Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C@@H:14]([CH3:26])[CH2:15][O:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N(CC)CC)C.[CH2:43]([OH:50])[C:44]1C=CC=CC=1>C(Cl)(Cl)Cl>[C:43]([C:3](=[C:2]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:14]([CH3:26])[CH2:15][O:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])(=[O:50])[CH3:44]
Reactant: OCc1ccccc1
Reactant: C[C@@H](COCOCc1ccccc1)C(=O)CC(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)C(C(=O)OCc1ccccc1)=C(NCc1ccccc1)[C@@H](C)COCOCc1ccccc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Benzyl (S)-3-oxo-4-methyl-5-benzyloxymethoxypentanoate (140 mg; 0.39 mmole) was dissolved in benzyl alcohol (0.9 ml), and molecular sieve 3A (0.2 g), benzylamine (50 mg; 0.47 mmole) and triethylamine hydrochloride (54 mg; 0.39 mmole) were added thereto, followed by stirring at 80° C. for 10 hours. The reaction mixture was diluted with chloroform (10 ml), and after removal of insoluble materials such as molecular sieve by filtration, the filtrate was washed with water. The organic layer was dried over anhydrous magnesium sulfate, followed by removal of the solvent under reduced pressure. Then, benzyl alcohol was removed under reduced pressure, and the residue was dissolved in dry toluene. Gaseous ketene was introduced therein at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl (R)-2-acetyl-3-benzylamino-4-methyl-5-benzyloxymethoxy-2-pentenoate.
Reaction SMILES: C([C:3]1[C:23]([C:24]2[CH:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[CH:22][C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=2[CH:17]([CH3:19])[CH3:18])=[O:8])=[C:5]([CH3:36])[C:4]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)C.[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.[C:52](O)(=O)[CH3:53].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:52]([N:37]([CH:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)[C:4]1[C:5]([CH3:36])=[C:6]([CH:22]=[C:23]([C:24]2[CH:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:53]
Reactant: CCc1c(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c(C)c1NC1CCOCC1
Reactant: CC(=O)O
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.3 g, 0.51 mmol) and 1-methylpiperidin-4-one (0.086 g, 0.76 mmol) in dichloroethane (5 mL), acetic acid (0.18 g, 3.06 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 34.38%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].Cl.[OH-].[NH4+:13]>>[CH3:8][C:7]1([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:2]([CH3:3])([CH3:1])[NH:13]1
Reactant: [NH4+]
Reactant: CC(C)=CC(=O)C=C(C)C
Agent: Cl
Agent: [OH-]
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 78 %

Procedure:
This compound was prepared according to the method of Sandris and Ourisson, Bull. Soc. Chim. Fr. 25: 345 (1958), in which 25 gms (180 mmoles) of phorone and 180 mls of ammonium hydroxide are stirred at 35° C. for 12 hrs. The solution is then cooled in an ice bath and concentrated HCl is added until the pH of the solution is 1. This solution is then saturated with NaCl and extracted with ether. The pH of the remaining liquid is raised to 10 with ammonium hydroxide followed by ether extraction. The ether solution is then dried with anhydrous sodium sulfate and evaporated to dryness, in vacuo, giving 20 gms (78%) of the desired product, B. P. 80°-85° C. at 15 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). After continuing stifling at rt for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1C=CC=CC=1.C(OCC)(=O)C>[C:19]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:31])=[O:30])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1Sc1ccccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1Sc1ccccc1NS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
A solution of methyl 2-[(2-aminophenyl)thio]benzoate (0.444 g, 1.71 mmol) and 4-(acetylamino)benzenesulfonyl chloride (0.440 g, 1.88 mmol) in pyridine (1.6 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with 0.5 N HCl (×2), water (×2), half brine and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 1-5% MeOH in DCM to provide the title compound. MS (ES, M+H+): 457.2. 1H NMR (400 MHz, CD3OD) δ 7.92 (bd, J=8 Hz, 1H), 7.75 (bd, J=8 Hz, 1H), 7.55 (bd, J=9.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.42 (bd, J=8 Hz, 1H), 7.18 (bt, J=7.6 Hz, 1H), 7.14 (bt, J=7.6 Hz, 1H), 7.05 (bt, J=8 Hz, 1H), 6.23 (bd, J=8 Hz, 1H), 3.95 (s, 3H), 2.14 (s, 3).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]=[O:5].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([S:12]([O-:14])(=[O:5])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:1](#[N:2])[CH3:4]
Reactant: C=O
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: CC#N
Product: O=S(=O)([O-])c1ccccc1
Reaction time: 0.5 h

Procedure:
104 g (1.6 mols) of potassium cyanide are dissolved in 100 ml of water. 160 g (1.6 mols) of a 30% strength formaldehyde solution are introduced at between 5° and 10° C. The mixture is stirred for 30 minutes. 212 g (1.2 mols) of benzenesulphonyl chloride are introduced dropwise at a temperature of between 10° and 20° C. The mixture is stirred at this temperature for 6 hours. The product is extracted with benzene. The benzene is washed with water. The benzene phase is decanted. Traces of water are removed by distilling the C6H6.H2O azeotrope. The benzene is evaporated to dryness and the residue is distilled in vacuo.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=O)C=O.[C:8]([OH:11])(=O)[CH3:9].Cl.C[NH:14][OH:15].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH2:6]([O:5][CH:1]=[N+:14]([CH:9]=[C:8]=[O:11])[O-:15])[CH3:7]
Reactant: CC(=O)O
Reactant: CCOC(=O)C=O
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC=[N+]([O-])C=C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The above mixture of ethyl glyoxylate and acetic acid (11.34 g, containing 70 mmol aldehyde) is dissolved in methanol (110 ml), N-methylhydroxylamine hydrochloride (5.8 g) and sodium acetate trihydrate (10.9 g) are added and the mixture is stirred at room temperature for 24 hours. It is then concentrated in vacuo, diluted with water and extracted with dichloromethane. The dichloromethane solution is then washed with a dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, evaporated and distilled to afford α-ethoxy-carbonyl-N-methyl nitrone as a colorless solid (5.0 g), boiling point 80°-85° C/0.4 mm of Hg., melting point 43°-49° C. This is a mixture of the syn- and anti-isomers on the basis of the nmr spectrum.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28]>CN(C=O)C.CS(C)=O.CO>[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:32][CH2:31]1)(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCN(S(=O)(=O)N(C)C)CC3)n2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and N,N-dimethylpiperazine-1-sulfonamide (145 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (101.3 mg, 81%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.20 (s, 1H), 3.79-3.82 (m, 4H), 3.39-3.48 (m, 4H), 3.07-3.16 (m, 2H), 2.39 (s, 3H), 1.66-1.82 (m, 2H), 1.45 (s, 6H), 1.01 (t, 3H); ESI-MS: m/z 502.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][NH:9][CH2:8][CH2:7][CH:6]=1)=[O:4].Cl.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:10][N:9]([CH:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:8][CH2:7][CH:6]=1)=[O:4]
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Yield: 44 %

Procedure:
To 7.338 g (41.31 mol) of guvacoline hydrochloride (Arzneim. Forsch. 1989, 39(5), 539. ) in dioxane (100 ml) was added 5-chloro-dibenzosuberane (14.933 g, 65.39 mmol), Nal (catalytic, ˜1 g), and triethylamine (17 mL, 122.0 mmol) to give a brown heterogeneous slurry that was heated at 90° C. overnight. The solvent was then concentrated and the resultant sludge was taken up in ethyl acetate and sequentially washed with Na2HPO4 buffer (pH 4), Na2CO3 (saturated aqueous), and brine. The organics were then dried over Na2SO4 and concentrated, resulting in a brown solid which was purified by chromatography on silica gel eluting with 1-5% ethyl acetate/hexanes to give 1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester as a white solid (9.584 g, 28.74 mmol, 67%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.22 (dt, J=9.28, 2.68 Hz, 2H) 2.41 (t, J=5.56 Hz, 2H) 2.73-2.83 (m, 2H) 2.99-3.05 (m, 2H) 3.65 (s, 3 H) 3.90-4.00 (m, 2H) 4.11 (s, 1H) 6.94-6.99 (m, J=3.98, 3.98, 1.89, 1.77 Hz, 1 H) 7.05-7.11 (m, 4H) 7.13-7.21 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](O)=[O:13].COC(Cl)=O>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:12][OH:13]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccc(F)c(Br)c1
Reaction time: 0.67 h
Yield: 49.6 %

Procedure:
2 g of triethylamine, dissolved in 5 ml of tetrahydrofuran, were added dropwise to a solution of 4.2 g of 3-bromo-4-fluoro-benzoic acid and 1.95 g of chloroformic acid methyl ester in 30 ml of tetrahydrofuran at 20° C., while stirring. Stirring was continued for a further 40 minutes at 20°-25° C. and the hydrochloride which had precipitated was then filtered off. 5.5 g of sodium borohydride, dissolved in 20 ml of water, were added dropwise to the filtrate at 10° to 20° C., while stirring. Stirring was then continued for a further 4 hours at 20° C. The reaction batch was subsequently poured into 100 ml of water and extracted by shaking with 80 ml of methylene chloride. The methylene chloride phase was separated off and dried over magnesium sulphate and the solvent was then distilled off in vacuo. 1.95 g (95% of theory) of 3-bromo-4-fluoro-benzyl alcohol were obtained as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.74 g (10.7 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.327 g (17.8 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (7.1 mmol) of nonanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue with chased with 5 mL of toluene below 45° C., under vacuum, to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,4-Dihydroxybenzonitrile (5.20 g, 38.5 mmol) and potassium carbonate (5.85 g, 42.4 mmol) were suspended in N,N-dimethylformamide (120 ml), benzyl bromide (4.58 ml) was added, and the mixture was stirred at 50° C. for 3 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 8:1-4:1) to give the title compound.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([I:23])=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[C:1]12([CH2:11][O:12][C:13]3[C:22]([I:23])=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (1.80 g, 4.05 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.85 g, 20.30 mmol) in water (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After addition of 1 N hydrochloric acid (10 mL) and ethyl acetate (150 mL), the organic phase was separated, washed with 1 N hydrochloric acid (10 mL) and brine (10 mL); dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo yielded the title compound (1.75 g, quant) as an off-white solid, which was used without further purification: MS (ES−) m/z 429.1 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:5][N:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnnc1C1CC(C(=O)O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
1-Benzyl 4-ethyl 2-(1-methyl-1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (1.14 g, 2.93 mmol) (from reference compound 36, step 6) was dissolved in THF (10 mL) and water (10 mL) and LiOH (0.280 g, 11.69 mmol) was added. The mixture was stirred at room temperature for 30 min and then diluted with water and acidified with 2 M HCl. The aqueous phase was extracted 3 times with EtOAc, the combined organic phase dried over Na2SO4 and evaporated to yield 1-(Benzyloxycarbonyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-4-carboxylic acid (990 mg, 98%). 1H NMR (400 MHz, cdcl3) δ 1.89-2.01 (m, 1H), 2.15-2.24 (m, 1H), 2.27-2.36 (m, 1H), 2.50-2.61 (m, 1H), 2.78 (p, 1H), 3.68-3.80 (m, 1H), 3.91-4.09 (m, 4H), 5.08 (q, 2H), 5.44 (t, 1H), 7.23-7.39 (m, 5H). MS m/z 346 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[C:17]([Si:21]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-nitrobenzyl alcohol (1.00 g, 6.50 mmol) and imidazole (0.97 g, 14.10 mmol) in DMF (10.0 mL), t-butyl-diphenyl-chlorosilane (1.98 g, 1.87 mL, 7.20 mmol) was added over 10 min under nitrogen at room temperature. The reaction mixture was stirred for an additional 5 h, diluted with 75 mL Et2O, washed with H2O (5 times, 15 mL), dried (MgSO4) and evaporated under vacuum. An oil which crystallised on standing, resulted; yield: 2.54 g. After recrystallisation from EtOH 70%, 2.36 g (93%) of a white soiid is obtained mp 80-81° C. νmax /cm-1 (film): 2931. 2857 (CH2, asym., sym.), 1521. 1345 (NO2); 1H-NMR, δH : 1.06(9H, s, t-Bu), 4.92 (2H, s, CH2), 7.42-7.46 (5H, m, Ph), 7.63-7.65 (7H, m, Ph+Harom2+6), 8.23, (2H, d, J=8.23 Hz, Harom3+5); MS, (EI), (391.54); m/z: 334 (M-t-Bu, 100), 288 (M-t-Bu-NO2, 10), 256 (M-t-Bu-Ph, 20), 199 (Ph2SiOH+, 100); C23H25NO3Si.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@@H:24]4[O:25]C(C)(C)[O:27][C@@H:23]4[C@@H:22]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:21]3)=[C:13]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:21][C@H:22]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:23]([OH:27])[C@H:24]3[OH:25])=[C:13]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound is prepared by dissolving N-{(3aR,4S,6R,6aS)-6-[2-[2-(4-Chloro-phenyl)-ethoxy]-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (Example 235, Step 2) in THF, adding an equal volume of 1.0M hydrochloric acid, and stirring at room temperature for 48 hours, before diluting with water, and extracting into ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and the volatile components removed under reduced pressure, to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:15][CH2:14]3)[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:15][CH2:14]3)[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(C)n(C2CC2)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(C2CC2)c2c(OCc3ccccc3)nncc12
Yield: 78.6 %

Procedure:
The title compound was prepared as a white powder in 78.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclopropyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].B1([O-])OO1.[OH2:16].[OH2:17].O.O.[Na+].O>C(O)(C(F)(F)F)=O.C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]([O-:17])=[O:16])=[C:4]([O:9][CH3:10])[C:3]=1[F:11]
Reactant: COc1c(N)ccc(Br)c1F
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc(Br)c1F
Temperature: 60 °C
Yield: 40 %

Procedure:
To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3 H) 7.40 (dd, J=9.0, 6.2 Hz, 1 H) 7.54 (dd, J=9.0, 1.9 Hz, 1 H).