Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][NH2:13]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in ethanol (100 mL) was added methylamine (40% in methanol, 34.8 mL) at room temperature, and the mixture was stirred for 1 hr. The obtained mixture was cooled to 0° C., and the resulting precipitate was collected by filtration and washed with ice-cooled ethanol and diisopropyl ether. The obtained solid was dried to give the title compound (24.8 g) as a yellow solid.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:32])[CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])[CH2:21][C@@H:20]([C:33](=[O:56])[N:34]([CH:53]4[CH2:55][CH2:54]4)[C:35]4[CH:36]=[CH:37][C:38]5[O:43][C:42]([CH3:45])([CH3:44])[C:41](=[O:46])[N:40]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:39]=5[CH:52]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1>CC#N>[CH:53]1([N:34]([C:35]2[CH:36]=[CH:37][C:38]3[O:43][C:42]([CH3:45])([CH3:44])[C:41](=[O:46])[N:40]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:39]=3[CH:52]=2)[C:33]([C@@H:20]2[CH2:21][C@H:22]([NH:24][C:25](=[O:32])[CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])[CH2:23][NH:18][CH2:19]2)=[O:56])[CH2:55][CH2:54]1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C(CO)C(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Solvent: CC#N
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@H]3CNC[C@@H](NC(=O)C(CO)C(C)C)C3)C3CC3)cc21

Procedure:
The title compound is prepared by Fmoc deprotection of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-(2-hydroxymethyl-3-methyl-butyrylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester analogously as described in Example 134. MS: 545 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.43, 2.61 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([OH:18])=O)(=[O:13])=[O:12].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:18])(=[O:12])=[O:13]
Reactant: COC(=O)CCCN
Reactant: O=C(O)CNS(=O)(=O)c1ccc2ccccc2c1
Product: COC(=O)CCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 30 which is concerned with the preparation of starting materials, N-(2-naphthylsulphonyl)glycine was reacted with methyl 4-aminobutyrate to give methyl 4-[2-(2-naphthalenesulphonamido)acetamido]butyrate in 56% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)=[CH:17][C:16]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Yield: 183.8 %

Procedure:
3-Aminophenylboronic acid (3.9 g), 5 g of 5-bromo-2-fluoronitrobenzene, 0.8 g of tetrakis(triphenylphosphine)-palladium and 23 mL of 2 M sodium bicarbonate solution in 50 mL of toluene under nitrogen was refluxed for 2.5 hours. The reaction was poured into 200 mL of ice water and the mixture extracted three times with 50 mL of ethyl acetate each time. The combined organic layers were washed with 50 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate and concentrated to give 9.7 g (92% yield) of 2-fluoro-5-(3-aminophenyl)nitrobenzene as a dark brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]([CH3:21])[CH2:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([O:19][CH3:20])[CH:6]=2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:19][CH3:20])[CH:6]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: COc1ccc2c(c1)CC(C)C(Br)=C2c1ccc(Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(-c3ccc(Cl)cc3)c(Br)c(C)cc2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 3-bromo-4-(4-chlorophenyl)-7-methoxy-2-methyl-1,2-dihydronaphthalene (5.5 g, 15.1 mmol) in toluene (100 mL) was vacuum flushed with Ar. DDQ (5.2 g, 22.7 mmol) was added and the mixture heated to reflux for 1.5 h. The heterogeneous red-brown mixture was cooled to room temperature and the toluene removed in vacuo. The resulting residue was taken up in DCM (300 mL) and filtered to remove precipitated DDHQ. The resulting mother liquor was absorbed on silica gel and purified by Yamazen column chromatography (15% DCM/Hex) to afford 5.21 g (95%) of the title compound as an amorphous yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 7.66 (s, 1H); 7.49 (br d, J=2 Hz, 2H); 7.24-7.18 (m, 3H); 7.07 (d, J=2 Hz, 1H); 6.97 (dd, J=9.2, 2 Hz, 1H); 3.91 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].N[C@H](C(O)=O)CCCNC(=N)N.N[C@@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)CCSC.N[C@@H](C(O)=O)CCSC.N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CCCN>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: CSCC[C@@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
D-Lys, Arg, D-Arg, homo-Arg, D-homo-Arg, Met, D-Met, lie, D-Ile, Orn, D-Om
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH3:24])[C:20]([CH2:22][OH:23])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH3:24])[C:20]([CH2:22][O:23][C:33](=[O:35])[CH3:34])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(CO)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Yield: 74.4 %

Procedure:
A mixture of 1.9 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazole-2-methanol, 1.55 parts of acetic acid anhydride and 45 parts of methylbenzene is stirred and refluxed for 2 hours. The reaction mixture is cooled, washed with a diluted ammonium hydroxide solution and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane (20:20 by volume). The product is filtered off and dried, yielding 1.5 parts (74.4%) of {5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-ylmethyl}acetate; mp. 201.1° C.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[O:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[O:51][CH:55]=[CH:54][N:53]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: NCc1ncco1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ncco1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 57% yield: mp 152-153° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (s, 1H), 7.41-7.32 (m, 2H), 7.09 (s, 1H), 7.07-6.98 (m, 2H), 6.54 (t, J=5.2 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J=5.2 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 415.1 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH2:12][C@H:11](OS(C)(=O)=O)[C@@H:10]([NH2:18])[C@H:9]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3].[CH2:25]([NH2:28])[CH:26]=[CH2:27]>>[CH2:2]([O:4][C:5]([C:7]1[CH2:12][C@H:11]([NH:28][CH2:25][CH:26]=[CH2:27])[C@@H:10]([NH2:18])[C@H:9]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]
Reactant: C=CCN
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](OS(C)(=O)=O)C1
Agent: Cl
Product: C=CCN[C@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@@H]1N
Temperature: 110 °C
Yield: 316.8 %

Procedure:
A solution of 6.95 g (19.9 mmol) of (3R,4S,5S)-4-amino-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester hydrochloride and 6.1 ml (79. 6 mmol) of allylamine in 82 ml of tert.-butyl methyl ester was sealed in a pressure vessel under argon and heated to 110° C., resulting in a 4 bar internal pressure. After 20 h the mixture was cooled to room temperature and partitioned between 30 ml of tert.-butyl methyl ester and 120 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted with 50 ml tert.-butyl methyl ester, and the combined organic phases were dried over sodium sulfate, filtered and evaporated to give 5.90 g (96%) of product as a slightly brownish oil. Purity: 77% (ISTD).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:34]C)=[CH:6][C:7]([O:32]C)=[C:8]([C:10]2[N:11]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[Cl-].[NH+]1C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][N:14]=2)[C:7]([OH:32])=[CH:6][C:5]=1[OH:34])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccccc2)n1-c1ccc2c(ccn2C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2nnc(Nc3ccccc3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O
Temperature: 210 °C
Yield: 66.7 %

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dimethoxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (27 mg; 0.06 mmol) and pyridinium chloride (2 g.). The reactants were placed under a nitrogen atmosphere, and the reaction was heated to 210° C. for 25 minutes. To the cooled reaction mixture was added dichloromethane and saturated ammonium chloride solution. The organic fraction was isolated, and the product was purified by column chromatography to give 4-Isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-phenylamino-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol (18 mg; 0.04 mmol.)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40]CC)=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].[ClH:45]>C(O)C>[ClH:45].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([OH:40])=[O:39])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)c1OC
Temperature: 25 °C
Yield: 86 %

Procedure:
0.51 g of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (Example 12a)) is held at reflux in 7 ml of ethanol and 7 ml of a 2N aqueous sodium hydroxide solution for one hour. The reaction mixture is cooled to room temperature and acidified with 25% aqueous hydrochloric acid. The precipitated substance is filtered off under suction, washed with 20 ml of water, 20 ml of ethanol and 20 ml of ether and dried. 444 mg (86%) of 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride are obtained as a colourless solid. M.p.>230°. Mass spectrum (ISP): peaks: inter alia at 548.5 (M++H, 100%).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:10])[CH2:8][OH:9].[CH3:11][C:12]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:25][O:26][CH3:27])[CH:23]=O>[Cl-].[Na+].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:27][O:26][N:25]=[C:22]([CH:23]1[O:10][CH2:7][CH2:8][O:9]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:13]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:12]=1[CH3:11]
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CON=C(c1ccccc1COc1cc(C)ccc1C)C1OCCO1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Benzene (4 ml), ethylene glycol (0.12 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.3 g, 1.0 mmol), and the mixture was subjected to azeotropic dehydration for 2 hours. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3-dioxolan-2-yl ketone O-methyloxime (0.30 g, yield 87.9%) as colorless crystals. mp 136-137° C.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C([Mg]Cl)(C)C.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([F:9])[C:7]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: COc1cc(OC)c(F)c(I)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (1.50 g, 5.00 mmol) in tetrahedrofuran (THF, 20 mL) was slowly added 2.0 M isopropyl magnesium chloride in THF (2.87 mL, 5.75 mmol) at −10° C. under an atmosphere of nitrogen. After 10 min., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.27 mL, 6.25 mmol)(Aldrich, Cat. No. 417149) was added. The reaction mixture was then stirred at ambient temperature for 2 h. The mixture was quenched with sat. NH4Cl, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue (solid) was treated with ethyl ether, filtered, and dried under reduced pressure to afford the desired product (1.20 g, 80%). 1H-NMR (400 MHz, CDCl3): 6.70 (t, J=8.2 Hz, 1H), 3.85 (s, 6H), 1.38 (s, 12H). LCMS (M+H)+=301.1.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:24])[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:25]>CO.CCOC(C)=O.[Pd]>[ClH:25].[CH3:24][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH2:22][CH2:23][NH:11][CH2:12][C:13]1=2
Reactant: Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c2c(c3ccccc31)CCNC2
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.17 g, 16.2 mmole) in methanol (100 mL), EtOAc (25 ml) and HCl (17 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (3.19 g, 92%) as a white solid: MS (ES) m/e 187 (M+H−HCl)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]3[CH3:16])=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:22](Cl)([CH3:25])([CH3:24])[CH3:23]>C(OCC)C>[CH3:16][C:11]1[C:10]2[C:15](=[C:2]([Sn:22]([CH3:25])([CH3:24])[CH3:23])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cccc2c(Br)c3ccccc3nc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc2c([Sn](C)(C)C)c3ccccc3nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 9-bromo-4-methylacridine 9 (1 g, 3.7 mmol) in 50 ml anhydrous diethyl ether was cooled to −78° C. under nitrogen. To the solution was added 1.6 M n-BuLi in hexanes (0.74 mmol, 0.46 mL) dropwise over a period of 15 min and a 1.0 M solution of Me3SnCl in hexanes (0.81 mL, 0.81 mmol). The reaction solution mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:10:1 hexanes:ethyl acetate:triethyl amine) afforded 11 (1.1 g, 84%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 4-methylacridine that could not be separated by chromatography. The stannane was therefore employed in the Stille coupling with 1,8-dibromonaphthalene without further purification. 1H-NMR δ=0.67 (s, 9H), 2.95 (s, 3H), 7.41 (dd, J=6.9 Hz, J=8.8 Hz, 1H), 7.52 (ddd, J=1.4 Hz, J=6.5 Hz, J=6.5 Hz, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.74 (ddd, J=1.4 Hz, J=7.4 Hz, J=7.4 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 8.28 (d, J=7.9 Hz, 1H). 13C-NMR δ=−4.63, 19.51, 125.33, 125.56, 128.42, 128.94, 129.30, 129.93, 131.38, 133.49, 133.62, 138.58, 147.36, 147.53, 156.78.
Reaction SMILES: [Si]([O:18][C:19]1[CH:63]=[CH:62][C:22]([O:23][CH2:24][C@@H:25]([OH:61])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:46]=[C:47]([NH:51][C:52]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[O:53])[CH:48]=[CH:49][CH:50]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:55]([NH:54][C:52]([NH:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][CH:25]([OH:61])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:63][CH:62]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)[CH:46]=1)=[O:53])[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCNCC(O)COc3ccc(O)cc3)cc2)c1
Yield: 49.1 %

Procedure:
N-(3-{3-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}phenyl)-N′-hexylurea (0.19 g, 0.22 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.067 g, 0.108 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[S:14])[NH:8][C:7]=2[O:6][C:5](=[O:15])[CH:4]=1)[CH3:2].O.[CH3:17]N(C=O)C>>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([S:14][CH3:17])=[N:8][C:7]=2[O:6][C:5](=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(=O)oc2[nH]c(=S)[nH]c(=O)c12
Reactant: CN(C)C=O
Solvent: O
Product: CCc1cc(=O)oc2nc(SC)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Mel (2.23 mL, 35.72 mmol) was added to a suspension of 5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (4.0 g, 17.86 mmol) in DMF (40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water (250 mL) and filtered through a sintered funnel. The solid residue was washed with water (2×50 mL) and dried under vacuum to give 5-ethyl-2-methylsulfanyl-3H-pyrano[2,3-d]pyrimidine-4,7-dione (4.1 g, 96%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N([CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=[CH:45][CH:44]=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=[CH:45][CH:44]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3cccc4ccccc34)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3cccc4ccccc34)c3c2CCNCC3)cc1

Procedure:
The title compound (0.015 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-naphthalen-methyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 3-(4-chloro-phenyl)-2-naphthalen-1-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C24H22ClN3, 387.15. found, m/z 388.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.79-7.18 (m, 11H), 5.74 (d, J=7.3 Hz, 2H), 3.42 (s, 2H), 3.21-3.19 (br m, 2H), 3.10-3.08 (br m, 2H), 2.92-2.90 (br m, 2H), 2.84-2.82 (br m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 29 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (3.56 g, 19.8 mmol; commercial) and (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (prepared according to J. Org. Chem. (2008), 73, 1093; 4.0 g, 19.8 mmol) in EtOH/H2O (9:1; 140 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (2.20 g, 29% yield).