Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][Br:5].N(C(C)(C)C#N)=N[C:9](C)(C)[C:10]#N.C=C>>[Br:5][CH:4]([CH2:9][CH3:10])[C:3]([OH:2])=[O:6].[CH3:1][O:2][C:3](=[O:6])[CH2:4][Br:5]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=C
Agent: COC(=O)CBr
Product: CCC(Br)C(=O)O
Reaction time: 0.33 h

Procedure:
136 g of methylbromacetate and 3.5 g of azo-bis-isobutyronitrile are charged at 20° C. into a rotary stainless steel autoclave of capacity 0.27 lit provided with a heating jacket and a thermocouple, after which ethylene is added with stirring until the pressure in the autoclave reaches 40 gage atm. Then, within 20 minutes, the temperature in the autoclave is brought to 100° C., and the stirring is carried on at the latter temperature until the pressure ceases to drop, which takes approximately 2 to 3 hours. The remaining ethylene is allowed to escape. The telomerizate (129 g) is subjected to fractional distillation under vacuum, the unreacted methylbromacetate (101 g) being distilled off at a temperature of 80 to 83° C. and a residual pressure of 80 mm Hg. The remaining telomer mixture (27 g) is subjected to fractional distillation in a fractionating column at a residual pressure of 10 mm Hg to yield 14g of methyl ester of γ -bromobutyric acid (35 percent in terms of the reacted methylbromacetate) having a boiling point of 75° to 78° C./10 mm Hg or 124° C./100 mm Hg. The distillation residue (9 g, or 18 percent in terms of the reacted methylbromacetate) is methyl ester of ε-bromocaproic acid having a boiling point of 116° C./12 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 330) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,5-dimethoxy-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: [CH2:1]([Cl:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Cl:7]
Reactant: C1=COCCC1
Reactant: OCCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: ClCCCCCOC1CCCCO1
Reaction time: 4.5 h
Yield: 62.5 %

Procedure:
A stirred solution of pentamethylene chlorohydrin (10.0 g, 0.0816 mol) in Et2O (165 ml) under nitrogen was treated with 3,4-dihydro-2H-pyran (10.3 g, 0.122 mol) and p-toluenesulfonic acid hydrate (0.5 g) and kept at ambient temperature for 4.5 hours. The mixture was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was distilled to give 4.06 g, bp 79°-82° C. (0.1-0.07 mm Hg) and 10.54 g, bp 82°-84° C. (0.1-0.07 mm Hg) of 5-chloropentyl 2-tetrahydropyranyl ether.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([CH2:26]OS(C)(=O)=O)=[CH:24][CH:23]=1)=[O:19]>O>[N:10]1[C:11]2[CH:2]([NH:1][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)=[O:19])=[CH:33][CH:32]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCCc2cccnc21
Reactant: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Solvent: O
Product: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using General procedure H: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with methanesulfonic acid 4-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyl ester (214 mg, 0.67 mmol) for 3 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 48:1:1) gave AMD9397 (81 mg, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.72-1.83 (m, 2H), 2 00-2.06 (m, 1H), 2.16-2.20 (m, 1H), 2.75-2.83 (m, 2H), 3.82-3.84 (m, 1H), 3.88 (d, 1H), J=13.2 Hz), 3.98 (d, 1H, J=12.9 Hz), 4.65 (d, 2H, J=6.0 Hz), 7.05-7.06 (m, 1H), 7.32-7.42 (m, 6H), 7.85 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.34 (br s, 1H), 8.37 (d, 1H, J=3.3 Hz), 8.52 (d, 1H, J=3.9 Hz). 13C NMR (75.5 MHz, CDCl3) δ 20.05, 29.00, 29.24, 43.68, 51.85, 57.85, 122.19, 122.70, 126.56, 128.37 (2C), 129.01 (2C), 132.83, 137.07, 137.23, 137.73, 140.41, 147.20, 148.46, 150.23, 157.82, 164.57. ES-MS m/z 373 (M+H). Anal. Calcd. for C23 H24N4O•0.3 H2O: C, 73.11; H, 6.56; N, 14.83. Found: C, 72.98; H, 6.58; N, 14.63.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1>C(O)(=O)C>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:20]4=[O:21])[CH2:15][CH2:14]3)=[O:12])=[CH:30][CH:31]=2)[CH:34]=[CH:38][CH:37]=[CH:36]1
Reactant: NCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(c1ccc(OCCCCn2cccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1

Procedure:
A mixture of 1-{1-[4-(4-aminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.50 g), acetic acid (10 ml) and 2,5-dimethoxytetrahydrofuran (0.17 ml) is refluxed with stirring under heating for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=100:1) to give 1-[1-{4-[4-(1-pyrrolyl)butoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (0.30 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19](Cl)=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1.[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][OH:30])[CH3:27].C(N(CC)CC)C.[K+].[Br-]>C(Cl)Cl.O.CN(C)C=O>[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19]([O:30][CH2:29][CH:28]([CH2:26][CH3:27])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)Cl)cc3C2=O)CC(C)(C)N1
Reactant: CCCCC(CC)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC(CC)COC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed 5.0 g (0.013 mol) of the acid chloride of Example 2, 1.7 g (0.013 mol) 2-ethylhexanol and 50 ml of 2% dimethylformamide in methylene chloride. This mixture was stirred during the addition of 2.8 g (0.028 mol) triethylamine in 5 ml methylene chloride. This addition produced an exotherm of about 10° C. The reaction was then refluxed for 1 hour. The mixture was cooled and transferred to a separatory funnel with 100 ml methylene chloride and 250 ml water. The ensuing emulsion was filtered, put back in the funnel and the phases separated. The organic phase was extracted with 50 ml water and 50 ml 5% sodium bicarbonate. The organic solution was dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum. Liquid chromatographic analysis of the white solid product indicated the presence of two components. The material was redissolved in methylene chloride and extracted with two 50 ml portions of 5% sodium hydroxide. The organic solution was again dried and stripped and the residue recrystallized from 80/20 ethanol/water. After isolation and drying, 1.5 g of slightly yellow product were obtained (melting 129°-131° C.). The infrared spectrum (KBr pellet) showed the carbonyl absorption at 1720 cm-1 (imide and ester). The NMR spectrum showed the anticipated aromatic ring (7.7-7.9 ppm, doublet, 1H; 8.2-8.5, multiplet, 2H) and the 2-ethylhexyl and HALS groups [4.4-4.9 ppm, multiplet, 1H; 4.2-4.3 ppm, doublet, 1H; 0.7-2.3 ppm, several multiplets including two singlets (1.2 and 1.3 ppm )].
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2>C([Sn](CCCC)(CCCC)C=C)CCC>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([C:3]([O:4][CH2:5][CH3:6])=[CH2:2])[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=C(OCC)C1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 220 mg) and tributyl(vinyl)tin (405 μL) were treated in the same manner as Reference Example 11(1) to give the titled compound (144 mg) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24].CN(C)C=O>O>[Cl:22][C:23](=[CH2:24])[CH2:25][O:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: CCCCCCNc1nc(C)cc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)COc1cc(C)nc(NCCCCCC)n1
Temperature: 25 °C

Procedure:
42.0 g 6-Hydroxy-4-methyl-2-n-hexylamino-pyrimidin (0.2 Mol), 27.6 g K2CO3 (0.2 Mol), 24.4 g 2,3-dichloro-1-propene (0.22 Mol) and 150 ml dimethylformamide are charged in a sulphonation flask. The mixture is heated for about 3 hours at a bath temperature of 110°, then cooled to room temperature and thereafter poured in 500 ml water. This mixture is extracted with ether, the ether extract dried with Na2SO4 and concentrated with the aid of a flask rotary vacuum evaporator at a temperature of up to 60°. The impure title compound is obtained as a brown oil, which is purified chromatographically with ether/hexane 1:3 on silicagel to give a yellow oil that slowly crystallises. m.p. 36°-37°.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:24])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)=[C:10]([OH:22])[C:9]=1[F:23])(=[O:3])[CH3:2].Cl.[C:26]([O:29][CH2:30][CH3:31])(=O)[CH3:27].C(O[CH2:36][CH3:37])(=O)C>>[C:1]([NH:4][C@@H:5]([CH3:24])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:12]2[CH:11]=[CH:10][C:26]([O:29][CH2:30][C:31]3[CH:37]=[CH:36][CH:24]=[CH:5][CH:6]=3)=[CH:27][N:13]=2)=[O:21])=[C:10]([OH:22])[C:9]=1[F:23])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)c(O)c1F
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ncc(NC(=O)c2ccc(OCc3ccccc3)cn2)c(O)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (6-(((2S)-2-acetamidopropyl)oxy)-5-fluoro-4-hydroxypyridin-3-yl)carbamate (453 mg), 4M hydrogen chloride/ethyl acetate (15 mL) and ethyl acetate (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Using the obtained residue and 5-(benzyloxy)pyridine-2-carboxylic acid, and in the same manner as in Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([CH:16]=[N:17][OH:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)[CH2:23][CH2:22][C:21]1=O.BrC(C)=C.C(N(CC)CC)C>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([C:16]2[CH:21]=[C:22]([CH3:23])[O:18][N:17]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(C=NO)C1
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(C)Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime (5,3 g, 20 mmol) in 100 ml dry dimethylformamide was added N-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml dry dimethylformamide. The reaction mixture was stirred at room temperature for 1 h. Now 2-bromopropene (2.2 ml, 25 mmol) and 4 ml triethylamine were added and the reaction mixture stirred at room temperature for 48 h. The compound was purified as described for 1-Benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. Yield: 3.1 g. M.p. 86°-87° C.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:5]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1.CCN(C(C)C)C(C)C.[Cl:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:37][C:38]1[CH:39]=[N:40][C:41]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:5]3[C:4]([CH2:3][OH:2])=[N:9][N:8]([C:10]4[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=4)[C:7](=[O:20])[CH:6]=3)[CH2:23][CH2:24]2)=[N:42][CH:43]=1
Reactant: Clc1cnc(I)nc1
Reactant: CS(=O)(=O)c1ccc(-n2nc(CO)c(OC3CCNCC3)cc2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2nc(CO)c(OC3CCN(c4ncc(Cl)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
To a stirring solution of 6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one HCl (18.97 mg, 0.05 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (19.4 mg, 0.150 mmol) and 5-chloro-2-iodopyrimidine (24 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 16 mg (62%) of 5-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)pyridazin-3(2H)-one was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.95 (m, 2H) 1.98-2.22 (m, 2H) 2.58 (s, 1H) 2.96-3.16 (m, 3H) 3.61-3.83 (m, 2H) 3.96-4.17 (m, 2H) 4.48-4.82 (m, 3H) 6.30 (s, 1H) 7.88 (d, J=8.79 Hz, 2H) 8.04 (d, J=8.35 Hz, 2H) 8.24 (s, 2H). MS (ESI) 492 (M+H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[Si:34]([O:41][CH2:42][C@@H:43]1[C@@H:50]2[C@@H:46]([O:47][CH:48](O)[CH2:49]2)[CH2:45][C@H:44]1[O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>O1CCCC1>[Si:34]([O:41][CH2:42][C@H:43]1[C@H:44]([O:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)[CH2:45][C@H:46]([OH:47])[C@@H:50]1[CH2:49]/[CH:48]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 184.6 %

Procedure:
A suspension of (4-carboxy butyl) triphenyl phosphonium bromide (289.3 g, 652.6 mmol) in tetrahydrofuran (1000 ml) was cooled on ice. To the suspension, potassium t-butoxide (146.3 g, 1304 mmol) was added and the mixture was warmed to room temperature. A solution of (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-ol (23) (97.2 g, 261 mmol) in tetrahydrofuran (500 ml) was added, and the resulting solution was stirred for approximately 1.5 hours. Ice water (800 ml) was added to the reaction and the mixture was concentrated under reduced pressure. Then, ice-cooled 1N-hydrochloric acid (600 ml) and ethyl acetate (800 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml). The organic layers were combined, and washed with saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, diethyl ether (1400 ml) was added to the residue and the mixture was stirred for 30 minutes. The resulting mixture was filtered, and the deposited white solid was eliminated. The filtrate was concentrated under reduced pressure to give crude (Z)-7-[(1R,2S,3R,5S)-2-(t-butyidimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (220 g) as white solid. The entire amount was used in the following step without purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([O:13]C)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[O:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Reactant: C1CCNC1
Product: O=C(C1CC2(CCN1)OCCO2)N1CCCC1
Temperature: 150 °C

Procedure:
A mixture of the product of stage (iv) (0.887 g) and pyrrolidine (2.2 ml) was heated at 150° C. in an autoclave for 2 h, allowed to cool to room temperature and evaporated to dryness giving an oil (1.27 g). This was purified by flash chromatography eluting with chloroformmethanol (9:1), to give an oil which crystallised on standing to give the title compound as a solid (841 mg), m.p. 72.5°-74.5°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=[N:32]\[OH:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-propionic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=481.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(I)n2n1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a stirred yellow solution of ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (6.4 g, 14.84 mmol) in anhydrous toluene (300 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (5.40 mL, 5.94 mmol). The mixture was cooled to −35° C. and a solution of 50% catechoborane/toluene (5.09 mL, 20.78 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h, then diluted with EtOAc (600 mL) and sat. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×100 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-100% EtOAc/hexane) to afford desired (S)-ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.3 g, 12.23 mmol, 82% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.33 (s, 1H), 5.75 (d, J=2.4 Hz, 1H), 4.52 (qd, J=7.1, 1.1 Hz, 2H), 4.38-4.29 (m, 2H), 3.59 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)=434.2.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O>[CH2:16]([O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.13 g, 53.41 mmol) was added portionwise to an ice-cooled solution of (S)-(−)-N-boc-3-pyrrolidinol (10 g, 53.41 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at 0° C. for 1 hour. Benzyl bromide (6.4 mL, 53.41 mmol) and tetrahydrofuran (50 mL) were added and the mixture was stirred for 6 hours allowing the temperature to rise to 25° C. The reaction mixture was then slowly diluted with water (50 mL), concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×70 mL). The combined organic solution was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 66:33, to afford the title compound as a colourless oil in 74% yield, 10.93 g.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19](=[NH:23])[O:20][CH2:21][CH3:22])C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19](=[NH:23])[O:20][CH2:21][CH3:22]
Reactant: CCOC(=N)c1c(OCc2ccccc2)ccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=N)c1c(O)ccc2ccccc12
Reaction time: 6 h
Yield: 94.3 %

Procedure:
Palladium on carbon (10%, 2.57 g) was introduced into a solution of 13 (15.21 g, 49.8 mmol) in ethanol (430 ml). The suspension was stirred under a hydrogen atmosphere for 6 hours. After filtration through Celite, the filtrate was concentrated, giving 10.11 g (94%) of 14 as yellow crystals, mp 145°-146° C. IR (KBr): 2980 (C--H), 1620 (C=C), 1085 (C--O) cm-1. 1H NMR: δ8.65 (d, 1 arom H), 7.76 (d, 1 arom H), 7.71 (d, 1 arom H), 7.47 (m, 1 arom H), 7.29 (m, 1 arom H), 7.15 (d, 1 arom H), 4.29 (q, 1 CH2, J=7 Hz), 1.42 (t, 1 CH3). Anal. (C13H13NO2) C, H, N.