Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:14](=[CH:23]\[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)/[C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][C:20]1[S:19][C:18]([NH:17][C:15](=[O:16])/[C:14](/[C:4]2[CH:5]=[CH:6][C:7]([N:8]3[C:12]([CH3:13])=[N:11][N:10]=[N:9]3)=[C:2]([Cl:1])[CH:3]=2)=[CH:23]/[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:22][CH:21]=1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A suspension of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide (300 mg, 0.69 mmol) and N-bromosuccinimide (123 mg, 0.69 mmol) in carbon tetrachloride (3 mL) at 25° C. was treated with benzoyl peroxide (8.4 mg, 0.035 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The organic phase was then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3 cycloheptyl-acrylamide (118 mg, 33%) as an amorphous solid: EI-HRMS m/e calcd for C21H22BrClN6OS (M+) 520.0448, found 520.0448.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:22][OH:23])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone, prepared as described in Procedure 4, (860 mg, 3.0 mmol) in pyridine (6 mL) was added hydroxylamine hydrochloride (830 mg, 12.0 mmol) and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 mL), washed with 1 N HCl (2×20 mL), water (20 mL) and sat. NaCl (20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure to yield (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime (912 mg, 100% yield) as a white solid. TLC (30% EtOAc/hexane) shows two spots, the cis and trans isomers of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime, that were not separated. LCMS: RT=1.59 min [M+H] 302.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.Cl.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1N

Procedure:
1.2 G. of 2-amino-4-(4-chlorophenoxy)-1-nitrobenzene in 3ml. concentrated hydrochloric acid is treated with a solution of 6 g. stannous chloride in 3 ml. concentrated hydrochloric acid. The mixture is heated briefly (about ten minutes) on a steam bath, then cooled and treated with potassium bicarbonate and chloroform. The chloroform layer is removed from the filtered mixture, dried and evaporated. 1,2-diamino-4-(4-chlorophenoxy)benzene is isolated as a gum. 1G. of 1,2-diamino-4-(4-chlorophenoxy)benzene in 20 ml. acetone is treated overnight at room temperature with 2.5 g. methoxy carbonyl isothiocyanate. The mixture is concentrated under vacuum and the residue triturated with methanol. Recrystallization from methanol gives pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-(4-chlorophenoxy)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-c5nnn[nH]5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting sequentially with dichloromethane/methanol/concentrated ammonium hydroxide) 95/5/0.1 dichloromethane/methanol/concentrated ammonium hydroxide) 80/20/0.2, the title compound: Rf=0.81 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide) 90/10/0.1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][NH:14][O:15][CH3:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.483 g (3 mmol) 1H-Indole-5-carboxylic acid, 0.351 mg (3.6 mmol) N,O-dimethylhydroxylamine, 1.155 g (3.6 mmol) TBTU and 1.163 g (9 mmol) DIPEA in 15 mL DMF was stirred at room temperature for 2 h and evaporated. NaHCO3 aq. was added and the mixture was extracted with DCM. The combined organic layers were dried with MgSO4, evaporated and the title compound was used crude in the subsequent reaction.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=C(F)F)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1CCCCC1.C(Cl)Cl.CC(C)=[O:42]>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[O:42])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1CC(=C(F)F)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: CC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3

Procedure:
Using the same reaction conditions described in Prepn. 31 and starting from 3,3:17,17-bis(ethylendioxy)androstane-7-one (Prepn. 42, 353 mg), 3,3:17,17-bis(ethylendioxy)-7-difluoromethyleneandrostane was obtained after flash chromatography (SiO2; cyclohexane:CH2Cl2:acetone 8:1:1) (115 mg, 30%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.85 (8H, m), 2.10-0.9 (20H, m), 0.96 (3H, s), 0.83 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[C:25]#[N:26])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cc1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,4-dichlorobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 91%).
Reaction SMILES: [NH2-].[Na+].N.[CH:4]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: ClCCCBr
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: ClCCCN1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (1.72 g) in 100 ml of liquid ammonia, 7 g (0.038 mol) of phenoxazine was added. After stirring for 30 minutes, 6.3 g (0.04 mol., 3.96 mL) of 1-bromo-3-chloropropane was added slowly with constant stirring. After one more hour, ammonia was allowed to evaporate and solid ice pieces were added carefully followed by cold water. When the reaction ceased, the mixture was extracted three times with ether. The ether solution was washed three times with water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel. Petroleum ether-ethylacetate (9 mL+3 mL) eluted the pure title compound (7.94 g) as white crystals. VU-λmax (MeOH) 218, 238 and 321 nm; IR (KBr) 3070, 2860, 1630, 1490, 1380, 1275, 920, 815 and 740 cm-1 ; 1H-NMR (δ) 6.47-6.82 (m, 8H, ArH, H1 -H4 and H6 -H9), 2.11 (m, 2H, H1), 3.63 (m, 2H, HK), and 3.69 (m, 2H, Hm); 13C-NMR (1H decoupled) 111.23 (C1 and C9), 115.50 (C4 and C6), 121.07 (C3 and C7), 123.70 (C2 and C8), 133.03 (C1' and C9'), 144.92 (C4' and C6'), 27.82 (C1), 41.09 (CK) and 42.63 (Cm); EIMS (m/z) 259 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+].Cl>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C=O)c3)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(CO)c3)c2)cc1
Yield: 101.2 %

Procedure:
A solution of methyl 4-[(3′-formyl-[1,1′-biphenyl]-3-yl) methoxy]benzenepropanoate (0.80 g, 2.1 mmol) in methanol (5 mL) and tetrahydrofuran (2 mL) was ice-cooled, and sodium borohydride (81 mg, 2.1 mmol) was added. The mixture was stirred under ice-cooling for 30 min. The reaction mixture was added to 0.2N hydrochloric acid (11 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to give the title compound 0.80 g (quantitative). oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=O)[CH2:3]2.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[ClH:15].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([Cl:1])=[O:12])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CN2CCC1CC2

Procedure:
500 mg (2.61 mmol) of 3-quinuclidinecarboxylic acid hydrochloride (Orlek et al., J. Med. Chem. 1991, 34, 2726) are boiled together with 1.9 ml (26.09 mmol) of thionyl choride under reflux for 2 h. The reaction mixture is freed of thionyl chloride under reduced pressure. 20 ml portions of toluene are twice added and evaporated to dryness. The product obtained in this way is reacted further without further purification.
Reaction SMILES: C[NH2:2].[O:3]([CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15]C1C=CC=C2C(NC(=O)C=12)=O)[Si:4]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C(O)C>[O:3]([CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][NH2:2])[Si:4]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Cc2cccc3c2C(=O)NC3=O)c1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Methylamine (a 30% ethanol solution, 400 mL) was added to a solution of 3-(tert-butyldimethylsiloxymethyl)benzylphthalimide (11.93 g, 31.3 mmol) in ethanol (200 mL) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes and then at 90° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diethyl ether and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure at 20° C. and the residue was diluted with diethyl ether (300 mL), and ultrasonic waves were applied thereto for 1 hour. The resulting cloudy liquid was filtered and the filtrate was concentrated under reduced pressure at 20° C. to obtain the title compound (6.23 g, 79%) as a white solid.
Reaction SMILES: C(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH2:18])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][CH2:2][CH:3]([CH3:5])[CH3:4])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isovaleraldehyde (0.374 mL, 4.10 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.750 g, 4.09 mmol) in methanol (12 mL) at 25° C. Sodium cyanoborohydride (0.643 g, 10.2 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-isobutylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a clear oil, which was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].Cl[CH2:15][CH2:16]Cl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:15]1[CH2:16][O:12][C:11]2[C:2](=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:13])[CH2:6][CH2:5][CH2:4]3)[O:1]1
Reactant: O=C1CCCc2c1ccc(O)c2O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccc1c2OCCO1

Procedure:
5,6-Dihydroxy-1-tetralone (6 g) was heated at 125° C. with 1,2-dichloroethane (7 ml) and K2CO3 (14 g) in DMSO (70 ml) under N2 for 45 min. The reaction was quenched with ice water then extracted with Et2O. The aqueous layer was removed, then EtOAc added to the remaining organics. This solution was dried (MgSO4), filtered and evaporated to qive the desired product.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[C:11]([O:15][C:16]([NH:18][CH:19]([CH3:23])[C:20]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1cccn1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccn1NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
Methyl 1-amino-1H-pyrrole-2-carboxylate (6 g, 48.1 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (8.10 g, 48.1 mmol) were dissolved in ethyl acetate (40 ml) and cooled in an ice-bath. Under an argon atmosphere, diisopropylethylamine (24.6 ml, 141.2 mmol) was added and, after stirring for 15 min, T3P solution (35.7 ml, 60 mmol, 50% in ethyl acetate) was dropwise added. After stirring for 20 min at 0° C., the reaction was left overnight at room temperature. The reaction mixture was poured onto water and extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent evaporated under reduced pressure. 8.6 g (83% yield) of the final product was obtained and use in the next synthetic step without further purification.
Reaction SMILES: [N:1]1([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)[C:8]#[N:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([CH:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=2)[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.2 %

Procedure:
A mixture of morpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile (200 mg, 0.735 mmol), Raney-Ni (200 mg), NH3 (aq) (1.5 mL) in MeOH (20 mL) was degassed and purged with Ar and H2 each 3 times. The mixture was stirred at room temperature under H2 (30 psi) for 25 minutes. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to yield the title compound (175 mg, yield: 86%). 1H NMR (CDCl3 400 MHz): δ ppm 8.83 (s, 2H), 3.80-3.61 (m, 4H), 3.44 (t, J=5.2 Hz, 1H), 3.19-2.99 (m, 2H), 2.52-2.35 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=O)[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2N=C3c4ccncc4CCC3CC2=O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(N2CCC3CCc4cnccc4C3=N2)cc1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
4,4a,5,6-Tetrahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnolin-3(2H)-one (0.14 g; from Example 1 above) was placed in a flask under nitrogen. Borane tetrahydofuran complex (1M, 2.4 ml) was added and the solution warmed to room temperature for 3.5 hours. Methanol (5 ml) was added. Water was added and the aqueous solution extracted thrice with ethyl acetate. The organics were washed with sodium hydrogen carbonate (saturated solution), and brine then dried, filtered and concentrated to give a yellow solid. The solid was adsorbed onto silica then chromatographed eluting with first 7:3 dichloromethane:ethyl acetate, then ethyl acetate to give a yellow solid. Recrystallisation from ethyl acetate/hexane gave the title compound (30 mg)
Reaction SMILES: [CH2:1]([C:18]([OH:56])([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([OH:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1.[O:63]=[C:64](Cl)OC(Cl)(Cl)Cl>CCOCC>[CH2:1]([C:18]1([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:37][C:64](=[O:63])[O:56]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)OC1CCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (6Z,9Z,28Z,31Z)-19-((8Z,11Z)-heptadeca-8,11-dienyl)heptatriaconta-6,9,28,31-tetraene-18,19-diol (540 mg, 0.67 mmol) in anhydrous ether (5 mL) was added pyridine (81 μL, 1.0 mmol). To this solution was added diphosgene (132 μL, 1.1 mmol) slowly over 5 minutes. The solution was stirred for 2 hours at room temperature then concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with 5% ether in hexanes) to afford 4,5-di((8Z,11Z)-heptadeca-8,11-dienyl)-4-((9Z,12Z)-octadeca-9,12-dienyl)-1,3-dioxolan-2-one as a colorless oil (310 mg, 57%).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Li+].[O:19]=[C:20]1[O:24][C@H:23]2[CH2:25][C@@H:26]([O:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])[C@H:27]([CH:28]=O)[C@H:22]2[CH2:21]1.O>COC(C)(C)C>[F:16][C:2]([F:1])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])/[CH:4]=[CH:28]/[C@@H:27]1[C@@H:22]2[C@@H:23]([O:24][C:20](=[O:19])[CH2:21]2)[CH2:25][C@H:26]1[O:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.969 g, 3.75 mmol) in anhydrous t-butyl methyl ether (15 ml), lithium hydride (28.6 mg, 3.60 mmol) was added and the mixture was stirred for two hours at room temperature. (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan-4-carbaldehyde (10) (0.686 g, 2.50 mmol) was added thereto and the mixed solution was stirred for approximately 6 hours at room temperature. Water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia RW-300SP: 28 g; ethyl acetate:hexane=1:2) to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (48.5 mg; 0.119 mmol; yield: 4.8%).