Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH2:12][C:13]#[N:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][NH2:14])([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(CC#N)(NC(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)N1CCC(CCN)(NC(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of 5 g (16.06 mmol) of 4-tert-butoxycarbonylamino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester in 107 ml of methanol was added 4.71 g of Raney Nickel catalyst. The suspension was hydrogenated under 55 psi pressure at room temperature during 3 h.
Reaction SMILES: [C:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[Cl:13])#[N:2].Cl.[NH2:15]C(C)(CC)C#C.[OH-].[Na+]>O>[C:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([NH2:15])=[O:8])=[CH:5][C:4]=1[Cl:13])#[N:2]
Reactant: N#Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Reactant: C#CC(C)(N)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c(Cl)cc(C(N)=O)cc1Cl
Temperature: 25 °C

Procedure:
To a well stirred mixture of 4-cyano-3,5-dichlorobenzoyl chloride (4.0 g, 0.017 mol) and water (100 ml) at 0° C. (ice-water bath) were added 3-amino-3-methyl-1-pentyne hydrochloride and 50 weight percent aqueous sodium hydroxide (10 ml). The resulting mixture was stirred 1 hour at 0° C., warmed up to room temperature and extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water (3×50 ml), and then dried over anhydrous sodium sulfate. The solvent was then eliminated in the rotavap, yielding the crude product as a yellow oil (2.79 g). The crude product was purified by Michel-Miller chromatographic column packed with Merck (grade 60) silica gel using ethyl acetate as solvent, yielding 0.75 g of N-[3'-methyl-1'-pentynyl)]-4-cyano-3,5-dichlorobenzamide.
Reaction SMILES: N(CCO)(CCO)CCO.Cl.[CH:12]([NH2:15])([CH3:14])[CH3:13].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[CH2:32]([CH:39]1[CH2:43][O:42][C:41](=[O:44])[N:40]1[C:45]([C@@H:47]1[CH2:52]CC(=O)C[C@H:48]1[C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CS(C)=O>[NH2:15][C@@H:12]1[CH2:14][CH2:52][C@@H:47]([C:45]([N:40]2[C@H:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:43][O:42][C:41]2=[O:44])=[O:46])[C@H:48]([C:54]2[CH:55]=[CH:56][C:57]([Br:60])=[CH:58][CH:59]=2)[CH2:13]1
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OCC2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Reactant: CC(C)N
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: Cl
Solvent: OCCN(CCO)CCO
Solvent: CS(C)=O
Product: N[C@@H]1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of aqueous triethanolamine (684 mL, 100 mM) was added isopropylamine hydrochloride (102.6 g), pyridoxal phosphate (Vitamin B6; 1.14 g), and the enzyme ATA24 (22.8 g) [ATA-024 is also known as CDX-010 and purchased from Codexis, Inc., Redwood City, Calif., USA.] The mixture was treated with DMSO (228 mL) and heated to 45° C. using a Multimax (Mettler Toledo). The pH was adjusted to 8.6 when 4-benzyl-3-{[(1R,2R)-2-(4-bromophenyl)-4-oxocyclohexyl]carbonyl}-1,3-oxazolidin-2-one (5.7 g, 12.49 mmol) was added as a solution in DMSO (228 mL) by syringe pump over 3 h. An additional amount of the enzyme ATA24 (2 g) was added in 10 mL of buffer and allowed to react for approximately 4 h. An additional amount of the enzyme ATA24 (3 g) was added in 30 mL of buffer and the reaction aged overnight. The reaction was treated with aq. 6 N HCl to lower the pH to 2, and then aged for about 30 min. The reaction was then filtered and the enzyme precipitate was rinsed with 250 mL of 10% DMSO/pH 2.5 H2O (3×). The filtrate was extracted with MTBE (1 L), and the aqueous layer was separated, brought to pH 9.5 and subsequently extracted with MTBE (1 L). The organic layer was separated, washed with pH 11 brine (2×250 mL), dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]#[C:24][CH2:25][OH:26])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(C#CCO)c3c2CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(CCCO)c3c2CC1
Reaction time: 3.5 h
Yield: 88.7 %

Procedure:
A mixture of 3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-propyn-1-ol (4.715 g, 13.69 mmol) and 10% Pd/C (0.548 g) in ethanol (75 mL) was hydrogenated under 35 p.s.i. H2 for 3.5 h. The mixture was filtered through celite, rinsed both ethanol, dichloromethane and evaporated. Crystallization from ethyl acetate/hexanes provided 4.230 g of the title compound (mp 144-147° C.). 1H NMR (CDCl3) δ 8.20-8.55, 7.30-7.50, 7.05-7.15, 6.95-7.05, 6.75-6.90, 3.90-4.10, 3.55-3.80, 3.35-3.45, 2.90-3.20, 2.80-2.90, 1.75-2.00.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])#[C-:11]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C@@H:6]2[O:7][CH:11]=[N:10][C@H:12]2[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: [C-]#[N+]CC(=O)N1CCCCC1
Reactant: O=Cc1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
SLA 09052B was prepared in accordance with method D using thiophene-3-carbaldehyde (0.778 mL, 5.43 mmol), KOH (0.273 mg, 4.94 mmol) in methanol (5 mL) and 2-isocyano-1-(piperidin-1-yl)ethanone SLA 07116B (0.75 g, 4.94 mmol). The solution was stirred for 2 h at 0° C. After work-up (without any further purification) and drying trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(piperidin-1-yl)methanone SLA 09052B was obtained as a yellow oil (1.29 g, 99% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1

Procedure:
A mixture of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)n1cc(C#N)c(=O)c2c(Cl)cccc21
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCC(CCC)n1cc(C#N)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Yield: 48.3 %

Procedure:
5-Choro-4-oxo-1-(1-propylbutyl)-1,4-dihydroquinoline-3-carbonitrile (0.015 g, 0.05 mmol), 2,4-dimethylbenzeneboronic acid (0.012 g, 0.079 mmol), and PdCl2(PPh3)2 (0.010 g, 0.015 mmol) were suspended in toluene (1 mL). K3PO4 (0.074 mL, 0.15 mmol, 2M in water) was added last. The reaction was stirred at 90° C. with stirring overnight. The mixture was cooled, filtered through GF/F paper and concentrated. Flash chromatography (40% Ethyl acetate/hexanes) gave the desired product (0.009 g, 50%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][C:57]([C:60](O)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[CH:58]=[CH:59][O:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(O)c1ccon1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccon2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-3-carboxylic acid as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (m, 2H), 8.30 (m, 2H), 8.20 (s, 1H), 7.64 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.80 (s, 1H), 4.52 (m, 1H), 3.83 (m, 1H), 3.18 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH:20]=[CH:19][C:18]4C(OC(=O)[C:16]5[C:17]=4[C:12]=3[C:13](=[CH:14][CH:15]=5)[C:8]3[C:9]=2[C:4]2[C:5]([C:26](O[C:29](=[O:30])[C:3]=2[CH:2]=1)=[O:27])=[CH:6][CH:7]=3)=O.N1C=CN=C1.[NH2:36][CH:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O.C(C1C=CC(C(C)(C)C)=CC=1N1C(=O)C2C3C4C(=CC=2)C2C5C(C=CC=2)=CC=CC=5C=4C=CC=3C1=O)(C)(C)C>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:38]([CH:37]([N:36]1[C:26](=[O:27])[C:5]2[C:4]3[C:9]4[C:8](=[CH:7][CH:6]=2)[C:13]2[C:12]5[C:17]([CH:16]=[CH:15][CH:14]=2)=[CH:18][CH:19]=[CH:20][C:11]=5[C:10]=4[CH:1]=[CH:2][C:3]=3[C:29]1=[O:30])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Reactant: CCCCCCC(N)CCCCCC
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6cccc(c7ccc(c3c47)C2=O)c65)c1
Agent: [Zn+2]
Solvent: O
Product: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54

Procedure:
1.2 g (3.1 mmol) of perylene-3,4,9, 10-tetracarboxylic dianhydride, 6.2 g of imidazole, 470 mg (2.36 mmol) of 7-aminotridecane (prepared according to J. Prakt. Chem. 1980, 322, 261), 150 mg (0.68 mmol) of zinc acetate dihydrate and 3.0 ml (170 mmol) of water are heated in an autoclave (100 ml) at 190° C. for 24 h. Workup is analogous to that used in the preparation of 2b. Yield 1.25 g (27%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([CH3:10])[NH:7][C:8]=1[Br:9].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>>[Br:3][C:4]1[N:5]=[C:6]([CH3:10])[N:7]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:8]=1[Br:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A 901 mg portion of 60% sodium hydride was added little by little to ice-cold N,N-dimethylformamide (50 ml) containing 4.91 g of 4,5-dibromo-2-methylimidazole. The reaction mixture was stirred at room temperature for 1 hour. 2-(Trimethysilyl)ethoxymethyl chloride (3.75 g) was added dropwise to the mixture on ice, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was washed subsequently with a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent, hexane:ethyl acetate=3:1) to obtain 7.6 g of colorless oily material of 4,5-dibromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[C:14]([S@@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]/[S:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To the mixture of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (6.0 kg, 23.7 mol) and (S)-(−)-tert-butanesulfinamide (3.3 kg, 27.2 mol) were added toluene (73 L) with stirring at ambient temperature. After 5 min, titanium ethoxide (6.5 kg, 28.5 mol) was added and the mixture was heated to 50˜55° C. The mixture was stirred at 50˜55° C. for 3 h and allowed to cool to ambient temperature before concentration in vacuo. The resulting crude product was used directly in next chemical transformation without further purification. ESIMS: 356 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:47]([C:44]3[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=3)(=[O:49])=[O:48])[CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (536, 291 mg, 0.85 mmol) in tetrahydrofuran (7 mL) was added 1.5 M of lithium diisopropylamide in cyclohexane (676 μl , 1.59 mmol) at −78° C. under an atmosphere of nitrogen. After 30 minutes, p-toluenesulfonyl chloride (209 mg, 1.10 mmol) was added in tetrahydrofuran and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the compound (537, 182 mg, 43%). MS (ESI) [M+H+]+=499.2.
Reaction SMILES: N[C@@H](CC1C=CC(OCCCC)=CC=1)C(OC)=O.N[C@@H](CC1C=CC(OCC#CC)=CC=1)C(OC)=O.[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:71]=[CH:72]/[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][S:79]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])(=O)=O)[C@@:58]([OH:70])([CH2:66][CH2:67][O:68][CH3:69])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:56])[C:50]([O:52][CH3:53])=[O:51])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40].C(OC1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCS(CCCCCCC)(=O)=O)[C@@](O)(CCOC)C(O)=O)=O)C(OC)=O)=CC=1)CCC>>[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:71]=[CH:72]/[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][S:79][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[C@@:58]([OH:70])([CH2:66][CH2:67][O:68][CH3:69])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:56])[C:50]([O:52][CH3:53])=[O:51])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Agent: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Product: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (ESI (LC/MS positive mode) m/z 722 (M+H); Rt 3.13 min.) was synthesized by using methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate and conditions at 50° C., for 2.5 days instead of methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate and the conditions in Step C-6. Then, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate was first synthesized (ESI (LC/MS positive mode) m/z 754 (M+H); Rt 2.32 min) under conditions similar to those in Step C-7. Subsequently, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoic acid (No. 5514406) was synthesized by the reaction under conditions similar to those in Step C-8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(C1C2N(CC(O)=[O:29])C=NC=2C=CC=1)#N>>[C:13]([C:9]1[C:8]2[N:4]([CH2:3][C:2]([OH:29])=[O:1])[CH:5]=[N:6][C:7]=2[CH:12]=[CH:11][CH:10]=1)(=[O:15])[CH3:14]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(=O)c1cccc2ncn(CCO)c12
Product: CC(=O)c1cccc2ncn(CC(=O)O)c12
Yield: 75 %

Procedure:
1-[1-(2-Hydroxyethyl)-1H-benzimidazol-7-yl]ethanone (0.30 g, 1.47 mmol) is oxidized to the desired acid according to the procedure described for the synthesis of (7-Cyano-1H-benzimidazol-1-yl)acetic acid (step f, intermediate 14) to give the desired product (0.24 g, 75%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:16][C:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[C:8]([F:12])[C:7]=1[F:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)c(F)cc(F)c1F
Product: O=C(Cl)c1c(F)c(F)cc(F)c1F

Procedure:
A mixture of 2,3,5,6-tetrafluorobenzoic acid (25 g) and thionyl chloride (40 cm3) was heated at the reflux temperature for 3 hours after which the excess thionyl chloride was removed by evaporation under reduced pressure to leave a residue of 1-chlorocarbonyl-2,3,5,6-tetrafluorobenzene. To this was added an excess of dry methanol and the mixture stirred for one hour at the ambient temperature. Removal of excess methanol by evaporation under reduced pressure gave methyl 2,3,5,6-tetrafluorobenzoate (19 g) as a mobile liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH:24](C)[CH2:25][CH2:26][OH:27]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(N)CCO
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 7-bromo-4-chloro-3-nitroquinoline (10.00 g, 34.78 mmol) in dichloromethane (140 mL) was added triethylamine (10.2 mL, 73.1 mmol). The solution was cooled to 0° C., and 3-amino-1-butanol (2.80 mL, 36.5 mmol) was added. The solution was stirred overnight at ambient temperature and then filtered to collect a precipitate. The precipitate was washed with dichloromethane and water. The filtrate was washed with saturated aqueous sodium bicarbonate and then added to the precipitate. The mixture was concentrated under reduced pressure. Methanol and toluene were added several times and removed under reduced pressure. The resulting solid was dried under high vacuum to provide 11.34 g of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: Cl[C:2](Cl)([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH-].[Na+].[Na].C([O-])(O)=[O:22].[Na+].C(=O)=O.Cl>O>[OH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([C:2](=[O:22])[C:3]([OH:5])=[O:4])([CH2:13]3)[CH2:7]1)[CH2:9]2
Reactant: O=C(O)C(Cl)(Cl)C12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 80 °C

Procedure:
A 500 ml three-necked flask was charged with dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid (Formula IX) (38.67 g, 138.5 mmol). To this material was added water (160 ml) and 1 N NaOH (138 ml, 138 mmol; 1 N NaOH was used to generate the sodium salt of dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid to avoid foaming problems which would occur with solid NaHCO3) to give a hazy solution. To this solution was added solid NaHCO3 (29.10 grams, 346 mmol, 2.50 equivalents). After the NaHCO3 was added the reaction mixture became a suspension as the sodium salt of dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid was forced from solution. The reaction vessel was fitted with a reflux condenser/argon inlet and heated to approximately 80° C. After heating for approximately 6 hours the mixture was allowed to cool to room temperature. The reaction mixture (pH 7.22) was carefully acidified (CO2 evolution) to pH 0.15 by the addition of concentrated HCl (32 ml required). The resulting mixture was extracted with ethyl acetate (4×300 ml). The aqueous layer (pH 0.37) after the first extraction with ethyl acetate was lowered to pH 0.18 by the addition of concentrated HCl (approximately 2 ml). The ethyl acetate fractions were combined and washed with brine (100 ml). After drying over anhydrous magnesium sulfate, the solvent was removed at reduced pressure to give 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula II) as a colorless granular solid: 30.77 gram (99%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:12])[CH:6]=1>O1CCCC1>[OH:12][CH:11]([C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)[CH2:1][CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cccnc1
Yield: 67 %

Procedure:
According to Reference Example 8-1, by use of ethylmagnesium bromide (a 1.0 mol/L solution in tetrahydrofuran, 3.18 mL, 3.18 mmol), 3-pyridinecarboxaldehyde (200 μL, 2.12 mmol) and tetrahydrofuran (2.0 mL), the mixture was stirred and reacted at 0° C. for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 3-(1-hydroxypropyl)pyridine (Compound CC) (194 mg, yield: 67%).