Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]([CH3:40])([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH3:38])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 100 °C
Reaction time: 22 h
Yield: 55.6 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (762.6 mg, 1.62 mmol), 2-methyl-2-morpholino-propanal (508.54 mg, 3.23 mmol), piperidine (0.08 mL, 0.81 mmol) and ethanol (6 mL). The tube was sealed and heated at 100° C. After 22 hrs, the reaction was cooled and evaporated. The residue was purified by Isolera (column size 100 g, 3%-7% MeOH/EtOAc) to obtain 550 mg (56% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:14])[C:8](I)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]=1[C:9]1[O:10][C:11]2[C:6]([C:7](=[O:14])[CH:8]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: COc1ccc2c(=O)c(I)coc2c1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)cc(-c3nc4ccccc4[nH]3)oc2c1
Temperature: 0 °C
Yield: 68.6 %

Procedure:
A mixture of 7-methoxy-3-iodochromone (151 mg) prepared in Example 21, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (100.2 mg; yield=68.2%) as white needle crystals. Melting point: 201°-203° C. 1H-NMR(CDCl3, δ ppm): 3.97 (s, 3H, CH3O), 6.52 (br, 1H, H3), 8.17 (d, 1H, H5'), 7.06 (d, 1H, H6), 6.99 (s, 1H, H8), 8.44 (s, 1H, H2'), 7.85 (d, 1H, H4'), 7.46 (m, H5'), 7.46 (m, 1H, H6'), 7.90 (d ,1H, H7').
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:36][CH2:35]OCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[N:12]1[CH:36]=[CH:35][CH:9]=[CH:10][C:11]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Yield: 93 %

Procedure:
In 40 ml of o-dichlorobenzene as solvent, 3.94 g of carbazole, 7.26 g of 2-iondopyridine, 13.10 g of potassium carbonate, 3 g of copper powder, and 0.62 g of 18-crown-6-ether were mixed and refluxed under a nitrogen atmosphere for 10 hours. Thereafter, copper and inorganic salts were removed, and the mixture was purified by column chromatography. Consequently, ligand Hpcz (9-(2-pyridyl)carbazole) was obtained (opal powder, the yield: 93%). The following is the synthesis scheme (b-1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)OCc2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in N,N-dimethylformamide (700 mL) with brisk mechanical stirring was added potassium carbonate (150 g, 1.08 mol) and the reaction was stirred for 10 min before the portionwise addition of benzyl bromide (95 mL, 0.80 mol). The reaction was stirred at room temperature overnight, then the solids were filtered off and washed thoroughly with ethyl acetate, and the solvent was removed under vacuum. The filter cake was dissolved in water and extracted with ethyl acetate. The residue after evaporation of N,N-dimethylformamide was combined with the ethyl acetate extracts (total volume 2 L of ethyl acetate) and the combined organic extracts washed with brine (5×500 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was refluxed with 1:1 diethyl ether:hexane for 30 min then the solids filtered off (warm), washed with diethyl ether:hexane (1:1), and dried. This solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material) and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; 1H NMR (DMSO-d6): δ 8.50 (1 H), 7.82 (1 H), 7.34-7.29 (5 H), 6.84 (2 H), 6.43 (1 H), 5.23 (2 H); m/z 229.4 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[C@H:3]([C:16]([OH:18])=O)[CH2:2]1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[CH3:45]>C(Cl)Cl.C(N(CC)CC)C>[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:49][C:16](=[O:18])[C@@H:3]1[CH2:2][CH2:1][CH2:5][N:4]1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:45]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of Z-L-proline (12.7 g, 0.051M) in CH2Cl2 (200 ml) cooled to 0° was added 1-hydroxy benzotriazole (7.0 g) followed by a solution of DCC (10.6 g) in CH2Cl2 (50 ml). After 30 min. at 0° L-leucine ethyl ester (10.0 g, 0.051 molM) was added followed by triethylamine (15 ml) and the reaction mixture was then left to stir and warm up to room temperature overnight. The reaction mixture was then filtered and washed in turn with saturated aq. NaHCO3 (250 ml×3), H2O (250 ml), dilute aq. HCl (1M, 250 ml×3) and water (250 ml×2). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to an oil which subsequently crystallised. Recrystallisation from ethyl acetate/hexane gave N-(benzyloxycarbonyl)-L-prolyl-L-leucine ethyl ester as a white crystalline solid, 15.5 g, (78%); m.p. 67°-68°; (Found: C,64.55; H,7.79; N,7.22. C21H30N2O5 requires C,64.61; H,7.74; N,7.17%); νmax (CHCl3) 1740 and 1680 cm-1 ; δ(CDCl3) 0.7-0.95 (6H,m,CH(CH3)2); 1.18 (3H,m,OCH2CH3); 1.3-1.95 and 2.05-2.25 (7H,m,CH2CH2, CH2CH(CH3)2); 3.4 (2H,m,CH2N); 4.05 (2H,m,OCH2CH3); 4.25 (2H,m,α--CH); 4.98 and 5.05 (together 2H, respectively q,J=7 Hz, and m, CH2C6H5); 7.35 (5H, broad s, C6H5) and 8.26 (1H,m,CONH); m/e 391 (100%, [m+1]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22](=O)[O:23]C2C=CC=CC=2)[CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=2)=[O:23])[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 164.9 %

Procedure:
To a stirred solution of 3-methyl-4-nitroaniline (566 mg, 3.7 mmol) in THF (10 mL) was added phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.0 g, 3.7 mmol), DIEA (972 mL, 5.6 mmol), and DMAP (50 mg, 0.41 mmol). The resulting mixture was refluxed for 60 h. The reaction mixture was then cooled to rt, partitioned between EtOAc (50 mL) and 3N HCl (15 mL). The organic layer was washed with sat. NaHCO3 (15 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford crude 1-(5-tert-butylisoxazol-3-yl)-3-(3-methyl-4-nitrophenyl)urea (2.0 g, 6.1 mmol). LC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14](CS(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31]>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:27])([CH3:28])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:31]=[CH:30][S:32]([CH3:35])(=[O:34])=[O:33])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=CS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C

Procedure:
{2-[7-(2-Methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and methyl vinyl sulfone as described for the preparation of Amine 23 (98%). FDMS m/e=392.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: OCCCNc1cccc(Br)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(NCCCOC2CCCCO2)n1
Reaction time: 15 h

Procedure:
A solution of 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol (4.2 g, 18 mmol), 3,4-dihydro-2H-pyran (1.6 mL, 18 mmol), TsOH (0.34 g, 1.8 mmol) and CH2Cl2 (100 mL) were stirred at RT. After 15 h, the reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a pale-yellow oil. MS m/z: 316.0 (M+H). Calc'd for C13H19BrN2O2 315.21.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:18])=[CH:5][C:6](=[O:17])[C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH3:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([O:17][CH2:19][CH2:20][CH3:21])[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: CCCBr
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(C)nc(C)c1C(=O)Nc1ccccc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 75.3 %

Procedure:
A mixture of 2.42 (10 m mol) of 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-3-pyridinecarboxamide, 1.84 g (15 m mol) of n-propyl bromide, 1.52 g (11 m mol) of potassium carbonate and 40 ml of N,N-dimethylformamide was stirred for 7 hours at 90° C. (bath temperature). About 100 ml of water was added to the reaction mixture. The mixture was cooled to room temperature to precipitate crystals. The crystals were filtered off, washed and dried under reduced pressure to obtain 2.14 g of 2,6-dimethyl-N-phenyl-4-propoxy-3-pyridinecarboxamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][C:19](OCC)=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][C:19]([NH2:27])=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Reactant: N
Solvent: CO
Product: NC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (Example 51, product from Step D, 200 mg, 0.54 mmol) was dissolved in a 7 N solution of ammonia in methanol (10 mL) and stirred at room temperature for 2 weeks. The resulting precipitate was collected by filtration, washed with methanol (3 mL) and was dried under vacuum to give the title compound as a white solid (111 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.53-7.33 (m, 5H), 7.06 (d, J=8.3 Hz, 1H), 6.85 (br s, 1H), 6.57 (dd, J=2.4, 8.3 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 5.05 (s, 2H), 2.93-2.70 (m, 2H), 2.71-2.54 (m, 2H), 2.11 (dd, J=8.5, 15.2 Hz, 1H). [M+H]=345.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.O.[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(N(CC)CC)C>[CH:8]1([NH:14][C:15]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ncc[nH]1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nccn1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a 8 to 12° C. solution of 9.8 g. (0.12 mol.) of 2-methylimidazole in 100 ml. of water there are added 12.5 g. (0.1 mol.) of cyclohexylisocyanate, followed by 0.5 g. of triethylamine. Upon the addition of the triethylamine catalyst the reaction immediately sets in, and a precipitate start to separate. The reaction mixture is stirred at room temperature for 3 hours. Thereafter the separated product is filtered off, washed and dried. 16.4 g. (80.0%) of 1-cyclohexylcarbamoyl-2-methylimidazole are obtained; m.p.: 100°-102° C.
Reaction SMILES: C(CC[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)(O)=O.[C:24]([CH2:27]CCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)([OH:26])=[O:25]>>[C:24]([CH2:27][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([OH:26])=[O:25]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CCCC(=O)O)cc2)s1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CCC(=O)O)cc2)s1
Product: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CC(=O)O)cc2)s1

Procedure:
In a similar manner 5-[4-(2-carboxyethyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 195°-197° C.) and 5-[4-(3-carboxypropyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 124°-126° C.) were synthesized.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:37][O:38]CC[Si](C)(C)C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].B(F)(F)F>C(Cl)Cl>[CH2:1]([C@@:4]1([CH2:37][OH:38])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Agent: FB(F)F
Solvent: ClCCl
Product: C=CC[C@@]1(CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Yield: 98.2 %

Procedure:
A solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 414, Step D, 1.85 g, 2.72 mmol) in DCM was treated with boron trifluoride (diethyl etherate, purified, redistilled, 0.672 ml, 5.44 mmol) for 2 hours. The reaction mixture was diluted with DCM and washed with satd NaCl. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography on a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the intermediate N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (1.55 g, 2.67 mmol, 98% yield) as an oil which was used directly in the next reaction.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([CH3:26])=[CH:8][C:9]1[S:10][C:11]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:13]=1)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([C:11]2[S:10][C:9](/[CH:8]=[C:7](\[CH3:26])/[C:6]([OH:27])=[O:5])=[CH:13][CH:12]=2)=[O:15])=[CH:18][CH:19]=1)(=[NH:24])[NH2:25]
Reactant: CC(=Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1)C(=O)O
Reaction time: 0.5 h

Procedure:
To 3-[5-(4-amidinophenoxycarbonyl)thiophen-2-yl]-2-methylpropenoic acid tert-butyl ester (0.63 g) was added trifluoroacetic acid (5 mL), and the mixture was stirred for 30 minutes. The solvent was evaporated to give the title compound (0.62 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Temperature: 100 °C
Yield: 102.4 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (260.6 g, 2.0 mol), toluene (300 g) and 1-bromo-5-chloropentane [V-1] (311.0 g, 1.68 mol) is heated to 80°-90° C. Thereto is added anhydrous potassium carbonate (300 g), and the temperature thereof is raised to 100° C. The mixture is reacted at the same temperature for 18 hours. After completion of the reaction, the mixture is filtered, and the toluene layer is washed with water, and concentrated under reduced pressure to give crude ethyl 7-chloro-2-(1-oxo-ethyl)-heptanoate [II-1] (403.8 g, content; 68.8 %, yield; 69.1 %).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([C:27]4[CH:28]=[C:29]([NH:33]C(=O)C(F)(F)F)[CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:33][C:29]1[CH:28]=[C:27]([C:19]2[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:6]=4)[N:17]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Reactant: C1CCNC1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Temperature: 50 °C
Yield: 74 %

Procedure:
N-(3-{3-[2-({3-[(2-Chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide (0.5 g, 0.85 mmol) was dissolved in pyrrolidine and heated to 50° C. for 18 h. Upon completion the reaction was then cooled and absorbed directly onto silica gel. Purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH afforded the desired product as a yellow solid, 310 mg, 74% yield. ES-LC/MS m/z 492 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH:20]1[CH2:19][CH:18]([C:13]2[C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:21]1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 3-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)azetidine-1-carboxylate (5.19 g, 13.43 mmol) and DCM (20 mL) was added 2,2,2-trifluoroacetic acid (7.24 mL, 94 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo. DCM was added and evaporated to remove extra TFA. Ether was added and evaporated. The product was obtained as a yellow oil after drying on vacuum overnight. MS: 287 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]([C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35])=[C:30]=[O:31]>C(Cl)Cl>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=1[NH:29][C:30]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:31]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.3 mg, 0.166 mmol) and methyl 2-isocyanatobenzoate (Aldrich, 150.7 mg, 0.851 mmol) in CH2Cl2 (9 mL) was stirred at rt for 18 hrs. The reaction mixture was then concentrated and purified by flash column to give rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (67.9 mg, 68.1%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+Na [(M+Na): 622.1446; Found: 622.1449.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:2]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:25])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Product: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 18 g of mannose and 19 g of dodecylamine.