Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33](O)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([OH:29])=[O:28])(=[O:4])[CH3:3].Cl[CH2:31][N:32]([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33]([N:32]([CH2:38][O:28][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:29])[CH3:31])=[O:34])[CH3:37]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reactant: CCOC(=O)N(C)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)COC(=O)C1=C(COC(C)=O)CSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Temperature: 0 °C

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2.5 mmole) in 50 ml of dimethylformamide (DMF) is treated at room temperature with 2.5 mmole of N-chloromethyl-N-methylurethane for 1 hour. The mixture is carefully poured into ice water and the precipitated solid is removed by filtration and is then washed with water. The filtered solid is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:18])C.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]2[CH:12]([O:18]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC(COCc2ccccc2)CCC1
Reactant: CC(=O)OO
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCC2CCC3OC3C2)cc1

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 13.1g (0.065 mol) 3-benzoxymethylcyclohexene, and 100 mL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to the above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature for 24 hrs, 250 mL of water was added to the above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C>>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[CH:15]=1
Reactant: Cc1ccnc(F)c1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCC(CO)CC2)c1
Temperature: 150 °C

Procedure:
Piperidin-4-ylmethanol (8.68 mmol, 1 g), 2-fluoro-4-methylpyridine (26.0 mmol, 2.89 g) and triethylamine (26.0 mmol, 3.63 mL, 2.64 g) were combined and heated to 150° C. for 1 hour in the microwave. The solvent was removed at reduced pressure and the residue purified by silica chromatography eluting with DCM—2% MeOH/CM to afford (1-(4-methylpyridin-2-yl)piperidin-4-yl)methanol. (0.75 g) MS m/z 207.2 (M+H).
Reaction SMILES: CN(C)C=[O:4].[F-].[K+].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Cl)=[O:19]>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]2[O:4][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:19])[C:10]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)C=O
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2oc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 900 mL of dimethyl formamide, 165 mL of toluene, 65.6 g (1.13 mol) of anhydrous potassium fluoride, and 74.6 g (0.252 mol) of (2-chloro-5-nitrophenyl)(2-chlorophenyl)methanone was stirred and heated to reflux. It was dried by distilling out 170 mL of distillate, and then heated under reflux overnight. It was cooled in an ice bath and diluted with 1 l of water and 100 mL of hexane. After 1 hr the gold-colored precipitate was collected and dissolved in 300 mL of methylene chloride. The solution, after separation of water, was dried over sodium sulfate and concentrated in vacuo. The residue was slurried in ether (cold) to leave crude 2-nitroxanthene-9-one. The ether solution was concentrated in vacuo and the residue recrystallized from methanol to give the product, 60°-64°.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].Cl[C:21]([O:23][CH:24]1[CH2:26][CH2:25]1)=[O:22]>N1C=CC=CC=1>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][C:21]([O:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: O=C(Cl)OC1CC1
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Solvent: c1ccncc1
Product: C#CCN1CCC(OC(=O)OC2CC2)N(c2nnc(S(C)=O)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and cyclopropyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-cyclopropoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]1([C@@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (S)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[C:14]([Br:28])[C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1
Reactant: BrBr
Reactant: Cc1cc(Cl)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The solution of 12.5 g (0.043 mol) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-5-chloropyrazole in the mixed solvent made of 100 ml of chloroform and 100 ml of acetic acid was added with 3.9 g (0.047 mol) of sodium acetate, followed by 7.2 g (0.045 mol) of bromine at 10° C. After stirred at the same temperature for 2 hours, the reaction mixture was poured into ice water and the chloroform layer was separated. The chloroform layer was washed with an aqueous sodium bicarbonate and water and concentrated to obtain 13.0 g of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4-bromo-5-chloropyrazole as pale yellow crystals, melting point: 135° to 137° C. in yield of 82%.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(-c2cccc(C#N)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(-c2cccc(CN)n2)cc1

Procedure:
16.23 g of 6-cyano-2-(p-ethoxycarbonylphenyl)pyridine is hydrogenated at atmospheric pressure in 254 ml of methanol with 12.9 ml of concentrated hydrochloric acid and 2.63 g of 10% palladium on charcoal until 2 molar equivalents of hydrogen have been consumed. Sodium methoxide (6.9 g) is added and the catalyst is filtered off. The solvent is evaporated. The residue is redissolved in 20 ml of methylene chloride and the salts are removed by filtration. Evaporation of the solvent yields a solid which is recrystallized from chloroform to yield the title compound b), m.p. 141°-143°.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH3:25][CH:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH3:36][CH:35]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 4.77 g (5.75 mL, 25.6 mmol, 1.01 eq) of 2-dodecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was diluted with 200 mL of MDC then washed with 4% aqueous sodium bicarbonate solution (1×500 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield the crude product which was shown to contain residual 2-dodecanol by 1H NMR. The crude product was chromatographed using 100 g of silica gel 60, 230-400 mesh, eluting with first 1 L of heptanes, then 500 mL of 3:1 heptane/EtOAc, 500 of 2:1 heptane/EtOAc and finally 500 mL of 1:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 5.35 g (10.16 mmol, 40%) of the product as a light purple viscous oil with an HPLC purity of 99.5 A %. 1HNMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.76 Hz, 1H), 4.8 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.42 (t, J=7.36 Hz, 2H), 2.00 (m, 2H), 1.50 (m, 2H), 1.25 (s, b, 16H), 1.14 (d, J=6.24, 2H), 0.84 (t, J=6.68 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([Li])CCC.B(OC)(OC)[O:19]C.OO>O1CCCC1.C(OCC)(=O)C>[F:12][C:4]1[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=[C:2]([OH:19])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)cc2c1OCCO2
Agent: OO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1cc(F)c2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (15.1 g, 64.8 mmol) in tetrahydrofuran (160 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (45 mL, 73 mmol). The reaction mixture was stirred at −78° C. for 15 min and trimethyl borate (8.5 g, 82 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 48 h and cooled to 5° C. 35% w/w aqueous hydrogen peroxide (12.6 mL, 129.6 mmol) was added, the reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was diluted with ethyl acetate (200 mL) and the organic phase was washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 70% gradient of ethyl acetate in hexanes afforded 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.5 g, 59%) as a colorless solid: MS (ES+) m/z 153.0 (M−17).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCNCCCN
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCCNCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50.4 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholestan-3β-ol as a light yellow solid (6.1 g, 50%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 11% yield.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Cl)C.C(O)C.[CH3:13][N:14]([CH3:16])[CH3:15]>>[CH3:13][N+:14]([CH2:7][CH2:6][CH2:5][C:4]([O-:3])=[O:9])([CH3:16])[CH3:15]
Reactant: CN(C)C
Reactant: CCOC(=O)CCCCl
Solvent: CCO
Product: C[N+](C)(C)CCCC(=O)[O-]
Temperature: 130 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
159 kg (0.92 kmol) of crude gamma-chlorobutyric acid ethyl ester (content 88 percent) and 107 kg (2.3 kmol) of ethanol were placed in a pressure agitator. Then 57 kg (0.96 kmol) of trimethylamine was added in 15 to 30 minutes. The temperature in this case rose to 30° to 50° C. Then heating to 130° C. was performed. The pressure in this case rose to 5 to 7 bars and then dropped back to about 4 bars. After a stable pressure was reached, it was cooled to 20° C. and the remaining triethylamine was removed. The reaction solution was adjusted to a pH greater than 11 with 138 kg of aqueous NaOH (30 percent). Then it was kept at 60° C. for 1 hour and the pH was optionally readjusted. Then it was cooled to 20° C. and the precipitated NaCl was filtered off. After removal by distillation of the excess triethylamine and solvent, the residue was diluted with water. This solution was adjusted to pH 8, filtered and desalted by electrodialysis. The resultant solution contained 32 percent of gamma-butyrobetaine corresponding to a yield of 80 percent, relative to the gamma-chlorobutyric acid ethyl ester. The content was 99.5 percent (HPLC determination of a dehydrated specimen).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:27]=[C:26]2[C:9]([C:10](=[O:28])[CH2:11][C:12]3([O:25]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:8][CH:7]=1.[OH-].[Na+]>>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:11][C:10](=[O:28])[C:9]3[C:26](=[CH:27][C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])=[CH:7][CH:8]=3)[O:25]2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C=C/c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)CC2=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(/C=C/C(=O)O)cc1O2
Yield: 96.4 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (602 mg, 1.5 mmol, Intermediate 2, Step B) was treated with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid as a white solid (560 mg, 96%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (572 mg, 81%). Finally, removal of the THP and the BOC protecting groups following the procedure described in Example 1, Step C gave (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-N-hydroxy-acrylamide (280 mg, 70%) as a yellow solid (hydrochloride salt).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24]C)=[O:23])[CH:4]=1)#[N:2].[OH-].[K+]>O.CO>[C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=[O:23])[CH:4]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Yield: 84.2 %

Procedure:
8.8 g of methyl 3-cyanoandrosta-3,5-diene-17β-carboxylate [prepared as described in step (a) above] and 4.3 g of potassium hydroxide were dissolved in a mixture of 20 ml of water and 200 ml of methanol, and the resulting solution was heated under reflux for 10 hours. At the end of this time, the methanol in the reaction mixture was removed by distillation under reduced pressure, the mixture was made acidic by the addition of dilute aqueous hydrochloric acid and extracted three times with methylene chloride. The organic extract was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 150 g of silica gel using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 16:84 by volume as the eluent, to give 7.1 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.Cl[Sn]Cl>CCO.CC1C=CC=CC=1>[NH:10]1[C:7]2=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]2[CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1cnc2[nH]ncc2c1
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cnc2[nH]ncc2c1
Temperature: 70 °C

Procedure:
5-Nitro-1H-pyrazolo[3,4-b]pyridine (prepared according to the procedure in Can. J. Chem. 1988, 66(3), 420) (133 mg, 0.81 mmol) was mixed with SnCl2 (1.09) in EtOH/CH3Ph (4 mL/2 mL) and heated at 70° C. for 3 hrs. The reaction was cooled to rt and concentrated to dryness. The residue was participated between 1.0 N NaOH (10 mL) and ethyl acetate (50 mL). The organic layer was washed with brine once, dried (MgSO4) and filtered. The filtrate was concentrated and the resulting crude was purified by prep. TLC using 10:2 CH2Cl2/Methanol (2 N NH3). The title compound (15.0 mg) was isolated as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:22]([NH:21][C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[CH3:24])=[S:23])[CH3:2]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCOC(=O)CNc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=S)Nc1cc(Cl)ccc1C)c1ccccc1
Yield: 94.9 %

Procedure:
A mixture of N-phenyl glycine ethyl ester (8.95 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), and chloroform (200 mL) was heated at reflux for 24 hours. The solvent was evaporated. The residue was crystallized from ethyl acetate/hexane mixture. The solid was collected and dried to give 17.2 g of 2-[3-(5-chloro-2-methylphenyl)-1-phenyl -thioureido]-acetic acid ethyl ester as a white solid, m.p. 148°-150° C. Anal. Calcd. for. C18H19Cl N2O S: C, 59.58; H, 5.28; N, 7.72. Found: C, 59.79; H, 5.38; N, 7.65. Mass spectrum (EI, M.+) m/z 262/264.