Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.C([C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1CCCCCCC)=O>CCO.[OH-].[Na+]>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:5][C:6]1=[O:1]
Reactant: CCCCCCCc1[nH]c2ccccc2c(=O)c1C=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Aqueous hydrogen peroxide (27.5 wt % solution in water, 145 μl) was added to a solution of 3-formyl-2-heptyl-4(1H)-quinolone (1 mmol) in EtOH (3 ml) and 1M NaOH solution (1.0 ml) under nitrogen, and the mixture was stirred at room temperature for 6 hours. The precipitate was removed by filtration, air dried and crystallised from EtOAc to give 2-heptyl-3-hydroxy-4(1M-quinolone in 70% yield as off-white needles, mp 195-197° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].O.[NH2:33][NH2:34]>C(O)C>[F:28][C:27]([F:29])([F:30])[C:23]1[CH:22]=[C:21]([CH2:20][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]5[NH:33][N:34]=[C:8]([NH2:9])[C:7]=45)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])[CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2cncc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added hydrazine monohydrate (0.266 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed 80% product and 20% SM. Additional hydrazine monohydrate (0.266 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and it was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was then transferred into a 40 mL vial with MeCN, water was added and the solution was freeze-dried to afford 4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (20 mg, 25.3% yield) as a white solid. LC/MS (ES) m/z=438.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.74 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.44 (s, 1H), 7.33 (d, J=8.34 Hz, 1H), 4.61 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.26-3.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]=[CH:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1C=CN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a suspension of 1.39 g (3,42 mmoles) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one (III) in 22 mL of absolute ethanol and 1 mL of glacial acetic acid under stirring at room temperature and in a protective atmosphere, 0.254 g (4.04 mmoles) of sodium cyanoborohydride in small portions was added for 1 hour. After 1.5 hour, the solvent was evaporated and the crude product obtained was dissolved in 250 mL of ethyl acetate. The organic phase was successively washed with 50 mL of 1M aqueous sodium bicarbonate solution, 50 mL of water and 50 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The resultant solution was filtered and the solvent was evaporated to yield 1.17 g of a residual solid (83%), which was diluted in methylene chloride and purified by column chromatography (silica gel). Elution of the column was with methylene chloride, methanol and triethylamine (95:5:1). The pure fractions were collected and the solvent was evaporated under reduced pressure to give 0.83 g (70.9%) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I). Optionally, the reaction crude product was purified by crystallization from a suitable organic solvent, preferably ethanol or 4-methyl-2-pentanone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[CH:10][C:2]1=2.CC(OC(C)=O)=O.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[N+:23]([C:9]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 50 °C
Yield: 99 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.42 g, 6.8 mmol) and Ac2O (3 mL), in AcOH (15 mL) was dropped fuming nitric acid (1 mL). The reacted ion was heated at 50° C. for 2 hours, to afford ethyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.720 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.18 (s, 1H), 4.36 (m, 6H), 1.33 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>Cl>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[C:31]([NH:30][C:2]3[N:29]=[CH:28][CH:27]=[CH:26][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:8]=3)=[O:5])[CH:39]=2)[CH:35]=[N:36]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Nc1ccc2cn[nH]c2c1
Temperature: 155 °C

Procedure:
2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide (2.95 g) was dissolved in a small volume of IpOH. 6-amino indazole (2.75 g) and 0.53 mL of TFA were added. The reaction mixture was heated to 155° C. in an open flask for 3.5 h. After cooling to RT the residue was dissolved in 2 N HCl. The aqueous solution was extracted 2 times with CH2Cl2, basified to pH 12 by the addition of Na2CO3 and 1 N NaOH. The solution was extracted 6 times with CH2Cl2 to isolate the product. The combined 5 extractions were dried over Na2SO4, filtered and stripped. The crude product was purified by silica gel chromatography eluting with a step gradient of 3-5% MeOH:CH2Cl2 to yield the titled compound. MS: 525 (M+1). Calc'd for C27H27F3N6O2-524.5.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:31][CH:32](OC)OC)[CH:12]=[C:13]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[CH:4][CH:3]=1.[ClH:39]>C(O)(=O)C>[ClH:39].[CH3:28][C:26]([CH3:29])([CH3:27])[C:25]([C:13]1[C:14](=[O:24])[C:15]([OH:16])=[C:10]2[C:8](=[O:9])[N:7]([CH2:6][C:5]3[CH:37]=[CH:38][C:2]([F:1])=[CH:3][CH:4]=3)[CH:32]=[CH:31][N:11]2[CH:12]=1)=[O:30]
Reactant: COC(Cn1cc(C(=O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1ccc(F)cc1)OC
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1cn2ccn(Cc3ccc(F)cc3)c(=O)c2c(O)c1=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-Benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg) was dissolved in acetic acid (1.5 ml) and conc. hydrochloric acid (0.5 ml) was added. The mixture was stirred at 90° C. for 3 hr. The reaction mixture was concentrated and crystallized from ethyl acetate to give 7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (92 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[C:41](B3OC(C)(C)C(C)(C)O3)[C:40]=2[CH3:58])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:34]4[CH:35]=[C:36]([C:39]5[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=5[CH3:58])[CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(Cl)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Yield: 22.7 %

Procedure:
(4S,5R)-5-[3,5-bis(3-trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 9) (500 mg, 0.966 mmol), methyl 4′-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (554 mg, 1.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (158 mg, 20%), aqueous potassium carbonate (966 μL, 2M, 1.93 mmol) and ethanol (5 mL) were heated in an 80° C. oil bath for 1 h. Volatiles were then removed from the crude mixture under reduced pressure. The pot residue was treated with water followed by EtOAc extraction. The combined extracts were dried over Na2SO4 followed by filtration and concentration to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge, 0-40% EtOAc in hexanes) to afford methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (152 mg), as a yellow glass. LCMS calc.=692.15; found=693.19 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:18])[NH:19][C:20]1([C:23](=[O:24])[NH:9][CH:6]2[C:5]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[O:8][CH2:7]2)[CH2:21][CH2:22]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: NC1COc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2COc3cc(Br)ccc32)CC1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B] and for the preparation of example 12, (rac)-6-bromo-2,3-dihydro-benzofuran-3-ylamine (intermediate A-8 [B]) has been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((rac)-6-bromo-2,3-dihydro-benzofuran-3-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester, which was then reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) and (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and subsequently with 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) to give the title compound as light yellow solid. MS: 529.2 (MH+, 1Cl).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[NH2:35])([CH3:25])[CH3:24]>>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[NH:35][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2c(C(C)C)cccc2C(C)C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-diisopropylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.13 (d, J=32.78 Hz, 12H), 2.12 (s, 3H), 2.31 (s, 3H), 3.00-3.12 (m, 2H), 4.40 (d, J=5.10 Hz, 2H). 5.40 (s, 1H), 5.65 (s, 1H), 6.85 (s, 1H), 7.04 (bs, 1H), 7.19 (d, J=7.52 Hz, 2H), 7.20-7.30 (m, 1H), 7.42 (t, J=7.52 Hz, 1H), 8.43 (d, J=4.03 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[C:6](=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:7]=O.[CH3:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][S:21]([CH2:24][C:25]([OH:27])=[O:26])(=[O:23])=[O:22])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]>C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][S:21]([C:24]2[C:25](=[O:27])[O:26][C:5]3[C:6]([CH:7]=2)=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:22])=[O:23])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc(O)c(C=O)c(OC)c1
Solvent: CC(=O)O
Product: COc1cc(OC)c2cc(S(=O)(=O)Cc3ccc(OC)c([N+](=O)[O-])c3)c(=O)oc2c1
Yield: 47 %

Procedure:
A solution of 4,6-dimethoxysalicylaldehyde (1 mmol) and 2-(4-methoxy-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 47% yield of the title compound; m.p. 224-225° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](O)=[O:18].C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([N:33]([O:34][CH3:35])[CH3:32])=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Carbonyldiimidazole (7.2 g, 0.045 mol) was added in portions to a stirred suspension of 3-bromo-4-chlorobenzoic acid (10.0 g, 0.042 mol) in dichloromethane (120 mL). The reaction mixture was stirred at room temperature for 30 minutes then at reflux for 30 minutes. Triethylamine (6.3 mL, 0.045 mol) and N,O-dimethylhydroxylamine hydrochloride (4.2 g, 0.043 mol) were added and the reaction mixture was stirred at room temperature overnight, then diluted with water (75 mL) and the layers separated. The aqueous fraction was extracted with dichloromethane (2×50 mL) and the combined organic extracts were washed with citric acid (10%; 2×50 mL), NaHCO3 (50 mL) and brine (50 mL), dried (sodium sulfate) and concentrated to give 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a colourless oil (9.3 g, 79%). 1H NMR (300 MHz; DMSO-d6) 7.98 (1H, s, Ar), 7.60 (1H, d, J 7.2, Ar), 7.48 (1H, d, J 7.2, Ar), 3.54 (3H, s, Me), 3.36 (3H, s, Me).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:43](#[N:46])[CH:44]=[CH2:45]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6]1[CH:7]=[C:2]([CH:45]=[CH:44][C:43]#[N:46])[CH:3]=[N:4][CH:5]=1
Reactant: C=CC#N
Reactant: CN1CCC[C@H]1c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC[C@H]1c1cncc(C=CC#N)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A mixture of (S)-3-bromo-5-(1-methylpyrrolidin-2-yl)pyridine (preparation 1) (300 mg, 1.24 mmol), palladium (II) acetate (14 mg, 0.06 mmol), tri(o-tolyl)phosphine (75 mg, 0.25 mmol) and triethylamine (0.35 mL, 2.48 mmol) in MeCN (10 mL) was degassed by bubbling argon through. Acrylonitrile (0.12 mL, 1.87 mmol) was then added and the reaction mixture heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the solvents evaporated to give a brown solid. The crude product was purified by flash chromatography (2% [20% ammonia in MeOH] in DCM) to give the title compound as a red-brown oil (188 mg, 71%, mixture of cis and trans isomers).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][Si](C)(C)C)[C:9]#N)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.BrC[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a solution of the TMS cyanohydrin from Example 1, Step 1 (3.70 g, 16.6 mmol) in THF (40 mL) under N2 at −78° C. was added slowly a solution of LHMDS (18.2 mL, 18.2 mmol, 1.0 M/THF). After 15 min. at −78° C., a solution of methyl 3-(bromomethyl)benzoate (3.99 g, 17.4 mmol) in THF (20 mL) was added via double-tipped needle. The reaction was allowed to warm slowly to r.t. over 1 h. and was then stirred at r.t. for 2.5 h. Bu4NF (33 mL, 33 mmol, 1M/THF) was then added and the mixture was stirred for 1 h. Saturated NH4Cl (20 mL) was then added and the product was extracted with EtOAc. The organic phase was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. The residue was stirred vigourously with 1:5 Et2O:hexane (50 mL) for 1 h, and the product was then obtained by filtration. This material was dissolved in CH2Cl2 and filtered through a plug of silica gel, washing with CH2Cl2. After removal of solvent, a pale yellow solid (3.4 g) was obtained.
Reaction SMILES: [CH:1](=O)[CH3:2].B(F)(F)F.CCOCC.[CH3:13][C:14]([OH:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15]>C(OCC)C>[CH3:13][C:14]1([CH3:15])[CH2:16][CH2:17][CH:18]([C:19]([CH3:21])=[CH2:20])[CH:1]([CH3:2])[O:22]1
Reactant: CC(C)=CCCC(C)(C)O
Reactant: CC=O
Agent: FB(F)F
Solvent: CCOCC
Product: C=C(C)C1CCC(C)(C)OC1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
42 g of acetaldehyde in 600 ml diethylether were placed in a 2 liter three-necked flask and cooled to 0° C. 140 g of a 48% solution of boron trifluoride diethyl etherate were then added and stirred for 10 minutes at 0° C. 124 g of 2,6-dimethyl-hept-5-en-2-ol dissolved in 100 ml diethyl ether were droppered into the reaction solution at 0° C. Once addition was complete stirring continued for a further hour at 0° C. followed by heating to room temperature. Once the reaction solution had been stirred for 12 hours at room temperature, quenching was carried out with saturated ammonium chloride solution (500 ml) and following conditioning of the raw product obtained distillation was performed via a 30 cm packed column. 82 g of 2,2,6-trimethyl-5-isopropenyltetrahydropyran with a purity of 98% were obtained (55% of theoretical yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9].[C:17]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][C:21]1=O)(=O)[CH3:18]>>[OH:11][C:6]1[C:7]2[CH:17]([CH3:18])[C:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][C:21]=3[O:9][C:8]=2[CH:10]=[C:4]([CH2:3][CH:2]([CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1
Reactant: CCCCCC(C)Cc1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCC(C)Cc1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
When 5-(2-methylheptyl)resorcinol is reacted with 2-acetyl-5-methylcyclohexanone as described in Example 1 the title compound is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CN(C)CCCN
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Product: CN(C)CCCNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
Using the conditions of Example 334 and N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 3-(dimethylamino)propylamine gives 900 mg of the desired product:M+ =508.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4]1)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 100 %

Procedure:
Ethyl 1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.13 (v br s, 1H), 9.66 (br s, 1H), 8.49 (s, 1H), 7.75 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (ddd, J=8.4, 2.0, 0.9 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.91 (q, J=7.1 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C14H12FIN2O3 (M+) 401.9877, found 401.9872.