Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:12]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
2.0 g (13.9 mmol) of 4-bromobenzoylhydrazine was put into a 300 mL three-neck flask, 7 mL of N-methyl-2-pyrrolidone was added thereto, and the mixture was stirred at a room temperature. A mixed solution of 5.0 mL of N-methyl-2-pyrrolidone and 2.5 mL (21.5 mmol) of benzoyl chloride was dripped into the solution through a 50 mL dropping funnel. The mixture was stirred at 80° C. for 3 hours. After the reaction, a solid was precipitated out with the addition of the reactive mixture to approximately 200 mL of water. The precipitated solid was collected by suction filtration. The collected solid was washed with water, a saturated sodium hydrogen carbonate solution, and saturated saline, in the order given. The obtained solid was recrystallized with a mixed solvent of acetate and hexane, so that 3.6 g of a white solid, which was the object of the synthesis, was obtained at a yield of 80%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:8]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C>[CH2:30]([N:11]1[CH2:12][C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH2:8][CH2:9][CH2:10]1)[CH2:29][C:28]#[CH:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: C#CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S-:16][C:17]#[N:18].[NH4+]>CO>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([S:16][C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
To a three-necked, round bottom 5 L flask, equipped with a mechanical stirrer, gas inlet, thermometer and gas outlet, was added 2,6-di-tert-butyl- phenol (474 g, 2.30 mole), ammonium thiocyanate (76.12 g, 4.83 mole) and methanol (1200 ml). The reaction mixture was stirred and cooled to 0° C. in an ice/salt bath. Maintaining the temperature at 0° C. to 10° C., chlorine gas was slowly bubbled through the mixture for about 1 hour whereupon the reaction mixture was a heterogeneous yellow color. Ammonia was then bubbled through the reaction for about 1-1/2 hours, maintaining the reaction mixture at a temperature of between 0 to 10° C. The reaction was stirred for an additional hour at 0° C., poured into 2 L of cold distilled water and refrigerated overnight. The aqueous phase was decanted and the solid taken up in methanol, precipitated from water, filtered and dried for 2 days over phosphorous pentoxide. The resulting gummy yellow solid was recrystallized from pentane and dried in vacuo to yield the product as a white powder, m.p. 61.5°-63° C. Analysis calc. for C15H21NSO: Calc: C, 68.40; H, 8.03; N, 5.32; S, 12.17. Found: C, 68.85; H, 8.05; N, 5.29; S, 12.12.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a 1 L RB flask equipped with magnetic stirring bar was added benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (25 g, 123 mmol) and CH2Cl2 (246 ml). The resulting solution was cooled in an ice bath to 0° C., whereupon mCPBA (42.5 g, 246 mmol) was added in three portions over ˜15 min. The resulting slurry was naturally warmed up to rt over 2 days. LCMS indicates a complete reaction. The reaction was worked up as follows: the heterogeneous mixture was cooled to −15° C. for 1 hour, filtered to remove the solid which was rinsed with cold DCM. The resulting filtrate was washed with 1N aq. NaOH (4×100 mL), water (100 mL) and brine, then dried with anhydrous sodium sulfate. DCM phase was concentrated to benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (24.5 g, 91% yield) as light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31-7.44 (5H, m), 5.08-5.21 (2H, m), 3.90 (2H, dd, J=19.70, 12.65 Hz), 3.65-3.77 (2H, m), 3.42 (2H, ddd, J=12.76, 6.16, 1.10 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.41 min; MS(ES+) m/z: 242.0 (M+Na+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine)palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74 (d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MS m/z 482 (M−1).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CC1CCCCC1O.[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:22]([OH:21])[CH:27]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: CC1CCCCC1O
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-methylcyclohexanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 120 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.15 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 76.0%) and 9.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[BH4-].[Li+].O>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 4-cyclopropylbenzaldehyde (0.71 g) in methanol (10 mL) was added lithium borohydride (2 mol/L tetrahydrofuran solution, 3.7 mL), and the mixture was warmed to room temperature and stirred for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 mol/L hydrochloric acid solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 4-cyclopropylbenzyl alcohol (0.69 g).
Reaction SMILES: [Na].COS(O)(=O)=O.[CH2:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15])[CH2:9][CH3:10].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C.O>C(O)C.C(O)(=O)C>[O:23]=[C:24]1[NH:16][C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:8][CH2:9][CH3:10])=[N:15][CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: COS(=O)(=O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Yield: 78.5 %

Procedure:
To a warm solution of sodium (181.7 g., 7.9 g-atoms) in ethanol (5 l) was added with stirring a slurry of 2-n-propoxybenzamidine methyl sulfate (1146.7 g., 3.95 moles) in ethanol 1.6 l). After 2-3 minutes diethyl ethoxymethylenemalonate 854 g., 3.95 moles) was added and the mixture stirred and heated under reflux for 2.25 hours. The mixture was cooled and then added to cold water (13 l). The mixture was acidified to pH 5-6 with glacial acetic acid. The solid was collected by filtration, washed with water, and dried to give the title compound (937.8 g.), m.p. 102°-104°. An additional crop of product (101.6 g., m.p. 105°-107°, was obtained from the filtrate and washings. Total yield of product, 1039.4 g. (87%).
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[H][H].[C:15]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:15]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][O:10][CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)c3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCC(CCOC/C=C/c2ccccc2)CC1
Reaction time: 18 h
Yield: 64.6 %

Procedure:
Cinnamyl alcohol (1.52 g, 11.3 mmol) and sodium hydride (0.56 g, 14 mmol, 60% oil disp.) were stirred in dry N,N-dimethylformamide (15 mL) at room temperature under a nitrogen atmosphere for 45 minutes. After the hydrogen gas evolution had ceased, a solution of 1-benzoyl-4[(p-toluene sulfonyl)oxyethyl]piperidine (3.93 g, 11.3 mmol) in dry DMF (40 mL) was added, and the mixture was stirred for 18 hours. Additional sodium hydride (0.53 g) was added, and the reaction was further stirred for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (500 mL). The organic phase was extracted with water (5×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with hexanes to 50% ethyl acetate in hexanes, then concentrated under vacuum to yield (E)-1-benzoyl-4-[(3-phenyl-2-propenyloxy)ethyl]piperidine (2.55 g, 65%) as a yellow oil. IR (neat): 1630 cm-1. HRMS: Calculated for C23H27NO2 : 349.2042; found: 349.2050.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) was treated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane (3.85 ml, 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up with ethyl acetate gave the title compound (6.1 g).
Reaction SMILES: [O:1]1CCO[C:2]21[CH2:21][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[N:15]([C:18](=[O:20])[CH3:19])[N:14]=[CH:13]3.[Li+].[OH-]>FC1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=CC=1.C1COCC1.O>[C:18]([N:15]1[C:16]2[C:12](=[CH:11][C:10]3[CH2:21][C:2](=[O:1])[CH2:6][CH2:7][CH2:8][C:9]=3[CH:17]=2)[CH:13]=[N:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)n1ncc2cc3c(cc21)CCCC1(C3)OCCO1
Agent: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1ncc2cc3c(cc21)CCCC(=O)C3
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59 %

Procedure:
In a 10 L 3 necked flask, 1-(5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolan]-1-yl)ethanone (79) (440 g, 1.54 mol) was dissolved in THF (5.2 L). A solution of LiOH (143 g, 5.97 mol) in water (3.5 L) was added. The mixture was stirred at rt for about 50 min. The mixture was extracted with EtOAc (2×15 L). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 1-acetyl-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (81) (220 g, 59% yield) as a light yellow solid. 1H NMR (300 MHz, CDCl3): δ 10.05 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.20 (s, 1H), 4.03 (m, 4H), 3.16 (s, 2H), 2.91 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].C([OH:26])C>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:14]([NH2:15]=[O:26])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=C([NH2+][O-])C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Combine 1-benzyl-4-phenyl-4-cyanopiperidine (535 g, 1940 mmol), aqueous sodium hydroxide (85 mL, 50% by weight), and ethanol (5 L). Heat to 50° C. Remove the heating and add a solution of hydrogen peroxide (856 mL, 30% by weight in water) at such a rate that the temperature of the reaction mixture does not rise above 50° C. After the addition of hydrogen peroxide is complete, maintain the temperature of reaction mixture at 50° C. After 20 hours, dilute the reaction mixture with water (3 L) and concentrate invacuo at 35° C. to remove the ethanol. Cool the reaction mixture to ambient temperature to give a solid. Collect the solid by filtration, rinse with water, and air dried to give 1-benzyl-4-phenylpiperidine-4-carboxylic acid amide N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 107.8 %

Procedure:
In DMF (65 ml) was dissolved 5-chloroindole (5.00 g, 33.0 mmol), followed by the addition of sodium hydride (60% in oil, 1.45 g, 36.3 mmol) in portions under stirring at 0° C. After the reaction mixture was stirred further for 30 minutes at the same temperature, methyl iodide (2.46 ml, 39.6 mmol) was added. The resulting mixture was stirred at 0° C. for 30 minutes. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (3:1, v/v) eluate fractions, 5-chloro-1-methylindole (5.89 g, 100%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:13][OH:14])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1(C)CO
Reaction time: 0.75 h

Procedure:
To a solution of commercially available (S)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 0.021 mol) dissolved in DCM (150 mL) was added BH3-DMS (3.3 mL 0.043 mol) at 0° C., dropwise over the course of 45 min with stirring. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was treated with DCM (150 mL) and water (50 mL). The organic layer was isolated, washed with saturated NaHCO3 solution (2×50 mL) followed by brine (2×50 mL), dried (anhydrous Na2SO4), and concentrated using rotary evaporator to give desired (rac)-2-hydroxymethyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester yellowish brown liquid (4.0 g, 86%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].ClCCl.C(OC)(C)(C)C>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCNC1
Yield: 50.8 %

Procedure:
Preparation according to preparation 4: (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (2.86 g, 9.88 mmol), ammonium formiate (1.25 g, 19.76 mmol), ethanol (50 mL) and palladium on carbon (130 mg). Refluxed for 90 min. Dichloromethane/methyl tert-butyl ether (1:1, 50 mL) was added and the mixture was filtrated through celite, the filtrate was evaporated and purified by flash column chromatography on silica gel (triethylamine/methanol, 0:1 to 1:4) to give the title compound (1.0 g). MS m/z (relative intensity, 70 eV) 199 (M+, bp), 141 (84), 113 (65), 127 (64), 63 (48).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)[Cl:8].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>ClCCl>[Cl:8][C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cl)=C(C=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To N,N-dimethylformamide (3.87 mL) at 0° C., POCl3 (3.73 mL) was added dropwise, maintaining the temperature below 5° C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then cooled in ice bath. Tert-butyl 4-oxopiperidine-1-carboxylate (4.98 g) was added slowly, as a solution in dichloromethane (20 mL). After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured over ice and solid sodium acetate, and stirred for 15 minutes, then extracted with dichloromethane. The extracts were washed thoroughly with water and with brine, and dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound, and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetonitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phase were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).