Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[N:19](COCC[Si](C)(C)C)[N:20]=[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[NH:19][N:20]=[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3ccccc3c21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A 10 ml round-bottomed flask is charged with 71 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline in 3 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the reaction mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt. The organic phase is dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and with a mixture of DCM and methanol (95/5 by vol.), to give 9 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline (beige solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (broad s, 1 H) 6.04 (broad m, 1 H) 7.32 (m, 2 H) 7.52-7.74 (m, 3 H) 7.92 (m, 1 H) 8.40 (d, 1 H) 12.76 (broad s, 1 H); LC-MS-DAD-ELSD: 458 (+)=(M+H)(+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[NH2:37][C:38]1[CH:48]=[CH:47][C:46](Br)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41].C([O-])(O)=O.[Na+]>C(#N)C>[NH2:37][C:38]1[CH:48]=[CH:47][C:46]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.6 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.167 g, 0.331 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide (0.088 g, 0.364 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (14 mg, 0.017 mmol), acetonitrile (5 mL) and saturated aqueous NaHCO3 (5 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 5 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and adsorbed onto silica gel. The crude material was purified by silica gel chromatography in an EtOAc (containing 10% MeOH) and hexane gradient. The purified material was dissolved in a MeOH/acetone solution (5 mL) and 200 uL of a 50% KOH solution was added and the solution was stirred at room temperature for 3 hours. The reaction was quenched by adding 1 M citric acid dropwise until pH=5. The quenched reaction mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted 2× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and adsorbed onto silica gel. The material was purified on amino silica in an EtOAc (containing 10% MeOH) and hexane gradient to afford the title compound as a pale yellow powder (13.5 mg, 11% yield). 1H-NMR (500 MHz, d6-DMSO) δ=11.80 (br. s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.68 (d, J=2.5 Hz, 1H), 7.58 (dd, J=1.5, 6.0 Hz, 1H), 7.44 (dd, J=2.0, 6.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.04 (t, J=7.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.95 (s, 6H). MS: m/z 387.1 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(N(CC)CC)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:24][CH:20]([CH3:21])[CH2:22][CH3:23])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCC(C)N
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)CC

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml. methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of sec. butylamine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized with methanol, yield: 107 g. (68%); m.p. 33°-35° (methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2C)[N:3]=1.ClC1C=CC(OCC)=[C:22](C=1)[C:23](O)=[O:24]>>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:24][CH2:23][CH3:22])[N:5]=1
Reactant: CCOc1ccc(Cl)cc1C(=O)O
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Product: CCOc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Yield: 31 %

Procedure:
Using the method described for the synthesis of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine, 5-chloro-2-ethoxybenzoic acid afforded 2,4-dichloro-6-(5-chloro-2-ethoxy-phenyl)-[1,3,5]triazine (9.5 g, 31% yield). 1H NMR (DMSO-d6) 7.62-7.86 (m, 2H), 7.20-7.31 (m, 1H), 4.20 (m, 2H), 1.37 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NCc2cccnc2)c1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a stirred mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), 3-pyridinecarboxaldehyde (32.3 ml, 0.342 mmol), and acetic acid (65.5 ml, 1.14 mmol) in anhydrous methanol (4 ml) under nitrogen was added sodium cyanoborohydride (21.5 mg, 0.342 mmol) and the mixture was stirred for 3 h. The mixture was quenched with saturated aqueous K2CO3 (0.5 ml) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.1162 g (93%) of the title compound as a yellow solid; mp 284-287° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.13 (3H, s), 4.34 (2H, d, J 6.1 Hz), 6.39 (1H, t, J 6.1 Hz), 6.64-6.68 (3H, m), 7.17 (1H, t, J 7.7 Hz), 7.35 (1H, dd, J 7.9, J′4.9 Hz), 7.42 (2H, d, J9.0 Hz), 7.77 (1H, dt), 8.11 (2H, d, J 9.0 Hz), 8.44 (1H, m), 8.51 (1H, s), 8.61 (1H, s), 12.34 (1H, br s); MS (ES+) m/z 442/444[MH]+, 221/222[(M2H)/2]+. Anal. found: C, 67.08; H, 4.50; N, 15.54. C25H20ClN5O.0.3H2O requires: C, 67.13; H, 4.64; N, 15.66%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]([CH3:17])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:18][CH2:19][CH3:20])[C:9]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:19]([N:18]1[C:10]2[C:9]([CH3:21])=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=[C:15]([CH3:17])[C:11]=2[C:12](=[O:14])[O:13][C:32]1=[O:34])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)oc(=O)c2c(C)cc(C(=O)OC(C)(C)C)c(C)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 253.3 %

Procedure:
4-(tert-Butoxycarbonyl)-2-(ethylamino)-3,6-dimethylbenzoic acid (115 mg, 0.392 mmol) was dissolved in tetrahydrofuran (1 mL) and then cooled in an ice bath. N,N-Diisopropylethylamine (0.07 mL, 0.403 mmol) and triphosgene (40 mg, 0.135 mmol) were added, and the mixture was stirred at ambient temperature for 0.5 h. The mixture was quenched with water and extracted with dichloromethane (2×). The combined organic portion was dried over sodium sulfate, then filtered and concentrated to provide tert-butyl 1-ethyl-5,8-dimethyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (109 mg, 0.342 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 4.06 (q, 2H), 2.70 (s, 3H), 2.46 (s, 3H), 1.62 (s, 9H), 1.28 (t, 3H); MS (EI) for C17H21NO5: 320 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[OH:14][CH:15]1[C:20]2([CH3:25])[CH2:21][N:22]([CH3:24])[CH2:23][C:16]1([CH3:26])[CH2:17][NH:18][CH2:19]2>>[OH:14][CH:15]1[C:16]2([CH3:26])[CH2:23][N:22]([CH3:24])[CH2:21][C:20]1([CH3:25])[CH2:19][N:18]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:17]2
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CN1CC2(C)CNCC(C)(C1)C2O
Product: CN1CC2(C)CN(c3ccc(C#N)c4ccccc34)CC(C)(C1)C2O
Yield: 7.6 %

Procedure:
The title compound (3 mg, 8% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane (86 mg, 0.468 mmol).
Reaction SMILES: [CH2:1]1N2CN3CN(C2)CN1C3.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[OH:20].[OH2:21].OS(O)(=O)=O>C(O)(C(F)(F)F)=O>[F:18][C:17]1[C:12]([F:11])=[C:13]([OH:20])[C:14]([F:19])=[CH:15][C:16]=1[CH:1]=[O:21]
Reactant: O
Reactant: Oc1c(F)ccc(F)c1F
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(F)c(O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add hexamethylenetetramine (7.10 g, 50.6 mmol) portion wise to a solution of 2,3,6-trifluorophenol (5.00 g, 33.7 mmol) in TFA (35 ml) at ambient temperature and reflux for 15 hours. After cooling, treat the reaction mixture with water (60 ml), followed by 50% aq. H2SO4 (30 ml), and stir at ambient temperature for 30 minutes. Extract with EtOAc (2×) and wash with 1N aq. HCl (3×) and water. Extract the organic with 2N aq. NaOH (2×) and acidify the alkaline extract with conc. HCl while cooling in an ice/water bath. Collect the resulting solid via filtration and dry to give 2,3,5-trifluoro-4-hydroxy-benzaldehyde (2.97 g) as an off-white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32]C)(C(O)=O)[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1CCC(C[C:41]([OH:43])=[O:42])CC1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([CH2:32][C:41]([OH:43])=[O:42])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(O)CC1CCNCC1
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [Na+]
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(CC(=O)O)CC4)ccc3c2)CC1
Yield: 60 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using Piperidin-4-yl-acetic acid (0.0554 g, 0.387 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.100 g, 0.322 mmol) and Sodium triacetoxyborohydride (0.212 g, 0.9 mol) to give 85 mg {1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidin-4-yl}-acetic acid (60%). ESI-LCMS (438 M+H). 1H NMR (DMSO-d6, 400 MHz): Shift (ppm) 7.71-8.01 (m, 3H), 7.43 (d, J=2.0 Hz, 2H), 7.10-7.30 (m, 1H), 4.38 (d, J=4.8 Hz, 3H), 3.28-3.55 (m, 2H), 2.82-3.14 (m, 2H), 2.20 (d, J=6.3 Hz, 4H), 1.85 (br. s., 5H), 1.38 (br. s., 7H), 0.89 (s, 9H)
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cc2ccccc2o1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzofuran-2-sulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (0.4 mg). MS m/z 369 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]2[C:23](=[O:24])[C:22](=O)[CH:21]([C:26](OCC)=[O:27])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(O)(=O)C.C(O)C>[CH:13]1([N:19]2[CH2:20][C:21]3[C:26](=[O:27])[N:9]4[N:10]=[CH:11][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[C:8]4[NH:12][C:22]=3[C:23]2=[O:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CN(C2CCCCC2)C(=O)C1=O
Reactant: Nc1n[nH]cc1-c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1c2[nH]c3c(-c4ccccc4)cnn3c(=O)c2CN1C1CCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
4-Phenylpyrazol-3-amine [Anderson, E. L. et al., "Synthesis . . . 3-Amino-4-Arylpyrazoles", J. Med. Chem., 7, (1964), pp. 259-268] (3.00 g, 18.8 mmole) and ethyl 1-cyclohexyl-4,5-dioxo-3-pyrrolidinecarboxylate (4.77 g, 18.8 mmole) were combined in glacial acetic acid (19 mL) and stirred under reflux for five hours. No precipitate was observed throughout the course of the reaction. Upon cooling, the reaction solidified to a light yellow mass which was dissolved in 95% ethanol (100 mL) at reflux and water (50 mL) was added slowly while maintaining reflux. After cooling to room temperature, the thick yellow solid was collected by suction filtration and washed with more ethanol/water. Drying under vacuum left 5.37 g homogenous by TLC. Unsatisfactory analysis prompted recrystallization from 95% ethanol (200 mL) to give 3.31 g (m.p.>148°, dec.). Yield: 51% of the subtitled compound. 1H NMR CDCl3, δ) 8.08 (s, 1H, pyrazole-H), 7.44 (d, 2H, J=8 Hz, 2-phenyl H), 7.36 (t, 2H, J=8 Hz, 3-phenyl H), 7.23 (t, 1H, J=8 Hz, 4-phenyl H), 4.37 (s, 2H, lactam CH2), 3.99 (m, 1H, cyclohexyl CH), 1.1-1.9 (m, 10H, chclohexyl CH2); IR (mull) 3519, 1692, 1638, 1613, 1455 cm-1 ; UV (ethanol) λmax(ε) 205 (29,400), 210sh (27,750), 237 (18,350), 268 (18,760), 370 (7700); MS m/e (rel. intens.) 349 (M+1, 23), 348 (M+, 97), 267 (18), 266 (100), 210 (8), 183 (9); Exact mass calc'd for C20H20N4O2 =348.1586; Found=348.1593; TLC (silica, 10% methanol/chloroform) Rf 0.52.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1.O>ClCCl>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:20]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc(F)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(F)nc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
[step 1] 6-Fluoropyridin-3-amine (600 mg, 5.35 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.49 mL, 10.7 mmol) and cyclobutanecarbonyl chloride (0.67 mL, 5.89 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitated crystals were collected by suction filtration to give N-(6-fluoropyridin-3-yl)cyclobutanecarboxamide (899 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:26]([C:24]2[S:25][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:22][CH:23]=2)(=[O:27])=[O:28])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 5-pyridin-2-yl-thiophene-2-sulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:14])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccncc2)=CC1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.81 g, 4.28 mmol) in CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.25 g, 21%) as a solid.
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26](OC)[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH3:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][CH:57]([CH3:59])[CH3:58])[C:46]1=[O:60])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.BrCC1C=CC(OC)=C(OC)C=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH3:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][CH:57]([CH3:58])[CH3:59])[C:46]1=[O:60])(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCC(C)C
Agent: COc1ccc(CBr)cc1OC
Product: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCC(C)C)c3ccc(C)cc32)cc1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 1-isopentyl-5-methyl-2-oxoindolin-3-yl benzoate and 4-(bromomethyl)-1,2-dimethoxybenzene. 1H-NMR δ 8.06 (d, 2H), 7.57 (t, 1H), 7.43 (t, 2H), 7.08 (d, 1H), 6.93 (s, 1H), 6.67 (d, 1H), 6.60 (t, 2H), 6.36 (s, 1H), 3.82 (s, 3H), 3.64 (m, 4H), 3.46 (m, 2H), 3.26 (d, 1H), 2.27 (s, 3H), 1.50 (m, 1H), 1.26 (m, 2H) 0.92 (dd, 6H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reaction time: 22 h
Yield: 62.2 %

Procedure:
Ethyl trifluoroacetate (6.32 g) was dissolved in tert-butyl methyl ether (10 mL) and a 28% sodium methoxide-methanol solution (9.40 g) and a solution of 4-acetylpyridine (4.90 g) in tert-butyl methyl ether (20 mL) were added successively at room temperature. The mixture was stirred for 22 hr. A 10% a aqueous citric acid solution was added until the reaction solution became about pH 4, and the precipitate was collected by filtration, washed with water and dried to give 4-trifluoroacetoacetylpyridine (5.46 g) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=399.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[S:7][C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH:19]([N:18]1[C:14]([C:8]2[S:7][C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cccc(S(C)(=O)=O)c3)cc1OCC2

Procedure:
Following the procedure for 114, 5 5-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole was reacted with 3-methylsulfonylphenylboronic acid to give 146. MS(ESI+) 466.1.