Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][C:17]=3[O:30][CH3:31])=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]3[N:35]=[CH:36][CH:37]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([O:1][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:7][CH2:6]3)[C:9]3[N:10]([N:35]=[CH:36][CH:37]=3)[C:11]=2[CH2:32][CH2:33][CH3:34])=[C:17]([O:30][CH3:31])[CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile (0.93 g) and rhodium acetate (dimer, 0.020 g) in methylene chloride (10 mL) was added dropwise ethyl diazoacetate (0.86 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.52 g, 47%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].Br[C:14]1C=CC(C(O)=O)=NC=1.Cl.N1CCC1>>[N:2]1([C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=2)=[O:4])[CH2:12][CH2:14][CH2:1]1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: C1CNC1
Agent: Cl
Product: O=C(c1ccc(Br)cn1)N1CCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyridine-2-carboxylic acid (1.50 g, 7.43 mmol) and azetidine hydrochloride (954 mg, 10.2 mmol) to give a yellow solid (1.38 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=2.02 Hz, 1 H) 7.93-7.99 (m, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 4.65 (t, J=7.71 Hz, 2 H) 4.20 (dd, J=8.34, 7.33 Hz, 2 H) 2.27-2.36 (m, 2 H); LCMS for C9HgBrN2O m/z 241.00 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][CH:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1
Reactant: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.7 g. of dry pyridine in 140 ml. of dry methylene chloride, stirred in a tap water bath is treated with 5.5 g. of dry chromium trioxide. The resulting deep red suspension is stirred at ambient temperature for 15 minutes. A solution of 3.78 g. of ethyl-9-ethylenedioxy-15-hydroxy-prostanoate (Example 55) in 15 ml. of methylene chloride is added, all at once, to the suspension. A black, tarry deposit is formed immediately. After stirring for 15 minutes at ambient temperature, the methylene chloride solution is decanted from the tarry deposit which is triturated with several portions of ether. The combined organic phases are washed with 5% aqueous sodium hydroxide, water, ice-cold 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 3.29 g. (88%) of a viscous oil; λ max 5.78 and 5.86 μ (carbonyl groups).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:25][CH2:24][C@@H:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[CH2:22][N:21]2[C:34]([CH2:37][C:38](OC(C)C)=[O:39])=[CH:35][N:36]=[C:20]12)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[C@H:23]1[CH2:22][N:21]2[C:34]([CH2:37][CH:38]=[O:39])=[CH:35][N:36]=[C:20]2[C@H:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:25][CH2:24]1
Reactant: CC(C)OC(=O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC=O)cnc21
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Diisobutylaluminum hydride (1.0 M in dichloromethane; 0.81 mL, 0.807 mmol) was added to a solution of isopropyl [(6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl]acetate (187 mg, 0.403 mmol) in dichloromethane (10 mL) at −78° C. After 1 h, an additional amount of diisobutylaluminum hydride (0.81 mL, 0.807 mmol) was added. After 2.5 h, saturated aqueous potassium sodium tartrate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (120 mg). MS 406.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
To a solution of 1G (62 mg, 0.2 mmol) in CH2Cl2 (1 mL) was added pyridine (0.049 mL, 0.6 mmol), followed by addition of benzoyl chloride (42 mg, 0.3 mmol). The resulting mixture was stirred at RT under argon for 6 h, then loaded on a silica gel cartridge (10 g), eluting with EtOAc (25-50%) in hexane to give the title compound as a white solid (72 mg, 88%). m.p. 174-175° C., HPLC: 99% at 3.01 min (retention time, Phenom. Luna C18, 4.6×50 mm elating with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 inn). MS (ES): m/z=418 [M+1]+. Chiral HPLC 100% e.e.; retention time=34.8 min; Conditions: OD (4.6×250 mm); Eluted with 40% isopropanol in hexane at 1 mL/min.
Reaction SMILES: [N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:14][CH2:15][CH2:16][CH3:17].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5].C(O)CCC>[C:21]1(=[O:22])[O:23][C:18](=[O:24])[C:19]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:20]12
Reactant: O=C1C=CC(=O)O1
Reactant: CCCC
Agent: [V+5]
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: CCCCO
Product: O=C1OC(=O)c2ccccc21

Procedure:
Catalyst B was prepared as in the preceding example, but with a P/V ratio of 1.15, and by adding bismuth nitrate at the same time as the vanadium oxide, in a Bi/V ratio of 0.1. In this case, in addition to the VOHPO4-0.5H2O phase, the precursor contained a BiPO4 phase. The catalyst was activated in a stream of 1.7% of butane in air. After activation, the catalyst contained the phases (VO)2P2O7 and BiPO4. The butanol was supplied in the stream of air so as to produce a partial pressure of butanol of 1%. At approximately 360° C., the yield of maleic anhydride was in the range 50% to 60%. As the temperature was progressively increased, yields of phthalic anhydride in the range 10% to 20% were observed intermediate between 250° C. and 350° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH2:20][NH3+:21])[CH:11]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>ClCCl>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[S:42]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([NH:16][C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[N:15]=[CH:14][N:13]=2)[CH:18]=1)(=[O:44])=[O:43]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccccc1-c1cc(Nc2cccc(C[NH3+])c2)ncn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1cc(Nc2cccc(CNS(=O)(=O)c3c(Cl)cccc3Cl)c2)ncn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
171 mg 3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-benzyl-ammonium chloride (prepared in Example 69) (0.5 mmol) was dissolved in 50 cm3 dry dichloromethane, 0.350 cm3 N,N-diisopropyl-ethylamine (259 mg, 2 mmol) was added and the mixture was cooled to 0° C. in an ice bath. After stirring it for 15 minutes 196 mg 2,6-dichlorobenzenesulfonyl-chloride (0.8 mmol) was added and the mixture was stirred for 2 hours at 0° C. and overnight at room temperature. Then 50 cm3 5% NaHCO3 solution was added and it was extracted three times with 50-50 cm3 of chloroform. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated under reduced pressure. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product as an yellow solid. Yield: 34 mg (13%). For analitical results and compound identification see Table 1.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[N:3]=[CH:2]1.[CH2:11]([O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[C:16](/[O:10][C:9]1[C:4]2[N:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)\[CH3:17])[CH3:12]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc2ocnc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc2ocnc12
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A stirred mixture of benzooxazol-4-ol (0.388 g, 2.87 mmol), ethyl-2-butynoate (1.93 g, 17.2 mmol) a catalytic amount of 4-dimethylaminopyridine and potassium carbonate (0.595 g, 4.30 mmol) in tetrahydrofuran (20 mL) was placed in a sealed tube and heated at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was collected and concentrated in vacuo. The resulting residue was purified by ISCO column chromatography (Silicycle 40 g, 2% to 15% ethyl acetate/hexanes) which afforded (E)-3-(benzooxazol-4-yloxy)-but-2-enoic acid ethyl ester (710 mg, 100%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:16])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].CO[CH:19]([N:22]([CH3:24])[CH3:23])OC>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:16]=[CH:19][N:22]([CH3:24])[CH3:23])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)OCC)n1N=CN(C)C
Temperature: 105 °C

Procedure:
A mixture of 406C (482 mg, 2.13 mmol) and dimethoxymethyl-dimethyl-amine (1.5 ml) in anhydrous DMF (5 ml) was heated at 105° C. overnight. After the solvent was removed, the residue was purified by silica gel flash column chromatography to give 406D (546 mg, 91%) as pink crystals (25% EtOAc—hexanes). MS Found: (M+H)+=282.1
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1>C(O)C.Cl.[Pd]>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(N)cc2O1
Yield: 89 %

Procedure:
A solution of ethyl 7-amino-4-oxo-4H-chromene-2-carboxylate (1.00 g, 4.3 mmol) in ethanol and concentrated HCl (5 mL) is hydrogenated over 10% Pd/C (0.5 g) at 50 psi for 72 h at ambient temperature. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The resultant residue is dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase is dried over MgSO4, and concentrated in vacuo to afford the title compound as an amber oil, 0.85 g (89% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2.[C:19]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:19][O:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C(=O)N=C2C1=C(O)C(=O)c1ccccc12
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC1=C2C(=NC(=O)C2(C)C)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (compound 1) (0.1 g, 0.415 mmol) in MeOH (5 mL) was added K2CO3 (0.132 g, 0.96 mmol) while stirring at RT. After 10 min. MeI (100 μL, 0.228 g, 1.6 mmol) was added via a syringe and the mixture was allowed to stirred over night. The solvent was removed in vacuum and the solid was dissolved in CHCl3, filtered and purified by prep. HPLC (SF/CHCl3). Yield: 0.051 mg (50%). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 6 H), 3.68 (s, 3 H), 7.58 (t, 1 H), 7.68 (t, 1 H), 8.02 (d, 1 H), 8.23 (d, 1 H). MS (CI) m/z: 256.31 (M+1).
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][C:13]#[N:14]>CO>[NH2:14][C:13]1[CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[S:6][C:5]=1[C:4]([O:8][CH3:9])=[O:7]
Reactant: CC(C)C(Cl)=CC#N
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(C(C)C)cc1N
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a solution of NaOMe (14 g) in MeOH (1 L) was added methyl thioglycolate (22.3 mL). The mixture was stirred for 5 min, then a solution of 3-chloro-4-methyl-2-pentenenitrile (32.4 g) in MeOH (200 mL) was added and the solution was heated at the reflux temp. for 90 min. After cooling to 20° C., the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with a 1N HCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane) to yield methyl 3-amino-5-isopropylthiophene-2-carboxylate (8.0 g, 16%).
Reaction SMILES: [CH2:1]1[CH2:9][CH:8]=[CH:7][C:6]2[N:5]3[CH2:10][CH2:11][CH2:12][CH2:13][C:4]3=[C:3]([C:14]([O:16]CC)=[O:15])[C:2]1=2.Cl>C(O)C.[OH-].[Na+]>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([OH:16])=[O:15])=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: CCOC(=O)c1c2c(n3c1CCCC3)C=CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c2n(c3ccccc13)CCCC2
Yield: 39.5 %

Procedure:
A solution of ethyl 6,7,8,9-tetrahydro-1H-pyrido[1,2-a]indole-10-carboxylate (1.20 g, 0.0047 mole) in ethanol (50 ml) and 10% NaOH solution (50 ml) was heated under reflux for 4 hours. The reaction was then acidified with 1M HCl acid (50 ml and extracted with ethyl acetate (50 ml). The organic layer was separated and extracted with 10% Na2CO3 solution (120 ml) and the aqueous solution then reacidified with 5M HCl acid and extracted into ethyl acetate (2×7 5ml). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo to afford the title compound (D3) as a white solid (400 mg, 40%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:8]=2[CH:9]=1)C.C(O)=O>O>[CH:4]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:8]=2[CH:9]=1)=[O:3]
Reactant: CCOC(OCC)c1cc2cc(C(=O)OC)ccc2o1
Solvent: O
Solvent: O=CO
Product: COC(=O)c1ccc2oc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.1 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate (2.6 g, 8.5 mmol) is combined with formic acid (15 ml) and water (3.8 ml). The reaction is stirred 6 h at RT, the volatiles are removed in vacuo, and the residue is neutralized with 50 ml saturated NaHCO3. The mixture is extracted with CH2Cl2 (4×20 ml), the organic layer is dried (K2CO3), and is concentrated in vacuo to provide 1.72 g (99%) of methyl 2-formyl-1-benzofuran-5-carboxylate as amber flakes. HRMS (EI) calcd for C11H8O4: 204.0423, found 204.0418 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[CH3:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)[nH]c(=O)n2C1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 4.5 g N-t-butyloxycarbonyl-4-piperidone, 4.7 g of 4-(5-methyl-2-oxo-1-benzimidazolinyl)piperidine, 65 mL of 1,2-dichloroethane, 1.3 mL of glacial acetic acid and 6.4 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Recrystallization of the crude product from50 mL of ethyl acetate gave in two crops 6.18 g of pure 5-methyl-1,3-dihydro-1-{1-[1-(t-butyloxycarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a white solid: mp 210°-211° C.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:14]([OH:15])=[CH:13][C:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[C:16]([F:19])([F:18])[F:17].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[BrH:1].[OH:15][C:14]1[C:3]([OH:2])=[C:4]([C:16]([F:19])([F:17])[F:18])[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[S:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN1CCc2cc(O)c(O)c(C(F)(F)F)c2CC1
Reactant: Sc1ccccc1
Agent: Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CN1CCc2c(c(C(F)(F)F)c(O)c(O)c2Sc2ccccc2)CC1

Procedure:
Following the procedures outlined in Example 2 the 7,8-dihydroxy-3-methyl-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give the 7,8-dione which is then reacted with, for example, thiophenol to yield 7,8-dihydroxy-3-methyl-6-phenylthio-9-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[N:23]=[N:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(c2ccccc2)C(=O)N=N1
Yield: 33.9 %

Procedure:
Phenylmaleic anhydride (20 g, 115 mmol), sodium acetate trihydrate (1875 g, 138 mmol), hydrazine monohydrate (6.68 ml, 133 mmol) and 40% aqueous acetic acid (400 ml) were heated at reflux for 15 h then allowed to cool. The reaction mixture was left to cool in the fridge for 1 h. The solid produced was filtered and washed with water and diethyl ether before drying in a vacuum oven at 40° C. to give the required product (7.26 g). 1H NMR (250 MHz, DMSO) δ 3.43 (2H, broad peak), 7.17 (1H, s), 7.44 (3H, m), 7.81 (2H, m); MS (ES+) m/e 189 [MH+].
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([OH:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]>COCCOCCOC.[Ni]>[CH2:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([OH:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(SC)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Ni]
Solvent: COCCOCCOC
Product: CCCc1ncnc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 55.8 %

Procedure:
29 g of 6-n-propyl-2-methylthio-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 101, are dissolved in 250 ml of diglyme, and 60 g of Raney nickel are added. The mixture is heated to reflux for 3 hours. The catalyst is filtered off and washed with ethanol, the filtrate is evaporated under vacuum and the residue is chromatographed on silica gel in a 2:8 acetone/chloroform eluent to give 14.2 g of 6-n-propyl-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 158° C.
Reaction SMILES: C(OC[C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:22]=[C:23]([NH:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1)[CH3:13])=[O:11])C1C=CC=CC=1.C[CH2:36][OH:37]>[Pd]>[CH:31]1([NH:30][C:23]2[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10](=[O:11])[O:37][CH3:36])=[CH:19][CH:18]=3)[N:22]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Reactant: CCO
Agent: [Pd]
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (0.012 g, 0.026 mmol) in EtOH (0.4 mL) was added Pd/C (10 mg), and was charged with H2 (1 atm). After stirring for 15 h at room temperature, it was purified by preparative HPLC to give N-(4-(4-(cyclobutyllamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-2-hydroxy-N-methylacetamide (MS calcd for C19H22N6O2 366.2. found [MH] 367.0; UV 208.7, 272.4, 304.5 nm).
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][CH2:3][NH:2]1.CS(O[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)(=O)=O>>[O:15]=[C:1]1[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][CH2:3][N:2]1[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reactant: O=C1NCCCn2nc3ccccc3c21
Product: CC(C)(C)OC(=O)N1CCCC(CN2CCCn3nc4ccccc4c3C2=O)C1

Procedure:
The product was prepared using the method described in example 1d), using 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one and tert-butyl 3-{[(metylsulphonyl)oxy]methyl}piperidine-1-carboxylate as reagents. Thus, 3.6 g of tert-butyl 3-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate were obtained.