Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(OCCCN2CCC(O)CC2)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cc1ccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[C:14]([O:15][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:13][CH:12]=[C:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)OC(C)(C)C)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COc1ccc(/C=C/CCCCOc2ccc(C(=O)OC(C)(C)C)nc2CCC(=O)OC(C)(C)C)cc1
Yield: 50.3 %

Procedure:
Under the conditions of example 1 D, 440 mg of 3-(6-tert-butoxycarbonyl-3-hydroxy-2-pyridyl)-propionic acid-tert-butyl ester is reacted with 367 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-8% ethyl acetate. 350 mg of 3-{6-tert-butoxycarbonyl-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid-tert-butyl ester is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:36])[CH2:13][CH2:14][C:15]1([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:37][CH3:38])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:36])[CH2:13][CH2:14][C:15]1([C:32]([OH:34])=[O:33])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:37][CH3:38])=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(C(F)CCC3(C(=O)O)CCN(CCSc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Yield: 58.6 %

Procedure:
A mixture of 0.07 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 0.9 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 70° C. for 4 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was chromatographed under atmospheric pressure, on a column of silica gel (particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). Fractions 10 to 15 were combined and then concentrated to dryness under the same conditions as above. 0.04 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]-piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=O)[O:11][C:12](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:12]([O:11][CH3:10])=[O:13]
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(OC)c1N
Yield: 101 %

Procedure:
To 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.8 g, 4.1 mmol) in anhydrous methanol (25 mL), was added sodium hydroxide (0.24 g, 4.1 mmol) and the mixture was heated to reflux for 2 hours. The solution was cooled, diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, then brine, and dried with sodium sulfate. It was filtered and concentrated to yield methyl 2-amino-3-methoxybenzoate (750 mg, 100%).
Reaction SMILES: [C:1]([N:4]1[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:26](/[CH:29]=[CH:30]/[C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=1)[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:28])=[O:27]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N+:26]([CH2:29][C@@H:30]([C:31]1[CH:44]=[CH:43][CH:42]=[C:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=1)[CH2:2][C:1]([N:4]1[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])=[O:3])([O-:28])=[O:27]
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Reactant: CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
At −78° C., titanium(iv) chloride (1.0 M solution in DCM) (17.8 mL, 17.8 mmol) was added slowly to a solution of (R)-3-acetyl-4-benzyloxazolidin-2-one (available from Aldrich) (3.55 g, 16.2 mmol) in DCM (80 mL), followed by slow addition of diisopropylethyl amine (3.38 mL, 19.4 mmol). The mixture was stirred at −78° C. for 30 minutes and then a solution of (E)-1-((3-(2-nitrovinyl)phenoxy)methyl)benzene (94.1A) (4.13 g, 16.2 mmol) (commercially available from Aldrich) in DCM (17 mL) was added dropwise (over 15 minutes). Then TiCl4 (16 mL, 1.0 M solution in DCM) was added slowly to the reaction. The mixture was stirred at −78° C. for 2 hours and then quenched with NH4Cl solution. The mixture was extracted with EtOAc (350 mL) and the organic phase was washed with sodium bicarbonate solution and brine, dried over anhydrous Na2SO4. After removing solvent, the residue was recrystallized from MeOH, 94.1B (727 mg), white solid was obtained. MS ESI (np0s.) m/e: 475 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:17](=[O:19])[NH:1][C:2]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:15][CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1NCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
[N-(2-Aminophenyl)]-benzylamine (15.1 mmol, 3.0 g) in dichloromethane (80 ml) is charged with triphosgene (5.3 mmol, 1.57 g) in dichloromethane (40 ml) and is stirred at room temperature over the weekend. The suspension is poured into water (100 g) and is extracted with dichloromethane (2×50 ml). The organic layer is a suspension The colorless solid is filtered off, is dried in vacuo and is recrystallized from ethyl acetate to give the title product (81%)(R1=H, R2=benzyl, n=0).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[CH:19]([C:21]([CH3:23])=[O:22])=[CH2:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:19][C:21](=[O:22])[CH3:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.6 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 0.70 g of methyl vinyl ketone were dissolved in 15 ml of acetone, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3-oxobutyl)malononitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.8 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)butan-1-one (43 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (30.9 mg, 63%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.77-7.70 (m, 2H), 7.65-7.58 (m, 2H), 7.08 (dd, J=11.5, 2.1 Hz, 1H), 6.95 (s, J=2.1 Hz, 1H), 4.46 (s, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.88 (s, 6H), 1.81 (h, J=7.4 Hz, 2H), 1.07 (t, J=7.4 Hz, 3H). ESI MS m/z 492 [C28H27ClFN3O2+H]+; HPLC>99% (AUC), tR=10.90 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:52])[C:32]([C:50]#[N:51])=[CH:33][C:34]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)([CH3:36])[CH3:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:33][C:34]([CH3:36])([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH3:35])[C:50]#[N:51])=[O:52])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCNCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a 30-mL round-bottom flask cooled to 0° C., was placed dichloromethane (8 mL), (R)-tert-butyl 4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate (170 mg, 0.24 mmol, 1.00 equiv), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was dissolved in DCM. The resulting mixture was washed with 20 mL of aqueous potassium carbonate. The organic layer was dried over anhydrous sodium sulfate, concentrated to give the crude product. The crude product was purified by re-crystallization from ether. This resulted in 27 mg of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile as a light yellow solid. LCMS (ESI, pos. ion) m/z: 610 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.Cl[CH:12]([CH3:15])[CH:13]=[O:14].C1([N+]([O-])=C)CCCCC1.S(=O)=O>C(Cl)Cl.[Ag]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][C:4]=1[CH:12]([CH3:15])[CH:13]=[O:14]
Reactant: COc1ccc(OC)cc1
Reactant: CC(Cl)C=O
Agent: [Ag]
Agent: C=[N+]([O-])C1CCCCC1
Agent: O=S=O
Solvent: ClCCl
Product: COc1ccc(OC)c(C(C)C=O)c1
Reaction time: 6 h

Procedure:
432 mg of silver tetrafluoborate and 305 mg of hydroquinone dimethyl ether are first introduced into a flask fitted with a cold finger. After fitting a dropping funnel sealed by a serum cap and equipped with a pressure compensating device, the apparatus is evacuated 5 times under a waterpump vacuum and is subsequently filled with dry nitrogen. Sulphur dioxide was then condensed in the apparatus at -20°C until the volume of the solution is 40 ml. A solution of 2-chloropropanal-N-cyclohexylnitrone in 10 ml of absolute methylene chloride is then introduced into the dropping funnel and is added dropwise over the course of 2 hours to the vigorously stirred sulphur dioxide solution. The temperature is kept at -10°C for a further 6 hours and the sulphur dioxide is then pumped off in a waterpump vacuum. Towards the end, fresh methylene chloride is added in portions in order to keep the volume at between 10 and 20 ml. After filtering off the silver chloride (through Celite, with rinsing with 3×15 ml of methylene chloride), the filtrate is vigorously stirred with 60 ml of 5% strength hydrochloric acid for 5 hours and then separated off. After washing with concentrated sodium bicarbonate solution and concentrated sodium chloride solution (each wash solution being extracted with 2×10 ml of methylene chloride), and drying with sodium sulphate, the solution is evaporated and the yellow-brown oil which remains is filtered through 10 g of aluminium oxide IV (column filled with hexane and eluted with 30 ml of hexane and 80 ml of 4:1 hexane-benzene). The concentrated eluate is distilled in a rotating bulb tube at 90°C/2 mm Hg. α-(2,5-Dimethoxy-phenyl)-propionaldehyde is thus obtained.
Reaction SMILES: Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1.[Cl:16][C:17]1[N:18]=[CH:19][N:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][C:21]=12.C(C1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1)#N>>[ClH:16].[Cl:16][C:17]1[N:18]=[CH:19][N:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][C:21]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3cnc(Cl)c3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Clc1ncn2ccc(C3CCNCC3)cc12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.2, except tert-butyl 4-(1-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 68.1) was used in place of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[C:18]([CH3:26])=[N:19][C:20]([O:24][CH3:25])=[C:21]([CH3:23])[CH:22]=2)[C:5](=[O:15])[N:6]([CH2:8][C@H:9]([CH:12]2[CH2:14][CH2:13]2)[O:10]C)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[C:18]([CH3:26])=[N:19][C:20]([O:24][CH3:25])=[C:21]([CH3:23])[CH:22]=2)[C:5](=[O:15])[N:6]([CH2:8][C@H:9]([CH:12]2[CH2:14][CH2:13]2)[OH:10])[CH:7]=1
Reactant: COc1nc(C)c(Nc2nc(Cl)cn(C[C@@H](OC)C3CC3)c2=O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1nc(C)c(Nc2nc(Cl)cn(C[C@@H](O)C3CC3)c2=O)cc1C
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
A solution of (S)-5-chloro-1-(cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (1.72 g, 4.39 mmol) from Part L in CH2Cl2 (50 mL) at −78° C. was treated with BBr3 (9.65 mL, 9.65 mmol, 1 M in CH2Cl2) dropwise via syringe. After the addition was complete, the reaction mixture was allowed to warm to −40° C., and was stirred at −40 to −35° C. for 45 min. The reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was then transferred to a separatory funnel containing saturated aqueous NaHCO3 (50 L). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel (30%→55% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(cyclopropyl-2-hydroxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (1.50 g, 94% yield) as a light yellow amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.87 (s, 1H), 6.89 (s, 1H), 4.07-4.00 (m, 3H), 3.95 (d, J=6.8 Hz, 1H), 3.94 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H), 1.27-1.23 (m, 1H), 0.83-0.79 (m, 1H), 0.66-0.62 (m, 1H), 0.55-0.51 (m, 1H), 0.35-0.32 (m, 1H); LRMS (ESI) m/e 365.08 [(M+H)+, calcd for C17H22N4O3Cl 365.14].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([N+:15]([O-])=O)=[CH:7][C:6]=1[O:18]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:15][C:8]1[C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[C:6]([OH:18])[CH:7]=1
Reactant: CC(C)(C)c1cc(C(F)(F)F)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1cc(C(F)(F)F)c(N)cc1O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a refluxing solution of 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 mL) was added 10% Pd—C (245 mg). The mixture was refluxed for additional 2 h, cooled to room temperature and filtered through Celite. After removal of solvent, the residue was purified by column chromatography to give 5-Amino-2-tert-butyl-4-trifluoromethyl-phenol (C-14) (120 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 6.05 (s, 1H), 1.28 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run; ESI-MS 234.1 m/z (MH+).
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(I)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.084 g, 0.44 mmol) and 4-iodoaniline (0.090 g, 0.44 mmol) in chloroform (6 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[CH:22]=[CH2:21]
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 34.8 %

Procedure:
Following the procedure of Example 3, step 4, 0.152 g (0.810 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.123 g (0.890 mmol) of anhydrous potassium carbonate and 0.074 ml (0.855 mmol) of allyl bromide. Chromatography on flash silica, eluting with 3-7% methanol/dichloromethane, then on alumina, eluting with 2-5% ethyl acetate/petroleum ether, gave 0.064 g (35%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 204°-214° C. NMR δ(D2O) 1.57 (1H, m), 1.69 (1H, m), 1.80-1.92 (2H, m), 2.66-2.77 (2H, m), 2.88-2.95 (3H, m), 3.18 (1H, t, J=11.4 Hz), 3.60 (1 H, m), 3.77 (1H, m), 3.81 (2H, d, J=7.2 Hz), 5.60-5.65 (2H, m), 5.98 (1H, m), 7.22-7.29 (3H, m), 7.35-7.37 (1H, m). m/z (CI+, NH3) 228 (M+H)+. Analysis calcd. for C16H22ClN: C, 72.85; H, 8.41; N, 5.31%. Found: C, 72.84; H, 8.40; N, 5.26%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:34]2[N:43]=[CH:42][C:41]3[C:36](=[C:37]([F:48])[CH:38]=[C:39]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:40]=3)[C:35]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:31]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:44]([C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([F:48])[CH:38]=1)[C:35](=[O:49])[N:34]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:31]=[C:22]5[CH2:23][N:24]([CH:27]6[CH2:30][O:29][CH2:28]6)[CH2:25][CH2:26][N:21]5[N:20]=4)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:43]=[CH:42]2)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Yield: 27.3 %

Procedure:
A mixture of 155d (117 mg, 0.175 mmol) and lithium hydroxide.water (73.5 mg, 1.75 mmol) in i-propanol/THF (1:1, 8 mL) and water (1 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (6 mL). It was then extracted with dichloromethane (3×50 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 155 (30 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 628.3. 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.77 (m, 1H), 7.61 (d, J=4.5 Hz, 1H), 6.04 (s, 1H), 7.61-7.60 (m, 1H), 4.61-4.59 (m, 2H), 4.50-4.45 (m, 4H), 4.01-3.99 (m, 2H), 3.78 (s, 3H), 3.69-3.65 (m, 1H), 3.54 (s, 2H), 2.79-2.76 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:6]2[NH:7][C:8](=[O:26])[CH:9]([NH:18]C(=O)OC(C)(C)C)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][CH:9]1[C:8](=[O:26])[NH:7][C:6]2[C:27]([O:29][CH3:30])=[CH:28][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10]1
Reactant: COc1cc(C#N)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)cc2c1NC(=O)C(N)N=C2c1ccccc1
Reaction time: 8 h

Procedure:
tert-Butyl 7-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (0.441 g, 1.086 mmol) was dissolved in DCM (4 ml) and TFA (1 ml, 12.98 mmol) and stirred at room temperature for 1.5 h. TFA (1 ml, 12.98 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, then dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted twice more, then the organic layers were dried with Na2SO4 and evaporated. The residue was purified silica gel chromatography (DCM/MeOH). The fractions containing product were evaporated, then the material was triturated with EtOAc to give 3-amino-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine-7-carbonitrile (Intermediate B-19). 1H NMR (400 MHz, chloroform-d) δ 7.54-7.45 (m, 3H), 7.42-7.37 (m, 2H), 7.26 (d, J=1.8 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 4.46 (s, 1H), 4.01 (s, 3H), 2.45 (br. s., 2H).