Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][N:30]=[C:31]([NH2:33])[CH:32]=2)=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:29][N:30]=[C:31]([NH:33][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH:32]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)n[nH]2)cc1

Procedure:
The named compound is prepared by substituting 4-(5-amino-2H-pyrazol-3-yl)-benzoic acid methyl ester for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2847 gms. of 4-(5-amino-2H-pyrazol-3-yl)-benzoic acid methyl ester by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]=[N+]=[N-])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H].N.CCOC(C)=O>CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:10][C@H:11]([NH2:13])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N)C1
Yield: 100.5 %

Procedure:
To the mixture of tert-butyl(trans-3-azidocyclobutyl)methylcarbamate (1.8 g, 7.95 mmol) and Pd/C (200 mg) in MeOH (5 mL) under hydrogen atmosphere (hydrogen balloon) was added NH3(g)/MeOH (saturated, 50 mL) via syringe. The resulting mixture was stirred at rt for three hours until TLC analysis (EtOAc:petroleum ether=1:2) showed the reaction was complete. Pd/C was filtered off and the resulting solution was concentrated and dried in vacuum to afford crude title compound (1.6 g), which was used for the next steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:23])=[O:22])[CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of aniline (0.324 ml, 3.55 mmol) in DCM (10 ml) is added pyridine (1.44 ml, 17.76 mmol) followed by a solution of 5-bromo-2-chloro-benzenesulfonyl chloride (1.03 g, 3.55 mmol) in DCM (10 ml). The reaction mixture is stirred at room temperature for 18 hours. DCM (20 ml) is added and the reaction mixture is washed with 2M HCl (50 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:31]=[N:32][CH:33]=[C:34]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: OB(O)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1
Yield: 65.4 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane: ethyl acetate) to give the desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ1.42-1.77 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.84 (1H, d, J=8.1 Hz) 7.21-7.63 (1H, m) 9.58 (1H, s); MS (ESI(−ve)) m/z 399 (M−H)−.
Reaction SMILES: [CH2:1]([O:3]C1C=CC(N)=C([N+]([O-])=O)C=1)[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2[CH:25]=[CH:26][C:27](C(F)(F)F)=[CH:28][C:23]=2[N:22]=[C:21]1/[CH:33]=[CH:34]/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C(OCC)(=O)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[O:3]([C:27]1[CH:26]=[CH:25][C:24]2[N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[C:21](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:22][C:23]=2[CH:28]=1)[CH2:1][CH3:2]
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-ethoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 435.05; mp: 215.5-216.0° C.; 1H-NMR (DMSO-d6) δ: 8.78-8.75 (1H. m), 8.17 (1H, td, J=7.7, 1.8 Hz), 7.85 (1H, d, J=15.8 Hz), 7.72 (1H, d, J=8.1 Hz), 7.65-7.59 (3H, m), 7.44-7.33 (4H, m), 7.24 (1H, d, J=2.6 Hz), 7.18 (1H, d, J=15.8 Hz), 6.89 (1H, dd, J=8.8, 2.2 Hz), 4.10 (2H, q, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CCOCC.C(O)C>[NH2:4][C@H:5]([C:18]([O:20][CH3:3])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC#CC[C@H](N)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)[C@@H](N)CC#CCNC(=O)OC(C)(C)C

Procedure:
Titrate a solution of diazomethane in ether into a solution of 1-amino-1-(S)-carboxy-5-(t-butoxycarbonyl amino)-3-pentyne (4 g) in ethanol (200 ml) until a yellow color remains. Evaporate the solvent to obtain 1-amino-1-(s)-methoxycarbonyl-5-(t-butoxycarbonylamino)-3pentyne.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([OH:67])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8].[N+](=[CH2:82])=[N-].C(O)(=O)C>CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([O:67][CH3:82])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: C=[N+]=[N-]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC
Reaction time: 7 h

Procedure:
Pyroglutamyl-tryptophyl-prolyl-arginyl-prolyl-glutaminyl-isoleucyl-prolyl-proline (1.6 g) is dissolved in 80 ml of methanol. To this, excess ethereal diazomethane is added and the solution is kept for 7 hours at room temperature. Acetic acid is added to destroy the excess diazomethane and the resulting mixture is concentrated to dryness in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[ClH:15].[OH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21][CH2:22][CH:23]=O)=[CH:19][CH:18]=1>CO>[ClH:15].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:23][CH2:22][S:21][C:20]3[CH:25]=[CH:26][C:17]([OH:16])=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=CCSc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(SCCN2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine (from 804 mg of the hydrochloride), 4-hydroxythiophenoxyacetaldehyde (560 mg, 3.33 mmol) and NaCNH3B (416 mg, 6.66 mmol) in MeOH (100 mL) as a colorless crystalline solid (430 mg): mp 177-178° C.; 1H NMR (CD3OD) 1.40-1.60 (m, 2H), 1.76-1.92 (m, 3H), 2.59 (d, J=6.3 Hz, 2H), 2.81-3.00 (m, 2H), 3.08-3.26 (m, 4H), 3.42-3.58 (m, 2H), 6.78 (d, J=8.7 Hz, 2H), 6.96-7.22 (m, 4 H), 7.36 (d, J=8.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=O)=[CH:21][C:16]=2[NH:15][CH:14]=1>>[N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[NH:1][C:2]4[C:3]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)=[CH:21][C:16]=2[NH:15][CH:14]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: COC(=O)c1cccc(N)c1N
Product: O=C(O)c1cccc2nc(-c3ccc4nc[nH]c4c3)[nH]c12
Temperature: 200 °C
Yield: 80.9 %

Procedure:
2 g (12 mmol) of methyl 2,3-diaminobenzoate and 2 g (12 mmol) of benzimidazole-5-carboxylic acid were successively introduced into 70 ml of polyphosphoric acid preheated to 90° C. The mixture was then heated at 200° C. for 1 hour. The reaction mixture was subsequently cooled to 50 to 60° C. and poured cautiously into ice-water. The resulting precipitate was filtered off with suction and dried. 2.7 g of the product were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2sc(C(=O)O)cc12
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(F)c2sccc12
Temperature: 190 °C

Procedure:
A mixture of 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (61.4 g, 271 mmol) and copper powder (22.4 g, 352 mmol) in quinoline (500 mL) was heated at 190° C. for 1 h. Cooled to ambient and poured onto aqueous hydrochloric acid (2 N, 750 mL). Stirred with ethyl acetate (500 mL) for 15 minutes. Filtered through Celite, washing with ethyl acetate. The aqueous layer was extracted into ethyl acetate and the combined organic layers were washed with aqueous hydrochloric acid (2 N, 500 mL), water (500 mL), brine (500 mL), dried over MgSO4 and evaporated in vacuo. Purified by column chromatography, eluting silica gel with iso-hexane/diethyl ether 0–5% to give the product as a brown oil which crystallised to give the title compound (41.3 g, 84%); δH (300 MHz, CDCl3) 7.51 (1H, m, ArH), 7.38 (1H, d, ArH), 6.98 (1H, t, ArH), 6.65 (1H, dd, ArH) and 3.92 (3H, s, OCH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:21])[CH2:18][N:19]([C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:20]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (25 g, 0.14 mol), sarcosine methyl ester hydrochloride (20.2 g, 0.15 mol), triethylamine (20 ml, 0.15 mol) and 4-dimethylaminopyridine (17.7 g, 0.15 mol) in dichloromethane (300 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.8 g, 0.15 mol). The mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M HCl (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (200 ml) and brine (200 ml). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using petrol:ethyl acetate (1:1) as the eluant, to afford the title amide (25 g, 68%) as a yellow oil. 1H NMR (360MHz, CDCl3) δ3.13 (3H, s), 3.75 (3H, s), 3.88 (2H, s), 4.16 (2H, s), 7.26-7.65 (2H, m), 8.09-8.14 (2H, m). MS (CI, NH3), 284 (M+NH4+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH:35]1([CH2:38][NH2:39])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][NH:39][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])(=[O:24])=[O:25])[CH:21]=3)[CH:5]=[CH:4][N:3]=2)[CH2:37][CH2:36]1
Reactant: NCC1CC1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCC3CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (60 mg, 0.11 mmol) and 1-cyclopropylmethanamine (0.1 mL, approx. 1.4 mmol) the title compound was obtained as an off-white solid (25 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.59-7.79 (m, 1H), 7.33-7.44 (m, 3H), 7.20-7.29 (m, 3H), 6.15 (br. s., 1H), 3.00-3.15 (m, 2H), 2.42-2.45 (m, 1H), 1.34 (d, J=7.0 Hz, 6H), 0.94-1.06 (m, 1H), 0.34-0.42 (m, 2H), 0.16-0.22 (m, 2H). MS (ESI): 560.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)[CH2:17][CH3:18]
Reactant: CCCBr
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(C(=O)O)c2ccccc21
Yield: 67.3 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (5.00 g) in DMF (40 ml) was gradually added 60% sodium hydride (1.55 g) at 0° C. with stirring, and the mixture was stirred at room temperature for one hour. Then 1-bromopropane (4.55 g) was added, and the mixture was stirred overnight. The reaction solution was distilled off, dissolved in water, and washed with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid, extracted with ethyl acetate, then the extract was dried over anhydrous magnesium sulfate, and decolorized with active carbon. After the solvent was distilled off, crystallization from ether gave the title compound (4.24 g) as crystals. Yield=67%.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1(C)C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Yield: 93.4 %

Procedure:
21.6 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved with 5.2 g of triethylamine in 200 ml of dry toluene. Then a solution of 5.4 g of chloroformic acid ethyl ester in 50 ml of toluene is added dropwise with stirring. Thereafter, the mixture is stirred for a further two hours. After filtration, the filtrate is washed free of halide with water and evaporated to dryness. A yellowish oil, which is recrystallized from diisopropyl ether, is obtained as the residue. 22.7 g (94 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine are obtained. m.p. = 113° C.
Reaction SMILES: [NH2:1][NH2:2].[C:3]1(=O)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[O:4]1>O.CC(O)=O>[C:5]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3](=[O:4])[NH:2][NH:1]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of hydrazine (392 μL, 13.1 mmol) in water (6 mL) and HOAc (2 mL) is added 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (2 g, 13.1 mmol). The reaction mixture is refluxed for 3 h, then cooled down to room temperature and the precipitate is collected by filtration, washed with water and dried under vacuum oven to give 2,3,5,6,7,8-hexahydro-phthalazin-1,4-dione (compound 10d) (2.09 g, 95.7%). m/z=167.05 [M+1]
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH2:17](I)[CH3:18].[ClH:20]>CN(C=O)C.CCOCC>[ClH:20].[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:17][CH3:18]
Reactant: CCI
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1ccc2c(N)cc(C(=O)OC)cc21
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (900 mg, 4,74 mmol, 1 equiv) in DMF (25 ml) at room temperature was added NaH (60% dispersion in mineral oil, 200 mg, 5 mmol, 1.05 equiv) and after 15 min ethyl iodide (400 μl, 5 mmol, 1.05 equiv). The resulting mixture was stirred for 30 min then most of the solvent was removed in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave an oil which was diluted with Et2O and treated with a 4N HCl solution in Et2O. The precipitate obtained was filtrated off to give methyl 4-amino-1-ethyl-1H-indole-6-carboxylate hydrochloride salt (D202) (800 mg, 66%) as a white solid. [M+H]+=219.0, RT=2.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[S:14])[CH3:11].[H-].[Na+]>CN1CCCC1=O>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[S:14])[O:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=1)[CH3:11]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CCN(CC)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=S)Oc1cc(Br)cc(Br)c1
Temperature: 20 °C
Yield: 91.3 %

Procedure:
A solution of 3,5-dibromophenol (prepared according to Recl. Trav. Chim. Pays-Bas. 1908, 27, 30) (10.08 g, 40 mmol) and diethylthiocarbamyl chloride (7.9 g, 52 mmol) in 1-methyl-2-pyrrolidinone (80 ml) was cooled to 0° C. under an atmosphere of nitrogen. Sodium hydride (60% dispersion in mineral oil, 1.92 g, 48 mmol) was added portionwise with stirring. The mixture was allowed to warm to 20° C. and stirred under nitrogen for two hours. The mixture was partitioned between diethyl ether (250 ml) and water (350 ml) and the aqueous layer was further extracted with diethyl ether (250 ml then 100 ml). The organic layers were combined, washed with water (150 ml) and brine (150 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:pentane (1:1, by volume) to provide the title compound (13.4 g) as a white solid, m.p. 72–74° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 2,5-difluorocinnamic acid (1.5 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.9 g, 98%) as an oily product.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH:23]=[CH:22][CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=1)=[O:7])[CH3:4]>CCOCC.C1COCC1.[Cu]I>[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH2:23][CH:22]([CH3:2])[CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:12]=1)=[O:7])[CH3:4]
Reactant: [Li]C
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CC(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MeLi (1.4M in ether, 2 ml) is added dropwise to a stirred suspension of CuI (268 mg, 1.40 mmol) in Et2O at 0° C. The reaction mixture is kept at 0° C. for 15 min. 4-oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (300 mg, 0.94 mmol) in THF is added slowly to the solution at 0° C., the reaction mixture is allowed to warm up to room temperature over a period of 30 min and then quenched with saturated NH4Cl(aq., 30 ml). 50 ml Et2O is added and stirring is continued for 5 min. The layers are separated; the organic layer is washed with water (20 ml), dried (Na2SO4), and evaporated. Flash chromatography (30% EtOAc/hexanes) provides the title compound as white powder. 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, d), 1.28 (3H, t), 1.56 (9H+1H, s+m), 1.92 (1H, m), 2.15 (1H, m), 2.48 (1H, q), 2.80 (1H, q), 3.15-3.25 (2H, m), 4.24 (2H, q), 7.57 (1H, s). MS (ES+) 336 (M+1) Step 2: 6-Methyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester