Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C1COCC1.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH:17]2[CH2:18][CH2:19][NH:15][C:16]2=[O:20])=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(Cl)cc1
Temperature: -76 °C
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
In a flask was added diisopropylamine (3.22 g, 31.8 mmole) and dry THF (60 ml). The content of the flask was kept under nitrogen, and was then cooled to −76° C. To the cool solution was dropwise added n-butyllithium (n-BuLi, 32 mmole, 20 ml, 1.6 M in hexane). After completed addition, the solution was stirred for 10 minutes, and a solution of 1-Trimethylsilanyl-pyrrolidin-2-one (5.00 g, 31.8 mmole, prepared according to literature methods) in dry THF (5 ml) was added dropwise. The solution was then stirred for an additional 20 minutes and a solution of 4-Chlorobenzyl chloride (5.13 g, 32 mmole) in THF (5 ml) was added via a syringe during 5 minutes. The resulting mixture was stirred at −76° C. for 1 hour, and was then allowed to reach the ambient temperature and was stirred over night. Water (40 ml) was added and the mixture was stirred vigorously for 60 minutes. The phases were separated and the organic phase was washed with brine, and was finally evaporated, giving an oil which crystallized on standing. The solid was triturated with heptane:EtOAc 2:1 and was filtered, giving a partly purified solid. The solid was purified on silica (DCM to DCM: MeOH 99:1 to 98:2 to 97:3 gradient) giving 1.3 g (20%) of the sub-title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:5][CH:4]=[N:3]1.O=S(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:12]1[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nccc1-c1ncccc1CO
Solvent: ClCCl
Product: Cn1nccc1-c1ncccc1CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (182 mg, 0.96 mmol) in DCM (5 mL) was added SOCl2 (1.5 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine (236 mg) as an off-white solid, which was used for next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
4-Formylbenzoic acid (1ad, 1.00 g, 6.7 mmol) was dissolved in dry methanol (200 ml) and stirred for 10 min at 0° C. Thionyl chloride (6 ml, 82.3 mmol) was added dropwise and the mixture stirred for 90 min at 0° C. and 3 hr at room temperature. The methanol was evaporated and the resulting residue extracted into dichloromethane, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from hexane to give 1.07 g (98%) of a white solid: mp 60-62° C. [expected mp 61° C.]; 1H NMR: δ 3.87 (s, 3H), 8.01 (d, 2H, J=7.9 Hz), 8.13 (d, 2H, J=7.6 Hz), 10.08 (s, 1H); 13C NMR: δ 52.7, 129.7, 129.9, 134.4, 139.1, 165.6, 192.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16]([Cl:22])[CH:15]=1>CN(C=O)C>[Cl:22][C:16]1[CH:15]=[C:14]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: OCCOC1CCCCO1
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (6.32 g, 43.30 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 1.09 g, 43.30 mmol) portion-wise. After 1 h at room temperature, this mixture was slowly added to a solution of 4,6-dichloro-nicotinonitrile (5.0 g, 28.90 mmol) in DMF (25 mL) at 0° C. After overnight, DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (4.9 g, 60%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (s, 1H), 7.10 (s, 1H), 4.70 (t, J=3.3 Hz, 1H), 4.32-4.45 (m, 2H), 4.19-4.08 (m, 1H), 3.91-3.80 (m, 2H), 3.59-3.50 (m, 1H), 1.83-1.68 (m, 2H), 1.65-1.50 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:7]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:16]>C1COCC1>[CH3:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:7]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:5][Br:16]
Reactant: BrP(Br)Br
Reactant: COc1c(C)ccc(C(C)C)c1CO
Solvent: C1CCOC1
Product: COc1c(C)ccc(C(C)C)c1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 211 %

Procedure:
To a solution of 3-methyl-6-(1-methylethyl)-2-methoxybenzyl alcohol (15.9 g, 80 mmol) in THF (160 ml) was added phosphorus tribromide (3.80 ml, 40 mmol) at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain 21.7 g of the title compound as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O:21]1[CH2:2][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)COC2=O
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethenyl-2-benzofuran-1(3H)-one (28.4 g, 177 mmol) was dissolved in DCM (400 mL) then mCPBA (47.7 g, 213 mmol) was added. The mixture was stirred at room temperature overnight. Some starting olefin remained. Another 25 g of mCPBA was added and the mixture was stirred overnight. The mixture was poured into ice cold Na2SO3 solution (saturated). The layers were separated and the organic layer was washed with 5% NaOH solution, brine, then was dried (MgSO4). The crude product was purified by MPLC (330 g column, eluting with 40% EtOAc/hexane, 2 L, then with 45% EtOAc/hexane, 2 L, to afford 5-(oxiran-2-yl)-2-benzofuran-1(3H)-one. LC-MS: M+1=177.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=1.93, min, m/z=482, 480
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1Br.[CH2:19]([N:26]1[CH2:31][CH2:30]C(=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:31][CH2:30][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:10])[CH:8]=3)[CH:3]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:2]2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COC(c1ccc(F)cc1)c1ccc(F)cc1Br
Product: Fc1ccc(C2OC3(CCN(Cc4ccccc4)CC3)c3cc(F)ccc32)cc1

Procedure:
By following the manipulative procedure described above in Example 45, 2-bromo-4,4'-difluorobenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce an oil.
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]>>[NH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: N
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 85 %

Procedure:
A 100 ml stainless steel autoclave was charged with about 50 ml of liquid ammonia. Then 4-chloro-3-nitrobenzenesulfonamide (5.0 g, 21 mmol) was added and the bomb was heated in an oil bath at 100° C. for 3 h. Excess ammonia was allowed to evaporate, and the solid residue was successively washed with water, cold ethanol and ether to give 3.9 g (85%) of the title compound. M.p. 211.5°-213° C. (ethanol); 1H-NMR (DMSO-d6): 6.97 (d,J=9Hz, 1H, H-5), 7.12 (s, 2H, NH2), 7.57 (dd, J6-5 =9 Hz, J6-2 2Hz, H-6), 7.70 (broad s, 2H, NH2), 8.22 (d,J 2Hz, H-2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1>>[OH:28][CH:27]([CH2:26][O:25][C:24]1[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=1[CH3:22])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Cc1ccccc1OCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1ccccc1OCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 173 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(2-methylphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 466 [M+H]; Rt=1.05 min.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[O:5]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:14]2[CH:13]=[C:12]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 15 °C
Yield: 65.3 %

Procedure:
20.5 g of ammonium thiocyanate were added to a solution of 25 g of 4-phenoxyaniline in 250 ml of acetic acid, and the mixture was stirred, whilst cooling. While the internal temperature was maintained at 12 to 18° C., 6.95 ml of bromine was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 2 hours, after which the solvent was removed by evaporation under reduced pressure. 300ml of ethyl acetate and 200 ml of water were added to the residue, and the resulting mixture was neutralized with sodium bicarbonate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, and then dehydrated over anhydrous magnesium sulfate after which it was concentrated by evaporation under reduced pressure. The solid obtained was triturated in diisopropyl ether, and filtered to give 21.34 g of the title compound, melting at 171-172° C.
Reaction SMILES: C(OC(NC1C(=O)N2C(C)(C(O)=O)CCC2=NC=1)=O)C1C=CC=CC=1.C([O:30][C:31]([C:33]1([CH2:54][O:55][CH3:56])[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)=[O:32])(C)(C)C>>[CH2:46]([O:45][C:43]([NH:42][C:39]1[C:38](=[O:53])[N:37]2[C:33]([CH2:54][O:55][CH3:56])([C:31]([OH:32])=[O:30])[CH2:34][CH2:35][C:36]2=[N:41][CH:40]=1)=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: COCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21

Procedure:
According to the procedure for the preparation of intermediate 19b, intermediate 23a (87 mg, 0.203 mmol) was deprotected to afford 76 mg (quantitative) of intermediate 23b. MS (ESI) 418.3 (M 2Na++H+), 372.2 (M−H+).
Reaction SMILES: [OH:1][CH:2]([C:8]1[O:12][C:11]2[C:13]([O:23]C)=[C:14]3[C:19](=[C:20]([O:21]C)[C:10]=2[CH:9]=1)[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].[N+]([O-])([O-])=O.[NH4+].[Ce].[K]>C(#N)C.O>[OH:1][C:2]([C:8]1[O:12][C:11]2[C:13](=[O:23])[C:14]3[C:19]([C:20](=[O:21])[C:10]=2[CH:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][S:4]([CH3:7])(=[O:6])=[O:5]
Reactant: COc1c2ccccc2c(OC)c2oc(C(O)CS(C)(=O)=O)cc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [K]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)C=C(O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of crude 2-(1-hydroxyl-2-methylsulfonylethyl)-4,9-dimethoxy-naphtho[2,3-b]furan from previous step in 40 mL of acetonitrile/water (4:1) in an ice bath, a solution of 4.4 grams (8 mmoles) of cerium ammonium nitrate and 1.34 gram (8 mmoles) of potassium bromated in 40 mL of acetonitrile/water (1:4) was added dropwise over 20 minutes. The resulting mixture was further stirred for 120 minutes in an ice bath, and then was evaporated to remove acetonitrile. The remaining aqueous solution was extracted with dichloromethane twice. The combined organic phase was washed with water, dried with anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to silica gel chromatograph purification using dichloromethane/ethyl acetate (4:1) as elution solvent. 0.64 gram (2 mmoles) of product was obtained with overall yield of 51% and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 3.20 (s, 3H), 4.68 (s, 2H), 7.84-7.87 (m, 3H), 8.23-8.33 (m, 2H). Mass (M+H) is 319.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[N:49]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)[N:49]=1
Reactant: COCc1nc(Cn2ncc(N)n2)co1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCc1nc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)co1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (14 mg, 0.06 mmol) in CH2Cl2 (0.3 mL) was treated at rt with DMAP (2 mg, 0.02 mmol), HOBt (10 mg, 0.08 mmol), EDC (31 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.26 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(methoxymethyl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (13 mg, 0.06 mmol) in CH2Cl2 (0.3 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5 mL), the org. phase was washed with water (5 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:2 hept-EA)=0.36. LC-MS-conditions 07: tR=0.88 min, [M+H]+=408.69.
Reaction SMILES: [F:1][C:2]1[C:41]([NH:42][S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:39]=[C:38]([F:49])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]=3)[N:13]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]2=[N:11][CH:12]=1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:41]([NH:42][S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:39]=[C:38]([F:49])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=3)[N:13]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:30])=[O:31])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCNCC2)n3S(=O)(=O)c2ccccc2)c1F
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A solution of tert-butyl 4-(5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.07 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (eluting with 90:10:1 CH2Cl2/MeOH/NH4OH) to afford 2,6-difluoro-N-(1-(phenylsulfonyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (29 mg, 67%) as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH3:14])[C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17](OC(C)C)=[O:18].[Na]>C(O)C>[C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH:14]=[N:17][OH:18])[C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1c(C)nn(-c2ccccc2)c1C
Reactant: CC(C)ON=O
Agent: [Na]
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(C)c1C(=O)C=NO
Temperature: 7 °C
Reaction time: 18 h

Procedure:
1-Phenyl-3,5-dimethyl-4-acetyl pyrazole (Chem. Abs. 63, 16332) (53 g) was dissolved in absolute ethanol (120 ml) and cooled to 7° C. Isopropyl nitrite (29.3 g) was added followed by a solution of sodium (5.7 g) in absolute ethanol (110 ml). The mixture was stirred 18 hours at 0°-10° C. and the fawn coloured sodium salt of the oxime filtered and washed with acetone (25 ml). The filter cake was then dissolved in water (40 ml) and the solution acidified with acetic acid (7 ml). The mixture was then extracted with chloroform (200 ml) and the chloroform extract dried over anhydrous sodium sulphate and then concentrated under vacuum to give 1-phenyl-3,5-dimethyl-4-(2'-oximino acetyl)-pyrazole as a yellow coloured solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][NH2:22])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:19]([C:18]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:17]=3[F:16])=[N:21][N:22]=2)[N:3]=1
Reactant: CC1(c2cc(Cl)nnc2Cl)CCCCC1
Reactant: NNC(=O)c1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Yield: 38.7 %

Procedure:
A mixture of 3,6-dichloro-4-(1-methylcyclohexyl)pyridazine (1.29 g, 5.27 mmol), 2,4-difluorobenzoic hydrazide (1.72 g, 10 mmol) and triethylamine hydrochloride (1.09 g, 7.9 mmol) in p-xylene (5 ml) was stirred and heated at reflux for 24 hours. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and water (100 ml) and NaHCO3 (100 ml). Undissolved solid was removed by filtration. The layers were separated and the aqueous was further extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.74 g): 1H NMR (250 MHz, CDCl3) δ 1.34-1.74 (6H, m), 1.50 (3H, s), 1.90-2.15 (4H, m), 7.01-7.14 (2H, m), 7.87-7.98 (1H, m), 8.18 (1H, s); MS (ES+) m/e 365 [MH], 363 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[O:14].[F:15][C:16]([F:40])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[F:40][C:16]([F:15])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:11]3/[C:12](=[O:13])[N:8]([CH2:7][C@@H:3]4[CH2:4][CH2:5][CH2:6][N:2]4[CH3:1])[C:9](=[O:14])[S:10]/3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CN1CCC[C@H]1CN1C(=O)CSC1=O
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from {[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (from Example 23) and [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) following General Procedure F.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[C:13]([NH2:14])=[C:12]([Cl:15])[N:11]=[CH:10][N:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([OH:23])[CH2:18]1>C1COCC1>[Cl:15][C:12]1[C:13]([NH2:14])=[C:8]([O:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([CH3:16])[CH2:18]2)[N:9]=[CH:10][N:11]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CN1CCC[C@@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H](Oc2ncnc(Cl)c2N)C1
Temperature: 70 °C

Procedure:
Sodium t-butoxide (586.0 mg, 6.098 mmol) was added to a solution of 4,6-dichloropyrimidin-5-amine (500 mg, 3.049 mmol) and (3R)-1-methylpiperidin-3-ol (351.2 mg, 3.049 mmol) in THF (25.00 mL) at RT. The reaction mixture was heated at 70° C. overnight. The reaction mixture was quenched with 1 mL water and concentrated in vacuo. The residue was extracted with DCM and the combined organic extract were dried and concentrated in vacuo to afford (R)-4-chloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-5-amine which was used in next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([NH:12][CH:13]1[CH2:19][C:18]2[CH:20]=[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[CH2:36](O)[CH3:37]>>[CH2:5]([NH:12][CH:13]1[CH2:19][C:18]2[CH:20]=[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([O:28][CH2:36][CH3:37])=[O:27])[CH:22]=[CH:23][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: CC(C)(Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: -10 °C

Procedure:
Thionyl chloride (0.2 ml) was added dropwise to ethanol (5 ml) with stirring at -10° C. After stirring for ten minutes, 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-2-methylpropionic acid (0.49 g) was added portionwise to the mixture. The reaction mixture was stirred at ambient temperature for 1 hour and then refluxed for 3 hours. After cooling, the mixture was poured into an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with chloroform-methanol (100:1) to give ethyl 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-2-methylpropionate (0.43 g).