Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[CH2:10][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:12][CH2:13][C:8]=2[C:7](=[O:27])[O:6]1)[CH:2]([CH3:4])[CH3:3].O.[Sn](Cl)Cl>CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1/[CH:16]=[CH:15]/[C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:27])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH2:10]1)=[O:26]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1[N+](=O)[O-])CC2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1N)CC2
Temperature: 25 °C

Procedure:
A solution of (E)-3-isobutyl-5-(3-(2-nitrophenyl)acryloyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (25 mg, 0.092 mmol) and tin(II)chloride hydrate (83 mg, 0.369 mmol) was heated in methanol (15 mL) for 2 hours. The reaction mixture was cooled to room temperature, concentrated to dryness, and re-dissolved in ethyl acetate (20 mL). The organic solution was washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated. Purification by column chromatography (4 g, SiO2, 0 to 5% chloroform/methanol/ammonium hydroxide 80:18:2 in dichloromethane) provided (E)-5-(3-(2-aminophenyl)acryloyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83-1.01 (m, 6H), 1.62-1.75 (m, 1H), 1.84 (dd, J=14.69, 7.16 Hz, 1H), 2.35 (dd, J=14.69, 4.52 Hz, 1H), 2.43-2.55 (m, 2H), 3.51 (m, J=5.70 Hz, 1H), 3.82-4.00 (m, 3H), 4.09 (d, J=19.59 Hz, 1H), 4.84 (d, J=19.21 Hz, 1H), 6.66-6.86 (m, 3H), 7.18 (t, J=7.54 Hz, 1H), 7.29-7.48 (m, 6H), 7.83 (d, J=15.07 Hz, 1H); MS m/z 417 (M+H)+, 439 (M+23)+, 415 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:6]1[OH:20])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:26]2=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:31]3[C:25]4[C:26](=[N:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:29]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)(=[O:42])=[O:43])[CH:30]=3)[N:13]=2)[CH:6]1[OH:20])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: COC(=O)C1(C)CCCC(Nc2nc(Cl)ncc2F)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Temperature: 25 °C

Procedure:
To a solution of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66e, (0.65 g, 2.05 mmol) and 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na2CO3 (3.52 mL of 2 M solution, 7.04 mmol). The solution was degassed with N2 for 20 minutes. Tetrakis triphenylphosphane palladium (O) (0.14 g, 0.12 mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion, but some starting materials remained. More degassed 2 N Na2CO3 was added followed by another portion of Tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was refluxed for another 4 hours. The mixture was cooled to room temperature, extracted with EtOAc. The organic phase was washed by brine and dried over Na2SO4. After evaporation of solvent the crude mixture was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100) to provide 1.0 g of racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f. LCMS: 588.26 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:28]([O:29][CH3:30])=[CH:27][C:12]([C:13]([N:15]2[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@H:16]2[CH2:25][OH:26])=[O:14])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:28]([O:29][CH3:30])=[CH:27][C:12]=1[C:13]([N:15]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@H:16]1[CH2:25][OH:26])=[O:14]
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2N)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A solution of the nitro-alcohol 20 (0.35 g, 0.77 mmol) and SnCl2/2H2O (0.87 g, 3.86 mmol) in methanol (16 mL) was heated to reflux and monitored by TLC (90% CHCl3/MeOH). After 1 hour the MeOH was evaporated in vacuo and the resulting residue cooled (ice), and treated carefully with saturated NaHCO3 (65 mL). The mixture was diluted with EtOAc (65 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give the crude amine 21 as a pale orange glass (0.29 g, 88%) which was carried through to the next step without further purification or analysis due to the instability of the amine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8]Cl)=[CH:6][CH:7]=1.[C-:10]#[N:11].[K+].C(OCC)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)nn1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
3-Chloro-6-chloromethyl-pyridazine (1.50 g) dissolved in dimethyl sulfoxide (7.5 mL) was added to a solution of potassium cyanide (0.90 g) in water (1 mL) and dimethyl sulfoxide (7.5 mL) stirred at 80° C. The solution was stirred at this temperature for 30 min and then cooled to room temperature. Water and ethyl acetate were added and the resulting mixture was filtered over Celite. The aqueous phase of the filtrate was separated and extracted twice with ethyl acetate. The extracts and the organic phase of the filtrate were combined and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give the title compound as a solid. Yield: 0.23 g (16% of theory); LC (method 2): tR=0.76 min; Mass spectrum (ESI+): m/z=154/156 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[I:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([I:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(I)c1
Product: CC(NC(=O)c1coc(Oc2cccc(I)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 92.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-iodophenol (58 mg, 0.26 mmol) to give the title compound (68 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:31]=[C:32]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:33]=2)[C:26]([O:28]CC)=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:31]=[C:32]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:33]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(C3(C#N)CCCC3)c2)o1

Procedure:
A solution of ethyl 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoate (0.17 g, 0.31 mmol) and LiOH.H2O (65 mg, 1.55 mmol) in 8.1 mL THF and 3.1 mL H2O was stirred at rt overnight. The reaction was concentrated, diluted with H2O, made acidic with 10% citric acid solution and extracted with EtOAc. The combined organic layers were washed with brine. Drying and solvent evaporation gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid. 1H NMR (400 MHz, CDCl3) δ 8.62 (bs, 1H), 8.36 (d, J=1.4 Hz, 2H), 7.28 (m, 3H), 7.09 (d, J=5.7 Hz, 2H), 5.22 (bs, 1H), 3.61 (d, J=13.4 Hz, 1H), 3.43 (m, 1H), 2.60 (m, 2H), 2.20-2.01 (m, 6H), 1.75 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH:25]=[O:26])[CH3:20]>>[CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[C:25]([C:24]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH3:32])=[C:22]([O:21][CH2:19][CH3:20])[CH:23]=1)([OH:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Product: CCOc1ccc(C(O)(c2ccccc2)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OCC
Yield: 76 %

Procedure:
2-bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal and 3,4-diethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-diethoxyphenyl-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethylacetal is obtained as pale yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:19]C(OC(C)=O)=O>C(OC(OCC)OCC)C>[Br:8][C:5]1[N:4]=[C:3]2[C:2](=[N:7][CH:6]=1)[N:1]=[CH:19][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:9]2=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccc(F)c1
Solvent: CCOC(OCC)OCC
Product: O=c1c2nc(Br)cnc2ncn1-c1cccc(F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 3-amino-6-bromo-N-(3-fluorophenyl)pyrazine-2-carboxamide (100 mg, 0.29 mmol) in triethoxymethane (5 mL) was added Ac2O (1 mL). The mixture was stirred at 130° C. for 1 h and 90° C. for 3 h. After being cooled and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (PE:EtOAc=1:1) to give the pure product of 6-bromo-3-(3-fluorophenyl)pteridin-4(3H)-one (60 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 8.35 (s, 1H), 7.49˜7.55 (m, 1H), 7.15˜7.24 (m, 3H). MS (M+H)+: 321/323.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[F:20][C:21]1[N:22]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[C:24]([CH:26]=O)[N:25]=1.CO>C(COC)OC.C1COCC1>[C:10]([CH2:26][C:24]1[N:25]=[C:21]([F:20])[N:22]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CO
Product: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.75 h

Procedure:
Examples 44, 45: Toluene-p-sulphonylmethyl isocyanide, dissolved in dimethoxyethane, was added to a suspension of potassium t-butoxide in the same solvent at -30°. The mixture was cooled to -50° and treated with a solution of 2-fluoro-4-formyl-1-triphenylmethylimidazole in THF plus dimethoxyethane. After 45 minutes, MeOH was added and the mixture heated under reflux briefly. Extractive work-up gave 4-cyanomethyl-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 3.53 (s, 2H); 6.57 (s, 1H); 7.05-7.45 (m, 15H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)N.C(O)(=O)C.Cl>O>[C:1]1([C:7]2[NH:16][C:18]3[C:26]([C:9]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Reaction time: 0.25 h

Procedure:
1.96 g (10 mmol) of deoxybenzoin and 1.52 g of 4-hydrazinobenzoic acid were ground in a mortar and then fused in an open flask at 160° C. for 15 minutes (min). The cooled melt was admixed with 100 ml of acetic acid and 30 ml of concentrated hydrochloric acid and heated under reflux for 3 hours (h). The cooled solution was admixed with water, resulting in the precipitation of the product 2,3-diphenyl-1H-indole-5-carboxylic acid. The product was filtered off with suction and the residue was washed with water and dried. For purification, the crude product was stirred with warm toluene, filtered off with suction and dried again. This gave 2,3-diphenyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH2:14][CH:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([OH:26])[CH:11]=2)[CH2:6]1)=[O:4].C(Cl)Cl.FC(F)(F)C(O)=O>O=[V].Cl.Cl.Cl.C(Cl)(Cl)Cl.CO>[F:30][C:2]([F:1])([F:29])[C:3]([N:5]1[CH2:6][C:7]2=[CH:8][C:9]([O:27][CH3:28])=[C:10]([OH:26])[C:11]3=[C:12]2[CH:13]([CH2:15][C:16]2[CH:17]=[C:18]([O:24][CH3:25])[C:19]([O:22][CH3:23])=[CH:20][C:21]=23)[CH2:14]1)=[O:4]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)CN(C(=O)C(F)(F)F)C2
Agent: O=[V]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(cc1OC)-c1c(O)c(OC)cc3c1C(C2)CN(C(=O)C(F)(F)F)C3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.7 g. (36.9 mMol) (±)-N-Trifluoroacetyl-6-hydroxy-7-methoxy-4-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline are dissolved in 145 ml. dry methylene chloride and mixed with 145 ml. trifluoroacetic acid, while cooling with ice water and with the exclusion of moisture. A solution of 2.8 ml. (5.15 g., 29.73 mMol) vanadium oxytrichloride in 65 ml. anhydrous methylene chloride are added dropwise in the course of 10 minutes to this solution at -10° C., while stirring and in an inert gas atmosphere. After 30 minutes, a further addition of 2.8 ml. vanadium oxytrichloride in 65 ml. anhydrous methylene chloride takes place. The dark coloured reaction mixture is stirred for a further 10 minutes at -10° C. The TLC analysis (silica gel, chloroform/methanol 9:1 v/v) shows that the starting material is completely gone. The reaction mixture is concentrated in a vacuum in a rotary evaporator at ambient temperature to about one third of its original volume and the residue than partitioned between water and methylene chloride. After working up the extracts and crystallising the crude product from acetone, there is obtained (±)-5-trifluoroacetyl-5,6,6a,7-tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenz(de,g)isoquinoline in practically quantitative yield; m.p. 210°-217° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[C:9]([CH:11]1[CH2:13][NH:12]1)#[N:10].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:4][CH2:5][C:6]([N:12]1[CH2:13][CH:11]1[C:9]#[N:10])=[O:8])(=[O:3])[CH3:2]
Reactant: N#CC1CN1
Reactant: CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)NCC(=O)N1CC1C#N

Procedure:
5.85 g. N-Acetylglycine, 3.4 g. 2-cyanoaziridine and 10.8 g. dicyclohexylcarbodiimide are stirred in 60 ml. tetrahydrofuran for 2 hours at ambient temperature. The precipitated dicyclohexylurea is filtered off, the filtrate is evaporated and the residue is stirred with diethyl ether, 5.2 g. of crude product thus being obtained. This water-soluble product is recrystallized from methanolic diethyl ether to give 1-(N-acetylglycyl)-2-cyanoaziridine, which melts at 102°-104° C.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:7]=[CH:8][C:9]2[S:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[S:14]1[C:13]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:22])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: O=Cc1ccccc1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccccc2s1
Reaction time: 1 h
Yield: 86 %

Procedure:
n-Butyl lithium (35 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (11.5 g, 85.6 mmol) in THF (300 mL) at -78° C. under a dry N2 atmosphere. After 1 h, benzaldehyde (9.6 mL, 94.4 mmol) was added and the cold bath was removed. After an additional 30 minutes, sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated. The resultant solid was triturated with pet. ether and filtered to provide the title compound as a white solid (17.7 g, 86%): NMR (CDCl3); δ 7.78 (m, 1H, thiopheneH), 7.68 (m, 1H, thiopheneH), 7.22-7.56 (m, 7H), 7.12 (s, 1H, thiopheneH), 6.12 (d, 1H, OH), 2.51 (d, 1H, CH).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[NH:31][C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:37]=O>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH3:37])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C)cn3)nc2n1C1CCCC1
Yield: 97.3 %

Procedure:
Following general reductive alkylation method 1, 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (90 mg, 0.184 mmol) was combined with formaldehyde (37% solution in water, 0.041 ml, 1.474 mmol) which after silica gel chromatography gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (90 mg) in 97% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.81 (s, 1H), 8.31 (d, J=9.09 Hz, 1H), 8.12 (d, J=2.53 Hz, 1H), 7.58 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (m, 1H), 4.16 (d, J=14.65 Hz, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.20 (t, J=6.57 Hz, 1H), 3.06 (br. s., 6H), 2.99 (m, 1H), 2.46 (m, 2H), 2.34 (s, 3H), 2.06 (m, 6H), 1.81 (m, 2H), 1.67 (m, 3H). MS m/z 503.6 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1)=[N+]=[N-].Cl.[OH-].[Na+]>O.C(#N)C>[NH2:20][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1
Reactant: CC1CN(C(=O)OCc2ccccc2)CC1N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 60 °C
Yield: 96.4 %

Procedure:
Triphenylphosphine (11.96 g, 45.6 mmol) was added to a stirred acetonitrile (164 ml) and water (16.44 ml) solution of benzyl 3-azido-4-methylpyrrolidine-1-carboxylate (11.3 g, 43.4 mmol). The reaction mixture was heated up to 60° C. overnight. The reaction mixture was concentrated. The resulting residue was diluted with 50 mL ice water, treated with 1N HCl (47.8 ml, 47.8 mmol). The aqueous acidic solution (pH 1) was extracted with EtOAc (4×100 mL) to remove Ph3P and Ph3PO by-products/impurities. The acidic aqueous portion containing the product was cooled in an ice bath. neutralized with 1N NaOH (52.1 ml, 52.1 mmol). The resulting cloudy mixture was then extracted with DCM (3×150 mL). The combined DCM phases were washed with brine, dried over anhydrous sodium sulfate. After concentration, (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (9.8 g, 96% yield) was obtained as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.47 (5 H, m), 5.09-5.23 (2 H, m), 3.42-3.69 (3 H, m), 3.12-3.38 (2 H, m), 2.17-2.36 (1 H, m), 1.31 (2 H, br), 1.06 (3 H, dd, J=6.82, 3.30 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: 1.97 min; MS (ES+) m/z: 235.1 (M+H+);
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH:22]=[CH:21]1>>[CH3:19][O:18][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:22]4[C:23](=[O:25])[NH:24][C:20](=[O:26])[C:21]=4[C:17]=3[C:16]=2[CH:15]=1
Reactant: C=C(c1ccccc1)c1cc2cc(OC)ccc2[nH]1
Reactant: O=C1C=CC(=O)N1
Product: COc1ccc2[nH]c3c(-c4ccccc4)cc4c(c3c2c1)C(=O)NC4=O
Yield: 73 %

Procedure:
Reaction of (818) prepared as described in example 418 with maleimide at 180° C. using the procedure described in example 69 gave the adduct (XCVIII; R=phenyl, R′═H) (819), which was used without further purification. The crude Diels-Alder adduct was aromatised with MnO2 using the procedure described in example 79 to give (820) (73%), mp 281–285° C. 1H NMR δ [(CD3)2SO] 11.63 (br s, 1H), 11.15 (br s, 1H), 8.45 (d, J=2.5 Hz, 1H), 7.78–7.76 (m, 2H), 7.68 (s, 1H), 7.65–7.62 (m, 2H), 7.57–7.53 (m, 2H), 7.22 (dd, J=8.8, 2.5 Hz, 1H), 3.89 (s, 3H). Found: C, 72.06; H, 4.57; N, 7.69. C21H14N2O3.1/3H2O requires: C, 72.41; H, 4.24; N, 8.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([C:23]2NN=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]1[O:16][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:24][N:25]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: c1ccc(-c2nnn[nH]2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cc1nnc(-c2ccccc2)o1

Procedure:
The title compound was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2.50) and 5-phenyltetrazole (1.59 g) according to the method of description 1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Product: O=C(O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
A mixture of 6.75 g of 4-chlorocinnamic acid and 0.3 g of CuSO4.5H2O dispersed in 50 ml of ethyl alcohol was stirred at room temperature for 10 minutes; and 23 ml of 95% hydrazine was added thereto. This reactant was stirred for 18 hours with air bubbling at the speed of 1 L/min. The reaction mixture was filtered through a Celite layer and 30 ml of 1N NaOH was added thereto. The solution was washed twice with 30 ml of dichloromethane, acidified with concentrated hydrochloric acid, extracted with 100 ml of ethyl acetate four times and dried over magnesium sulfate. The solvent was evaporated to give 6.05 g(yield 89%) of 3-(4-chlorophenyl)propanoic acid as a yellow solid.