Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH:26]([Sn](C=C)(C=C)C=C)=[CH2:27].O.CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([CH:26]=[CH2:27])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: C=C[Sn](C=C)(C=C)C=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (190 mg, 0.389 mmol) in dioxane (3 mL) was degassed with Ar before being charged with tetravinyltin (0.105 mL, 0.576 mmol) and Pd(Ph3P)4 (41 mg, 0.035 mmol). The mixture was stirred at 100° C. for 3 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 2-chloro-N-cyclopropyl-7-tosyl-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (39 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:14]=[C:13]3[N:15]([CH3:19])[N:16]=[C:17](N)[C:12]3=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[O:28])=[CH:22][CH:21]=3)[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:14]=[C:13]3[N:15]([CH3:19])[N:16]=[CH:17][C:12]3=[C:11]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[O:28])=[CH:24][CH:25]=3)[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c3c(N)nn(C)c3n2)CC1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1(c2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c3cnn(C)c3n2)CC1
Yield: 47.5 %

Procedure:
In analogy to GP 6, reaction of 210 mg of 1-(3-Amino-1-methyl-4-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopropanecarboxylic acid ethyl ester (0.39 mmol, 1 eq.) with 31 μL concentrated sulphuric acid and 64.6 mg sodium nitrite (0.94 mmol, 2.4 eq.) yielded 97 mg of the desired product (48% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Li+:16]>CO>[F:13][C:2]([F:1])([F:14])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([O-:12])=[CH:10][CH:11]=1)(=[O:4])=[O:5].[Li+:16]
Reactant: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccc([O-])cc1)C(F)(F)F

Procedure:
Compound (2) from Example 2, in anhydrous methanol, was neutralized with equivalent amount of lithium hydroxide: The solvent was then removed, and the residue dissolved in a small amount of anhydrous THF. Ether was subsequently added and the solution stored in a refrigerator. The precipitated crystals were filtered and washed with ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:17]=[C:16]([C:18](=[O:25])[NH:19][CH2:20][CH2:21][C:22](=[NH:24])[NH2:23])[N:15]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[CH:14]=2)=[O:11])=[CH:8][CH:7]=1.C[N:34]([CH:36]=O)C.C([N:41](C(C)C)CC)(C)C>>[C:22]([CH2:21][CH2:20][NH:19][C:18]([C:16]1[N:15]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:14]=[C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:30]=[CH:31][C:6]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:36]([NH2:34])=[NH:41])=[O:32])=[CH:7][CH:8]=2)[CH:17]=1)=[O:25])(=[NH:23])[NH2:24]
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Reactant: N=C(N)CCNC(=O)c1cc(NC(=O)c2ccc(C(=O)NCCN)cc2)cn1CC1CC1
Product: N=C(N)CCNC(=O)c1cc(NC(=O)c2ccc(C(=O)NCCNC(=N)N)cc2)cn1CC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 150 mg (0.23 mmol) 99 in 5 mL DMF 336.4 mg (2.3 mmol) pyrazole-1-carboxamidine hydrochloride and 396 μL (2.3 mmol) diisopropylethylamine was added. The solution was stirred overnight at ambient temperature. Next morning the solvent was evaporated, the oily residue was dissolved in 20 mL aqueous 0.1% TFA solution and was purified on a preparative reverse phase HPLC column using acetonitrile gradient. The fractions containing the pure product were pooled, evaporated to dryness dissolved in 3 mL methanol and treated with 1 mL 4.0M HCl in dioxane. 100 was precipitated with ether as bis-HCl salt, filtered off and dried to yield 62 mg (49%). MS: 241.70 (M+2H+). 1H-NMR (DMSO d6) 10.22 (s, 1H); 8.72 (s, 2H); 8.61 (t, 1H); 8.38 (s, 2H); 8.02 (t, 1H); 7.72 (s, 4H); 7.52 (t, 1H); 7.11 (d, 3H); 6.70 (d, 2H); 3.85 (d, 2H); 3.26–3.08 (m); 2.34 (m, 2H); 0.90 (m, 2H); 0.19–0.0 (m, 4H);
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18]/[C:19](/[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:39]\[OH:40])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)c2ccccc2C(F)(F)F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 3-(4′-methanesulfonyl-biphenyl-4-yl)-1-(2-methyl-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=539.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4]O.[Cr](Cl)([O-])(=O)=[O:9].[NH+]1C=CC=CC=1.[CH3:19][CH2:20][O:21][CH2:22][CH3:23]>ClCCl>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH:19][C:20]([O:21][CH2:22][CH3:23])=[O:9]
Reactant: CC(C)(C)CCO
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CCOCC
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C=CCC(C)(C)C
Reaction time: 8 h

Procedure:
3,3-dimethyl butan-1-ol (1.3 g) was stirred for 2 hours in dichloromethane (30 ml) with pyridinium chlorochromate (5.5 g) at room temperature, diluted with ether and filtered. Wittig reagent Ph3P=CH--CO2C2H5 (carbethoxymethylenetriphenylphosphorane)(3.6 g) was added to the filtrate and stirred overnight. The mixture was evaporated under vacuum and the residue purified by silica gel chromatography to yield 1.25 g of ethyl 5,5-dimethylhex-2-enoate.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:27])[CH2:4][CH2:3]2.[CH3:28]I>>[CH3:28][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:27]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3ccc4ccccc4c3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5ccccc5c4)cc3CC[C@@H]12

Procedure:
A 282 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-naphthylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated with methyl iodide following the process of Example 95 to obtain 137 mg of the desired product. mp 138°-139.5° FDMS: m/e=387. α[D]589 =+69.6, α[D]365 =+261.4 (chloroform).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20].[OH-].[NH4+]>O>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1S
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCC(c2nc3ccccc3s2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a mixture of 1.43 g of 1-acetylpiperidine-4-carboxylic acid and 1.05 g of 2-aminothiophenol was added 5 mL of polyphosphoric acid. After stirring at 110° C. for 18 hours, the reaction was cooled to 40° C. The syrup was poured onto ice and water was added to keep the solution temperature below 10° C. The resulting dark brown solution was basified with ammonium hydroxide. Aqueous phase was extracted with EtOAC (3×). The combined organic phases were washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded 1.41 g of the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)[N:8]=1.[ClH:24]>O>[ClH:24].[ClH:24].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[N:8]=1
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3ccccn3)n2)cc1
Agent: Cl
Solvent: O
Product: Nc1ccc(Nc2nccc(-c3ccccn3)n2)cc1

Procedure:
A 12.86 g portion of N-[4-[[4-(2-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide in a mixture of 40 ml of water and 40 ml of concentrated hydrochloric acid was refluxed for 30 minutes and then cooled. The solid was collected and dried, giving 10.84 g of the desired product, mp 285°-288° C.
Reaction SMILES: [N+:1]([CH:4]([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:5][CH3:6])([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:17][O:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[CH:7]=[C:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CCC(C1OC(=O)c2ccccc21)[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCC(=Cc1ccccc1C(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A suspension of 1,3-dihydro-3-(1-nitropropyl)-isobenzofuran-1-one (53 g, described in Example 27), potassium carbonate (64 g) and dimethyl sulfate (45.4 g) in acetone (1.5 l) is stirred at room temperature for 18 hr and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using hexane-diethyl ether (4:1). The eluates are evaporated to give the title compound (49 g), nmr (CDCl3) δ1.15(t), 2.65(q), 3.94(s), 7.55(m), 8.2(m) and 8.45(s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([CH3:27])[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]([OH:36])[C:33](O)=[O:34]>>[OH:36][CH:32]([C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([OH:28])[CH:30]=1)[C:33]([NH:14][NH:13][C:11](=[O:12])[C:10]1[C:15]([CH3:27])=[CH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NN
Reactant: O=C(O)C(O)c1cccc(O)c1
Product: Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NNC(=O)C(O)c1cccc(O)c1
Yield: 47 %

Procedure:
The substance is prepared analogously to Example 1 from 2,4-dibenzyloxy-6-methylbenzohydrazide and 3-hydroxymandelic acid in a yield of 47%, m.p. 181-1820 (from Me2COHoEt2O).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N(CC)CC)C.IC>O1CCOCC1>[CH3:6][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CI
Product: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5.00 g (13.3 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester in a 4 N solution of hydrochloric acid in dioxane was stirred at room temperature for 16 hours. The precipitate that has formed was filtered off and the filtrate was evaporated to dryness. This residue was dissolved in 20 ml DMF and 2.6 ml (18.5 mmol) triethylamine and 0.6 ml (9.7 mmol) iodomethane were added. The reaction mixture was stirred for 16 hours at room temperature. The precipitate that had formed was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on a silica gel column with toluene/ethylacetate as eluent yielding 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine as colourless crystals; HPLC-MS: 1.29 min, [M+H] 292.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:21][NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH3:20])[C:14]=2[OH:35])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:21][NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH3:20])[C:14]=2[OH:35])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To methyl 4-[(2-{1-[5-(4-n-hexylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.158 mmol, 75.2 mg), methanol was added, and 1 M aqueous sodium hydroxide (5 eq., 0.789 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.789 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (29.4 mg, yield 40%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][C:19](Cl)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29][O:28]2)[CH2:24][CH2:23]1>>[ClH:17].[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH:2]([NH:1][CH2:18][CH2:19][N:22]3[CH2:27][CH2:26][C:25]4([C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][O:28]4)[CH2:24][CH2:23]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: NC1c2ccccc2CCc2ccccc21
Reactant: c1ccc2c(c1)CCOC21CCNCC1
Product: Cl
Product: c1ccc2c(c1)CCc1ccccc1C2NCCN1CCC2(CC1)OCCc1ccccc12

Procedure:
The title compound, m.p. 190° C. and MS: m/e=439.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, chloroacetyl chloride, spiro[isochroman-1,4'-piperidine] and Hcl.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH2:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH2:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)CCC2
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3c(c2)CCC3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and indan-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C21H24O5 [M−H]−: 355.3.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@@H]1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 80%), MS (ISP) m/z=459.5 [(M+H)+], mp 193.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-[1,4]dioxan-2-yl-acetic acid.
Reaction SMILES: [N-:1]=[C:2]=S.[CH3:4][C:5]([CH3:7])=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])C>O1CCCC1.O1CCOCC1>[CH2:5]1[CH2:7][CH2:17][N:19]2[C:20](=[N:1][CH2:2][CH2:23][CH2:22]2)[CH2:21][CH2:4]1
Reactant: [N-]=C=S
Reactant: CCN(CC)CC
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CC#N
Product: C1CCC2=NCCCN2CC1

Procedure:
Namely, the substituted iminosulfonamide derivative (7) is reacted with the isothiocyanate derivative (9) in a solvent such as acetone, acetonitrile, dioxane or tetrahydrofuran in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine or DBU, to obtain the compound of the present invention (1:X=S, L=H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[C:18]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:17]1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[C:18]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:17]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reaction time: 0.13 h
Yield: 63.9 %

Procedure:
The mixture of methyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-butanoate (280 mg), in DCM/TFA (15 mL, 2:1) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (24.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 150 mg product was obtained. This resulted in 148.4 mg (73%) of methyl (2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate formate as an off-white solid. LCMS (Method 28) [M+H]+=520.1, RT=0.82 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.01 (t, 1H, J=73.2 Hz), 4.40-4.26 (m, 2H), 3.64 (s, 3H), 3.50-3.43 (m, 1H), 2.32-2.18 (m, 1H), 2.11-1.99 (m, 1H).
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][C@:15]12[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:19][NH:18][CH2:17][CH2:16]2>>[OH:14][C@:15]12[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[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][CH2:16]2
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O[C@]12CCCCC1CNCC2
Product: N#Cc1ccc(N2CC[C@@]3(O)CCCCC3C2)c2ccccc12
Yield: 22.3 %

Procedure:
The title compound (8 mg, 22% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and (S)-4a-hydroxyoctahydroisoquinoline (73 mg, 0.468 mmol).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[C:6]1[C:13]([O:15][CH3:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>C(Cl)Cl.O>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:11]2[S:10][C:9]3[S:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=3[CH:12]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc2ccsc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
Anhydrous aluminium chloride (136 g) is added in small portions, over a period of 30 minutes, to a mixture of methyl thieno[2,3-b]thiophene-2-carboxylate (40.3 g) and 4-fluorobenzoyl chloride (32.3 g) in methylene chloride (1000 cc) at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then hydrolysed, with care, by the addition over a period of 30 minutes of 0.5 N aqueous hydrochloric acid (500 cc), the internal temperature being maintained at about 20° C. by external cooling with a bath of cold water. The methylene chloride solution is diluted with methylene chloride (5000 cc), decanted off, washed three times with distilled water (total 3000 cc), three times with a saturated aqueous sodium bicarbonate solution (total 1000 cc), and again three times with distilled water (total 3000 cc), then dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (1 g), filtered and evaporated. The residue is triturated in diethyl ether (250 cc), the resulting crystals are filtered off, washed three times with diethyl ether (total 375 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. Methyl 5-(4-fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylate (51.8 g), melting at 220° C., is thus obtained.