Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:13]2/[C:12](=[O:17])[CH2:16][CH2:15][CH2:14]/2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1CCC/C1=C\c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A solution of KOH (1.5 g, 26.7 mMol) in water (27 mL) was added to 4-fluoro-benzaldehyde Compound 3a (7.45 g, 60.0 mMol) and cyclopentanone Compound 1a (5.0 g, 59.4 mMol). The mixture was heated to 65° C. and stirred for 24 hrs at 65° C. The reaction mixture was allowed to cool to ambient temperature, acidified to pH 3 using 1N HCl and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, then filtered and concentrated. The resulting residue was purified on a silica gel column (using 5% EtOAc/Hexane) to give (2E)-2-(4-fluoro-benzylidene)-cyclopentanone Compound 3b (2.60 g, 13.7 mMol).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:24])[NH2:25]
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Product: NC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-2-amino-2-phenyl-acetamide (CAN 6485-52-5, 52.6 mg, 0.53 mmol) as starting materials, and isolated (25 mg, 17.07%) as light brown solid; LC-MS (UV peak area, ESI) 98.31%, 418.0 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:13]=[C:14]([C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:20]=1)[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[O:5]([C:12]1[CH:13]=[C:14]([C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:20]=1)[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)Cl

Procedure:
To thionyl chloride (3 ml), a mixture of 2-phenoxy-5-ethoxycarbonylethylisonicotinic acid (1.0 g) and dimethylformamide (a small amount) is added, and the resultant mixture is stirred at room temperature for 20 minutes. The reaction mixture is evaporated under reduced pressure to remove the thionyl chloride. The residue is mixed with dry benzene and evaporated again. The residue is dissolved in anhydrous ether, and the insoluble part is filtered off. The ether solution is evaporated to give 2-phenoxy-5-ethoxycarbonylethylisonicotinoyl chloride (1.05 g). IR (CHCl3): 1775, 1735 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>COCCOC.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc([N+](=O)[O-])c4)nc4ccccc34)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reaction time: 16 h

Procedure:
A suspension of product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (9.0 g, 18.65 mmole) in a mixture of DME/MeOH (300 mL/100 mL) was hydrogenated in the presence of 10% Pd/C (1.25 g) at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through Celite™. The pad of Celite™ was washed with a 1:1 mixture of MeOH/CH2Cl2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (8.8 g, mmol, %).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([CH2:21]Br)[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>>[OH:9][N:8]([CH:6]1[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]1)[CH2:21][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:8]([OH:9])[CH:6]2[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Reactant: BrCc1ccc(CBr)cc1
Product: CC1(C)CC(N(O)Cc2ccc(CN(O)C3CC(C)(C)NC(C)(C)C3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and p-xylylene dibromide
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11]>CCCCCC>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:11]=[CH:10]/[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C=CC1CCCCC1
Reactant: Nc1ncc(Cl)cc1Br
Solvent: CCCCCC
Product: Nc1ncc(Cl)cc1/C=C/C1CCCCC1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and vinylcyclohexane. Purification by column chromatography on silica gel eluting with hexane—EtOAc (80:20) gave a pale yellow oil. An analytical sample was prepared by crystallisation from hexane:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH2:43][CH2:44][OH:45])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CCO)c4)cc3n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 30.0 mg, 0.0613 mmol) in acetonitrile (1 mL), cesium carbonate (20.0 mg, 0.0613 mmol) and (2-bromoethoxy) (tert-butyl)dimethylsilane (13.1 μL, 0.0613 mmol) were added sequentially at ambient temperature. The reaction mixture was then warmed up to 60° C. After 2 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated. The residue was dissolved in methylene chloride (1.0 m)/trifluoroacetic acid (1.0 mL) at ambient temperature. After 2 hours, the volatiles were removed under vacuum and the residues were dissolved in methanol (2.0 mL). Potassium carbonate (16.9 mg, 0.122 mmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.5 mg) as its TFA salt. LCMS calculated for C21H24N5O3 (M+H)+: m/z=394.2. Found: 394.2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[O:6][CH:7]=1.Cl.C[O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27]>>[F:20][C:2]([F:1])([F:21])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]([CH3:19])[C:16]([NH:27][C@@H:26]([CH3:28])[C:25]([OH:29])=[O:24])=[O:18])=[CH:13][CH:14]=2)[O:6][CH:7]=1
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)co2)cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](C)c1ccc(Nc2nc(C(F)(F)F)co2)cc1)C(=O)O
Yield: 74.4 %

Procedure:
Following the same procedure described for 16 and starting from (2S)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoic acid (19) (0.118 g, 0.39 mmol) and L-alanine methyl ester hydrochloride (0.035 g, 0.39 mmol), after workup and methyl ester hydrolysis, pure compound 24 (0.112 g, 0.29 mmol) was isolated as pale yellow oil (75%).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[NH:11][C:12](=[O:14])[N:13]=[C:6]2[CH:5]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[NH:11][C:12](=[O:14])[N:13]=[C:6]2[C:5]=1[Br:20])[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCc1cc2nc(=O)[nH]n2c(C)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C)n2[nH]c(=O)nc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of 7-n-propyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, prepared in Example 193, in 120 ml of acetic acid containing 12 g of sodium acetate, and to which a solution of 2.6 ml of bromine in 50 ml of acetic acid has been added dropwise, is stirred at room temperature for 3 hours. The reaction mixture is then concentrated under vacuum and thereafter treated with water. The crystals formed are drained, washed with water and dried. 7 g of 7-n-propyl-5-methyl-8-bromo-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one are thereby obtained in the form of crystals of melting point 221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.0 g, 17.1 mmole, prepared according to procedure described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine (50 mL) was added at room temperature and heated at 80° C. for 18 hrs. The excess pyridine was evaporated, reaction mixture was diluted with water (250 mL), washed with 1N dil. HCl (50 mL) extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][N:15]2[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]2)=[O:13])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][N:15]2[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]2)=[O:13])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)NN2CC=CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)cc1)NN1CC=CCC1
Yield: 56.6 %

Procedure:
To a solution of N-[[(4-methoxycarbonylphenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.21 g) in a mixture of methanol (30 ml) and chloroform (30 ml) was added. 1N sodium hydroxide (10 ml) and the mixture was stirred at ambient temperature for 18 hours. After evaporation of the solvent, the residue was extracted with chloroform (20 ml×3). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40 g) eluting with chloroform, to give N-[[(4-carboxyphenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.65 g).
Reaction SMILES: [NH2:1]/[C:2](=[N:4]\[O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)/[CH3:3]>C1(C)C=CC=CC=1>[CH3:3][C:2]1[N:1]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[O:5][N:4]=1
Reactant: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2nc(C)no2)c1

Procedure:
A solution of (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate in toluene (1 L) was heated at reflux overnight. The obtained mixture was evaporated and purified by silica gel column chromatography to afford methyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)isonicotinate as a white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 3-fluorophenylhydrazine hydrochloride (488 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (201 mg, 25%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:36][C:27]1[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:26]=1[O:25][S:22]([C:19]1[CH:20]=[CH:21][C:13]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[C:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=3)[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A vial was charged with perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (EXAMPLE 46, STEP 1) (134.9 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104 mg, 0.335 mmol), Pd(AmPhos)2Cl2 (7.90 mg, 0.011 mmol), potassium phosphate (142 mg, 0.670 mmol), dioxane (1116 μL), and water (372 μL). The vial as sealed and heated in a microwave reactor for 1 h at 100° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chomatography on silica gel (12 g, 0 to 40% EtOAc/Heptane) to give tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (125.5 mg, 0.178 mmol) as a clear oil. m/z (ESI) 729.4 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]1[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:9]1=[N:8]2.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]1[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:9]1=[N:8]2
Reactant: Cn1c2ccccc2c2nc3cccc(CO)c3nc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1c2ccccc2c2nc3cccc(CCl)c3nc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a solution of 304 mg (1.16 mmol) of 4-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline in 30 ml of methylene chloride was added 0.126 ml (1.73 mmol, 1.5 eq.) of thionyl chloride under ice-cooling, followed by stirring for 3 hours. The reaction solution was poured into 50 ml of ice water, and extracted with methylene chloride. The organic layer was washed 3 times with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 335 mg of the crude product 4-chloromethyl-6-methylindolo[2,3-b]quinoxaline, which was used for the next reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:32])([F:15])[C:28]([F:29])([F:30])[F:31])=[CH:20][CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Agent: Cl
Product: CC(c1ccc(OCC(F)(F)C(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (133 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (174 mg, 0.57 mmol, Amine-20, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)s1
Yield: 65.5 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(l-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 400 mg (1.8 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 600 mg (65%) of the expected compound were obtained, which compound had a melting point of 170°-1° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O>O.C(Cl)(Cl)Cl>[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:36]
Reactant: CNCCN(C)C
Reactant: O=C(O)c1ccnc(F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
N,N,N′-trimethylethane-1,2-diamine (0.92 ml, 6.84 mmol), 1-hydroxybenzotriazole monohydrate (1.05 g, 6.84 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.31 g, 6.84 mmol) were added to a chloroform solution (15 ml) of 3-chloro-2-fluoroisonicotinic acid (1.0 g, 5.70 mmol), and stirred under a nitrogen atmosphere at room temperature for 30 minutes. Saturated saline water was added to the reaction solution, and extracted with chloroform/methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 to 1:1) to obtain 3-chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (1.27 g, yield: 85%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:12][CH:13]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
4-(2-Hydroxyethyl)phenylcarbamic tert-butyl ester (described in Example 38b) (170 g; 0.716 mole) was suspended in dichloromethane (1.7 l) and placed in an ice bath. Pyridine (113 g; 1.43 mole) was added giving a clear yellow solution. p-Toluenesulfonyl chloride (205 g; 1.07 mole) was dissolved in dichloromethane (850 ml) and added slowly with stirring to the reaction mixture during 45 minutes. The reaction mixture was allowed to reach room temperature over night. The solution was then washed with water (4×1 L) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure until the weight was 440 g. The remaining brownish oil was slowly poured into heptane (1.6 L) with vigorous stirring. After approx. 20 seconds the oil started to crystallize. The heavy precipitate was filtered off, washed with heptane (200 ml) and dried in vacuo at 40° C. over night. This procedure gave 274 g (97.8% yield) of crude 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:13])[CH2:9][C:10](=[O:12])[CH3:11].[CH2:23]([O:25][CH:26]([O:32][CH2:33][CH3:34])[C:27](OCC)=[O:28])[CH3:24]>C(O)C>[CH2:23]([O:25][CH:26]([O:32][CH2:33][CH3:34])[C:27](=[O:28])[CH2:11][C:10](=[O:12])[CH2:9][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:7])[CH3:13])[CH3:24]
Reactant: CC(=O)CC(C)(C)NC(=O)c1ccccc1
Reactant: CCOC(=O)C(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)C(=O)CC(=O)CC(C)(C)NC(=O)c1ccccc1
Yield: 88.6 %

Procedure:
Sodium tert-butoxide (5.98 g, 62.2 mmol) was added to a solution of 4-methyl-4-benzamido-2-pentanone (12.4 g, 56.5 mmol) and ethyl diethoxyacetate (11.0 g, 62.2 mmol) in ethanol (40 mL), and the reaction was heated at reflux under a nitrogen atmosphere for 3.5 hours. The solvent was removed under reduced pressure, and the residue was partitioned between saturated aqueous ammonium chloride and tert-butyl methyl ether. The aqueous solution was extracted twice with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17.5 g of N-(6,6-diethoxy-1,1-dimethyl-3,5-dioxohexyl)benzamide as a brown oil.