Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[C:4]([CH3:36])=[CH:3][C:2]([N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: Cc1cc(Cl)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Reactant: OCCN1CCNCC1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Temperature: 150 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 0.530 g (1.02 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 1.4 from Example 1, 0.266 g (2.05 mmol) of 1-(2-hydroxyethyl)piperazine (CAS 103-76-4) and 0.14 ml (1.0 mmol) of triethylamine in 5 ml of pentanol is stirred for 2 days at 150° C. The reaction medium is diluted with 20 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The brown oil obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.220 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in the form of an amorphous powder which is used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([CH3:35])([CH3:34])[C:31](=N)[NH2:32].C[O-].[Na+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:32][C:31]([C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])([CH3:35])[CH3:34])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C(=N)N)c1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(c1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1)c1ccccc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
60 mg (0.20 mmol) of the compound from Example 21A were dissolved in 1 ml of DMF, and 63 mg (0.29 mmol) of 2-(2-fluorophenyl)-2-methylpropaneimidamide hydrochloride and 17 mg (0.31 mmol) of sodium methoxide were added. The suspension was stirred at 150° C. for 8 h. The reaction was then brought to completion by 45 min of stirring in a microwave reactor at 200° C. The suspension was diluted with about 1 ml of methanol and filtered, and the filtrate was purified by preparative HPLC [Method 19]. This gave 13 mg (15% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2cc[nH]c2n1
Product: Nc1nc(Cl)c2cc[nH]c2n1
Temperature: 110 °C

Procedure:
A mixture of 2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-ol (Sigma, 150 mg, 1.0 mmol) in phosphorus oxychloride (1.5 mL) was heated at about 110° C. for about 30 minutes. Phosphorus oxychloride was carefully removed under reduced pressure and the reaction mixture was quenched by slow addition of ice water (10 mL). The resulting mixture was neutralized with saturated aqueous sodium carbonate (about 5 mL) to pH 7. The crude product was extracted into dichloromethane (20 mL) and washed with water (15 mL). The organic layer was separated and the aqueous phase was further extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (0.036 g, 0.21 mmol) as a light yellow solid; LC/MS (Table 1, Method a) Rt 1.17 min; MS m/z: (M+H)+ 169.
Reaction SMILES: [C:1](=[O:21])([O:7][C:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15](F)=[C:16]([F:17])[C:11]=2[O:10][N:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH3:31][C@H:32]1[O:37][C@@H:36]([CH3:38])[CH2:35][NH:34][CH2:33]1>C(#N)C>[C:1](=[O:21])([O:7][CH:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15]([N:34]3[CH2:33][C@H:32]([CH3:31])[O:37][C@H:36]([CH3:38])[CH2:35]3)=[C:16]([F:17])[C:11]=2[O:10][NH:9]1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(c2F)ONC3OC(=O)OC(C)(C)C)C[C@H](C)O1
Temperature: 80 °C

Procedure:
To an ice cooled and stirred solution of tert-butyl 6,7-difluoro-5-formyl-1,2-benzisoxazol-3-yl carbonate (Intermediate 531, 3.0 g, 10.0 mmol) in anhydrous acetonitrile was added DIPEA (2.56 g, 20.0 mmol) followed by cis 2,6-dimethylmorpholine (1.27 g, 11.0 mmol) and the mixture heated at 80° C. for 12 hours. It was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the filtrate evaporated under reduced pressure. The residue was purified on a silica gel column using a gradient of ethyl acetate in pet.ether to give product as a solid. Yield: 2.9 g (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)([Cl:38])=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-1H-imidazole (475 mg, 1.152 mmol) and triethylamine (321 uL, 2.304 mmol) in methylene chloride (6 mL) cooled to 0° C. was added phosgene (895 uL, 1.728 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The residue was taken in ethyl acetate, and the solids were filtered off. The filtrate was concentrated to give crude 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride as yellow solids (450 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:4]=2[N:3]=1.[P:29]([O:40][Si](C)(C)C)([O:35][Si](C)(C)C)[O:30][Si](C)(C)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([C:27]([P:29](=[O:30])([OH:40])[OH:35])=[O:28])=[CH:26][C:4]=2[N:3]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C(=O)P(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9—Step 1) (1.0 equiv.) in toluene (0.27 M) was added tris(trimethylsilyl) phosphite (1.0 equiv.). The reaction was stirred at 80° C. for 60 minutes, then solvents were removed, and the resulting residue was taken up in DMSO (0.27 M), and IBX (1.5 equiv.) was added. The reaction was stirred at room temperature for 2.5 hour, and was filtered and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonylphosphonic acid (14) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.84 (s, 1H), 9.35 (s, 1H), 9.09 (s, 1 H), 8.89 (s, 1 H), 8.76 (d, 1H, J=8.4 Hz), 8.60 (s, 1H), 8.19 (d, 1H, J=8.8 Hz), 7.04 (d, J=8.8 Hz, 1H), 6.70 (d, 1H, J=2.8 Hz), 6.62 (dd, 1H, J=2.8, 8.4 Hz), 3.64 (s, 3H), 3.15-3.09 (m, 2H), 2.97-2.91 (m, 2H), 2.23 (s, 3H). LRMS [M+H]=452.1
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)methylthio-3-cephem-4-carboxylate (71 mg) was dissolved in dimethylformamide (1 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (66 mg) thereto, was stirred at a temeprature of -20° to 10° C. for 30 minutes, after which cold water (10 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (10 ml) and the organic layer separated was washed with an aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purifed by a column chromatography on a silica gel column (40 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (77 mg; 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH:12]([N:22]([CH3:21])[CH:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)[CH2:13][CH3:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2ccccc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: CCC(N1CCc2cc(OC)c(OC)cc2CC1=O)N(C)C1CCc2ccccc2C1

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 140°-142° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCNC2)nc1)C1CC1
Yield: 44.7 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (43 mg, 45% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.26-8.07 (m, 3H), 8.00 (d, J=8.9 Hz, 1H), 7.57 (dd, J=8.9, 2.7 Hz, 1H), 7.34 (s, 2H), 6.85-6.77 (m, 1H), 4.65-4.56 (m, 1H), 3.66-3.49 (m, 2H), 3.44-3.30 (m, 2H), 2.86 (br s, 1H), 2.47-2.36 (m, 1H), 2.18-2.07 (m, 1H), 1.27-1.15 (m, 4H). ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.64 min.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([OH:22])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>C(O)=O>[CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([O:22][CH2:29][C:30]([OH:32])=[O:31])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(c1cc(I)c(O)c(I)c1)c1c(Cc2ccccc2)oc2ccccc12
Solvent: O=CO
Product: O=C(O)COc1c(I)cc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1I

Procedure:
This compound was prepared from (2-benzyl-benzofuran-3-yl)-(3,5-diiodo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2. Formic acid was used in the place of trifluoroacetic acid. The product was obtained as an off-white solid, mp 144-146° C.; MS m/e 638 (M+); Analysis for: C24H16I2O5Calc'd: C, 45.17; H, 2.53 Found: C, 44.19; H, 2.42
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:17]=O)[CH:7]=[CH:6]2.C(OP([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:17]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C=O)cc2c(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)C=Cc1ccc2cc(OC)c(OC)c(OC)c2c1

Procedure:
6,7,8-Trimethoxynaphthalene-2-carboaldehyde (985 mg) and ethyl diethylphosphonoacetate (1.05 mL) were treated in the same manner as in Preparation Example 17 to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 65 mg, 0.19 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 38 mg, 0.21 mmol) and DIPEA (99 μl, 0.57 mmol) in dry DMSO (630 μl). The reaction was subjected to microwave irradiation at 140° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[C:9](Cl)(=[O:11])[CH3:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:11])[CH3:10])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 102.1 %

Procedure:
Four point three grams (32 mmol) of aluminum chloride was placed into 30 milliliter of 1,2-dichloroethane and a solution made by dissolving 2.0 g (25 mmol) of acetyl chloride, subsequently 5.0 g (21 mmol) of 4-bromo biphenyl into 20 milliliter of 1,2-dichloroethane was added while cooling with ice. The mixed solution was stirred as it is while cooling with ice for 4 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Further, washing with water, dried with the use of sodium sulfate. Removing the solvent by distillation, 5.9 g of crude 1-(4′-bromo-biphenyl-4-yl)-ethanone was obtained.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:5][N:6]=1.[CH3:29][NH:30][CH3:31].O1CCCC1>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:5][N:6]=1
Reactant: CNC
Reactant: O=C1N(Cc2cnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added 2 M dimethyl amine in tetrahydrofuran (2.0 mL, 4.0 mmol) under nitrogen in a sealed tube. The reaction mixture was heated at 120° C. for 16 h. The reaction was quenched with the water, then extracted with ethyl acetate (2×50 mL). The combined organic solution was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography with 30% ethyl acetate in hexanes to afford 1′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.08 g, 76%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.08-6.95 (m, 2H), 6.51 (s, 1H), 6.14 (s, 1H), 5.91-5.84 (m, 2H), 5.05 (d, J=15.6 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.84 (d, J=15.6 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 3.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ177.2, 172.0, 156.1, 149.0, 142.5, 141.5, 139.1, 132.4, 129.1, 124.1, 123.7, 119.7, 119.5, 109.2, 103.3, 101.6, 93.7, 80.5, 58.2, 40.4, 37.2; MS (ES+) m/z 422.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=S)[NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)[CH3:2].IC.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]1[N:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8](=[O:10])[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)[CH3:18]
Reactant: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Reactant: NNC(=O)Cc1ccccc1
Solvent: CO
Solvent: CI
Product: CCN(CC)c1nc2ccccc2c(=O)n1NC(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Methyl 2-(3,3-diethyl-thioureido)benzoate (0.500 g, 1.88 mmol) was dissolved in methanol (10 mL), followed by addition of iodomethane (234 μL, 3.75 mmol). The reaction mixture was heated at 80° C. for 10 minutes under microwave conditions making sure the temperature did not exceed 80° C. The reaction mixture was evaporated to dryness and then redissolved in ethanol (20 mL), followed by addition of phenylacetic acid hydrazide (0.367 g, 2.44 mmol). The mixture was stirred for 48 h at reflux. After cooling the mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (EtOAc/Heptane) giving the title compound (0.089 g, 14%). LC-ESI-HRMS of [M+H]+ shows 351,1818 Da. Calc. 351,182101 Da.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CS(C)=O.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:15][C:13](=[O:16])[CH3:14])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CC([O-])=S
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)SCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
A solution of 2.00 g (8.69 mmol) of 1-(2-bromo-ethyl)-4-nitro-benzene in DMSO (10 mL) was treated with 1.99 g (17.4 mmol) of potassium thioacetate and stirred at RT for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (6×60 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 1.48 g (76%) of the title compound as a brown oil: 1H-NMR (CD3OD; 400 MHz): δ 8.23-8.15 (m, 2H), 7.60-7.53 (m, 2H), 3.27-3.10 (m, 4H), 3.03-2.94 (m, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C(OC(C)(C)C)=O)[C:10]([O:12]C(C)(C)C)=[O:11])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]([CH:9]([CH2:8][CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([OH:12])=[O:11]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O

Procedure:
A mixture of di-tert.-butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)malonate (104.12 g., 0.187 mole), p-toluenesulfonic acid monohydrate (3.30 g.) and toluene (330 ml.) is heated under reflux for 9-1/2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:41])[CH3:40]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)nc2)ccn1
Temperature: 30 °C
Reaction time: 12 h
Yield: 60.1 %

Procedure:
To a solution of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.72 mmol) in acetic anhydride (4 mL) was added Et3N (400 mg, 4 mmol), the reaction mixture was stirred at 30° C. for 12 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light yellow solid (197 mg, 60.1%).