Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][O:12][C:13](=[O:18])[CH:14]=[CH:15]OC.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OC)(C)(C)C>[CH3:11][O:12][C:13](=[O:18])[CH2:14][CH:15]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]#[N:10]
Reactant: COC=CC(=O)OC
Reactant: N#CCc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CC=C(C#N)c1ccccc1Br
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2×80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96%). Major isomer 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=7.6, 1.2), 7.57–719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz , CDCl3) δ 169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm−1. Minor isomer 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, 1H, J=7.6, 1.0), 7.57–7.19 (m, 3H), 6.9 (t, 1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 126–128° C.; 1H NMR (300 MHz, CDCl3): δ 6.99 (s, 1 H), 6.74 (s, 2 H), 5.00–4.90 (m, 1 H), 4.35 (t, J=8.0 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.09 (t, J=7.7 Hz, 2 H), 1.92–1.72 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3Cl2 (M+H)+: 398.1038; Found m/z 398.1064.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([O:18][CH2:19][O:20][CH3:21])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: COCOc1cc(OCc2ccccc2)ccc1CCN
Agent: [Pd]
Solvent: CCO
Product: COCOc1cc(O)ccc1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
A mixture of 18.00 g of 2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine, 3.6 g of 10% palladium on carbon (Degussa Inc.: E101 NE/W) and 230 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the catalyst was filtered off through a diatomaceous earth, the filtrate was concentrated under reduced pressure to give 12.65 g of 4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[F:9]
Reactant: Clc1ccccc1Br
Reactant: COc1cccc(F)c1B(O)O
Solvent: COCCOC
Solvent: O
Product: COc1cccc(F)c1-c1ccccc1Cl
Yield: 122.2 %

Procedure:
Treatment of 2-bromochlorobenzene (9 mL, 77.6 mmol) with 2-fluoro-6-methoxybenzene boronic acid (10.0 g, 58.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 17.0 g of 2′-chloro-2-fluoro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Yield: 100.6 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:10][C:3]1[CH:4]=[C:5]([CH2:6][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(CN2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (3.27 g, 24 mmol) and 1-methylpiperazine (2.7 g, 27.0 mmol) in dichloroethane (100 mL) was stirred at rt for 30 min. Sodium triacetoxyborohydride (6.2 g, 29 mmol) was added in portions and the reaction mixture was stirred at rt over night. A further portion of 1-methylpiperazine was added and stirring was continued for 24 h. Aqueous NaHCO3 (sat.) was added, the phases were separated and the aqueous phase was saturated with sodium chloride and extracted with DCM twice. The combined organic solutions were dried (MgSO4) and evaporated and the residue was purified by column chromatography on SiO2 using 0-20% MeOH in EtOAc:MeOH 95:5 as eluent. There was obtained 3.50 g (66%) of 9A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.21 (2, 3H), 2.29 (s, 3H), 2.32-2.72 (bm, 8H), 3.42 (s, 2H), 6.55 (d, 1H), 6.90 (d, 1H), 7.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:15][CH:14]=3)=[O:9])=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example No. 166 (1.0 g), collidine (0.45 mL), and DMAP (60.0 mg) in 50 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.25 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 h. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC were combined and condensed to afford 352 mg of the title compound as a white solid.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[CH:10]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[ClH:2].[ClH:1].[ClH:2].[CH:10]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[N:5]=[C:6]([CH3:9])[S:7][CH:8]=2)[CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(CCl)cs1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 70 °C
Yield: 84.6 %

Procedure:
A mixture of 4-chloromethyl-2-methylthiazole hydrochloride (1.84 g), 1-benzhydrylpiperazine (2.52 g) and potassium carbonate (2.7 g) in N,N-dimethylformamide (15 ml) was stirred at 70° C. for an hour. After the reaction mixture was poured into ice-water, it was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (2.0 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-methylthiazole trihydrochloride, mp 166°-170° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2].[Br:23][C:24]([CH2:26]Br)=[CH2:25]>O1CCCC1>[Br:23][C:24](=[CH2:25])[CH2:26][CH:5]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: C=C(Br)CC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 21.7 %

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 7.20 mL, 7.20 mmol) was added to solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (2.0 g, 6.55 mmol) in tetrahydrofuran (30 mL) at −78° C. After 40 min, 2,3-dibromoprop-1-ene (0.70 mL, 7.20 mmol) was added. After 2 h, the reaction mixture was warmed to ambient temperature. After 18 h, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (80% hexanes/ethyl acetate→40% hexanes/ethyl acetate) gave the title compound (603 mg). MS 424.0 (M).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:30])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1.N1C(C)=CC(C)=CC=1C.Cl[C:41]([O:43][CH3:44])=[O:42].Cl>C1(C)C=CC=CC=1>[CH3:44][O:43][C:41](=[O:42])[N:30]=[C:3]([S:2][CH3:1])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 23.8 g of the crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]thioacetimidic acid methyl ester in 100 ml of toluene there were added 32 ml of collidine and 15 ml of methyl chloroformate, and the mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, 1N hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.98 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>[Cu]>[F:7][C:6]([F:9])([F:8])[CH2:5][O:4][CH:3]1[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1([CH3:10])[CH3:1]
Reactant: CC(C)=COCC(F)(F)F
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Product: CCOC(=O)C1C(OCC(F)(F)F)C1(C)C

Procedure:
2,2,2-Trifluoroethyl 2-methyl-1-propenyl ether (3.2 g) is combined, under nitrogen, with approx. 150 mg copper powder and heated to 130°. Ethyl diazoacetate (2.36 g) is very slowly added to the solution over 1.5 hr. The solution is then cooled and filtered, and the filtrate is washed with ether. The ether phase is distilled in vacuo to yield ethyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([OH:52])([CH2:45]3)[CH2:43]1)[CH2:49]2>CN(C=O)C>[OH:52][C:44]12[CH2:50][CH:48]3[CH2:47][CH:46]([CH2:51][C:42]([NH:41][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:9])([CH2:49]3)[CH2:43]1)[CH2:45]2
Reactant: O=C(O)c1ccccn1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC12CC3CC(CC(O)(C3)C1)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
To a 40 ml vial was added picolinic acid (0.68 g, 5.5 mmol), DMF (15 ml), triethylamine (0.90 mL, 6.4 mmol), and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 2.3 g, 6.0 mmol). The mixture was stirred at rt for 5 minutes to get a clear solution. 3-Amino-adamantanol (0.84 g, 5.0 mmol; AK Scientific, 897-4G Independence Ave., Mountain View, Calif. 94043) was added to the above solution and stirred at rt for 2 hours. DMF was removed in Genevac and the residue was dissolved in DCM (20 mL), washed with 1N aqueous NaOH, water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 1.32 g (97%) of crude title compound, pyridine-2-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide, as an oil, which became a colorless solid upon standing at room temperature. LC/MS (Gradient: acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® ODS-3, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 0.79 min; purity (UV254): 100%; ESI-MS m/z: 273 (M+H)+. It was used in the next step without further purification.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:17][C:18]([CH3:20])=O>>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:5]3[CH:6]([CH3:15])[CH2:7][CH2:17][CH:18]3[CH3:20])=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Reactant: CC(C)=O
Agent: Cl
Product: CC1CCC(C)N1CCNc1ccnc2cc(Cl)ccc12

Procedure:
0.35 g (isomer mixture cis:trans=15:1) from 1.3 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; yellowish crystals from acetone, m.p.: 127°-130° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:33][C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26]4=[O:34])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(I)C>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:33][C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26]4=[O:34])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCI
Product: Cc1cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (28 mg, 0.044 mmol) in pyridine (2 mL) was added ethyl iodide (200 mg, excess). The reaction mixture was heated at 170° C. in microwave reactor for 90 minutes and the crude was concentrated and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C32H28ClN4O4S: 599.1 (M+H+); Found: 599.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.80 (s, 1H), 8.58 (s, 2H), 8.18 (d, 1H), 7.57 (m, 2H), 7.50-7.43 (m, 4H), 7.33 (s, 1H), 5.14 (s, 1H), 4.68 (d, 2H), 2.33 (s, 3H), 0.90 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].Cl[CH2:13][C:14](=[N:18][OH:19])[C:15](=[O:17])[CH3:16]>>[CH2:7]([O:9][CH:10]1[O:19][N:18]=[C:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:11]1)[CH3:8]
Reactant: CC(=O)C(CCl)=NO
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC1CCC(C(C)=O)=NO1
Reaction time: 21 h
Yield: 97.9 %

Procedure:
A 1000 ml three-neck flask equipped with a mechanical stirrer, a reflux condenser, and a nitrogen inlet adapter was heat dried and charged with nitrogen. When the flask was at room temperature, it was loaded in order: 39.5 g (0.37 mole) of anhydrous sodium carbonate; (with stirring) 132 g (1.83 mole) of ethyl vinyl ether; and (portionwise over a period of 7 minutes) 10.0 g (0.074 mole) of 1-chlorobutan-2,3-dione-2-oxime [Oglobin et al., J. Gen. Chem. U.S.S.R. 34, 2710 (1964)]. Stirring was continued for 21 hours. The reaction mixture was filtered, the solid cake rinsed with diethyl ether, and the combined filtrate and rinses were evaporated under reduced pressure (bath temperature maintained at <40° C.). There was obtained 12.4 g (98%) of the title compound as an oil; nmr spectroscopy indicated it to be essentially 100% pure. This procedure is essentially that described by T. L. Gilchrist, G. M. Iskander and A. K. Yagoub (J. Chem. Soc., Chem. Commun. 1981, 696-698).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(Br)c(C)c1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
In accordance with Scheme 15, to the solution of 4-bromo-3-methyl-phenylamine (2 g, 1 eq.) in 5 mL of CH2Cl2 was added 10 mL of 2 M NaOH followed by dropwise addition of 3,3-dimethylacryloyl chloride (1.32 mL, 1.1 eq.) in 5 mL of CH2Cl2. The reaction was allowed to stir overnight and then partitioned between EtOAc and brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to afford 2.84 g (98.6%) of product Compound 53A as beige solid. Crude product was used for the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][OH:1]
Reactant: N#Cc1cccc(CO)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cccc(CO)c1
Yield: 40 %

Procedure:
A solution of 3-(hydroxymethyl)benzonitrile in THF was slowly added to a refluxing solution of LiAlH4 in THF with vigorous stirring, maintained under nitrogen atmosphere. The solution was heated at reflux overnight and water was thereafter slowly added dropwise to quench the reaction (until no further evolution of H2 was apparent). The THF was evaporated under reduced pressure and ether/acidified water was added. The ether phase was discarded. The aqueous phase was washed with ether and the organic phase was discarded. NaOH was added until the pH of the aqueous phase reached pH 7. The solution was extracted with THF three times, dried over MgSO4 and evaporated under reduced pressure to furnish a slightly yellow residue which was purified by chromatography on a silica gel column using a gradient eluent starting from ethyl acetate and ending with a mixture of 1:1 ethyl acetate:MeOH), to give the intermediate in a 40% yield.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:23][NH2:24]>C(O)C>[CH:9]1([CH2:8][C@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][NH:24][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Reactant: CN
Solvent: CCO
Product: CNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 47 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (28 g, 83.6 mmol) was dissolved into a solution of methylamine in ethanol (about 30% by weight, 300 mL). The reaction was heated at 50-60° C. overnight and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine (2×100 mL), dried over MgSO4, and concentrated to give the crude product. This crude product was purified by flash chromatography (AcOEt:Hex.=2:1 first, then EtOAc:MeOH=1:1) to afford pure (S)-tert-butyl 1-cyclohexyl-3-(methylamino)propan-2-ylcarbamate (10.6 g, 47%). 1H NMR (400 MHz, CDCl3): 4.81 (brs, 1H), 3.89 (m, 1H), 2.77 (m, 2H), 2.54 (s, 3H), 2.44 (m, 2H), 1.78 (m, 1H), 1.67 (m, 4H), 1.44 (s, 9H), 1.50-1.10 (m, 6H), 1.00-0.77 (m, 2H), 0.05 (s, 9H). MS (E/Z): 271 (M+H+).