Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10](N)[CH2:11][NH2:12]>O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:5]1[CH2:10][CH2:11][N:12]=[C:4]1[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1ccccc1N
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: Nc1ccccc1C1=NCCN1
Temperature: 0 °C
Yield: 81.4 %

Procedure:
2-Aminobenzonitrile (9.00 g, 76.2 mmol) was added at 0° C. to ethylenediamine (25.5 ml, 381 mmol) in small portions with stirring. After phosphorus pentasulfide (200 mg, 0.900 mmol) was added, the mixture was stirred at 100° C. overnight. After cooling to 0° C., the reaction was diluted with water. The resulting white precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (10.0 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]([CH3:20])=[CH:18][CH3:19])[CH2:15][C:14](=[O:21])[CH2:13][CH:12]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:29]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16](/[C:17](/[CH3:20])=[CH:18]/[CH3:19])[CH2:15][C:14](=[O:21])[NH:29][CH2:13][CH:12]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC=C(C)C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: C/C=C(\C)C1CC(=O)NCC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 10.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(1-methyl-propenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (120 mg, 0.29 mmol) was reacted with NaN3 (47.1 mg, 0.72 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.29 mL) (Aldrich) in acetonitrile (10 mL) followed by chiral chromatography separation to give 3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5(E)-(1-methyl-1-propenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (13.5 mg): HRMS (ES+) m/z Calcd for C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3(E)-(1-methyl-1-propenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (15.8 mg): HRMS (ES+) m/z Calcd for C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131; (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5(E)-(1-methyl-1-propenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (13.7 mg): HRMS (ES+) m/z Calcd for C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131; and (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3(E)-(1-methyl-1-propenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.5 mg): HRMS (ES+) m/z Calcd for C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131.
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]([O:11][CH3:12])([O:9][CH3:10])[CH2:5]1)[CH3:3].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:27]([O:1][CH:2]([C:4]1([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8][CH2:7][C:6]([O:11][CH3:12])([O:9][CH3:10])[CH2:5]1)[CH3:3])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclopentanecarboxylate (8.64 g, 31.5 mmol) in 100 mL of DCM was treated with triethylamine (8.78 mL, 63.0 mmol) followed by acetic anhydride (5.94 mL, 63.0 mmol). Then DMAP (˜200 mg) was added and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM, washed twice with 1N HCl solution, once with saturated NaHCO3 solution, and once with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, 20% ethyl acetate/hexanes) provided tert-butyl 1-[1-(acetyloxy)ethyl]-3,3-dimethoxycyclopentanecarboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:15]=[C:16]([C:20](=O)[CH3:21])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[F:13][C:14]1[CH:15]=[C:16]([CH:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(NCCCNC(=O)OC(C)(C)C)c1cccc(F)c1
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (0.7 g, 4.05 m. mol) and 1-(3-fluorophenyl)ethanone (0.5 g, 3.6 m. mol) in titanium(IV) isopropoxide (1.8 mL, 6 m. mol) was stirred at room temperature for 3 h. It was diluted with methanol (10 mL) and then sodium borohydride (0.22 g, 5.76 m. mol) was added carefully and stirred for 10 minutes. The reaction mixture was quenched with 0.1 N NaOH (10 mL) solution. It was filtered through celite and washed with dichloromethane (2×20 mL). The organic layer was separated, dried over CaCl2 and evaporated to get the title product (1.07 g, 100%)as thick liquid. 1H NMR (400 MHz, CDCl3): δ 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.10 (bs, 1H), 3.75 (q, 1H), 3.15 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.60 (m, 2H), 1.45 (s, 9H), 1.35 (d, 3H). MS (ESI) m/z: Calculated: 296.38; Observed: 297.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH2:20][NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1c2cc(F)ccc2nc(CNc2cccc(CN3CCCC3)c2)n1-c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloro-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.150 g, 0.49 mmol), 3-pyrrolidin-1-ylmethylaniline (0.044 g, 0.25 mmol), and acetic acid (0.14 mL, 2.45 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.312 g, 1.47 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (45 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (200 mL), nil; (50 mL), unweighed impurity; (25 mL), nil; (75 mL), unweighed mixed fraction; (200 mL), 0.010 g (8%) of 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a pale yellow solid which had: 1H NMR δ 8.60 (d, J=5 Hz, 1 H), 7.80 (t, J=5 Hz, 1 H), 7.76 (d, J=9 Hz, 1 H), 7.71 (dd, J=3, 9 Hz, 1 H), 7.58-7.50 (m, 2 H), 7.35 (dd, J=5, 8 Hz, 1 H), 7.14-7.08 (m, 2 H), 6.80 (dd, J=4, 9 Hz, 1 H), 4.44 (s, 1 H), 3.90-3.65 (m, 4 H), 2.79 (br s, 4 H), 1.90 (br s, 4 H); APCI MS m/z=464 (P+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[CH:25]=[O:26])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2].[C:28]([Mg]Br)#[CH:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[CH:25]([OH:26])[C:28]#[CH:29])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C=O)cc2)cc1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(C)noc1-c1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 3-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-propionic acid ethyl ester and ethynylmagnesium bromide.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32].CN(C=O)C>O>[OH:17][CH2:16][C@H:15]([NH:14][C:12]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]2=[N:10][C:9]=1[CH3:11])=[O:13])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)CCI
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C)C)cccn12
Reaction time: 0.5 h

Procedure:
100 mg (0.34 mmol) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide, 246 mg (0.76 mmol) of caesium carbonate and 75 mg (0.38 mmol) of 1-iodo-3-methylbutane were added to 4.9 ml of dry DMF, and the mixture was stirred for 30 min in an oil bath preheated to 60° C. After cooling, about 40 ml of water were added to the reaction mixture and the solution formed was extracted three times with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: water/methanol gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. This gave 82 mg of the target compound (66% of theory, purity 100%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.9 %

Procedure:
The title compound was synthesized by referring to J. Med. Chem., 1989, 32, 2548. To a solution of 3-methoxybenzenethiol (26.9 g) in acetone (100 ml) was added potassium carbonate (27 g), then 2-bromo-1,1-diethoxyethane (29 ml) was added dropwise thereto followed by stirring overnight at room temperature. To the reaction solution was added acetone, the solution was filtered, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (39.1 g). To dichloromethane (2 l) was added boron trifluoride diethyl ether complex (12.7 ml) under a nitrogen atmosphere, then a solution of 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (25.6 g) in dichloromethane (200 ml) was added dropwise over 1.5 hours, the solution was stirred for 40 minutes at room temperature, then a saturated aqueous solution of sodium carbonate (1 l) was added thereto followed by stirring for 1 hour at room temperature. The solution was extracted with dichloromethane, then dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (10.8 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CO.O1CCCC1.O>[CH3:16][CH:9]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)C=CC=CCC(C)CCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCCC(C)CC=CC=CC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2.3 g of 7,11-dimethyl-2,4-dodecadienoic acid methyl ester is dissolved in 46 ml of methanol and 18 ml of tetrahydrofuran. The mixture is cooled to 0°C., and 4.9 g of potassium hydroxide in 18 ml of water is added. The mixture is stirred overnight (18 hours) at room temperature (22°C.), poured on to water, and extracted with diethyl ether. The aqueous phase is made slightly acidic with 3-N sulphuric acid and again extracted with diethyl ether. The latter, ether extract is washed to neutrality, dried and evaporated. There is obtained 7,11-dimethyl-2,4-dodecadienoic acid, obtained as a slightly-yellow, colored oil, which is uniform according to thin-layer chromatography and which can be utilized without further processing.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.CO>[C:20]1([CH2:26][C:27]([NH:2][CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a suspension of 0.55 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 30 ml of anhydrous dimethylformamide are added successively, at a temperature in the region of 5° C., 0.63 g of phenylacetyl chloride and, over 5 minutes, a solution of 0.4 g of triethylamine in 2 ml of anhydrous dimethylformamide. After stirring for 1 hour at the same temperature and then for 30 minutes at 20° C., the insoluble product formed is isolated by filtration and washed twice with 3 ml in total of dimethylformamide. The filtrate and the washing are combined, 80 ml of distilled water are added and the insoluble product formed is isolated by filtration, washed twice with 2 ml in total of distilled water and then air-dried. The product obtained (0.27 g) is suspended for 5 minutes in 3 ml of boiling methanol and, after cooling and storing for 1 hour at 5° C., the solid formed is isolated by filtration, washed twice with 1 ml in total of methanol and dried under reduced pressure (5 mmHg; 0.65 kPa) at 60° C. 0.16 g of 10-phenylacetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [300 MHz; (CD3)2SO-d6 ; δ in ppm): 3.56 (s, 2H: Ar--CH2 --CO--); 6.12 (d, J=8.5 Hz, 1H: --CH-- 10); from 7.25 to 7.60 (mt, 7H: --H of the phenyl --H 7 and --H 8); 7.38 and 7.48 (2s, 1H each: --H of the imidazole); 7.45 and 7.86 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 8.83 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.50 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[OH-].[K+].C(Cl)(Cl)=[O:20]>O>[C:11]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[O:2][C:1](=[O:20])[NH:10][C:9]=3[CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Methyl-3-amino-5-phenylthiophene-2-carboxylate (0.25 g, 1.07 mmol) in water (6 mL) was reacted with potassium hydroxide (0.12 g, 2.14 mmol) at 90° C. for 24 hours. The reaction was cooled to 0° C. and phosgene (1.9M in toluene, 0.70 mL, 1.40 mmol) was added dropwise. After stirring at room temperature for 1 hour, the resulting solid was collected by filtration, washed with excess water and dried to give the title compound as a tan solid (0.175 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[N:28]1([CH2:16][C@@H:14]2[CH2:13][C@H:12]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([I:11])=[CH:9]3)[CH2:15]2)[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Reactant: C1CNC1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1

Procedure:
The DMF (3 mL) solution of cis-toluene-4-sulfonic acid 3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester (see above for its preparation) (63 mg, 80% purity, 0.10 mmol) and azetidine (12 mg, 2 eq.) was stirred at 50° C. overnight in a sealed tube. The reaction mixture was used directly for further reaction. MS (ES+): 384.1 [MH+]. HPLC: tR=1.4 min (polar—5 min). For 1H NMR analysis, a small sample was taken out for HPLC purification. 1H NMR (DMSO-d6, 400 MHz): δ=1.99-2.06 (quintet, 2H, J=6.9 Hz), 2.08-2.22 (m, 3H), 2.49-2.53 (m, 2H), 2.54-2.56 (d, 2H, J=6.4 Hz), 3.15-3.19 (d, 4H, J=7.2 Hz), 5.01-5.10 (quintet, 2H, J=8.7 Hz), 6.69 (brs, 2H), 7.80 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:26](=[O:27])[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: CCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), hexyl isocyanate (0.174 ml, 1.2 mmol) and triethylamine (1 ml) in dry chloroform (10 ml) was heated with stirring for 48 hours. The reaction mixture was cooled, washed with water (2×5 ml), dried over sodium sulphate and concentrated under vaccum. The residue so obtained was chromatographed with 20:80 chloroform:hexane as eluant to give 2 h; yield. 0.25 g. (68.3%).
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2][CH3:3].Br[C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][P:1]([C:12]1[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:13]=1)([O:2][CH3:3])=[O:6]
Reactant: COP([O-])OC
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COP(=O)(O)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
Dimethyl phosphite (0.089 ml, 0.971 mmol), tert-butyl (2E)-3-(3-bromophenyl)acrylate (0.25 g, 0.883 mmol), triethylamine (0.369 ml, 2.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.153 g, 0.132 mmol) were combined and allowed to heat for approximately eight hours at 100° C. The reaction was cooled and filtered over celite, washing with ethyl acetate. The filtrate was concentrated under reduced presesure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane, followed by CH2Cl2/MeOH. MS: calc'c 299 (MH+), exp 299 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:17][CH3:18])=[C:7]([CH:9]([OH:16])[CH2:10][NH:11][C:12]([CH2:14]N)=[O:13])[CH:8]=1.Cl.[Cl:20]CC(Cl)=O>>[Cl:20][CH2:14][C:12]([NH:11][CH2:10][CH:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:17][CH3:18])[OH:16])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(OC)c(C(O)CNC(=O)CN)c1
Agent: Cl
Product: COc1ccc(OC)c(C(O)CNC(=O)CCl)c1

Procedure:
The synthesis of Midodrine HCl consists of reacting the key intermediate (2) with chloroacetyl chloride to afford 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (3). The reaction of (3) with sodium azide will provide 2-azido-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (4) which is subsequently subjected to hydrogenation to afford Midodrine base (6).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[CH:5]2[CH2:20][C:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2>C(O)C.CO>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3CC23CCC1C3
Solvent: CO
Solvent: CCO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3C[C@@]23CC[C@@H]1C3

Procedure:
6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one [1.8 g, (8R,10aS):(8S,10aR) enantiomeric ratio ˜2:1] was dissolved in 1/1 ethanol/methanol (130 mL) and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (4 mL injections, elution with 35% EtOH:Heptane at 7.5 L/min, fractions monitored at 310 nm). The pure fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to give (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one as a white solid which had a negative rotation. The fractions containing the second enantiomer to elute (enantiomer B) were combined and concentrated to give (8S,10aR)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5d][1,2,3]triazol-7(8H)-one as a solid which had a positive rotation.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)CCCCCCC.BrCCCC#[N:30].[OH-].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O.C1C=CC=CC=1>[C:1](#[N:30])[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCOCCCC(=O)O
Reactant: N#CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCCCCCO
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCOCCCC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
5-Oxatridecanoic acid (O5, C13)--n-Octanol [CH3 (CH2)7OH, 8.0 g, 61.43 mmol] and 4-bromobutyronitrile [Br(CH2)3CN, 9.09 g, 61.43 mmol] were added to a solution of NaOH (50% aqueous, 50 mL), benzene (50 mL) and Bu4NHSO4 (2.61 g, 7.68 mmol). The mixture was stirred for 3 days at room temp. Water (50 mL) was added and then the mixture was extracted with ethyl acetate (4×60 mL), washed with water (2×40 mL) dried over Na2SO4 and distilled (Kugelrohr) to yield 5-oxatridecanonitrile (1.90 g, 16%) as a colorless oil that was used directly in the subsequent reaction.