Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]=[CH:20][CH:19]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:30]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2ccc3ccc4c(-c5cccc6ccccc56)ccc5ccc2c3c54)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 7 g (17.2 mmol) of 1-bromo-6-(naphthalen-1-yl)pyrene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)Palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.4 g (yield 47%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 670.1; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.11 (s, 1H), 8.89 (d, J=8.00 Hz, 1H), 8.82 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J=8.00 Hz, 2H), 8.38 (d, J=9.20 Hz, 1H), 8.30˜8.26 (m, 3H), 8.19˜8.05 (m, 7H), 8.02˜7.98 (m, 2H), 7.83˜7.82 (m, 2H), 7.78˜7.68 (m, 5H), 7.61˜7.59 (m, 2H), 1.79 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1.OO.S(=O)(=O)(O)[OH:32]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]([OH:32])=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3cccc(F)c3)ccc2c1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3cccc(F)c3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Charge a 100 mL round-bottom flask with 4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-benzaldehyde (2.5 g, 6.71 mmol) and ethyl acetate (5 mL). At room temperature add 2 mL of 35% hydrogen peroxide. To this solution slowly add 2 mL of concentrated sulfuric acid. The mixture warms to approximately 40° C. and returns to room temperature where it is stirred for 2 hours. Dilute the reaction with water and ethyl acetate (100 mL) and dry the organic layer over sodium sulfate, filter and concentrate in vacuo. Purify the crude product using radial chromatography eluting with CH2Cl2 to yield 540 mg (22%) of the title compound: mass spectrum (ion spray) m/z=359 (M−H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8]1([CH2:18][CH2:19][CH2:20]I)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1.O>[C:3]([CH:2]([CH2:20][CH2:19][CH2:18][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:1]#[N:5])#[N:4]
Reactant: N#CCC#N
Reactant: ICCCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A solution of 0.7 gram (0.011 mole) of malononitrile in 50 mL of tetrahydrofuran was stirred, and 0.5 gram (0.011 mole) of sodium hydride (60% in mineral oil) was added portionwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for 30 minutes at ambient temperature. After this time a solution of 3.0 grams (0.010 mole) of 3-(naphth-1-yl)propyl iodide (prepared as in Example 9, Steps A-D) in about 5 mL of tetrahydrofuran was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. The reaction mixture was acidified with aqueous 6N hydrochloric acid and then was further diluted with 100 mL of water. The mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated to a residue which was subjected to column chromatography on silica gel. Elution was accomplished using 40% to 65% methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of 2-cyano-5-(naphth-1-yl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1>CO.[Ni]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)nc(Cl)c1N
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-nitro-pyridin-4-amine (2.6 g, 14.4 mmol) from Step A in MeOH (150 mL) was added Raney Nickel catalyst (2 g) and the reaction agitated under a hydrogen atmosphere in a Parr apparatus (35 p.s.i.) for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated to yield the title compound. MS: m/z=179 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH:3]([C:14]([O-])=O)([C:9]([O:11]CC)=[O:10])[CH2:4][CH2:5][C:6]([O-:8])=O.Br[CH:18]([CH2:24][CH2:25][CH2:26][CH2:27]CC)[C:19](OCC)=O>CN(C)C=O.CCCCC>[CH2:19]([CH:14]1[C:6](=[O:8])[CH2:5][CH2:4][CH:3]1[C:9]([OH:11])=[O:10])[CH2:18][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: CCOC(=O)C(CCC(=O)[O-])C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCCCCCC1C(=O)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
In a 1 L three necked flask fitted with a mechanical stirrer, a thermometer, a nitrogen inlet tube and a calcium chloride drying tube, is placed a suspension of 5.75 g of sodium hydride in 250 ml of dry dimethylformamide. Dry nitrogen is let in and 69 g of ethyl propane-1,1,3-tricarboxylate (G.A. Swan, J.Chem.Sooc., 1039 (1955)) is added dropwise with vigorous stirring. The rate of addition is adjusted to maintain an internal temperature of about 25° C. The reaction mixture is stirred at room temperature until all the sodium hydride has reacted. 60 g of ethyl α-bromocaprylate (K. Bernhard, Helv.Chim.Acta, 29, 1462 (1964)) are added over a period of 1 hour. After the addition has been completed, the reaction mixture is stirred at 100° C for 5 hours. The reaction mixture is cooled to 10° C and added dropwise to a well stirred suspension of 5.75 g of sodium hydride in 50 ml of pentane under nitrogen atmosphere over a period of 2 hours. When the addition is completed, the mixture is stirred at room temperature for an additional 12 hours. The solvent is removed at a reduced pressure and the residue is poured into 1500 ml of cold 5% hydrochloric acid. The organic layer is separated and the water phase is extracted with ether. The combined organic layer and the ether extract are washed with water and sodium carbonate solution and dried over anhydrous sodium sulphate. After removal of the solvent, the unreacted ethyl propane-1,1,3-tricarboxylate is distilled off at 100°-105° C/0,15 mm (16 g) and the residue is boiled for 20 hours with a mixture of 750 ml of acetic acid and 750 ml of concentrated hydrochloric acid. The volatile acids are distilled off at a reduced pressure and the residue is poured onto a large excess of crushed ice. The solid product is collected on a Buchner funnel, washed repeatedly with cold water and dried. The product is recrystallized from cyclohexane-pentane to yield 21,5 g (78%) of 2-n-hexyl-3-oxo-cyclopentane-carboxylic acid melting at 73°-74° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CCN
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
To the solution of 2,4-dichloro-6-isopropylamino-s-triazine in toluene remaining in the reactor are added, under strong agitation, about 915 g of an aqueous solution containing 50% by weight of ethylamine (10.15 moles) and about 1353 g of an aqueous solution containing 30% by weight of sodium hydroxide (10.15 moles). The said solutions are added in the same manner as in the first reaction step. During the second addition the temperature rises from 25° to 50° C. and the final pH is equal to 11.-12. The dense suspension thus obtained is divided into two parts as quickly as possible. One part (A) is submitted to distillation to remove the toluene in the form of an azeotropic toluene-water mixture, by operating at 85°-100° C. To the distillation residue are added 3,700 ml of water and the suspension thus obtained is filtered at 60° C. The filtered solid is washed until the sodium chloride has been removed completely. After drying for ten hours in an oven at 100° C., 2-chloro-4-ethylamino-6-isopropylamino-s-triazine is obtained with a yield of the orde of 96%.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: ClCCCBr
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
mixture of 2.0 g of ethyl mercaptoacetate, 3.13 g of 1-bromo-3-chloropropane, 2.29 g of anhyrous potassium carbonate and 10 ml of dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide and water in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure The residue was applied to silica gel column chromatography and eluted with a mixture of hexane-ethyl acetate (15:1) to obtain 2.65 g of oily ethyl [(3-chloropropyl)thio]acetate.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:35][C:36]1([CH3:39])[CH2:38][O:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([OH:37])([CH3:39])[CH3:38])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CC1(C)CO1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.48 g) in N,N-dimethylacetamide (10 mL) were added 2,2-dimethyloxirane (0.77 g) and cesium carbonate (0.70 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a pale-yellow solid (0.36 g, 64%).
Reaction SMILES: C(O[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[C:22]([F:23])=[C:21]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:20]=[CH:19][C:18]=3[N:32]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[N+](C1C=CC(S([O:45][CH2:46][C@H:47]2[CH2:49][C:48]2([F:51])[F:50])(=O)=O)=CC=1)([O-])=O>>[F:51][C:48]1([F:50])[CH2:49][C@@H:47]1[CH2:46][O:45][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[C:22]([F:23])=[C:21]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:20]=[CH:19][C:18]=3[N:32]=2)=[N:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CC(=O)N[C@@H](C)COc1ncc2nc(-c3ccc(OCc4ccccc4)cn3)oc2c1F
Product: CC(=O)N[C@@H](C)COc1ncc2nc(-c3ccc(OC[C@H]4CC4(F)F)cn3)oc2c1F

Procedure:
Using N-((2S)-1-((2-(5-(benzyloxy)pyridin-2-yl)-7-fluoro[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step A of Example 4 and Example 5, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-3-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H)+: m/z=613.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13](C1C=CC=C(C#N)C=1)#[N:14]>>[N:12]1[NH:11][N:10]=[N:9][C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(C#N)c1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Product: N#Cc1cccc(-c2nn[nH]n2)c1

Procedure:
Following the procedure in COMPOUND 3 for the synthesis of 5-(3-bromophenyl)-2H-tetrazole, 1,3-dicyanobenzene (2.0 g, 15.63 mmol) was employed to obtain 3-(2H-tetrazol-5-yl)benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CSC1CCCCC1
Solvent: ClCCl
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CS(=O)C1CCCCC1

Procedure:
Treating the resultant compound of Example 3 with 1.05 equivalents of 3-chloroperoxybenzoic acid in dichloromethane, gave the desired compound after chromatography. Mass spectrum: M+ =361.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Yield: 54 %

Procedure:
N-[3-Chloro-4-(2-pyridylmethoxy)phenyl]-6-nitro-quinazolin-4-amine 4d (4.07 g, 10 mmol) and concentrated hydrochloric acid (2 mL, 24 mmol) were dissolved in 130 mL of the solvent mixture of 95% ethanol and water (V/V=10/3), followed by addition of iron powder (11.17 g, 200 mmol). The reaction mixture was heated to reflux for 2 hours, filtered while hot and the filtrate was concentrated under reduced pressure to remove ethanol. The resulting residue was adjusted to pH>7 with ammonium hydroxide, filtered and the filter cake was dried under vacuum, purified by silica gel column chromatography with elution system A to obtain the title compound N4-[3-chloro-4-(2-pyridylmethoxy)phenyl]quinazoline-4,6-diamine 4e (2.04 g, yield 54.1%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:3]1=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:3]2=[O:27])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 1-{[(3-amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 193°-194° C.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:29][CH:30]=1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)c2cccnc2)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)c2cccnc2)cc1
Yield: 55.6 %

Procedure:
The procedure of Preparation Example 9 was repeated, except that 222 mg of 4-[N-(4-benzyloxybenzyl)-N-(3-pyridyl)amino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]-phenyl methanesulfonate, and 3 ml of ethyl acetate was used in place of dioxane. The resulting mixture was stirred for 3 days under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 95 mg of 4-[N-(4-hydroxybenzyl)-N-(3-pyridyl)amino]benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]([CH3:44])[CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:34]1([N:37]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH3:44])[CH2:35][CH2:36]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CN(C[C@H]1CCCN1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (146 mg, 0.29 mmol), cyclopropyl-methyl-(R)-1-pyrrolidin-2-ylmethyl-amine (71 mg, 0.46 mmol), HOBt (54 mg, 0.4 mmol), EDAC (74 mg, 0.39 mmol) and TEA (0.085 mL) in DMF (3 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give 133 mg (71%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
Using the method of Example 12, 6-amino-2-nitro-3-phenylbenzofuran is reacted with acetic anhydride to provide 6-acetamido-2-nitro-3-phenylbenzofuran, m.p. 212°-214° C.