Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CN(C)C=O>[C:22]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-4-hydroxy-cinnoline-3-carboxamide (1 g) is reacted with acetic anhydride (5 ml) in dimethylformamide (50 ml) in the presence of pyridine (5 ml) at 80° C. for 2 hours. After cooling the reaction mixture is diluted with ice water and the precipitate is filtered and washed with water: washing with hot ethanol gives 0.75 g of N-(3-acetylamino-phenyl)-4-hydroxy-cinnoline-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][C:21]=1B(O)O>COCCOC.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>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([O:26][CH:27]([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)F)cc1Cl
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 70 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (5.0 g, 18.9 mmol) in DME/H2O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454, which is incorporated by reference herein in its entirety) (4.20 g, 18.9 mmol), Ba(OH)2 8H2O (5.96 g, 18.9 mmol), and Pd(PPh3)2Cl2 (0.769 g, 1.10 mmol) were treated as in Part A of Example 113 to give 5.40 g (70%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil. The crude intermediate was used in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A mixture of methyl 2-amino-5-bromobenzoate (23.34 g, 101 mmol) in pyridine (100 mL) was treated with a solution of benzenesulfonyl chloride (14 mL, 110 mmol), stirred for 16 hours at ambient temperature, and concentrated. The concentrate was dissolved in dichloromethane, washed twice with 1N NaHSO4, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from 3:1 ethanol/water (200 mL) to provide the desired product (33.4 g). MS (DCI) m/e 387, 389 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.77 (s, 1H), 7.75 (dd, 1H), 7.66 (d, 1H), 7.61-7.53 (m, 2H), 7.39 (d, 1H), 3.79 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH2:51])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH:51][C:7]([C:5]3[N:4]=[CH:3][C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=3)=[O:9])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cnc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)cn1
Reaction time: 5 h

Procedure:
Pyrazine-2,5-dicarboxylic acid (0.58 g; 3.42 mmol), anhydrous HOBt (0.69 g; 5.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) were added to 5 ml of DCM. 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (1.0 g; 3.42 mmol) and DIPEA (0.89 ml; 5.13 mmol) were dissolved in 5 ml of DCM and added dropwise to the previous mixture. The reaction mixture was stirred overnight after which pyrazine-2,5-dicarboxylic acid (0.58 g; 1.59 mmol) and DIPEA (0.60 ml; 3.42 mmol) were added and the mixture was again stirred for 5 h. Anhydrous HOBt (0.69 g; 5.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) and DIPEA (0.89 ml; 5.13 mmol) were again added to drive the reaction to completion. After overnight stirring the mixture was diluted with 20 ml of DCM and washed with 3×10 ml water. The organic phase was dried over Na2SO4, filtered and used as such without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A solution of indole (5.6 g 48 mmol,) in DMF at 0° C. was treated with sodium hydride (1.84 g, 48 mmol), stirred for 10 minutes at room temperature, treated with methyl 4-(bromomethyl)benzoate (10 g, 44 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 30%) to give the title product in 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 266 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl trans-4-aminocyclohexylcarbamate as in previous examples gave tert-butyl trans-4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexylcarbamate in 88% yield: mp (CH2Cl2/hexanes) 218-221° C.; 1H NMR (DMSO-d6) δ 8.10 and 7.97 (2d, J=8.3, 8.1 Hz, 1H), 7.87 and 7.72 (2t, JHF=53.1, 53.0 Hz, 1H) 7.83 and 7.77 (2d, J=7.7, 8.10 Hz, 1H), 7.38 (q, J=8.3 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.75-6.70 (m, 1H), 3.98 and 3.97 (2s, 3H), 3.97 (m, 4H), 3.71-3.69 (m, 4H), 1.98-1.91 (m, 2H), 1.85-1.82 (m, 2H), 1.40-1.22 (m, 4H), 1.38 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H, 6.5; N, 19.3%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(Cl)=O)(C)C.C(N(CC)CC)C.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>CS(C)=O>[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][N:53]([C:13]([C:11]5[O:12][C:8]([CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)=[CH:9][CH:10]=5)=[O:15])[CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:32])=[O:33]
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(CN6CCOCC6)o5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Morpholin-4-ylmethyl-furan-2-carboxylic acid (0.12 mmol, 25 mg), and isopropylchloroformate (0.12 mmol, 17 μL) and triethylamine (0.12 mmol, 17 μL) were dissolved in DMSO (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.12 mmol, 50 mg) and excess triethylamine were added. The mixture was heated in a microwave for 5 minutes at 120° C. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided compound A116 as a white solid. LCMS (ESI), m/z 567.3 (MH+, 100%).
Reaction SMILES: [N:1]([CH2:4][CH2:5]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:13][S:14]([O:17][CH2:18]CN=[N+]=[N-])(=[O:16])=[O:15]>>[CH3:13][S:14]([O:17][CH2:18][CH:4]([N:1]=[N+:2]=[N-:3])[CH3:5])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCCO
Agent: CS(=O)(=O)Cl
Product: CC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 3-azidopropanol (1.00 g, 9.90 mmol) and mesyl chloride (1.14 mL, 14.85 mmol) within 3 h as described for synthesis of 156a gave compound 156b (1.18 g) as a crude colorless oil.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:68]=[CH:67][CH:66]=[CH:65][C:62]=1[C:63]#[N:64].CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[N:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])=[CH:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#Cc1cccnc1Cl
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1cccnc1-c1ccc(O)cc1

Procedure:
Compound 56A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 2-chloronicotinonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: ESI (+)/LC/MS: 197 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]2=[O:22])=[CH:4][CH:5]=1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Schemes 1 and 2, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with 1,3-Dihydro-benzoimidazol-2-one (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[CH:27]=[O:28]>CO>[CH2:2]([S:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[CH:27]=[O:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CO
Product: O=CC1=C(SCc2ccccc2)c2ccccc2OC1c1ccccc1
Reaction time: 0.25 h

Procedure:
1.25 g sodium is allowed to react with 150 ml absolute methanol. When all the sodium has disappeared, one adds 6 ml benzylmercaptan and 13.5 g 4-chloro-3-formyl-flav-3-ene and refluxes over 15 minutes. After solvent evaporation and extraction with methylene chloride the residue is crystallized in a mixture of hexane and diisopropylether. Pure 4-benzylmercapto-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 99°-100° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][C:27]([N+:28]([O-])=O)=[C:20]4[C:21]=3[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15]2=[O:31])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].C(Cl)Cl>C(O)(=O)C>[NH2:28][C:27]1[CH:26]=[CH:25][C:22]2[C:23](=[O:24])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[C:15](=[O:31])[C:16]3[C:21]=2[C:20]=1[CH:19]=[CH:18][CH:17]=3
Reactant: O=C1c2cccc3c([N+](=O)[O-])ccc(c23)C(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc2c3c(cccc13)C(=O)N(C1CCN(Cc3ccccc3)CC1)C2=O
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of stannous chloride (5.0 g; 22.2 mmol) and 2-(1-benzylpiperidin-4-yl)-2,3-dihydro-6-nitro-1H-benz[de]isoquinoline-1,3-dione (1.9 g; 4.75 mmol), prepared as in Example 3, in glacial acetic acid (5 mL) was added 10% hydrochloric acid (7 mL). The reaction mixture was stirred for 2 hours and then a mixture of 10% sodium hydroxide and methylene chloride was added. The aqueous layer was extracted three additional times with methylene chloride and then the combined extracts were dried over potassium carbonate. Filtration and concentration of the methylene chloride extracts gave 6-amino-2-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (1.5 g; 3.90 mmol), m.p. 226°-228° C. Anal.: Calcd. for C21H21N3O3Cl2 . 0.333 H2O: C, 57.30; H, 4.96; N, 9.54. Found: C, 57.39; H, 5.06; N, 9.52.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH2:18][CH3:19])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([CH:30]=O)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1>>[Cl:21][C:22]1[C:23]([CH2:30][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]3([CH2:18][CH3:19])[C:14]([F:15])([F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]3)[CH:7]=2)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1
Reactant: CC[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=Cc1nn(C(F)F)cc1Cl
Product: CC[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COCC1(F)F
Yield: 23.2 %

Procedure:
In an analogous manner as described for example 2 the reductive amination of (R)-5-(5-amino-2-fluoro-phenyl)-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (intermediate A10F) (28.7 mg, 100 μmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol) yielded the title compound (10.5 mg, 23.2%) as a colorless oil. MS (ISP): m/z=452.1 [M+H]+and 454.1 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].ClC(Cl)C.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]1[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1c(Br)cccc1Br
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1cccc(Br)c1-n1cccc1

Procedure:
To a 200 mL round bottom flask was added 2,6-dibromoaniline (8.63 g, 34.7 mmol, 1.0 equiv.), dichloroethane (35.0 mL, 1.0 M), acetic acid (35.0 mL, 1.0 M), and 2,5-dimethoxytetrahydrofuran (10.5 mL, 3.3 M). A reflux condenser was fitted to the flask and the mixture was heated to reflux for 2 hours. During this time the solution slowly changes colors from clear to yellow. An aliquot was removed and the reaction was judged complete by NMR. The mixture was diluted with CH2Cl2, rinsed with H2O, and then rinsed with saturated aqueous K2CO3. The organic layer was dried over MgSO4 and filtered through a pad of SiO2 with CH2Cl2 as eluent. The oil was place under high vacuum overnight to remove the excess 2,5-dimethoxytetrahydrofuran. During this time 1-(2,6-dibromophenyl)-1H-pyrrole, 2, changes to a white solid (8.72 g, 29.1 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ7.68 (d, J=8.0 Hz, 2H), 7.18 (t, J=8.4 Hz, 2H), 6.72 (t, J=2.0 Hz, 2H), 6.42 (t, J=2.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(N)c2)cc1
Yield: 70.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(2-phenylethyl)amine (2.70 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.52 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (1.74 g) as a clear colorless oil.
Reaction SMILES: Cl.Cl.[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>ClCCl>[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[CH2:20][CH2:21]2)[CH:10]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
N-tert-Butyl-3-(piperazin-1-ylmethyl)benzamide dihydrochloride (0.50 g, 1.44 mmol) was suspended in stirred dichloromethane (20 mL) at 0° C. (ice-bath) under an argon atmosphere. N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 5.75 mmol) was added slowly. After 10 minutes stirring, the resulting solution was treated with a suspension of 4-nitrobenzoyl chloride (0.267 g, 1.44 mmol) In dichloromethane (10 ml). The ice-bath was removed and stirring continued for 1 hour. The solution was diluted with dichloromethane (70 mL) and washed with water (×4). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give the title compound (0.58 g) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CC(C)=O.O>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:11]([F:16])[CH:10]=2)[CH:7]=1
Reactant: Nc1cc(Oc2ccc(N)c(F)c2)ncn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ncn1
Reaction time: 3.5 h
Yield: 44 %

Procedure:
After dissolving 4-amino-6-(4-amino-3-fluorophenoxy)pyrimidine (730 mg) in acetone (60 ml)-water (30 ml), sodium hydrogencarbonate (335 mg) and benzyl chloroformate (0.550 ml) were added while cooling in an ice water bath and the mixture was stirred at the same temperature. After 3.5 hours, sodium hydrogencarbonate (140 mg) and benzyl chloroformate (0.120 ml) were added and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate (50 ml)-tetrahydrofuran (100 ml) and saturated aqueous sodium hydrogencarbonate (50 ml) were added to the residue, and the mixture was stirred. The organic layer was separated and washed with a small amount of brine, and then the organic layer was concentrated under reduced pressure. Ethyl acetate (25 ml) was added to the residue and the mixture was stirred. The precipitated insoluble portion was filtered prior to washing with ethyl acetate (5 ml×3). The filtrate was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2 to 1:4) to provide the title compound (514 mg, 44%) as pale brown powder.