Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[CH3:4]/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH:13]OS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:4][C@@H:5]1[O:13][C@H:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C/C=C/c1ccccc1
Reactant: O=S([O-])OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1O[C@H]1c1ccccc1

Procedure:
To a 100 mL three-neck round bottom flask, were added buffer (0.05 M Na2B4O7.10H2O in 4×10−4 M aq. Na2EDTA, 10 mL), acetonitrile (15 mL), trans-β-methylstyrene (0.118 g, 1 mmol), tetrabutylammonium hydrogen sulfate (0.015 g, 0.04 mmol), and ketone 1 (0.0774 g, 0.3 mmol). The reaction mixture was cooled by an ice bath. A solution of Oxone® (0.85 g, 1.38 mmol) in aq. Na2EDTA (4×10−4 M, 6.5 mL) and a solution of K2CO3 (0.8 g, 5.8 mmol) in water (6.5 mL) were added dropwise through two separate addition funnels over a period of 1.5 h (under this condition, the reaction pH is around 10.5. It is recommended that both Oxone® and K2CO3 be added uniformly over 1.5 h). At this point, the reaction was immediately quenched by addition of pentane and water. The mixture was extracted with pentane (3×30 mL), washed with brine, dried over Na2SO4, purified by flash chromatography [the silica gel was buffered with 1% Et3N in pentane, pentane/ether (1/0 to 50/1, V/V) was used as eluent] to afford trans-β-methylstyrene oxide as colorless liquid (0.124 g, 93 yield, 92%ee).
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>>[CH3:18][NH:19][CH2:1][C:3]1([CH3:17])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: Cn1c2c(c3ccccc31)SCCC2(C)C=O
Product: CNCC1(C)CCSc2c1n(C)c1ccccc21
Yield: 97.4 %

Procedure:
In the same procedure as described in Example 2, 4-formyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole is allowed to react with methylamine to give the title compound: Yield 97.4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:19](=[O:28])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]2=[O:27])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 4-hydroxy-benzoic acid methyl ester (3.01 g, 19.8 mmol), 2-(5-bromo-pentyl)-isoindole-1,3-dione (3.9 g, 13.2 mmol), and K2CO3 (1.82 g, 13.2 mmol) in acetone (150 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude was diluted in EtOAc and washed with 1N NaOH and brine. The organic layer was dried over sodium sulfate. The solvents were removed in vacuo. The crude was recrystallized from EtOAc to afford the title compound as a white solid (4 g, 83%). 1H-NMR (CDCl3): δ 7.95–7.98 (m, 2H), 7.83–7.86 (m, 2H), 7.70–7.73 (m, 2H), 6.86–6.89 (m, 2H), 4.00 (t, 2H, J=6.22 Hz), 3.88 (s, 3H), 3.73 (t, 2H, J=7.29 Hz), 1.82–1.89 (m, 2H), 1.73–1.81 (m, 2H), 1.50–1.57 (m, 2H).
Reaction SMILES: CC1(C)COB([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])OC1.Br[C:32]1[N:33]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:34]=[C:35]([C:37]([N:39]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:41][CH2:42][CH3:43])=[O:38])[N:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:40]([N:39]([CH2:44][CH2:45][CH2:46][CH3:47])[C:37]([C:35]1[N:36]=[C:32]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[N:33]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:34]=1)=[O:38])[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Reactant: COC(=O)c1ccc(B2OCC(C)(C)CO2)c(C(=O)N2CCc3ccccc3C2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 100 °C
Yield: 58.9 %

Procedure:
To a solution of methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (2.0 g, 5.05 mmol) in dioxane (40 mL) was added Pd(dppf)2Cl2 (77 mg, 0.10 mmol), 2-bromo-N,N-dibutyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-carboxamide (910 mg, 2.10 mmol) and K3PO4 (1.34 g, 6.31 mmol). The reaction mixture was degassed for 30 min, heated at 100° C. for 16 h and concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with water, dried over Na2SO4, and concentrated to give the crude product. The crude material was purified by flash chromatography (gradient from 0% to 80%, EtOAc/hexanes) to provide the title compound (800 mg, 57%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.23 (dd, J=6.4, 1.6 Hz, 1H), 8.13-8.12 (m, 1H), 7.98 (dd, J=14.4, 8.0 Hz, 1H), 7.78 (s, 0.5H), 7.67 (s, 0.5H), 7.24-7.12 (m, 3.5H), 6.93 (d, J=7.2 Hz, 0.5H), 5.39 (s, 1H), 5.30 (s, 1H), 4.85-4.75 (m, 2H), 4.58-4.35 (m, 1H), 3.99 (s, 3H), 3.71-3.62 (m, 3H), 3.56 (t, J=6.0 Hz, 2H), 3.45-3.36 (m, 2H), 2.90-2.80 (m, 2H), 1.65-1.31 (m, 8H), 1.00-0.91 (m, 5H), 0.80-0.73 (m, 3H), 0.04 (s, 4.5H), 0.02 (s, 4.5H); MS (ESI−) m/z 646.2 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:19]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:18][N:5]2[CH2:6][CH2:7][C:8]3[C:13]([C@H:4]2[CH2:3]1)=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3>CCCCCCC.C(O)C>[NH2:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:18][N:5]2[CH2:6][CH2:7][C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3
Reactant: COc1cc2c(cc1OC)[C@H]1C[C@@H](N)[C@H](N3CCCCC3=O)CN1CC2
Solvent: CCCCCCC
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@@H]1C[C@H](N)[C@@H](N3CCCCC3=O)CN1CC2

Procedure:
Light yellow semisolid, 220 mg (38%), tR=32.0 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20, flow rate 1 mL/min). (+)-(R,R,R)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-piperidin-2-one: Light yellow semisolid, 207 mg (36%), tR=55.4 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20, flow rate 1 mL/min).
Reaction SMILES: [OH-].[OH-].[C:3]1([B+2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)C.O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cl)cc1
Reactant: [B+2]c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.2 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 0.5 mol %), ligand 2 [Example 1] (5.9 mg, 0.015 mmol, 0.75 mol %), phenylboron dihydroxide (366 mg, 3.0 mmol), and potassium phosphate (850 mg, 4.0 mmol). The tube was purged with argon, and dioxane (6 mL), and 4-chloroanisole (0.24 mL, 2.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for two minutes, then heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (40 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (40 mL), and the layers were separated. The aqueous layer was extracted with ether (40 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 347 mg (94%) of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[N:27]1([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:15]([CH2:14][NH:13][C:11](=[O:12])[CH:10]([O:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:38][CH:37]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)NCC#N
Product: CC(C)CC(OC(c1ccc(-c2ccc(N3CCNCC3)cc2)cc1)c1ccccn1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 21, 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide from example 7, step 4 (241 mg, 0.58 mmol) was coupled with 4-piperazin-1-ylphenylboronic acid (155 mg, 0.64 mmol). The crude residue obtained was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=[N:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35])(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1COCC1>[NH2:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35]
Reactant: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C#CCC1(N)CCN(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.2 %

Procedure:
Citric acid monohydrate (10.39 g, 49.46 mmol) was added to a solution of 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (6.26 g, 19.79 mmol) (which may be prepared as described in Description 2) in THF (150 mL) and the reaction was stirred at room temperature for 18 hours. A colourless solid precipitated out. The solvent was evaporated to give a gummy white solid. This was trituated with Et2O and the solid was washed with further Et2O. The solid was suspended in water/MeOH and purified by SCX (70 g Silca), eluting with water/MeOH, MeOH and finally 0.5M NH3 in MeOH. Fractions containing product were evaporated to afford 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (3.23 g, 21.223 mmol) as a pale yellow oil;
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:33]N>CO>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:33]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: CN(C)C=C1CC(N2CCC(Cc3ccc(-c4cnn(C)c4)cc3Cl)C2=O)CCC1=O
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccc(CC3CCN(C4CCc5n[nH]cc5C4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-[2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one (Preparation 30) (0.327 g, 0.745 mmol) in methanol (3.0 mL), and hydrazine hydrate (0.038 mL) stir the resulting orange solution for 17 hours at room temperature. Filter the mixture, rinse with cold methanol and vacuum dry to 0.138 g of a solid. MS (m/z): 410 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[O:29]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: S=C=Nc1cc(Oc2ccccc2)ncn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc(Oc2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.170 g, 0.742 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.604 g, 1.854 mmol) and 4-isothiocyanato-6-phenoxypyrimidine (0.17 g, 0.742 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.347 mL, 2.225 mmol) was then added and the mixture was continued to stir at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (R)—N-(6-phenoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.21 g, 0.72 mmol, 48.2% yield) as a pale yellow solid. 1H NMR (500 MHz, MeOD) δ ppm 8.43 (1H, s), 7.47 (2H, t), 7.30 (1H, t), 7.16 (2H, d), 6.21 (1H, br. s.), 4.03 (1H, d), 3.72 (1H, d), 3.22 (1H, d), 3.11 (1H, d), 2.73-2.99 (4H, m), 2.00-2.18 (2H, m), 1.54-1.88 (3H, m). LCMS R.T.=1.46; [M+H]+=352.19.
Reaction SMILES: [OH-].[Na+].Cl.[SH:4][CH2:5][CH2:6][NH2:7].Cl.N1C=CC=CC=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C(O)C>[N:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:4][CH2:5][CH2:6][NH2:7])=[CH:18][CH:19]=1
Reactant: NCCS
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: NCCSCc1ccncc1
Temperature: 25 °C

Procedure:
34.1 g of sodium hydroxide was dissolved in 500 ml of ethanol under an argon atmosphere and 48.6 g of 2-mercaptoethanamine hydrochloride and 35 g of 4-chloromethylpyridine pyridine hydrochloride were added with ice bath cooling. The reaction mixture was allowed to warm to room temperature over 2 hours, was concentrated, diluted with 300 ml of water and was extracted with 3×150 ml of dichloromethane. The combined organic layers were washed with 100 ml of saturated brine, dried over potassium carbonate and were evaporated to a dark oil which was distilled. The fractions bp 120°-130° C./0.1 mm amounted to 30.68 g (85%) of 2-[[(4-pyridyl)methyl]thio]ethanamine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:16][C:13](=[O:15])[CH3:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([n+]([O-])c1)CCCC2
Product: CC(=O)OC1CCCc2cc(C)cnc21
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
7.02 Grams of 3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was dissolved in acetic anhydride, and the solution was heated at 90° C. with stirring for 3.5 hours. Acetic anhydride was removed by evaporation under reduced pressure, then an aqueous solution of sodium carbonate was added to make the residue alkaline and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue thus obtained was purified by a silica gel column chromatography (eluent:dichloromethane) to obtain 7.18 g of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24].CC(O)=O>CC(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([NH:24][CH3:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (commercial, 40 g, 126 mmol) in i-PrOH (440 mL) was added methylamine (41% in water, 320 mL). The mixture was heated in a 1.6 L-Parr reactor for 3.5 h at 75° C. (1.5-2 bar). After cooling to rt the solution was concentrated, diluted with water and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO4 and concentrated. The residue was suspended in TBME (150 mL) and treated with AcOH (7.28 mL, 126 mmol). The mixture was stirred for 1 h at rt and the resulting crystals were filtered, washed with TBME and dried under HV to afford the title intermediate as its AcOH salt (15.07 g, 38%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:34](=O)[CH2:35][CH2:36][CH3:37])[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)#[N:14].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:30]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)=[C:34]([CH2:35][CH2:36][CH3:37])[N:12]2[N:11]=[CH:10][CH:9]=[C:8]2[N:7]1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1cc(NC2CCOCC2)[nH]n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.00 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4.20 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.39 g, 88%).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29]C)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.CN.N[C:48]1C=CC=C[CH:49]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH3:29])=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:48][CH2:49]1)[CH2:5][O:12][CH2:9]2
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: CN
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)NC)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing methylamine (2M in THF) as the aniline component. (51%, MS=408.4 (M+H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:12]([OH:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:22])[CH:19]([F:21])[F:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:22])[CH:19]([F:20])[F:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC1c2cc(C(O)C(F)F)ccc2C=Cc2ncc(Cl)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=c1c2cc(C(O)C(F)F)ccc2ccc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese dioxide (0.16 g, 1.9 mmol) was added to a solution of 3-chloro-7-(2,2-difluoro-1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol (60 mg, 0.19 mmol) in ethyl acetate (2 mL) and the mixture was stirred at room temperature for 8 hours. The slurry was then filtered through celite, eluting with ethyl acetate. The filtrate was concentrated in vacuo, and purified via flash chromatography (silica, 0-50% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.75 (d, 1H), 8.39 (d, 1H), 8.25 (d, 1H), 7.81 (dd, 1H), 7.65 (d, 1H), 7.29 (d, 1H), 7.19 (d, 1H), 5.89 (dt, 1H), 4.93 (dt, 1H). Hydroxyl proton was not observed.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[N+:19]([O-])([OH:21])=[O:20].O.[K+].[Br-]>C(Cl)Cl>[CH:1]([C:3]1[C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a pale pink solution of methyl 4-(4′-formyl-2′-methoxyphenoxy)butanoate (4) (3 g, 12.3 mmol) in DCM (20 cm3) was added dropwise, at 0° C. fuming nitric acid (1.5 cm3, 37.0 mmol). The resulting green solution was stirred at 00° C. for a further 30 mins before being allowed to spontaneously warm to r.t., where it remained for 3 hours. The subsequent bright yellow suspension was poured onto iced water (50 cm3) and extracted with DCM (3×30 cm3). The combined organic phase was washed with sat. NaHCO3 solution (2×50 cm3), followed by water (2×50 cm3) before being dried and concentrated in vacuo providing a bright yellow solid. The desired compound 5 was used without further purification (2.48 g, 68%). A small amount of material (250 mg, 0.84 mmol) was purified via column chromatography (SiO2, CH2Cl2) so that complete characterisation data could be obtained, m.p. 75° C. [lit. (D. L. McMinn and M. M. Greenberg, Tetrahedron, 1996, 52, 3827.) m.p. 76-78° C.]. Found C, 52.7; H, 5.2; N, 4.8; C13H15NO7 requires C, 52.5; H, 5.1; N, 4.7%; Rf 0.44 (SiO2, CH2Cl2); νmax (KBr disc)/cm−1 3100-2700 (m), 1735 (s), 1690 (s), 1290, 1220; 6, (200 MHz, CDCl3) 2.23 (2H, q, J=7.1 Hz, CH2), 2.57 (2H, t, J=7.1 Hz, CH2), 3.71 (3H, s, OCH3), 3.99 (3H, s, OCH3), 4.21 (2H, t, J=7.1 Hz, CH2), 7.40 (1H, s, H-3′), 7.61 (1H, s, H-6′), 10.44 (1H, s, CHO) ppm; δC (100 MHz, CDCl3) 24.1 (CH2), 30.2 (CH2), 51.8 (OCH3), 56.6 (OCH3), 59.6 (CH2), 108.1 (CH), 109.9 (CH), 125.5, 143.8, 151.7, 153.4, 173.2 (COOCH3), 187.8 (CHO) ppm; m/z (FAB) 298 [(MH+), 40%].