Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: COc1ccc(C(=O)O)cc1
Agent: N
Product: COc1ccc(C(=O)NC2C3CC4CC2CN(C4)C3)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-methoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.92-1.99 (m, 4H), 2.12 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.39 (s, 1H), 3.50 (s, 2H), 3.60 (s, 3H), 3.84-3.87 (m, 3H), 4.37 (s, 1H), 6.97-7.03 (m, 2H), 7.75-7.88 (m, 2H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:17](O)(=O)C>>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:2][C:3]([CH3:12])([CH3:17])[CH:4]=[O:11]
Reactant: CC(=O)O
Agent: Nc1ccc(Br)cc1C(O)c1ccccn1
Product: CC(C)(C)C=O

Procedure:
In 20 ml of acetic acid was dissolved 2.0 g of 2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol obtained in (1) together with 0.86 ml of trimethylacetoaldehyde. To the solution was added 0.36 g of sodium borohydride under ice-cooling. The reaction mixture was stirred for 30 minutes at room temperature and then subjected to extraction with a mixture of 100 ml of water and 150 ml of ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to afford 5-bromo-2-neopentylamino-α-(2-pyridyl)benzyl alcohol (2.4 g) as am oily product.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[NH:7][C:8](=[O:14])[NH:9]2)[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C.O>[CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[N:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8](=[O:14])[NH:9]2)[CH:2]=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=CCc1cccc2[nH]c(=O)[nH]c(=O)c12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1cccc2[nH]c(=O)n(C(=O)OCC)c(=O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Step 4 intermediate (1.28 g, 6.33 mmol) in dry DMF (6.3 ml) was added triethylamine (4.38 ml, 31.35 mmol) and ethyl chloroformate (3.03 ml, 31.65 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with water, extracted with ethyl acetate, washed with brine and dried over Na2SO4. Purification of the crude product by silica gel column chromatography using 1% ethyl acetate in chloroform afforded 1.3 g of the title compound; 1H NMR (δ ppm, CDCl3, 300 MHz): 9.56 (br.s, 1H); 7.49 (t, J=7.8, 1H); 7.05 (d, J=7.2, 1H); 6.93 (d, J=8.4, 1H); 6.11-5.90 (m, 1H), 5.07-4.98 (m, 2H); 4.53 (q, J=7.2, 2H); 3.96 (d, J=6.3, 2H); 1.46 (t, J=7.2, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.O>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Reactant: COc1cncc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1cncc(-c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)c1
Temperature: 100 °C

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.12 g, 0.25 mmol) isolated in step 2, (5-methoxypyridin-3-yl)boronic acid (0.046 g, 0.30 mmol), 10% sodium carbonate (0.60 mL, 0.62 mmol), 1,4-dioxane (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol), the mixture was bubbled with N2 for 5 min and then heated at 100° C. for 2 hours. The resulting mixture was cooled to room temperature and then treated directly with 6.0 M hydrogen chloride in water (0.4 mL, 2 mmol) for ˜30 minutes. The mixture was diluted with MeOH, filtered and purified on Prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired single enantiomer product. LCMS calculated for C21H22ClN6O2 (M+H)+: m/z=425.1. found: 425.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.27-7.99 (6H, m), 7.63 (1H, s), 5.71 (1H, m), 3.79 (3H, s), 3.40 (3H, s), 1.94 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([NH2:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[NH2:20]
Reactant: NC(=O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: NC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 370 (M+1). 1H-NMR (400 MHz, DMSO-d6), δ (ppm) 3.02-3.07 (m, 1H); 3.17-3.22 (m, 1H); 4.90-4.95 (m, 1H); 7.09-7.24 (m, 6H); 7.49-7.62 (m, 3H); 7.96 (d, 2.4 Hz, 1H); 8.52 (d, 6.4 Hz, 1H); 8.72 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]([C:21]#[N:22])=[N:16][C:17](Cl)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:25].[K+].C(OCC)(=O)C.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]([C:21]#[N:22])=[N:16][C:17]([F:25])=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nc(Cl)cnc1Oc1ccc(OCc2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nc(F)cnc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
In 70 ml of dimethyl sulfoxide was dissolved 3.50 g of 3-[4-(benzyloxy)phenoxy]-6-chloro-2-pyrazinecarbonitrile. After adding 3.01 g of potassium fluoride, the mixture was stirred at 100-110° C. for 3 hours. The reaction mixture was returned to room temperature and added to a mixture of 70 mL of ethyl acetate and 350 mL of water, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:ethyl acetate=5:1] to obtain 1.88 g of 3-[4-(benzyloxy)phenoxy]-6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14]SC2SC3C=CC=CC=3N=2)[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:56](OC(=O)C)(=[O:58])[CH3:57]>C(O)(=O)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14][C:56](=[O:58])[CH3:57])[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:8])[CH3:9]
Reactant: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reaction time: 1.25 h

Procedure:
A solution of 3.26 g of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4 ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine are added. After stirring under nitrogen at the same temperature for 75 minutes, 24.8 ml of pyridine are added to the mixture. After stirring for a further 3 hours at 0°, the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is purified by chromatography over silica gel with toluene and toluene/ethyl acetate (19:1). IR spectrum (in methylene chloride): characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90μ.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12])([CH3:3])[CH3:2].C([Li])CCC.[C:18](=[O:20])=[O:19]>C1COCC1.CCCCCCC>[F:12][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: CC(C)Oc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 639 mg (2.74 mmol) 1-isopropyloxy-2-fluoro-4-bromobenzene (from Step A) in 10 mL of THF at −78° C. was treated with 1.64 mL of 2.0 M n-butyllithium in heptane. After stirring at −78° C. for 30 min, the mixture was poured onto 300 g of crushed dry ice and allowed to warm up to rt. The mixture was partitioned between 100 mL of 2.0 N NaOH and 100 mL of Et2O. The aqueous layer was separated, acidified using 5.0 N HCl to pH 2, and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford 380 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.65-4.73 (m, 1H), 7.00 (t, J=8.5, 1H), 7.79-7.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:23]([NH:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([Cl:38])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:35]2[CH:34]=[C:33]([Cl:38])[N:32]=[C:31]([NH:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:36]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: Clc1cc(Cl)nc(NCc2ccccc2)n1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(Cl)nc(NCc3ccccc3)n2)cc1)Oc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (60 mg, 0.2 mmol), benzyl-(4,6-dichloro-pyrimidin-2-yl)-amine (50 mg, 0.2 mmol) and Cs2CO3 (76 mg, 0.22 mmol) were combined in anhydrous N,N-dimethylformamide (DMF) (5 mL) and stirred at 90° C. in dry atmosphere for 5 h. The DMF was removed in vacuo, the residue was purified in silica to provide a white oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (1.0 g, 3.4 mmol), 2-amino-N,N-dimethylbenzamide (587 mg, 3.5 mmol), di-isopropyl-ethylamine (712 μL, 4.08 mmol) and 15 mL of isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (896 mg, 94%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=[CH:37][C:38]2N(O)N=[N:41][C:39]=2C=1.C(N)CC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:41][CH2:39][CH2:38][CH3:37])=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCN
Solvent: ClCCCl
Product: CCCNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (0.125 g, 0.28 mmol) in DMF (5 mL) was added EDC (0.108 g, 0.56 mmol), HOBT (0.076 g, 0.56 mmol) and n-propylamine (0.12 mL, 1.4 mmol). The mixture was stirred at rt for 2 d. After this time, the mixture was diluted with ethyl acetate and then washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.113 g, 83%) as a light yellow solid. MW=485.00. 1H NMR (DMSO-d6, 500 MHz) δ 8.79 (s, 1H), 8.22-8.16 (m, 2H), 8.06-8.00 (m, 1H), 7.65-7.61 (m, 1H), 7.59-7.53 (m, 3H), 7.33 (d, J=8.5 Hz, 2H), 3.77-3.71 (m, 2H), 3.43 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.43-2.35 (m, 2H), 1.45-1.38 (m, 2H), 0.84 (t, J=7.5 Hz, 3H); APCI MS m/z 485 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:7])[NH:22][N:21]=1
Reactant: Nc1cc(C=C2OC(=O)c3ccccc32)ccc1Cl
Reactant: NN
Solvent: O
Product: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1Cl
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A stirred mixture of the above 3-(3-amino-4-chlorobenzylidene)-3H-isobenzofuran-1-one (0.815 g, 3 mmol), industrial methylated spirit (10 ml) and hydrazine monohydrate (0.15 g, 3 mmol) was heated under reflux for 1 hour then cooled to ambient temperature. The resulting solid was collected by filtration, washed with industrial methylated spirit (5 ml) and water (5 ml), and dried in vacuo to give a pale grey solid. The crude material was recrystallised from acetonitrile (140 ml) and the resulting solid was collected by filtration and dried in vacuo to give 4-(3-amino-4-chlorobenzyl)-2H-phthalazin-1-one (0.607 g) as an off-white solid, m.pt. 227–228° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 4.05 (s, 2H) (ArCH2—), 5.2 (s, 2H) (—NH2), 6.4–6.5 (m, 1H) (ArH), 6.6–6.7 (m, 1H) (ArH), 6.95–7.05 (m, 1H) (ArH), 7.65–7.85 (m, 3H) (3×ArH), 8.1–8.2 (m, 1H) (ArH), 12.5 (s, 1H) (CONH) ; m/z (M+H)+. 286/288, 100% purity.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][N:42]1[CH:46]=[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:3]=2)[CH:44]=[N:43]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (intermediate 66B) (200 mg, 0.322 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (147 mg, 0.483 mmol) using Pd(PPh3)2Cl2 (12 mg, 0.016 mol) and sodium carbonate (86 mg, 0.806 mmol) in toluene/ethanol/water (10/2/2 ml) to afford 200 mg (93.2% yield) of the titled compound after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=669.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH:18]([C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:23][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH:18]([CH3:20])[CH3:19])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CC(C)C1(c2ccncc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccncc2)C(C)C)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
To a stirred solution of sodium hydride (0.192 g, 50-60%) in dry DMF (5 mL) at 0° C. was added 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (0.3 g). The reaction mixture was stirred at RT for 30 min. To the reaction mixture was added 4-(2-isopropyloxiran-2-yl)pyridine (0.317 g in 2 mL DMF) at RT. After 12 h stirring, the reaction mixture was diluted with ice-water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel 100-200 mesh, 5% MeOH:DCM) to obtain pure product (50 mg). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.30 (d, 2H), 7.30 (d, 2H), 7.15 (s, 1H), 7.10 (d, 1H), 6.82 (d, 1H), 4.40 (m, 2H), 4.22 (m, 2H), 3.4 (m, 2H), 3.20 (m, 1H), 2.80 (s, 3H), 2.62 (m, 1H), 2.5 (m, 1H), 2.25 (s, 3H), 1.15 (d, 3H), 0.6 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C)C=O>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][C:38](=[O:39])[NH:37][CH2:35][CH3:36])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (540 mg), triethylamine (0.51 mL) and ethyl isocyanate (0.29 mL) was stirred in dry N,N-dimethylformamide (3 mL). The product slowly precipitated from the reaction mixture and was collected by filtration and washed with ether to yield the title compound as a yellow solid (210 mg).
Reaction SMILES: [B-][N+](C)(C)C.Cl.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2>O1CCOCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2
Reactant: COc1cccc2[nH]ccc12
Agent: Cl
Agent: [B-][N+](C)(C)C
Solvent: C1COCCO1
Product: COc1cccc2c1CCN2
Yield: 82.6 %

Procedure:
Borane-trimethylamine complex (3.00 g) and 10.5N hydrochloric acid (2.25 ml) were added to 4-methoxyindole (1.29 g) in dioxane (20 ml), and the mixture was heated to reflux for 30 minutes. To this mixture, 6N hydrochloric acid (7.00 ml) was added and the mixture was heated to reflux for 15 minutes. The solvent was removed under reduced pressure and 1N aqueous sodium hydroxide solution was added to change the aqueous layer to alkaline condition, followed by extracting the aqueous layer with ether (3×20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (1.08 g, yield: 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH:12]([NH2:14])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[Br:10].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1
Reactant: Fc1cc(Br)c(Br)cc1F
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cc(F)c(F)cc2Br)cc1
Yield: 175.2 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IV, 40 g (147 mmol) of 1,2-dibromo-4,5-difluorobenzene was reacted with 12.3 g (73 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2). Purification by silica gel chromatography with hexane gave 40.3 g of 1-bromo-4,5-difluoro-2-[4-(methylthio)phenyl]benzene as a yellow oil which was used without further purification.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1.CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-fluoro-3-trifluoromethylbenzoyl chloride (200 uL) was added directly into the solution. It was left to stir for 18 hours. The reaction mixture formed a red solution with a yellow precipitate. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (105.1 mg). Yield 47.3%.