Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52]Cl)[C:43]=1[CH2:42][CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]([C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1)[CH3:55].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52][C:59]3[CH:60]=[CH:61][C:56]([CH2:54][CH3:55])=[CH:57][CH:58]=3)[C:43]=1[CH2:42][CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: ClCc1cccc2c3c(sc12)[C@@]1(OCC3)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cccc3c4c(sc23)[C@@]2(OCC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Yield: 56.3 %

Procedure:
Under a nitrogen stream, to a mixture of (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-8-chloromethyl-3,3′,4,4′,5′,6′-hexahydro-spiro[2-oxa-9-thia-fluorene-1,2′-[2H]pyran] (41 mg, 0.05 mmol), 4-ethylphenylboronic acid (13.0 mg, 0.08 mmol), potassium phosphate (21.0 mg, 1.00 mmol), palladium acetate (1.2 mg, 0.005 mmol) and triphenylphosphine (2.6 mg, 0.01 mmol) was added toluene (2.6 mg, 0.5 mmol), and the resultant solution was stirred for 4 hours at 80° C. Solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:3)), to thereby obtain the titled compound (23 mg, 56%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:14](=[NH:17])[NH:15][OH:16])([CH3:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:13])([C:14]1[N:17]=[C:19]([CH3:20])[O:16][N:15]=1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Product: Cc1nc(C(C)(CC2CC2)NC(=O)OC(C)(C)C)no1
Reaction time: 5 h
Yield: 46 %

Procedure:
To a solution of [2-cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.16 mmol) in acetic anhydride (10 mL) was heated to 100° C. and stirred for 5 hours. After evaporation of solvents, the residue was dissolved in H2O (20 mL) and basified by aqueous NaHCO3 solution (pH˜7-8). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 20 g, eluting with 20% ethyl acetate in petroleum ether) to give the title compound (0.15 g; 46%) as colorless sticky solid. 1H-NMR (DMSO, 400 MHz): 0.012-0.014 (m, 2H); 0.31-0.38 (m, 2H); 0.56-0.58 (m, 1H); 1.32 (s, 9H); 1.55 (s, 3H); 1.69-1.98 (brs, 2H); 2.56 (s, 3H), 7.19 (br s, 1H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3C[CH:41]([CH2:43][CH:37](C3)C1)[CH2:42]2.C1(CO)CCCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH:35]2[CH2:42][CH2:41][CH2:43][CH2:37][CH2:39][CH2:44]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC1CCCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cycloheptylmethanol, the title compound was obtained as a colorless solid (0.08 g, 20%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.3 Hz, 1H), 3.94 (d, J=6.6 Hz, 2H), 2.87 (s, 6H), 2.00-1.25 (m, 13H); MS (ES−) m/z 405.1, 407.1 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O>[Pd].CO>[F:19][C:16]([F:17])([F:18])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[NH2:1]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 4-(4-nitro-2-(trifluoromethyl)phenyl)morpholine (5.0 g, 18.1 mmol), MeOH (20 mL) and Pd/C (500 mg, 10%) under H2 was stirred at rt overnight. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a pale yellow solid (4.01 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:47])[C:34]2[CH:39]=[C:38]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:37]=[C:36]([F:46])[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[F:46][C:36]1[CH:35]=[C:34]([CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:37]=1)[C:33]([NH:32][C:27]1[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([NH:24][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH:16]=2)[CH:26]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCCCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 50, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-fluoro-5-piperidinobenzamide to give N-[5-(3-fluoro-5-piperidinobenzamido)-2-methylphenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.59 (m, 8H), 1.95 (m, 1H), 2.19 (s, 3H), 3.20 (m, 6H), 3.64 (m, 2H), 4.63 (m, 1H), 6.90 (d, 1H), 7.02 (d, 1H), 7.22 (m, 3H), 7.41 (t, 1H), 7.57 (m, 3H), 7.78 (s, 1H), 9.83 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 631.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[NH:12][C:13](OCC)=[O:14])[CH:10]=1)=[O:5])[CH3:2].ClCCCl.O.CO>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:14])[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1cc(F)cc(F)c1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Titanium (IV) chloride (0.39 mL, 3.5 mmol) was carefully added to a solution of 1-[(3,5-difluoro-phenylimino)-ethoxycarbonylamino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.321 g, 0.876 mmol) and DCE (2.7 mL), and the resulting solution was heated to 110° C. for 1.5 h. The reaction mixture was cooled to room temperature and water (50 mL), methanol (1 mL), and DCM (40 mL) were added. The biphasic mixture was stirred for 30 min, and the layers were separated. The aqueous layer was further extracted with DCM (2×30 mL). The combined organic layers were washed with brine (40 mL), dried (MgSO4), and concentrated. The residue was triturated from EtOH to yield the titled compound (0.172 g, 60% yield). MS (ESI/Cl): mass calcd. for C14H10F2N4O3, 320.1; m/z found, 321.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.09 (s, 1H), 8.99 (d, J=0.5 Hz, 1H), 8.35 (s, 1H), 7.42-7.32 (m, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:21][NH2:22].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Yield: 90.1 %

Procedure:
(2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (3.58 g, 12.1 mmol) was dissolved in tetrahydrofuran (50 mL). Hydrazine monohydrate (26 mL, 536 mmol) was added and the reaction mixture was heated to reflux over night. The next day water was added and the resulting solid was collected by filtration, washed with water and dried to give (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (3.16 g, 90%) as a white crystalline compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=CC=1.C[O:22]C1C=C(C=CC=1)C(O)C1OC2C=CC=CC=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[O:22][C:12]2[CH:13]=[CH:14][CH:15]=[CH:10][C:11]=2[CH:16]=1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Reactant: COc1cccc(C(O)c2cc3ccccc3o2)c1
Product: COc1cccc(C(Cl)c2cc3ccccc3o2)c1

Procedure:
The compound 12 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indazol-1-yl)butanoate (500 mg, 1.19 mmol) in dry THF (8 mL) was treated by NaH (95 mg, 2.38 mmol, 60% in oil) at 0° C. for 30 min, then was added (2-(chloromethoxy)ethyl)trimethylsilane (295 mg, 1.78 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=6/1) to afford the title compound as a pale yellow solid. LC/MS m/z=551.8 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[BrH:18]>>[Br:18][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: O=C1CCc2ccc(CO)cc2N1
Solvent: CC(=O)O
Product: O=C1CCc2ccc(CBr)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg of 7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (2.82 mmol, 1 eq.) were dissolved in 1.77 ml of 33% hydrogen bromide in glacial acetic acid (31.0 mmol, 11 eq.) under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was partitioned between aq. saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4+1. The aqueous layer was extracted three times with dichloromethane/isopropanol 4+1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The crude product was purified by flash chromatography to yield 175 mg (0.66 mmol, 23.3%) of the analytically pure target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[CH3:2].[C:27]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)#[N:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][O:14][C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CCc1c(CO)cnc(C)c1OCc1ccc(C#N)cc1
Product: CCOC(=O)CCc1c(COc2ccc(C#N)cc2)cnc(C)c1OCc1ccc(C#N)cc1
Yield: 93.2 %

Procedure:
The coupling of 3-[3-(4-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (36) (3.5 g, 9.89 mmol) and 4-cyanophenol (1.2 g, 9.9 mmol), as described in Example 9, gave 3-[3-(4-cyano-benzyloxy)-5-(4-cyano-phenoxymethyl)-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (37) (4.2 g, 91% yield).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>O>[CH3:33][O:32][C:30]([O:20][CH2:19][N:15]1[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]2[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:30]([O:32][CH3:33])=[O:31])[C:4](=[O:22])[CH2:5]2)[CH2:17][C:16]1=[O:18])=[O:31]
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)OC)C(=O)C2)CC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (2.20 g, 7.0 m mol) and pyridine (20 ml), methyl chloroformate (1.41 g, 14.9 m mol) was added gradually at 0° C., and the mixture was stirred for 1.5 hours at 0° C., then successively for 3 hours at room temperature. The reaction mixture was added to water and was extracted with chloroform. The extract solution was washed with 10% sulfuric acid solution and successively with water, and was dried over magnesium sulfate. The crystals obtained by concentrating the extract solution under reduced pressure were washed with ethyl acetate and dried under reduced pressure to give the titled compound (1.76 g; yield 58.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12]([S:16][CH3:17])[C:13](O)=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH:12]([S:16][CH3:17])[C:13](=[O:14])[NH:20][N:21]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: CSC(CC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)O
Solvent: O
Solvent: CCO
Product: CSC1CC(c2cc(Cl)c(C)c(Cl)c2)=NNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1.54 g (0.005 mole) of 4-(3,5-dichloro-4-methylphenyl)-2-methylthio-4-oxobutyric acid, prepared as described in step (c) above, were suspended in 5 ml of ethanol and then 0.25 g of hydrazine monohydrate was added, at room temperature, to the suspension, after which the mixture was stirred for 1 hour at room temperature. The mixture was then heated under reflux for 6 hours, after which it was cooled and the resulting crystals were collected by filtration and washed with a small amount of ethanol, to give 1.32 g (yield 87.1%) of the desired Compound No. 22, melting at 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17](Cl)[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:22](O)C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:16]=[CH:17][F:18])[C:10]2[CH:14]([CH3:22])[O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)Cl)CO1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CC1OC(=O)C=C1N(C=CF)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
68 mg (0.22 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2-chloro-2-fluoroethyl)amino]furan-2(5H)-one (17) are initially charged in 5 ml of ethanol, 38 mg (0.67 mmol) of potassium hydroxide are added and the reaction mixture is stirred at room temperature for about 18 hours. The reaction mixture is then partitioned between ethyl acetate and water, and the organic phase is separated off. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 57 mg (94% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2-fluorovinyl)amino]-5-methylfuran-2(5H)-one as an (E/Z) isomer mixture (15:85).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(Cl)Cl>[F:17][C:5]1[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[N:7][C:2]([NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1-n1ccc2ccccc21
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC1CCC(Nc2ncc(F)c(-n3ccc4ccccc43)n2)CC1

Procedure:
1-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1H-indole (0.095 g, 0.38 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide (0.17 g, 0.76 mmol), and DIEA (0.13 mL, 0.76 mmol) were stirred in NMP (2 mL) at 170° C. for 4.5 hours. The solvent was removed at 100° C. in vacuo to yield an oil which was then dissolved in DCM, washed with cold water and brine, and fried with sodium sulfate. The solvent was removed in vacuo to yield an oil. The product was purified using flash chromatography (SiO2) eluting with 1% MeOH/DCM to obtain N-[4-(5-fluoro-4-indol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide as a white solid (Compound 115, 0.025 g, 16%, mp 270.0-270.5° C.).
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][N:14]=[CH:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC=NNc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stifling for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated via filtration, washed with water and dried in air to obtain N-(3-nitro-phenyl)-N′-propylidene-hydrazine, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[N:7]=1.N[C:28](C)(C)CO.FC(F)(F)C(O)=O>>[F:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([NH:17][C:18]([CH3:28])([CH3:21])[CH2:19][OH:20])[N:7]=1
Reactant: Cc1cccc(CSc2nc(N[C@H](C)CO)cc(NS(C)(=O)=O)n2)c1F
Reactant: CC(C)(N)CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CSc2nc(NC(C)(C)CO)cc(NS(C)(=O)=O)n2)c1F

Procedure:
The title compound was prepared as a white solid by the method of Example 115 using the subtitle product of Example 115 step (1.0 g), 2-amino-2-methyl-1 propanol (1.5 ml) and trifluoroacetic acid (2 ml). Yield: 0.19 g.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@H:4]1[OH:9].[CH3:12]C([O-])(C)C.[K+].S(OC)(OC)(=O)=O.O>C1COCC1.C(Cl)Cl>[CH3:12][O:9][C@H:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: CC(C)(C)[O-]
Reactant: COC1(OC)CCOC[C@H]1O
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1COCCC1(OC)OC
Reaction time: 0.75 h
Yield: 99 %

Procedure:
A 12-L 4-neck round bottom flask equipped with a overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser, and thermocouple was charged with (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol (as prepared in the previous step, 163 g, 1.0 mol) in THF (2.4 L) and stirred in ice/acetone bath until <0° C. KOtBu (113 g, 1.0 mol) was added in one portion, and after stirring 45 min, dimethyl sulfate (95 mL, 1.0 mol) was added via addition funnel over 15 min. The reaction was allowed to stir at room temperature for 2 h. The reaction mixture was poured into a reparatory flask containing H2O (1.2 L) and CH2Cl2 (1.2 L) and the layers were separated. The aqueous layer was back-extracted with CH2Cl2 (900 mL). The combined organic layers were washed with brine (1.0 L; Note: organic layer was on top), dried over MgSO4, filtered and evaporated to afford the title compound (177.1 g, 99%, chiral GC 94.4% ee) as a light yellow oil.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[N:14][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:12]2O.O=S(Cl)[Cl:26]>>[Cl:26][C:12]1[C:11]2[C:16](=[C:7]([CH3:6])[CH:8]=[CH:9][CH:10]=2)[N:15]=[N:14][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc2c(O)c(-c3ccccc3)nnc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cccc2c(Cl)c(-c3ccccc3)nnc12

Procedure:
Step 3: 2 Drops of DMF was added to a suspension of 8-methyl-3-phenylcinnolin-4-ol (60 mg) in SOCl2 (10 mL) and the reaction was refluxed for 0.5 hours. The reaction was concentrated, dilute with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give crude 4-chloro-8-methyl-3-phenyl-cinnoline which was used for the next reaction without further purification. MS (ESI) m/z 255, 257;