Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]2[CH:21]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[C:20](=O)[C:19]3[C:18]([C:29]([O:31]CC)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13]2)[CH:8]=[CH:9][C:10]=1[F:11])=[O:4].O.[NH2:36][NH2:37]>CO>[F:11][C:10]1[CH:9]=[CH:8][C:7]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:29](=[O:31])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:21]2[C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:34])=[O:4]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)c(C(=O)N(C)C)c1)N2
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1cc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (130 mg) in hydrazine monohydrate (85%, 2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain the title compound (30.0 mg, yield 30%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.72 (s, 3H), 2.97 (s, 3H), 3.43 (s, 3H), 4.67-4.70 (d, J=10.8 Hz, 1H), 4.95-4.97 (d, J=10.8 Hz, 1H), 6.72-6.73 (d, J=1.2 Hz, 1H), 6.89-6.89 (d, J=0.8 Hz, 1H), 7.15-7.23 (m, 2H), 7.34-7.41 (m, 3H), 7.48-7.49 (m, 1H), 7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)+.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@@H:29](F)[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@@H](F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
87 μl (490 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.8 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 3 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 60 mg (120 μmol) of 5-(4-fluorophenyl)-6-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 22A) in 3 ml of tetrahydrofuran are then slowly added dropwise, and the mixture is stirred at room temperature for 3 days. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 20:1) gives the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:20]([CH3:33])=[CH:19]2.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:20]([CH3:33])=[C:19]2[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1cc2cc(Cl)ccc2n1CCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3ccc(Cl)cc23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (106 mg, 0.52 mmol) and 4-(2-(5-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (154 mg, 0.55 mmol) in 8 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.63 mL, 1.14 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX002 (141 mg, 0.32 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.32 (s, 3H), 2.47 (t, J=4.3 Hz, 4H), 2.66 (t, J=6.9 Hz, 2H), 2.79 (s, 3H), 3.68 (t, J=4.4 Hz, 4H), 4.19 (t, J=6.9 Hz, 2H), 7.14-7.21 (m, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.69, 19.92, 41.47, 54.08, 57.34, 66.87, 110.25, 115.09, 121.16, 122.69, 124.45, 125.75, 125.99, 126.06, 126.23, 126.66, 127.98, 128.34, 130.46, 132.95, 134.43, 137.27, 138.21, 146.37, 193.24. MS m/z 447.5 [M+H]+.
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][OH:23]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCBr
Yield: 108.1 %

Procedure:
According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6); δ 4.42 (s, 1 H), 3.45 (t, 2 H, J=6.6), 3.08 (s, 2 H), 1.84-1.69 (m, 2 H), 1.27 (t, 2 H, J=8.3), 0.78 (s, 6 H). 13C NMR (DMSO-d6); δ 69.7, 35.7, 34.5, 27.4, 24.0.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14]Br.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[CH2:14][C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[CH:6]=3)[C:3]2=[O:16])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(OC)c(OC)cc1CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)N(c1ccc(Cl)cc1)C2

Procedure:
A solution of 2-bromomethyl-4,5-dimethoxy-benzoic acid methyl ester (2.9 g), 4-chloroaniline (1.28 g) and triethylamine (1.4 ml) was refluxed in toluene for six hours. The reaction mixture was stirred in an ice bath, filtered and washed with 1 M hydrochloric acid and water.
Reaction SMILES: [F:1][C:2]([F:8])=[C:3]([CH3:7])[CH2:4][CH2:5][OH:6].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCCC1>[CH3:9][S:10]([O:6][CH2:5][CH2:4][C:3]([CH3:7])=[C:2]([F:8])[F:1])(=[O:12])=[O:11]
Reactant: CC(CCO)=C(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CCOS(C)(=O)=O)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To 100 ml of tetrahydrofuran, 4.45 g (36 mmol) of 4,4-difluoro-3-methyl-3-butenol and 4.59 g (40 mmol) of methanesulfonyl chloride were dissolved, followed by drop-wisely adding 4.42 g (44 mmol) of triethylamine under ice-cooling. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 7.20 g (yield: 99%) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCO[CH2:18][CH3:19]>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH2:1][NH2:8])=[CH:3][CH:4]=2)[CH2:19][CH2:18][CH2:3][CH2:2][CH2:1]1
Reactant: CCOCC
Reactant: N#Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Benzonitrile 18m (1.2 g, 6.48 mmol) dissolved in 10 ml of ether was added dropwise at 0° C. to LiAlH4 (2 equiv., 493 mg) suspended in diethyl ether (40 ml). The mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and filtrated and the salts were washed with ether. The organic phase was separated, anhydrified and evaporated giving 1 g of an orange oil. Yield=82%. 1HNMR (DMSO, 200 MHz) δ 1.57 (6H, m), 3.06 (4H, m), 3.58 (2H, s), 6.84 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.4 Hz), 7.33 (2H, bs).
Reaction SMILES: C(OC(=O)[N:7]([CH:43]1[CH2:45][CH2:44]1)[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:42])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]3=4)=[O:25])=[CH:20][C:19]=2[CH3:41])[CH2:11][CH2:10]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH:43]1([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:42])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:35][C:34]5[CH:33]=[N:32][N:31]([CH3:36])[C:30]=5[NH:29][C:28]5[CH:37]=[CH:38][CH:39]=[CH:40][C:27]4=5)=[O:25])=[CH:20][C:19]=3[CH3:41])[CH2:11][CH2:10]2)[CH2:44][CH2:45]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CNC2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester from Example E86.3 (220 mg, 0.35 mmol) was dissolved in methanol (5 ml) and 4M HCl solution in dioxan (5 ml) was added. The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give an off-white solid identified as the title compound (189 mg, 95%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][O:46][CH3:45])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (2.5 mg, 18%). MS (m/e): 341.3 (MH+).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH:33]5[CH2:35][CH2:34]5)[CH:31]=[N:30][N:29]=4)[CH:23]=3)=[O:20])[CH:14]=2)=[CH:9][N:8]=1>CN1C=CC=CC1.O1CCCC1>[CH:33]1([N:32]2[CH:31]=[N:30][N:29]=[C:28]2[C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[N:8][C:7]([CH:1]5[CH2:3][CH2:2]5)=[N:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:35][CH2:34]1
Reactant: Br[Mg]C1CC1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(Cl)nc2)ccn1
Agent: CN1C=CC=CC1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(C3CC3)nc2)ccn1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
Cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran, 6.3 mL, 3 equiv) was added to a solution of 4-(2-chloropyrimidin-5-yl)-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide (440 mg, 1.06 mmol) and Fe(acac)3 (37 mg, 10 mmol %) in N-methylpyridine (20 mL) and tetrahydrofuran (5 mL). After stirring for 5 minutes, the brown solution was quenched with 1 M hydrochloric acid (6 mL) and concentrated under reduced pressure at 70° C. The residue was purified by reverse-phase HPLC to give N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-cyclopropylpyrimidin-5-yl)picolinamide as a pale-yellow powder (200 mg, 45% yield).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1>CO>[NH2:6][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:30])([CH3:31])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Yield: 77.2 %

Procedure:
Hydrazine hydrate (1.17 ml, 24 mmol) was added to a methanol solution (60 ml) of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.70 g, 6.0 mmol), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to thereby obtain 1.48 g (yield: 77%) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCl>[C:18]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:20])[CH3:19]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A dichloromethane (1 L) solution of fluorene (150 g) was cooled down to 0° C., and anhydrous aluminum chloride (126 g) was added thereto little by little. Next, a dichloromethane (400 mL) solution of acetyl chloride (74 g) was dropwise added and stirred for one hour while maintaining 0° C. The reaction mixture was poured into 6M-hydrochloric acid (1 L) containing ice, and the solid matters deposited were obtained by filtering under reduced pressure. They were dried and then recrystallized from toluene to obtain 2-acetylfluorene (165 g) of colorless needle crystal. The melting point of this compound was 129° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][S:11](/[CH:14]=[CH:15]/[C:16]2[S:26][C:25]3[N:27]4[C:18](=[CH:19][N:20]=[C:21]4[CH:22]=[CH:23][CH:24]=3)[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:32]1([CH2:31][CH2:30][CH2:29][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][S:11](/[CH:14]=[CH:15]/[C:16]3[S:26][C:25]4[N:27]5[C:18](=[CH:19][N:20]=[C:21]5[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)(=[O:13])=[O:12])[CH2:5][CH2:4]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCCc1ccccc1
Reactant: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)NCC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.285 g (0.634 mM) of (E)-N-(piperidin-4-ylmethyl)-2-(5-thia-1,8b-diazaacenaphthylen-4-yl)vinylsulfonamide dihydrochloride, 0.15 g (0.76 mM) of 1-bromo-3-phenylpropane, and 0.31 ml (2.22 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was then poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol : 9/1) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[N+:1]([C:4]1[C:5]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3,5-dinitro-1-carboxy-2-chlorobenzene (53 g) in acetonitrile (500 mL) and triethylamine (100 mL) was added benzylamine at 0° C. in a dropwise fashion. The reaction was allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to afford the crude product, 3,5-dinitro-1-carboxy-2-(benzyl)aminobenzene. The product was dissolved in methanol/12N HCl (400 mL, 3:1, v/v), and was hydrogenated at 60 psi for 3 hours until H2 intake stopped. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-triamino-1-carboxybenzene. To the product in pyridine (400 mL) was added isobutyric anhydride (200 mL), and the reaction mixture was stirred at ambient temperature for 14 hours. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-tri(isopropylcarbonylamino)-1-carboxybenzene. The product was refluxed in methanol/12N HCl (500 mL, 4:1, v/v) for 16 hours to afford the desired product, 2-isopropyl-4-methoxycarbonyl-6-aminobenzimidazole, after removal of the solvents under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14](N)=[O:15].[OH-:17].[K+].CO>O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14]([OH:15])=[O:17]
Reactant: COc1ccc2c(c1OC)CCC2C(N)=O
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1OC)CCC2C(=O)O
Temperature: 25 °C
Yield: 91.2 %

Procedure:
The mixture of 4,5-dimethoxyindane-1-carboxamide (8.4 g, 38.0 mmol), KOH (6.4 g, 114.0 mmol), MeOH (31.0 mL) and water (62 mL) was heated to refluxed for 14 h. The reaction mixture was cooled to room temperature, and MeOH was removed in vacuo. The residue was diluted by 50 mL of water, and the aqueous mixture was extracted with EtOAc (50×2). The aqueous layer was added conc. HCl to adjusted pH ˜1. The solid was filtered, washed by water (100 mL), and dried over P2O5 to afford 4,5-dimethoxyindane-1-carboxylic acid as off-white solid (7.7 g, 92%). M. P.: 128-130° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:15]([O-:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[CH2:17]([O:16][P:15]([O:19][CH2:20][CH3:21])([C:2]([OH:1])([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:22])[CH3:18]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCN1CCCC1
Product: CCOC(=O)C(O)(CCN1CCCC1)P(=O)(OCC)OCC
Reaction time: 108 h

Procedure:
A mixture of 9.96 g (0.05 mole) of ethyl 2-oxo-4-(1-pyrrolidinyl)butanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for 3-6 days. The excess diethyl phosphite is removed on a rotary evaporator under high vacuum at a bath temperature of 50°-70° to yield the crude product as a viscous oil. This is purified by chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1=[N:12][C:11]([CH3:13])=[N:10][N:9]1[C:19]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:26]
Reactant: N#Cc1ccccc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
2.0 g (10.3 mmol) of 3-(4-Chlorophenyl)-5-methyl-1,2,4-triazole is dissolved in 50 ml of tetrahydrofuran (THF) (freshly distilled from lithium aluminum hydride) mechanically stirred in a 250 ml round-bottom 3-necked flask equipped with a septum and nitrogen inlet and cooled in an ice bath. 13.6 ml (22.7 mmol) of n-butyllithium (1.67 mol/liter in hexane) is injected with a syringe and the mixture is stirred in the ice bath for 30 minutes. 2.12 g (20.6 mmol) of benzonitrile is added in a little THF. After stirring for 30 minutes in the ice bath and for 30 minutes at room temperature, the mixture is poured into a chilled stirred mixture of 100 ml of 2.5 M ammonium chloride and 200 ml of chloroform. The layers are separated and the aqueous layer washed with chloroform. The combined chloroform layers are washed with water and dried (Na2SO4). The chloroform is removed under vacuum and the residue is recrystallized from toluene to yield 1.5 g of the title compound, m.p. 173°-175°.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:3]#[CH:4].Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[C:3]#[C:4][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: C#CC(O)c1ccc(O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(O)cc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne (120 mg, 0.84 mmol) (from Example 17 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-hydroxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 62 mg, 47%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cscn1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cscn1
Yield: 77.2 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 4-thiazolecarboxylic acid (4.8 g), N,N'-carbonyldiimidazole (7.5 g) and 2-amino-7-chloro-1,8-naphthyridine (4.8 g). The product obtained by precipitation in water is purified by recrystallization in dimethylformamide (350 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-thiazolecarboxamide (6 g), m.p. 325° C., is thereby obtained.