Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(=O)CCN(C2NN=CC=2[N+]([O-])=O)C1.[F:17][CH:18]1[CH2:24][N:23]([C:25]2[NH:29][N:28]=[CH:27][C:26]=2[N+:30]([O-:32])=[O:31])[CH2:22][CH2:21][CH:20](C(OCC)=O)[C:19]1=[O:38].[N+](=CC(OCC)=O)=[N-].B(F)(F)F.CCOCC.Cl>ClCCl>[F:17][CH:18]1[C:19](=[O:38])[CH2:20][CH2:21][CH2:22][N:23]([C:25]2[NH:29][N:28]=[CH:27][C:26]=2[N+:30]([O-:32])=[O:31])[CH2:24]1
Reactant: CCOC(=O)C1CCN(c2[nH]ncc2[N+](=O)[O-])CC(F)C1=O
Agent: CCOC(=O)C=[N+]=[N-]
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCCN(c2[nH]ncc2[N+](=O)[O-])CC1F

Procedure:
FIG. 10 shows an exemplary synthesis of 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3. Heating 3 with piperidin-4-one hydrochloride hydrate and potassium fluoride in a suitable solvent such as dimethylsulfoxide or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 46. Heating 46 with trimethylsilyl chloride and triethylamine in a suitable solvent such as DMF or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine 47. Fluorination of 47 using SelectFluor® in acetonitrile at a suitable temperature or using methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 48. Ring expansion of 48 to ethyl 6-fluoro-1-(4-nitro-1H-pyrazol-5-yl)-5-oxoazepane-4-carboxylate 49 may be achieved using ethyl diazoacetate and boron trifluoride diethyl etherate in a suitable solvent such as dichloromethane at suitable temperatures or using methods described in the literature. Decarboxylation of 49 by heating with hydrochloric acid at a suitable temperature or by methods described in the literature to give 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-one 50. Reductive amination of 50 by methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 51. The amine of 51 can be protected with a suitable protecting group such as trifluoroacetamide using trifluoroacetic anhydride with diisopropylethylamine in a suitable solvent such as dichloromethane, or using other methods described in the literature, to give amine-protected 52.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([OH:39])=[CH:29][C:28]=3[OH:40])[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C(=O)([O-])[O-].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(C(C)=O)C(C)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)[N:12]=[C:13]([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([O:39][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:29][C:28]=3[OH:40])[N:14]=2)=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCc1cc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)c(O)cc1O
Reactant: CCCCCCCCI
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCOc1cc(O)c(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1CCCCCC
Temperature: 117.5 °C

Procedure:
A stirred mixture of 2,4-bis(4-tert-butylphenyl)-6-(2,4-dihydroxy-5-hexylphenyl)-1,3,5-triazine, 5 g of 1-iodooctane, 1 g of Aliquat® 336 (tricaprylmethylammonium chloride), 14 g anhydrous potassium carbonate, and 200 mL methyl isobutyl ketone (MIBK) was heated at 115-120° C. for 5 hr, and then allowed to cool to room temperature. The mixture was extracted with methylene chloride and the combined methylene chloride extracts were concentrated under reduced pressure. The resulting semi-solid residue was recrystallized from acetone to give 12 g of 2,4-bis(4-tert-butylphenyl)-6-(2-hydroxy-4-octyloxy-5-hexylphenyl)-1,3,5-triazine as a yellow solid in 97% purity as determined by HPLC (area % at 290 nm). A second recrystallization from acetone yielded an analytical sample (100% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][S:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=3)(=[O:29])=[O:28])=[N:13][C:14]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1nc(N)ccc1COCc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1nc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 5-(4-fluoro-benzyloxymethyl)-6-methyl-pyridin-2-ylamine (0.08 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.087 g) as an amorphous orange solid (0.1 g). MS (ESI−): 453.2 ([M−H]−)
Reaction SMILES: [BH4-].[Na+].[ClH:3].Cl.Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.Cl.C[OH:34]>>[ClH:3].[ClH:3].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([OH:34])[CH2:19][C:21]3[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1
Reactant: O=C(O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2)cc1
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)COc1ccc(CC(O)N2CCN(C3CCNCC3)CC2)cc1
Reaction time: 8 h

Procedure:
8.5 mg (0.22 mmol) of sodium borohydride are added to a solution of 100 mg (0.22 mmol) of 4-[[4-(4-piperidinyl)-piperazin-1yl]acetyl]phenoxyacetic acid trihydrochloride in 10 ml of methanol and the mixture is stirred overnight. 2 ml of a 0.1N hydrochloric acid are then added and the solution is concentrated to dryness under reduced pressure. The residue is partitioned between saturated sodium chloride solution and ethyl acetate and, after drying over sodium sulphate, the organic phase is concentrated to dryness. Mass spectrum: (M+H)+ =364;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:22])[CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:22])[CH2:10][NH2:11]
Reactant: COc1ccccc1C(C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: COc1ccccc1C(C)CN
Reaction time: 18 h
Yield: 71 %

Procedure:
As shown in step 4-iv of Scheme 4, to a stirred solution of 2-(2-(2-methoxyphenyl)propyl)isoindoline-1,3-dione (363 mg, 1.23 mmol) in MeOH (4.0 mL) was added hydrazine (39.4 mg, 38.6 μL, 1.23 mmol) and the reaction was stirred for 18 hours. The precipitate that had formed was filtered, washed with MeOH, and the filtrate concentrated under reduced pressure to give 2-(methoxyphenyl)-1-propanamine as a light yellow oil (Compound 2011, 144 mg, 71% yield): 1H NMR (CDCl3) δ 7.27-7.13 (m, 2H), 6.95 (ddd, J=18.2, 12.3, 4.6 Hz, 2H), 3.84 (s, 3H), 3.39-3.18 (m, 1H), 2.86 (qd, J=12.7, 6.8 Hz, 2H), 1.44 (s, 2H), 1.24 (d, J=7.0 Hz, 3H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccc(Cl)c2ccccc12
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=467.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](O)=O.C1(O)C2C(=CC=CC=2)C=CC=1.[H][H]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].CO>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1]
Reactant: [H][H]
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: [Cr+3]
Agent: Oc1cccc2ccccc12
Agent: [O-2]
Solvent: CO
Product: Cc1ccc2ccccc2c1O
Temperature: 400 °C
Reaction time: 3 h

Procedure:
Inoue et al (Chem. Pharm. Bull., 24 (9), 2199-2203, 1976) disclose ferric oxide and chromium oxide to be new alkylating catalyst of phenols. The activity and selectivity of these oxide catalysts were examined by liquid-phase reaction. 1-Naphthol, methanol and ferric oxide were charged in an autoclave equipped with a magnetic stirrer. After air in the autoclave was replaced by hydrogen, the temperature was raised to 400° C. over a period of 45 to 50 minutes. At such temperature, the pressure reached 100 atm. After 3 hours. 2-methyl-1-naphthol was produced in a conversion of 57.6 mol %. The remainder was starting material.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([CH:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[Br:1][C:20]1[S:21][CH:22]=[CH:23][C:19]=1[CH2:18][CH:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of N-bromosuccinimide (2.58 g, 14.5 mmol) in 100 mL of dimethylformamide (DMF) was added drop-wise into a solution of 3-(2-octyldodecyl)thiophene (4.90 g, 13.2 mmol) in 300 DMF at −20° C. The mixture was stirred overnight at room temperature. Next, the DMF was removed under vacuum and 100 mL water was added. The mixture was extracted with hexane three times and the organic layers were collected. After removal of hexane, a crude product was obtained and was purified by column to afford 5.60 g of the final product in the form of colorless oil (96%). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.18-7.17 (d, 1H, J=5.6 Hz), 6.76-6.75 (d, 1H, J=5.6 Hz), 2.50-2.48 (d, 2H, J=7.2 Hz), 1.64 (m, 1H), 1.30-1.25 (br, 32H), 0.90-0.87 (t, 6H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:6][N:5]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[CH:8]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)on1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-Ethylisoxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B28) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [N:1]([C:4]1[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1)=[N+]=[N-].[CH3:40][P:41]([CH3:43])[CH3:42]>C1COCC1>[Cl:9][C:7]1[N:8]=[C:4]([N:1]=[P:41]([CH3:43])([CH3:42])[CH3:40])[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=2)[C:15]=1[F:31])=[O:11]
Reactant: CP(C)C
Reactant: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(N=P(C)(C)C)nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a 0° C. solution of 2-azido-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1.86 g, 3.05 mmol) in THF (25 ml) was added a 1M solution of trimethylphosphine in THF (6.10 ml, 6.10 mmol). Gas evolution occurred and the reaction mixture was stirred at RT for 1 h. The reaction mixture was evaporated and taken up in EtOAc and water. The organic phase was dried (Na2SO4), filtered and evaporated to provide the title compound (1.96 g, 97%) as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C=O)[CH2:7]2.B(Br)(Br)Br.CO>ClCCl>[CH3:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: COc1ccc2c(c1C)CCN(C=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1c(O)ccc2c1CCNC2
Reaction time: 1.42 h

Procedure:
To a solution of 5-methyl-6-(methyloxy)-3,4-dihydro-2(1H)-isoquinolinecarbaldehyde (Preparation 12; 1.49 g; 7.26 mmol) in dichloromethane (25 ml) at 0° C. under nitrogen was slowly added boron tribromide (9.09 g; 36.3 mmol). After 85 min at 0° C., methanol (25 ml) was added slowly, and the resulting mixture was left standing at room temperature for three days. Removal of the solvent and trituration with methanol/dichloromethane gave a white solid residue; the mother liquors were concentrated and the residue applied to an SCX solid phase extraction cartridge (20 g) and eluted with methanol followed by 2N ammonia in methanol to elute the product. After evaporation of the solvent the title compound (780 mg) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C:19](=[O:21])[C:18]3[C:9](=[C:10]([OH:24])[C:11]4[CH2:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]=4[C:17]=3[OH:22])[C:8](=[O:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:26]#[N:27].[K+].CC(O)=O>C(Cl)(Cl)Cl.CCO.O>[CH3:1][O:2][C:3]1[C:20]2[C:19](=[O:21])[C:18]3[C:9](=[C:10]([OH:24])[C:11]4[CH2:12][C:13]([C:26]#[N:27])([OH:23])[CH2:14][CH2:15][C:16]=4[C:17]=3[OH:22])[C:8](=[O:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)CC(=O)CC3
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)CC(O)(C#N)CC3
Reaction time: 5 h
Yield: 77.6 %

Procedure:
4-Methoxy-6,11-dihydroxy-7,8-dihydro-5,9 (10H),12-naphthacenetrione (IV) (45.3 mg, 0.134 mmole) and KCN (300 mg) were placed in 50% CHCl3 /EtOH (8 ml) and cooled to 0°. HOAc (0.4 ml) was added and the mixture was stirred at 23° for 5 hr. The reaction mixture was diluted with H2O (15 ml), the organic phase separated and the aqueous phase extracted with CHCl3 (10 ml). The organic solutions were combined, dried over Na2SO4 and evaporated. The residue was chromatographed (8 g silica gel, 98.2 CHCl3 /MeOH) to afford 38.0 mg (77%) of (V): mp 232°-235° (dec); irnujol 2.93 (OH), 6.20, 6.31 μ (chelated quinone); pmr 100 MHz CDCl3 δ 2.1-2.4 (m, 2H, 8-H2), 2.8-3.4 (m, 5H, benzylic H's and 9-OH), 4.08 (s, 3H, OMe), 7.36 (dd, 1H, J = 8Hz and J = 1Hz, 3-H), 7.74 (t, 1H, J = 8Hz, 2-H), 7.99 (dd, 1H, J = 8Hz and J = 1Hz, 1-H), 13.28 (s, 1H, phenolic OH), 13.68 (s, 1H, phenolic OH); ms 12 ev m/e (%) 338 M-HCN (100).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][N:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]3)=[CH:4][CH:3]=2)[CH:28]=[N:27]1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ccccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccc(-c3cnn(C)c3)nc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-oxo-1,4-dihydrocinnoline-3-carboxylate [(Example 83, Step 1), 748 mg, 1.93 mmol] and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (682 mg, 3.28 mmol, 1.7 equiv) were suspended in tetrahydrofuran (15 mL) and treated with an aqueous solution (1.5 mL) of cesium carbonate (1.26 g, 3.85 mmol, 2 equiv). The mixture was sparged under nitrogen, treated with bis(tri-tert-butylphosphine)palladium(0) (197 mg, 0.385 mmol, 0.2 equiv) and placed in an oil bath preheated to 80° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (75 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:22]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23]3)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:6][CH:7]=1.[CH2:35]=O.[OH-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:22]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23]3)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:6][CH:7]=1
Reactant: COc1ccccc1Nc1ncc(Cl)c(Nc2ccc(N3CCNCC3)c3c2C(=O)N(C)C3)n1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1ccccc1Nc1ncc(Cl)c(Nc2ccc(N3CCN(C)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
To a solution of 7-[5-chloro-2-(2-methoxy-phenylamino)-pyrimidin-4-ylamino]-2-methyl-4-piperazin-1-yl-2,3-dihydro-isoindol-1-one (2.0 g, 4.17 mmol) in dichloroethane (50 mL), formaldehyde (380 μL, 5.0 mmol) is added and the mixture is stirred at room temperature for 1.5 hours. After addition of triacetoxy sodium borohydride (1.06 g, 5.0 mmol), the mixture is stirred at room temperature for 1.5 hours. The mixture is poured into 1N sodium hydroxide and stirred at room temperature for 10 min, then extracted twice with dichloromethane. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solids are washed with methanol and ethyl acetate to give 7-[5-Chloro-2-(2-methoxy-phenylamino)-pyrimidin-4-ylamino]-2-methyl-4-(4-methyl-piperazin-1-yl)-2,3-dihydro-isoindol-1-one (1.2 g) as pale yellow solids in 58% yield. Rf=0.30 (MeOH/AcOEt=½). ESI-MS m/z: 494 [MH]+. 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.38 (s, 3H), 2.66-2.57 (m, 4H), 3.09-3.07 (m, 4H), 3.21 (s, 3H), 3.92 (s, 3H), 4.37 (s, 2H), 6.92 (dd, 1H), 7.03-6.96 (m, 2H), 7.13 (d, 1H), 7.45 (s, 1H), 8.11 (s, 1H), 8.33 (dd, 1H), 8.67 (d, 1H), 10.5 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-n2cncn2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[Cl:42][C:43]1[CH:44]=[C:45]([N:50]=[C:51]=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49].ClCCl>O>[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Nc5ccc(Cl)c(Cl)c5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reaction time: 2 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 37.3 mg of 3,4-dichlorophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 2 hours at ambient temperature, 0.5 ml of water are added and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 35 mg of expected product are obtained.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14](CC([O-])=O)=[CH:13][CH:12]=1.Cl>O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:1])=[CH:13][CH:12]=1
Reactant: O=C([O-])Cc1ccc(-c2ccc(F)cc2F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A 30 liter resin pot is fitted with stirrer, thermometer and reflux condenser, and charged with 2.62 kg of 50% aqueous sodium hydroxide and 11.34 liters of water. 4-(2',4'-Difluorophenyl)phenylacetate (1.876 kg., 7.55 m) is added and the batch is heated to reflux over 2.5 hours. The batch is refluxed for 2 hours (in solution at 75°), then cooled to 100° and added to a solution of 3.27 liters of concentrated hydrochloric acid in 9.8 liters of water in a 50 liter resin pot over a 30 minute period.