.5 g., 0.046 mole) is dissolved in t-butyl alcohol (250 ml.) under a stream of nitrogen. The mixture is heated to reflux and then a solution of potassium t-butoxide (7.5 g., 0.067 mole) dissolved in t-butyl alcohol (175 ml.) is added. The dark solution is refluxed for 1 hour, cooled to 20° C. and methyl iodide (14.2 g., 0.1 mole) is added. The mixture is refluxed for 10 minutes. Potassium iodide precipitates and the color of the mixture becomes lighter. The mixture is cooled, water (25 ml.) is added and the mixture is evaporated to dryness. The crude product is collected, washed with water and air dried to obtain 2-cyclopentyl-2,7,8-trimethyl-6-methoxy-1-tetralone.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
Triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 h to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonyl chloride (3.27 g, 18.5 mmol) in dichloromethane (20 mL) at 0° C. The temperature was not allowed to exceed 1° C. After stirring the reaction mixture for an additional 2 h, a further portion of benzenesulfonyl chloride (0.5 g, 1.85 mmol) was added. Then a further portion of triethylamine (0.187 g, 1.85 mmol) was added dropwise to the mixture. After stirring for 0.5 h more, the mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was dried (MgSO4) and evaporated to provide the title product as an orange solid (7.18 g, 94% yield). Product recrystallized from ethyl acetate/hexanes melted at 84-85° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][CH:3]([CH2:2][NH:14][CH2:15][CH2:16][CH2:17][OH:18])[O:4]2)=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: Oc1ccc2c(c1)OC(CBr)CC2
Solvent: O
Product: OCCCNCC1CCc2ccc(O)cc2O1
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 2-bromomethyl-7-hydroxychroman (4.57 g, 18.8 mmol) and 3-amino-1-propanol (18.3 mL, 240 mmol) is heated at 100° C. for 2 hr, cooled, diluted with water and extracted with CH2Cl2. The combined extracts are concentrated in vacuo to give a residue. The residue is purified by column chromatography (silica gel/5% methanol in CH2Cl2 as eluent) to give the title product as a clear oil, 3.27 g (73% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1C=CC=CC=1>[CH3:15][S:16]([O:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCC#N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCC#N)OS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a cooled (ice bath) stirred solution of 4-hydroxypentanonitrile (18.8 g, 0.19 mol) in benzene (100 ml) and triethyl amine (20 g, 0.198 mol) was added dropwise a solution of methanesulphonyl chloride (22.34 g 0.195 mol) in benzene (20 ml) over a period of 40 min. After addition was complete the stirring was continued for 20 min at room temperature. The solid (TEA.HCl) was filtered off and washed with benzene. The filtrate and washings were combined and concentrated in vacuo to give 37.7 g of the title compond containing approximately 12% of benzene: 1Hmr (CDCl3) δ: 7.38 (3H, benzene), 4.82 (1H, q, J=13 Hz), 3.1 (3H, s), 2.48 (2H, dt), 2.0 (2H, dt) and 1.46 ppm (3H, t, J=13 Hz); ir (neat) νmax : 2243 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I)=[CH:14][CH:13]=3)[CH:10]([CH2:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1.[CH3:37][NH:38][CH2:39][CH:40]([OH:49])[CH:41]([OH:48])[CH:42]([OH:47])[CH:43]([OH:46])[CH2:44][OH:45]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:38]([CH3:37])[CH2:39][CH:40]([OH:49])[CH:41]([OH:48])[CH:42]([OH:47])[CH:43]([OH:46])[CH2:44][OH:45])=[CH:14][CH:13]=3)[CH:10]([CH2:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
170 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(5-iodopentyloxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 220 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C36H46F2N2O8 (672) MS (ESI): M+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.S(Cl)([Cl:41])(=O)=O>C(Cl)Cl>[Cl:41][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3Cl)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a stirred mixture of (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (282 mg, 0.7 mmol) from Example 162, DIEA (247 μL, 1.4 mmol), and CH2Cl2 (15 mL) at 0° C. under argon was added sulfuryl chloride (142 mg, 2.0 mmol). The mixture was warmed to rt and stirred for 15 h, and then stirred at 60° C. for 15 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase. The product was further purified by triturating in CH2Cl2 (5 mL) to afford N-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine (29 mg, 10%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.24 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63-1.75 (m, 3H), 1.29-1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:38]([C:35]1[CH:36]=[C:37]3[C:32]([CH:31]=[CH:30][NH:29]3)=[CH:33][CH:34]=1)=[O:39])=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc3cc[nH]c3c2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[(1H-Indole-6-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-di-hydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 1H-indole-6-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.35 (br. s., 1H) 8.90 (d, J=8.15 Hz, 1H) 8.36 (br. s., 1H) 7.96 (d, J=8.15 Hz, 1H) 7.89 (s, 1H) 7.37-7.59 (m, 8 H) 6.46 (br. s., 1H) 4.47 (d, J=4.83 Hz, 2H) 3.37 (s, 3H) MS calcd. for C27H19F3N4O4 [(M+H)+] 521.1 obsd. 521.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].[H-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>O1CCCC1.C(Cl)Cl>[Cl:17][C:15]([O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11])=[O:16]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cl)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dichloro-4-nitrophenol (5.0 g, 24.0 mmol) in 10 ml of tetrahydrofuran is added dropwise to a suspension of sodium hydride (1.33 g, 50% NaH, 27.6 mmol) in 20 ml of THF. After the addition, stirring is continued for 1 hour at RT and is the mixture is then added dropwise to a solution of phosgene (14.0 g) in 50 ml of methylene chloride at -10°. The mixture is allowed to warm to RT and is purged with N2 to remove excess phosgene. The solvent is stripped and the residue is taken into methylene chloride. The precipitated sodium chloride is filtered and the filtrate is concentrated to give 2,6-dichloro-4-nitrophenyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+].[C:13](O)(=O)[CH3:14].O>C(#N)C>[CH2:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCNc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture composed of 4-aminobenzoic acid (30 g), sodium borohydride (32.3 g) and acetic acid (550 cc) is left stirring for 26 hours at 25° C. The reaction mixture is then concentrated to dryness at 70° C. under reduced pressure (4 kPa). The product obtained is treated with distilled water (2000 cc) and the precipitate formed is separated by filtration, washed with distilled water (20 cc) and dried in the air. The product obtained is dissolved in boiling acetonitrile (250 cc). After 2 hours' cooling at 25° C., the crystallized solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 4-Ethylaminobenzoic acid (18 g), m.p. 174° C., is obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][CH:40]4[CH2:42][CH2:41]4)=[O:38])=[CH:32][C:31]=3[F:43])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=O)C.[Li+].[OH-]>C1COCC1.O>[CH:40]1([NH:39][C:37](=[O:38])[NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:21]=[C:20]([C:17]5[N:18]([CH3:19])[C:14]([CH2:13][N:8]([CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:7])[CH2:5][OH:4])=[CH:15][N:16]=5)[S:28][C:27]=34)=[C:31]([F:43])[CH:32]=2)[CH2:41][CH2:42]1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of 208 (104 mg, 0.170 mmol) in THF (18 mL) was added a solution of LiOH (32.6 mg, 1.362 mmol) in water (6 mL) and the mixture was stirred for 2 hr at room temperature before concentration. The residue was purified by Biotage (MeOH/DCM, 0-20%, SNAP 25 g cartridge) to give title compound 209 (40 mg, 0.070 mmol, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.55 (d, 1H, J=5.3 Hz), 7.94 (s, 1H), 7.75 (dd, 1H, J1=2.3 Hz, J2=13.5 Hz), 7.41 (t, 1H, J=9.0 Hz), 7.24-7.22 (m, 1H), 7.09 (s, 1H), 6.70 (d, 1H, J=5.5 Hz), 6.60 (m, 1H), 4.74 (s, 2H), 4.68-4.66 (m, 1H), 4.24 (d, J=5.7 Hz), 3.87 (s, 3H), 3.45 (m, 2H), 3.35 (s, 3H), 3.28 (m, 2H), 2.60-2.57 (m, 1H), 0.71-0.67 (m, 2H), 0.48-0.45 (m, 2H). MS: 569.6 (MH)+
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.) in a 1 N aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystalized from ethanol to give colorless needles of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.1 g.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:14][C:15]1[N:16]([CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[NH3:30]>CO>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[CH2:20][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH2:14][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[CH2:4][C:3]([NH2:30])=[O:2]
Reactant: N
Reactant: COC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: CO
Product: NC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
[[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-acetic acid methyl ester (7e) (81 mg, 0.19 mmol) was dissolved in a 7N solution of NH3 in MeOH (10 mL). The solution was heated at 100° C. with stirring in a sealed tube reaction vessel for 18 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH in CH2Cl2) to provide the desired product 7f (40 mg, 51%): ESI MS m/z 421 [C20H19Cl2FN4O+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC(Cl)=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CC(N)CN1C
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of equal molar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0°-5° C.) was treated dropwise with a slight excess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, the organic phase separated and concentrated to give the product which melted at 169°-171° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30]C(C5C=CC=CC=5)[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:38]1(CO)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:6]1([CH2:1][O:7][C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:12]([C:8]([O:9][CH:38]5[CH2:39][CH2:40][CH2:41][CH2:42]5)=[O:7])[CH2:28][CH2:27]4)=[N:22][CH:21]=3)=[O:18])=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(OC2CCCCC2)nc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCN(C(=O)OC3CCCC3)CC2)nc1)c1oc(OCC2CCCC2)nc1C(F)(F)F

Procedure:
Compound 287 was prepared by the general procedure for compound 284, by using intermediates A-41 and cyclopentanemethanol as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, 1H, J=2.4 Hz), 8.07 (dd, 1H, J=9.2, 2.5 Hz), 7.23 (br s, 1H), 6.68 (d, 1H, J=9.1 Hz), 5.17 (m, 1H), 4.45 (d, 2H, J=9.1 Hz), 3.64-3.52 (m, 8H), 2.45 (m, 1H), 1.92-1.84 (m, 4H), 1.80-1.56 (m, 10H), 1.42-1.32 (m, 2H); LCMS (ESI) Rt=4.13 min, calcd for [M+1]+ 552.2. found 552.3.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH:3]=[O:4].[C:8]([Si](C)(C)C)([F:11])([F:10])[F:9]>>[F:9][C:8]([F:11])([F:10])[C@@H:3]([CH:2]1[CH2:5][CH2:6][CH2:7][NH:1]1)[OH:4]
Reactant: O=C[C@H]1CCCN1
Reactant: C[Si](C)(C)C(F)(F)F
Product: O[C@H](C1CCCN1)C(F)(F)F

Procedure:
Compounds of Structures 2 and 4 are prepared from D-proline or D-pyroglutamic acid. For example, (R)-2,2,2-trifluoro-1-(pyrrolidin-2-yl)ethanol (Compound 2, Scheme I, R3=hydrogen) is prepared by oxidation of D-prolinol (Compound 4, Scheme I, R3=hydrogen) to afford D-prolinaldehyde (see e.g., Smith et al., March's Advanced Organic Chemistry, 6th ed., Wiley, N.J., 2007, p. 1715-1728). The resulting D-prolinaldehyde is reacted with CF3-TMS (trimethyl(trifluoromethyl)-silane) to afford the (R)-2,2,2-trifluoro-1-(pyrrolidin-2-yl)ethanol (see e.g., Prakash et al., J. Am. Chem. Soc. 111: 393, 1989).