Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][N:27]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:26]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 97 %

Procedure:
In the presence of triethylamine, 59 g of benzoyl chloride was reacted at room temperature with 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine in methylene chloride, whereby 120 g of trans-3-tert-butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained. Hydrochloric acid was then reacted at room temperature with 123 g of the compound (a) in ethanol, so that 83 g of trans-3-amino-4-methyl-1-benzoylpyrrolidine (b) was obtained. In methylene chloride, 68.4 g of (R)-(-)mandelic acid was then reacted at room temperature with 83 g of the compound (b) in the presence of 87.3 g o 1-hydroxybenzotriazole, 87.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine. 34 g of trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer (A), (c) was obtained. Acetic acid and hydrochloric acid were then reacted with the compound (c) under reflux, whereby 16.8 g of (-)-trans-3-amino-4-methylpyrrolidine dihydrochloride was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].O.C(OCC)C>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
51.0 g of 4-(p-cyanophenyl)cyclohexanone were almost completely dissolved in 1.5 l of ethanol/water (vol. 4:1) and then treated within 10 minutes with 9.68 g of sodium borohydride. The mixture was stirred for a further 30 minutes and then left to stand overnight. The reaction mixture was subsequently treated cautiously with 350 ml of dilute, ice-cold hydrochloric acid (1 part of concentrated hydrochloric acid to 4 parts of water), then treated with 2 l of water and 1 l of diethyl ether and shaken. The aqueous phase was separated and extracted four times with 0.5 l of diethyl ether each time. The combined organic phases were washed with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product, which still contained water, was dried further by dissolution in toluene and acetone and concentration. The beige, solid residue (48.9 g) was dissolved in 300 ml of hot toluene and a fine, insoluble residue was filtered off while the mixture was hot. The filtrate was cooled to -20° C. and the crystallizate obtained was filtered off under suction, washed with 50 ml of toluene/hexane (vol. 9:1) and dried. There were thus obtained 31.72 g (61.6%) of pure, light beige trans-4-(p-cyanophenyl)cyclohexanol of m.p. 119.5°-122.4° C. A further 3.21 g (6.2%) of trans-4-(p-cyanophenyl)cyclohexanol of m.p. 116.5°-122.1° C. were obtained from the mother liquor by crystallization from 60 ml of toluene at -20° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:27]=[C:28]([N:30]5[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]5)[CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(NC5CCCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.2 mmol) and cyclopentylamine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A yellow solid (13 mg); Mp: 88-90° C.; 1H NMR (300 MHz, CDCl3) δ 0.98(d, J=6.6 Hz, 3H), 1.23-1.87(m, 13H), 2.77-2.85(m, 2H), 3.76(d, J=12.3 Hz, 2H), 4.08-4.15(m, 1H), 5.15(bs, 1H), 6.04(s, 1H), 6.76(d, J=12.3 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 7.26-7.30(m, 2H), 7.49-7.55(m, 2H), 7.87-7.97(m, 3H), 8.07-8.11(m, 1H), 8.20(s, 1H);
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OCC)=[NH:19])[CH3:9].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:33][NH:32][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:9]
Reactant: CCOC(=N)CCCCCCC(=O)OCC
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCC(N)=NNC(=O)c1ccccc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Add triethylamine (5.6 mL, 40 mmol) to a solution of 7-ethoxycarbonimidoylheptanoic acid ethyl ester (11.0 g, 41 mmol) and benzoic acid hydrazide (5.5 g, 40 mmol) in ethanol (110 mL) at room temperature under nitrogen and stir the mixture for 12 hours. Remove the solvent under reduced pressure, dissolve the residue in ethyl acetate (200 mL), wash with saturated NaHCO3 (200 mL) and brine (200 mL) solutions, and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 8-amino-8-(benzoylhydrazono)octanoic acid ethyl ester (8.3 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:12][C:11]([F:14])([F:13])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:31]=[C:32]([C:34]1[CH:35]=[CH:36][C:37]([CH3:52])=[C:38]([NH:40][C:41]([C:43]2[N:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]3=[N:45][CH:44]=2)=[O:42])[CH:39]=1)[NH2:33]>CN1C(=O)CCC1.C(OCC)(=O)C.O>[F:14][C:11]1([F:13])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:15]2[O:17][N:31]=[C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH3:52])=[C:38]([NH:40][C:41]([C:43]4[N:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]5=[N:45][CH:44]=4)=[O:42])[CH:39]=3)[N:33]=2)[CH2:12]1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutanecarboxylic acid (164) (45 mg, 0.18 mmol) in anhydrous NMP (1.3 mL) was added 1,1′-carbonyldiimidazole (CDI) (29 mg, 0.18 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (69 mg, 0.22 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for 15 minutes. The crude product was taken up in ethyl acetate and water. The organic was washed with 2× water/brine mixture and dried over magnesium sulfate. The solvent was concentrated and the crude product was purified using silica gel chromatography using 60% ethyl acetate/hexanes to afford tert-butyl (3,3-difluoro-1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)carbamate (165). MS m/z 525.2 (M+1)+
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:38][C:39]([F:47])([F:46])[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>N12CCCN=C1CCCCC2.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([N:43]3[CH2:44][CH2:45][CH:40]([C:39]([F:47])([F:46])[F:38])[CH2:41][CH2:42]3)=[N:20][CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(F)ccc1-c1cc(N2CCC(C(F)(F)F)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 34.1 %

Procedure:
A mixture of 150 mg (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.16 g (0.84 mmol) 4-(trifluoromethyl)piperidine hydrochloride in 2 ml 1,8-diazabicyclo[5.4.0]undec-7-ene was heated at 140° C. for 20 h. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 62 mg (34%) of the title compound as a light yellow solid.
Reaction SMILES: C(C1C2[O:10]C(C)=CC=2C(NC(=O)C(C)(C)C)=CC=1)#N.Cl.NC1C2CCCCC=2C(C#N)=CC=1.[OH:34][C@H:35]1[C@@H:42]2[N:38]([C:39](=[O:56])[N:40]([C:44]3[C:53]4[CH2:52][CH2:51][CH2:50]C[C:48]=4[C:47]([C:54]#[N:55])=[CH:46][CH:45]=3)[C:41]2=[O:43])[CH2:37][CH2:36]1>>[OH:34][C@H:35]1[C@@H:42]2[N:38]([C:39](=[O:56])[N:40]([C:44]3[C:53]4[CH:52]=[C:51]([CH3:50])[O:10][C:48]=4[C:47]([C:54]#[N:55])=[CH:46][CH:45]=3)[C:41]2=[O:43])[CH2:37][CH2:36]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: Cc1cc2c(NC(=O)C(C)(C)C)ccc(C#N)c2o1
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cc1cc2c(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc(C#N)c2o1

Procedure:
The title compound was prepared from compound 10E by procedures analogous to those described in Experiment 2 (2D to 2F). HPLC: 99% at 4.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=10.99 min (99%); Conditions: OD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min. MS (ES) m/z 312 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of acryloyl chloride (64 μL, 0.79 mmol) in CH2Cl2 (4 mL) was added dropwise over 10 minutes to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 153, 336 mg, 0.76 mmol) in CH2Cl2 (11 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat.NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (296 mg, 79%) as an orange solid after trituration with diethyl ether; 1H NMR: 1.70-1.81 (1H, m), 2.05-2.13 (1H, m), 2.18 (6H, s), 2.68-2.76 (1H, m), 3.17-3.27 (3H, m), 3.35-3.42 (1H, m), 3.84 (3H, s), 5.67 (1H, dd), 6.17 (1H, dd), 6.51 (1H, dd), 6.56 (1H, s), 7.05 (1H, dd), 7.21 (1H, d), 7.40-7.45 (1H, m), 7.84 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.46 (1H, d), 8.76 (1H, s), 8.78 (1H, d), 9.35 (1H, s); m/z: ES+ MH+ 499.69.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=1>O>[C:4]1([CH2:3][S:10][C:12]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CCCSc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCSc1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a stirred suspension of 0.62 g (0.013 mol) of 50% sodium hydride (in mineral oil), which had been washed withh hexanes, in 20 mls dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.6 g (0.013 mol) benzyl mercaptan such that the temperature was maintained below 5°. The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 2.0 g (0.012 mol) of the product from Example 1 was added dropwise while maintaining the temperature between 0° and 5°. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporatd to an oil which was purified by flash chromatography to afford 0.9 g (27%) oil: NMR (CDCl3, 200 MHz), 1.02 (3H, t J=7 Hz), 1.6 (2 H, m), 2.9 (2H, t, J=7 Hz), 4.45 (2H, s), 6.9-7.6 (7H, m), 8.3 (1H, m); IR (neat) 1560, 1370 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:42])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:42])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:22]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 90.6 %

Procedure:
To a solution of 1,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-[4-(ethyloxy)-4-oxobutyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 28; 110 mg, 0.184 mmol) in ethanol (3 ml) was added 2M aqueous sodium hydroxide (0.184 ml, 0.368 mmol) and the resulting mixture was stirred at room temperature for 100 min. More 2M aqueous sodium hydroxide (0.1 ml) was added and stirring continued at room temperature for 5.5 h. Most of the solvent was removed, and the residue partitioned between ether and water. Aqueous 2M sodium hydroxide was added to make sure the phase was basic, causing precipitation of the carboxylate. The aqueous layer was acidified with 2N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo to give the title compound (95 mg) as a white foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([F:30])=[C:22](B(O)O)[C:23]([F:26])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[C:21]([F:30])=[C:22]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[C:23]([F:26])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: OB(O)c1c(F)ccc(OCc2ccccc2)c1F
Product: COC(=O)c1cccc(-c2c(F)ccc(OCc3ccccc3)c2F)n1
Yield: 95 %

Procedure:
Method 6 was followed using methyl 6-bromopicolinate (1.0 equiv.) and 3-(benzyloxy)-2,6-difluorophenylboronic acid (2.5 equiv.) to give methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)picolinate as a light yellow solid in 95% yield. LC/MS=356.2 (M+H), Rt=1.03 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54]C)=O)=O.[NH2:56][NH2:57]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]1[NH:50][CH2:51][C:52](=[O:54])[NH:57][N:56]=1
Reactant: COC(=O)CNC(=O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: NN
Solvent: CO
Product: O=C1CNC(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)=NN1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of methyl 2-(2-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)acetamido)acetate (compound 54, 1.1 g, 1.44 mmol) in MeOH (20 ml) was added hydrazine anhydrous (2 ml) at room temperature. Then, the reaction temperature was raised to 60° C., and maintained for overnight. After reaction complete, the solution was evaporated in vacuo, and the residue was dissolved in acetic acid (10 ml) with ammonium acetate (1 g). The reaction solution was refluxed for 1 day. The resulting solution was cooled to room temperature, and then evaporated under reduced pressure. The residue was purified with column chromatography (Hx/EtOAc=1/1) to afford to title compound (826 mg, 77% overall yield) as white solid.
Reaction SMILES: [I:1]C1NC(C2(C)COC2)=NC=1C.[CH3:13][C:14]1([C:18]2[NH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[CH2:17][O:16][CH2:15]1.CC1N=C(C2(C)COC2)NC=1>>[I:1][C:20]1[NH:19][C:18]([C:14]2([CH3:13])[CH2:17][O:16][CH2:15]2)=[N:22][C:21]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1nc(C2(C)COC2)[nH]c1I
Reactant: CC1(c2nc(C(F)(F)F)c[nH]2)COC1
Agent: Cc1c[nH]c(C2(C)COC2)n1
Product: CC1(c2nc(C(F)(F)F)c(I)[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 175.2, except 2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole (compound 202.1) was used in place of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1). m/z (ES+) 333 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH2:24][C:25]([O:27]C)=[O:26])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+]>C(O)(C)C>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:24][C:25]([OH:27])=[O:26])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(-n2cccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(-n2cccc2)c1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 0.8 g (2 mmol) of the compound from Example XXX and 0.2 g (5 mmol) of sodium hydroxide in 50 ml of isopropanol.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[C:20]([CH:21]2[CH2:23][CH2:22]2)=[CH:19][N:18]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=[C:17]2[CH:16]=1)(C)(C)C>ClCCl>[CH:21]1([C:20]2[C:15]([NH2:14])=[CH:16][C:17]3[N:18]([CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:26]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of (6-cyclopropyl-2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (470 mg, 1.35 mmol) in dichloromethane (3 ml), and the mixture was stirred at r.t. (1 h). The mixture was then taken up in dichloromethane and washed. The organic layers were dried (Na2SO4) and evaporated. The title compound (204 mg, 61%) was isolated from the residue by column chromatography (silica gel, dichloromethane:methanol=100:0-90:10). MS (m/e)=250.1 [M+H+].
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:15]2[N:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.CN1CCOCC1.Cl[C:39](=[O:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCCCCC.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:15]2[N:20]=[CH:19][C:18]([CH2:21][NH:22][C:39](=[O:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a dichloromethane (4 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.0734 mmol) obtained in Example 63 were added N-methylmorpholine (10 μl, 0.0881 mmol) and ethyl chloroglyoxylate (9 μl, 0.0807 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated under reduced pressure to give the title compound (28 mg, 0.0550 mmol, 76%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.N1C=CC=CC=1.C(OC(=O)C)(=O)C>>[CH3:15][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][N:8]=1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C(C)=NCC2
Reaction time: 0.17 h

Procedure:
6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, conversion>99%, ee 82% (GC, sample derivatised by treatment with acetic anhydride pyridine, Chirasil DEX CB, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 170° C. for 20 minutes then ramp at 5° C./min to 200° C., hold for 10 minutes, retention times 30.18 minutes and 30.45 minutes).