Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([S:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([S:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](=[O:50])(=[O:49])[NH2:8])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CCCCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-n-butylthio-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-n-butylthio-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 75°-77° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1ncccn1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ncccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p.: 147°-148° C.) and 2-mercapto-pyrimidine.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[N:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=1
Reactant: O=CCCCCCCl
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NN=CCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a mixture of 4-cyanophenylhydrazine HCl (3.44 g, 20.3 mM) and 6-chlorohexanal (2.5 g, 18.6 mM) in toluene (30 mL) was added triethylamine at 0° C. (2.82 mL, 20.3 mM). The mixture was allowed to stir for 2 hours at ambient temperature. The mixture was filtered and the resultant filter cake was washed with toluene. The combined filtrate was concentrated under vacuum to give 4.92 g of a crude product, which was purified using conventional methods to yield 4.16 g (89.6%) of 4-(2-(6-chlorohexylidene)hydrazinyl)benzonitrile as a mixture of cis:trans isomers (ratio 5:1). NMR (400 MHZ, CDCl3): 7.6-6.6 (6H, (4H, dd-aromatic; 1H (m)-NH, 1H (t)-N═CH-t)), 3.57 (2H (t), CH2Cl), 2.2-2.4 (2H (m), ═CH—CH2), 1.75-1.90 (2H (m), CH2Cl—CH2), 1.49-1.65 (4H (m), CH2—CH2); m/z: 250 [M+H]+, calcd for [C13H16ClN3+H]+ 250.10.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (10.85 mmol) cis-4-tert-Butylcyclohexanecarboxylic acid (Example 42A) are dissolved in 50 ml dichloromethane, 1.65 g (13.02 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 150 °C
Yield: 52.3 %

Procedure:
Into a microwave reaction vial, a mixture of (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (168.4 mg, 0.82 mmol), sodium carbonate (116.0 mg, 1.10 mmol) and Pd(PPh3)4 (31.6 mg, 0.027 mmol) were placed in dioxane (4 mL) and water (1 mL). The reaction mixture was placed in the microwave reactor and heated at 150° C. for 30 min. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 52.0 mg (52.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (dd, J=1.8, 1.2 Hz, 2H), 8.162 (s, 1H), 7.896-7.863 (m, 3H), 7.383 (s, 1H), 5.438-5.398 (m, 1H), 3.551-3.492 (m, 1H), 3.22 (t, J=9.5 Hz, 1H), 3.03 (dd, J=6.6, 6.6 Hz, 1H), 2.701-2.633 (m, 1H), 2.15 (dd, J=2.3, 1.7 Hz, 2H), 1.24 (d, J=6.5 Hz, 3H), 1.0-0.828 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C20H21N5O2: 363.17; found 364.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: ClCc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g), thionyl chloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours. After cooling the mixture was concentrated in vacuo, the residue was taken up in ether, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give 3,5-dichlorobenzyl chloride as a light yellow solid, which was used without further purification, 28 g, mp. 32°-36° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-methyl-benzenesulfonamide [CAS 459434-40-3] according to general procedure II. Yellow solid. MS (ISP) 524.1 [(M−H)−]; mp 255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH3:25][O:26][CH2:27]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:25][O:26][CH3:27])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Reactant: COCCl
Agent: [Na+]
Product: COCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and chlorodimethyl ether there is obtained methoxymethyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.93 ppm (d, 1H), 7.36 ppm (d, 1H), 5.45 ppm (s, 2H), 3.54 ppm (s, 3H), 3.41 ppm (s, 3H), 2.95 ppm (m, 2H), 2.81 ppm (m, 2H), 2.17 ppm (m, 2H),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([C:15]([OH:17])=O)=[CH:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][N:19]1[C:23]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])=[CH:22][N:21]=[C:20]1[CH3:31].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:18][N:19]1[C:23]([C:24]2[CH:25]=[C:26]([NH:27][C:15]([C:9]3[C:10]4[NH:11][C:12]5[C:4](=[CH:3][C:2]([F:1])=[CH:14][CH:13]=5)[C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:17])[CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]=[C:20]1[CH3:31]
Reactant: O=C(O)c1cccc2c1[nH]c1ccc(F)cc12
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccc(F)cc34)c2)n1C
Reaction time: 40 h
Yield: 59.1 %

Procedure:
To a suspension of 6-fluoro-9H-carbazole-1-carboxylic acid (37 mg) and 3-(1,2-dimethylimidazol-5-yl)aniline (43 mg) in dichloromethane (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg) and 4-dimethylaminopyridine (11 mg), and the mixture was stirred for 40 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 2-3% methanol/dichloromethane to give N-[3-(1,2-dimethylimidazol-5-yl)-phenyl]-6-fluoro-9H-carbazole-1-carboxamide (38 mg, 51.4%).
Reaction SMILES: [Cl:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[N:27][CH:28]=1>COCCOC.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[C:12]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: Cn1c(=O)oc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cn1c(=O)oc2cc(Cl)c(-c3cncc(CO)c3)cc21
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A mixture of 6-Chloro-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (60 mg, 0.194 mmol), (5-Bromo-pyridin-3-yl)-methanol (36.4 mg, 0.194 mmol), polymer bound Pd(PPh3)4 (44.1 mg, 4.85 μmol) in DME (5 mL) was heated to 100° C. for 4 hr. After filtration through a pad of Na2SO4, the solution was concentrated, and the residue was purified by column (MeOH—CH2Cl2, v/v, 1%-2.5%-4.0%) and yielded colorless solid (25 mg). 1H NMR (400.3 MHz, CDCl3): δ 3.35 (s, 3H), 4.77 (s, 2H), 6.85 (s, 1H), 7.31 (s, 1H), 7.74 (s, 1H), 8.53 (s, 1H), 8.57 (s, 1H). HRMS (ESI): calculated for C14H11ClN2O3: 290.04582. Found: 290.04666.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:30](OC(=O)C)([F:32])[F:31]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:30]([F:32])[F:31])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Br)cc1
Reactant: CC(=O)OC(F)(F)Cl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [3-(4-bromobenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[NH2:21]
Reactant: NN
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NN)nn2)cc1

Procedure:
A suspension of N-(4-(6-chloropyridazin-3-yl)phenyl)methanesulfonamide (2.82 mmole) in hydrazine monohydrate (6 mL) was heated at 120 C for 1 hour and evaporated in vacuo. The residue was dissolved in dicholomethane, washed with water, dried over Na2SO4, and evaporated in vacuo to afford N-(4-(6-hydrazinylpyridazin-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[C@@H:14]2[CH2:25][CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:28])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO.OO.S(=O)(=O)(O)O>O>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[C@@H:14]2[CH2:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[OH:28])=[CH:11][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
5.00 g (9.6 mmol) (3R,4S)-4-[4-(tert-butyl-dimethyl-silanyl-oxy)-phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxo-propyl]-azetidin-2-on was solved in 9.6 ml water-free dichloromethane, and then 1.92 ml (0.96 mmol) (R)-o-tolyl-CBS-oxazaborolidine 0.5 M-toluenic solution was added. The mixture was cooled to a temperature between 0 and −5° C., and at this temperature a dichloromethanic solution of 1.9 ml 1.0 M borane-dimethyl was added for 6 h. The reaction mixture had been stirred at this temperature until the spot of the starting keton disappeared according to the thin-layer chromatographic investigation. Then 10 ml methanol, 0.5 ml 5% hydrogen-peroxide solution, and 10 ml 2M sulphuric acid were added. Having been stirred the mixture for 0.5 h, the phases were separated. The organic phase was washed with 50 ml 2N sulphuric acid and then 50 ml 5% sulphite-solution. The solution was dried on anhydrous sodium-sulphate, filtered and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[F:24][C:25]1([F:38])[CH2:30][CH2:29][CH:28]([N:31]2[CH2:34][CH2:33][CH:32]2[C:35]([O-])=[O:36])[CH2:27][CH2:26]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([CH:32]2[CH2:33][CH2:34][N:31]2[CH:28]2[CH2:29][CH2:30][C:25]([F:38])([F:24])[CH2:26][CH2:27]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1CCN1C1CCC(F)(F)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCC(F)(F)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(4,4-difluorocyclohexyl)azetidine-2-carboxylate 20B carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4,4-difluorocyclohexyl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (47%). MS ISP (m/e): 555.1 (100) [(M+H)]]+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH2:8]([C:15]1([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][CH2:19][C:18]([NH:23][CH3:24])([C:21]#N)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)C>[CH2:8]([C:15]1([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:16][CH2:17][C:18]([C:21]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)([NH:23][CH3:24])[CH2:19][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: CNC1(C#N)CCC(Cc2ccccc2)(CN(C)C)CC1
Solvent: CCOCC
Product: CNC1(c2ccccc2)CCC(Cc2ccccc2)(CN(C)C)CC1

Procedure:
Phenyl lithium (33 mL, 60 mmol, 1.8 M solution in dibutyl ether) was mixed in drops with a solution of the title compound from step 1 (5.70 g, 20 mmol) in diethyl ether (60 mL) in argon and at room temperature. During this, the temperature of the reaction solution rose to 35° C. and a solid separated out. The reaction mixture was stirred with reflux for 30 min, then hydrolysed in an ice bath with 20% NH4Cl solution (40 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1→9:1→1:1→1% TEA). The polar diastereomer was obtained in clean form. The non-polar diastereomer was isolated in impure state.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromopyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([CH3:25])[C:11]=2[C:10](=O)[CH2:9]1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([CH3:25])[C:11]=2[C:10](=[N:31][NH:30][C:27]([NH2:29])=[NH:28])[CH2:9]1
Reactant: Cc1nn(CCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(CCc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 74.5 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-1-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.055 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (15 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-1-(2-phenylethyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 151) (0.07 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=2[F:27])=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][N:62]1[CH2:68][CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:65]3[CH2:66][CH2:67][CH2:68][N:62]([CH3:61])[CH2:63][CH2:64]3)=[O:23])=[CH:20][C:19]=2[F:27])=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(C(=O)O)cc2F)o1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(C(=O)c2ccc(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c(F)c2)CC1
Temperature: 25 °C

Procedure:
To 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-3-fluorobenzoic acid (40 mg, 0.104 mmol) in DMF was added HBTU (60 mg, 0.157 mmol) and DIEA (55 μL, 0.313 mmol). The mixture was stirred at room temperature then was added 1-methylhomopiperazine (16 μL, 0.125 mmol) and allowed to stir at room temperature. The solid formed was isolated by filtration and purified by HPLC to yield 5-chloro-3-((5-(2-fluoro-4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=480).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH:17]=[CH2:18].C(Cl)(Cl)Cl>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: C=CCn1c2ccccc2c2ccccc21
Yield: 100 %

Procedure:
Carbazole (10.1 g, 0.057 mol) and potassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11 mol) were stirred in 100 mL DMSO at 50° C. for 30 min before dropwise addition of allyl bromide (14.7 g, 0.118 mol). After 15 min the reaction mixture was poured into a 500 mL separatory funnel containing 100 mL chloroform and washed 5 times with 200 mL water to give, after solvent evaporation at 60° C. under reduced pressure, compound 15 in >99% purity as a dark brown, viscous syrup which solidified upon cooling (11.9 g, 0.057 mol, 100% yield). 1H NMR (300 MHz, CDCl3): δ=8.14-8.06 (m, 2 carbazole H), 7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2 carbazole H), 6.04-5.90 (m, CH═CH2), 5.19-5.10 (m, Z-HCH═CH), 5.07-4.97 (m, E-HCH═CH), 4.92-4.85 (m, NCH2). 13C NMR (300 MHz, CDCl3): δ=140.34, 132.27, 125.67, 122.90, 120.33, 119.00, 116.74, 108.74, 45.21.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:16][C:17]([O:21][CH:22](Cl)[CH3:23])([CH3:20])[C:18]#[CH:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH:22]([O:21][C:17]([CH3:20])([CH3:16])[C:18]#[CH:19])[CH3:23]
Reactant: C#CC(C)(C)OC(C)Cl
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CC(C)(C)OC(C)Oc1ccc(NC(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a well-stirred suspension of the potassium salt of 3-chloro-4-hydroxyphenyl-1,1-dimethylurea (0.04 mole) in dry acetone (150 ml.) is added dropwise 1-chloroethyl 1,1-dimethyl-2-propynyl ether (5.9 grams, 0.04 mole). During the addition, an exotherm to 35° C. is observed; the reaction is stirred at room temperature overnight, then poured into an aqueous 10% sodium carbonate solution containing 200 grams of ice, and the mixture stirred vigorously for 30 minutes. The resulting solid is filtered off, water-washed and dried to give 8.5 grams, melting point 99° C. to 101° C., crystallization from hexane-cyclohexane-benzene gave 4.69 grams (36%), melting point 101° C. to 103° C.