Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[N:31]=[C:30]3[N:32]([CH3:39])[C:33]4[CH2:38][CH2:37][NH:36][CH2:35][C:34]=4[C:29]3=[CH:28][CH:27]=2)[C:22](=[O:40])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:36]1[CH2:37][CH2:38][C:33]2[N:32]([CH3:39])[C:30]3[C:29]([C:34]=2[CH2:35]1)=[CH:28][CH:27]=[C:26]([N:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][C:22]1=[O:40])[N:31]=3)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Triethylamine (33 μL, 0.24 mmol), DMAP (5.8 mg, 0.048 mmol) and acetyl chloride (25 μL, 0.36 mmol) were added to a solution of 4-(benzyloxy)-1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one (93 mg, 0.24 mmol) in CH2Cl2 (14 mL) and the resulting solution was stirred at ambient temperature for 2 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 5 column volumes) gave the title compound (86 mg, 83%) as an off-white powder and a mixture of rotomers: mp 206-208° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.01 (t, J=8.5 Hz, 1H), 7.80 (dd, J=7.5, 2.5 Hz, 1H), 7.49-7.36 (m, 5H), 7.33-7.26 (m, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.71-4.66 (m, 2H), 3.90-3.81 (m, 2H), 3.67 (m, 3H), 3.00-2.86 (m, 2H), 2.16-2.10 (m, 3H); ESI MS m/z 429 [M+H]; HPLC (Method A)>99% (AUC), tR=18.2 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[OH:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[N:7][CH:6]=2)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
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: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.35 g) in a mixed solvent of THF (8.40 mL)-water (2.80 mL) were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53 g), potassium carbonate (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (0.14 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.35 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2].Cl.[CH3:36][O:37][NH2:38]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:38][O:37][CH3:36])[C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21
Reactant: CON
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NOC)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-methoxyimino-2-(4-methoxyphenyl)ethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.23 g, 0.5 mmol) and O-methylhydroxylamine hydrochloride (0.08 g, 1 mmol) by a method similar to that described for Example 3 (68% yield). Mp: 165° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.0), 2.61 and 3.23 (two m, 8H), 3.69 and 3.79 (m, 6H), 3.89 (s, 2H), 4.54 (q, 2H, J=7.0), 6.93 (m, 2H), 7.13 (d, 1H, J=7.2), 7.73 (m, 2H), 7.89 (d, 1H, J=13.2), 8.90 (s, 1,H) 15.35 (br s, 1H). Anal. Calcd. for C26H29FN4O5H2O: C, 60.69; H, 6.07; N, 10.88. Found: C, 60.90; H, 5.77; N, 10.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][NH:20][C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].ClCCl>CS(C)=O>[CH2:27]([N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(Br)cn3)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCn1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (250 mg, 0.704 mmol) was dissolved in dimethylsulfoxide (3 mL) and treated with sodium hydride (70.4 mg, 1.76 mmol, 2.5 equiv) and allyl bromide (170 mg, 1.41 mmol, 2.0 equiv). The mixture was stirred at ambient temperature for 18 hours, poured into dichloromethane (50 mL) and washed with sodium bicarbonate (2×50 mL, aqueous saturated) and brine (1×50 mL). The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound: 1H-NMR (400 MHz, CD3OD) δ 8.90 (1H, s), 8.56 (1H, s), 8.34 (1H, d, J=9.0 Hz), 7.99 (1H, d, J=6.2 Hz), 7.74 (1H, d, J=8.2 Hz), 7.63-7.55 (2H, m), 7.42 (1H, d, J=8.4 Hz), 6.07-5.98 (1H, m), 5.81 (2H, s), 5.24-5.16 (2H, m), 4.86 (2H, s), ppm; low resolution mass spectrometry (ES+) m/z 396.8 (81Br) [(M+H)+; calculated for C19H15BrN4O: 397.0].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:12]([N:15]2[CH2:20][CH:19]3[CH2:21][CH:16]2[CH2:17][S:18]3)(=[O:14])=[O:13])[CH:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1.[H-].[Na+]>CN(C=O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([S:12]([N:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][S:18]4)(=[O:14])=[O:13])[CH:3]=2)[CH:24]=1
Reactant: ClCc1cccnc1
Reactant: O=S(=O)(c1cc(O)c2ccccc2c1)N1CC2CC1CS2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(OCc2cccnc2)c2ccccc2c1)N1CC2CC1CS2
Temperature: 90 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
The product from Example 62 (66 mg, 0.20 mmol), 3-picolylchloride hydrochloride (40 mg, 0.20 mmol and a crystal of KI were combined in DMF (30 ml). Sodium hydride (41 mg, 1.1 mmol, a 60% dispersion in oil) was added and the mixture was stirred at 90° C. for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between 1N aq KOH and CHCl3. The CHCl3 phase was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography using 5% acetone in CHCl3. The pure product was obtained as a tan foam (49 mg, 58% yield): 1H NMR (CDCl3) δ 1.52 (1H, d, J=10.57 Hz, 1/2 CH2), 1.69 (1H, J=10.74 Hz, 1/2 CH2), 1.81 (1H, br s, CH), 2.91 (1H, dd, J=10.12, 2.53, 1/2 CH2), 3.09 (1H, d, J=10.15 Hz, 1/2 CH2), 3.50 (2H, m, CH2), 3.61 (1H, dd, J=10.21, 1.14 Hz, CH), 4.62 (2H, s, CH2Ar), 7.19 (1H, d, J=1.39 Hz, ArH). 7.39 (1H, dd, J=11.61, 4.87 Hz, 7.60-7.69 (2H, m, ArH), 7.82-7.98 (2H, m, ArH), 8.01 (1H, s, ArH), 8.30-8.38 (1H, m, ArH), 8.68 (1H, dd, J=10.19, 1.35 Hz, ArH), 8.81 (1H, d, J=1.86 Hz, ArH).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:17]2[C:4]([CH2:5][CH2:6][C@@H:7]3[C:16]=2[C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]([CH2:34][C:35]([F:44])([F:43])[C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[CH3:33])=[O:31])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:45])=[CH:3]1.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(Br)(=O)C>>[C:46]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]([CH2:34][C:35]([F:43])([F:44])[C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40])[CH3:33])=[O:31])([CH3:13])[C:11](=[O:45])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(F)(F)C(F)(F)C(F)(F)F)C(=O)CCCCCCCCCC[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CCC3=C12
Agent: CC(=O)Br
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](CCCCCCCCCCC(=O)N(C)CC(F)(F)C(F)(F)C(F)(F)F)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
One operates as in Stage B of Example 3 starting with 345 mg of the product obtained in Stage A above using 0.4 cm3 of acetic anhydride and 0.2 cm3 of acetyl bromide. One obtains 323 mg of expected product.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7](O)=[O:8])[CH2:4][O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.Cl.[N:47]1([C:53]2[CH:58]=[CH:57][C:56]([N:59]3[CH2:63][C@H:62]([CH2:64][O:65][C:66]4[CH:70]=[CH:69][O:68][N:67]=4)[O:61][C:60]3=[O:71])=[CH:55][C:54]=2[F:72])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[OH:6][C@H:5]([CH2:7][OH:8])[C:4]([N:50]1[CH2:49][CH2:48][N:47]([C:53]2[CH:58]=[CH:57][C:56]([N:59]3[CH2:63][C@H:62]([CH2:64][O:65][C:66]4[CH:70]=[CH:69][O:68][N:67]=4)[O:61][C:60]3=[O:71])=[CH:55][C:54]=2[F:72])[CH2:52][CH2:51]1)=[O:3]
Reactant: CC1(C)OC[C@H](C(=O)O)O1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C([C@H](O)CO)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 19.8 %

Procedure:
A solution of 2,2-dimethyl-1,3-dioxolane-4(R)-carboxylic acid (162 mg, 1.1 mmol) in dichloromethane (20 ml) under nitrogen was cooled with stirring to 4°, and treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (147 mg, 1.1 mmol), then stirred at the same temperature for 1 hour. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added, followed by 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (399 mg, 0.92 mmol). The mixture was stirred for 2 hours, allowing the temperature to rise to ambient. Solid was filtered off, and the organic solution washed with water (2×20 ml), dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (82 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: Fc1cccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)c1
Reactant: C1CNCCN1
Product: Fc1cccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3-fluorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and piperazine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)[CH3:10])[CH:6]=[CH:5][N:4]=1.[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH2:40])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH:40][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)[CH3:10])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoic acid (Step B, 800 mg, 2.94 mmol) in CH2Cl2 (40 mL) was added 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (812 mg, 2.94 mmol), TBTU (1.0 g, 3.23 mmol), and DIEA (1.5 mL, 8.81 mmol). The reaction was stirred at RT under N2 for 20 h. The reaction was quenched with sat. NH4Cl, washed with water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with Hexanes:acetone mixture (80:20) gave final compound. MS m/z: 531.2 (M+H). Calc'd. for C30H37N6O3-531.66.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:15]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:9]([C:1]3[CH:6]=[CH:5][N:15]=[CH:3][CH:2]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1NN=C(c2ccccc2)CC1c1ccncc1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 200 ml, three-necked, round-bottomed flask equipped with a magnetic stir bar, 150 ml pressure-equalizing addition funnel, reflux condenser and a glass stopper, was added 21 g (135 mole) of 4-bromopyridine and 70 of anhydrous THF. The system was oven-dried and flushed with argon before use, 135 ml (135 mmole) of THF solution of phenylmagnesium bromide (1M) was placed in the pressure-equalizing addition funnel. Then, the Grignard solution was added dropwise over a period of 10 minutes. After the addition, the reaction was stirred for 15 minutes for completion. The solution of Grignard reagent was then obtained. A solution of 4-pyridylmagnesium bromide obtained above was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 252.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][C:3]1[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg), methanesulfonyl chloride (120 mg) and triethylamine (162 mg) in dichloromethane (3 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with 1N-hydrochloric acid, aqueous saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate and concentrated in vacuo. The residual oil was crystallized from ethanol to give 6-[2,6-dichloro-3-bis(methanesulfonyl)aminobenzoyl-amino]-1,2,3,4-tetrahydrodibenzofuran (87 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazine-2-carbonitrile (45 mg, 0.108 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (24 mg). MS 432.3 (M+H); UV 209.6, 308.9 nm; t 0.422 min.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α -isomer), product of Example 23, Step F.), for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A and B, 5-(3-methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer) is obtained in the form of a yellow oil. The product is converted to the hydrochloride that melts at 273°-274.5°C. (sintered, 271.5°C.) after recrystallization from mixtures of methanol and ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C:17]3[CH:16]=[CH:15][C:20]([CH3:21])=[C:19]([NH:13][C:9]4[N:8]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:12]=[CH:11][N:10]=4)[CH:18]=3)=[O:38])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Reactant: Nc1nccc(-c2cccnc2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-(3-pyridyl)-2-pyrimidine-amine (172.2 mg, 1.0 mmol), N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (402.4 mg, 1.0 mmol) and sodium tert.-butylate (144.2 mg, 1.5 mmol) is added a mixture of rac-BINAP (31.2 mg, 0.050 mmol) and Pd2(dba)3*CHCl3 (13 mg, 0.013 mmol) under argon. After addition of 3 ml of xylene the suspension is sonicated for 10 minutes then stirred for 5 hours under reflux. After cooling to room temperature, water (10 ml) is added to the dark brown oil and the product extracted 4 times with methylene chloride (10 ml each). The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The brown oil is purified by flash-chromatography (SiO2, methanol). The product, a pale yellow solid is dissolved in methylene chloride, filtered and concentrated in vacuo. Yield: 484.3 mg of the title compound, 72% of theory, (99.9% area by HPLC). The product contains typically roughly 10% of isomers which can be eliminated by preparative reversed phase chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][C:23]#[C:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][CH2:24][C:23]#[C:22][CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC#CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#CCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 10.7 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (3 g) is alkylated using 1-iodo-3-pentyne (4.42 g; 22.8 mmol) and K2CO3 (4.29 g; 30.4 mmol) at 40° C. for 5 d. After aqueous work-up and purification by RP chromatography a part of the material (0.4 g) is de-acetylated in MeOH (30 ml) using DBU (0.4 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-pent-3-ynyl-1,3-dihydro-indol-2-one (0.35 g) is obtained and used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:41])[N:33]=[N:32]1
Reactant: O=C(Cl)CCCCc1c[nH]nn1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCCCc3c[nH]nn3)CC2)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (195 mg, 0.591 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.206 mL, 1.182 mmol). 5-(1H-1,2,3-Triazol-4-yl)pentanoyl chloride (111 mg, 0.591 mmol) in DCM (2 mL) was then added and the reaction mixture stirred for 20 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM to afford the title product.