Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][N:24]([CH3:29])[CH:25]1[CH2:28][NH:27][CH2:26]1>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:25]([N:24]([CH3:29])[CH3:23])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 1.5 g (5.3 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (8 mmoles) of 3-dimethylaminoazetidine dihydrochloride and 6.6 g of triethylamine is heated under reflux in 15 ml of pryidine for 3 hours. It is evaporated, water is added and the resulting mixture is made alkaline with 1N sodium hydroxide, heated, filtered while hot, acidified with acetic acid, and filtered. After washing with water, 1.7 g (88%) of 1-cyclopropyl-6,8-difluoro-7-(3-dimethylamino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 256°-60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][NH2:30])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]>C(O)(=O)C.C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][N:30]=[C:11]([CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[C:12]([OH:14])=[O:13])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1[N+](=O)[O-])=NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 133 %

Procedure:
3-(2-Nitro-phenyl)-2-oxo-propionic acid (1.0 mmol, 209 mg) in 5% acetic acid (2 mL) was added in to solution of 4-(3,4-dichloro-phenyl)-thiazol-2-yl-hydrazine (1.0 mmol, 259 mg) in ethanol (4 mL). The reaction mixture was stirred at 90° C. for 1 h and cooled to 0° C.; the orange solid was precipitated out, filtered and washed by water. Recrystallization from MeOH—H2O afford the final product as a yellow powder (600 mg, 66.7%). mp ; Z/E isomer was further separated by HPLC-MS, using gradient eluting solvents: 0.05% HOAc in acetonitrile 50%: 0.05% HOAc in water 50% to 0.05% HOAc in acetonitrile 75%: 0.05% HOAc in water 25% in 20 min. 1H NMR (400 MHz) δ 12.85 (br, 1H), 12.10 (br, 1H), 8.06 (d, J=8.4 Hz, 1H), 8.03(s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=6.0 Hz , 2H), 7.61(s, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 4.28 (s, 2H). 13C NMR (125.78 MHz) δ 166.097, 164.759, 149.785, 134.607, 134.281, 133.663, 132.596, 132.182, 131.543, 130.680, 129.559, 128.927, 127.854, 126.318, 125.795, 125.299, 108.552, 36.896. Z-isomer: 1H NMR (400 MHz) δ 12.35 (br, 1H), 12.10 (br, 1H), 8.06 (dd, J=8.4 Hz, 1H), 8.03(s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=6.0 Hz, 2H), 7.61(s, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 4.12 (s, 2H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12]/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C1COCC1>[OH:23]/[C:22](/[C:19]1([CH3:18])[CH2:21][CH2:20]1)=[CH:16]\[C:15](=[O:17])/[CH:14]=[CH:13]/[O:12][CH3:11]
Reactant: CC1(C(=O)Cl)CC1
Reactant: CO/C=C/C(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CO/C=C/C(=O)/C=C(\O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
LiHMDS (1M in THF, 845 mmol) was added dropwise to a solution of trans-4-methoxy-3-buten-2-one [51731-17-0] (845 mmol) in THF (2 L) at −78° C. After stirring for 15 min, a solution of 1-methyl-cyclopropanecarbonyl chloride [16480-05-0] (407 mmol) in THF (100 mL) was added. The resulting mixture was allowed to warm to rt over 2.5 h and then quenched by addition of a saturated solution of NH4Cl. The mixture was extracted with Et2O (2×). The combined organic phases were successively washed with a saturated solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid. ESI-MS: [M+H]+ 183; TLC: Rf=0.29 (9:1 Hex/EtOAc).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:11]2([C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19]C3CCCCO3)[C:13](=[O:26])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].C(OCC)(=O)C>C(OCC)(=O)C.CCO>[ClH:29].[OH:19][CH2:18][CH2:17][N:14]1[C:13](=[O:26])[CH2:12][C:11]2([CH2:27][CH2:28][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(CCOC1CCCCO1)C2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC2(CCNCC2)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 1,3-dioxo-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.6 g) in ethyl acetate (1 ml), EtOH (1.0 ml) and 4N HCl/ethyl acetate (4 ml) are added at room temperature. The reaction mixture is stirred for overnight at room temperature. The solvent is removed by evaporation to give 1.06 g of crude 2-(2-hydroxy-ethyl)-2,8-diaza-spiro[4.5]decane-1,3-dione. hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=2[O:18][CH3:19])[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[NH2:24].[H-].[Na+].O1CCCC1>C(OCC)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=3[O:18][CH3:19])[CH:5]=[CH:4][N:3]=2)[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2ccnc(Nc3cc(C)cc(C)c3)n2)c(OC)c1OC

Procedure:
In a vial was placed 28 mg (100 μmol) of chloropyrimidine 5, 3,5 dimethylaniline (24 mg, 200 μmol), 60% NaH (6 mg, excess), and tetrakis(triphenylphospine)palladium (6 mg, catalytic). Tetrahydrofuran (2 mL) was added and the vial was sealed and heated to reflux for two hours. The reaction was diluted with diethyl ether and washed with 1N hydrochloric acid. The organic layer was separated, washed with 1N NaOH solution, water, and brine. The organic extract was dried (MgSO4), filtered, and evaporated in vacuo to afford the crude product. The compound was purified on silica gel using an eluent of 20% acetone/hexane to afford the pure product II-14 as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 8.41 (d, 1H), 7.78 (d, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 6.82 (d, 1H), 6.68 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 2.34 (s, 6H).
Reaction SMILES: [C:1](O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[Ca+2].[Cl-].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].C(Cl)(Cl)Cl>O.[Cl-].[Zn+2].[Cl-]>[C:1]([C:23]1[CH:24]=[CH:25][C:18]([OH:19])=[CH:20][C:21]=1[OH:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)c1ccc(O)cc1O
Yield: 41.4 %

Procedure:
68 g of granular zinc chloride and 250 g of lauric acid were melted togerther at 125° C., under nitrogen and with protection from moisture by calcium chloride. The mass was stirred and 55 g of resorcinol were added portionwise over 15 minutes. The mixture was stirred a further 2 hours, cooled and drowned in 500 ml of water. 100 ml of chloroform was added to break up the solid mass, and the crystalline solid remaining was filtered, washed with chloroform, then water, to give 60.4 g of a solid with a melting point of from 79°-83° C. This was used without further purification. The analytical sample was recrystallised from light petroleum (b.p. 60°-80° C.). The pure product had a melting point of from 83.5°-85° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:24][C:25]([C:27]1[C:28]([CH3:36])=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31])=[O:26]>C1COCC1>[C:30]([C:29]1[C:28]([CH3:36])=[C:27]([C:25](=[O:26])[CH2:24][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:34]=[CH:33][C:32]=1[F:35])#[N:31]
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc(F)c1C#N
Reaction time: 0.25 h

Procedure:
To a THF solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.080 g, 0.43 mmol) was added Lithium diisopropylamide (0.20 mL, 0.39 mmol) drop wise at −78° C. After stirring for 15 min., a THF solution of 3-(bromoacetyl)-6-fluoro-2-methylbenzonitrile (0.10 g, 0.39 mmol) was added to the reaction mixture slowly. Analysis of the reaction mixture by LC indicated formation of the desired product. To the reaction mixture was sat. NH4Cl followed by extraction of the aqueous layer with EtOAc. The extractions were combined and washed with brine, dried with Na2SO4, and concentrated under reduced pressure to provide a residue which was then subjected for purification by silica gel column chromatography (10% MeOH in DCM) to provide the title product. LC/MS (IE, m/z): [M+1]+=376.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:24])=[C:11]([CH2:13][C:14]([NH:16][CH2:17][C@@H:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]=O)=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][C:10]=3[CH3:24])[CH2:19]2)=[CH:28][CH:27]=1
Reactant: O=CCCc1ccc(Cl)cc1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CN(CCCc2ccc(Cl)cc2)CCO1
Temperature: 20 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
A mixture of Intermediate 28 (0.04 g), 3-(4-chlorophenyl)propanal (0.026 g) and acetic acid (0.02 ml) in dichloromethane (4 ml) was treated with sodium triacetoxyborohydride (0.080 g). The mixture was stirred at 20° C. for 72 h. The mixture was partitioned between chloroform (6 ml) and saturated aqueous sodium hydrogen carbonate (6 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (2 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml) and the appropriate fractions were concentrated in vacuo to give the title compound as a colourless gum (0.055 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=3)[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1cc(N)ccc1F
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and methyl 5-amino-2-fluorobenzoate as a white powder (74%). 1HNMR (CDCl3, 300 MHz) δ 7.51 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 3H), 6.97 (m, 1H), 6.76 (m, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 414.0. HPLC, Rt: 5.78 min (Purity: 98.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.C(O)(=O)C.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(C2=CCN(CCC(F)(F)F)CC2)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C2CCN(CCC(F)(F)F)CC2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
1.65 g (5.0 mmol) of the product prepared in step 16.2 are placed in 120 mL of an ethanol/acetic acid mixture (v/v=1/1) in a hydrogenation autoclave, and 0.150 g of platinum (IV) oxide is added, under an inert atmosphere. The mixture is stirred under a hydrogen pressure of 4 bar at room temperature for 4 hours. After filtering through thin glass fibre paper and evaporating to dryness under reduced pressure, the oily residue is taken up in chloroform and washed with aqueous 1N NaOH solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. 1.5 g of the expected product are obtained in the form of a brown oil, which is used as obtained in the following step. Crude yield=quantitative.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)(C)C.O>[CH2:13]([NH:31][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
60 g of D-galactose are suspended in 330 ml of isopropanol and 170 ml of water, and the mixture is heated to 50°. After addition of 90 g of stearylamine, the mixture is stirred until all the amine has gone into solution. On cooling, the glycosylamine crystallizes out. The solid is filtered off with suction, washed consecutively with ethanol and with ether, and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1cn(-c2ncccn2)cn1
Yield: 73 %

Procedure:
As described for Example 49, 3-(4-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (61 mg, 0.2 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (56 mg, 73%) which was obtained as a light yellow solid. MS: m/e=382.0/384.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CC(=O)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Yield: 70.5 %

Procedure:
A mixture of 11.1 g of 3-amino-2-cyclohexenone, 24.2 g of ethoxymethylenemalonic acid diethyl ester, and 0.12 g of p-toluenesulfonic acid was heated on an oil bath at 120°-130° C. for 2 hours. Using column chromatography, the reaction product was purified to obtain a yield of 19.8 g of N-(3-oxo-1-cyclohexen-1-yl)aminomethylenemalonic acid diethyl ester in the form of a pale-yellow viscous oil. The n.m.r. spectrum (d6 -DMSO, 60Mc, TMS) of this compound had signals at δ values of 1.24 (3H, t, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.7-2.75 (6H, m), 4.10 (2H, q, J=7 Hz), 4.18 (2H, q, J=7 Hz), 5.75 (H, s), 8.05 (1H, d, J=13.8 Hz), and 10.2 (1H, d, J=13.8 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=S)[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12]2=[N:25][N:24]=[C:21]([CH3:22])[N:11]2[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: O=C1CC(=S)Nc2ccccc2N1Cc1ccccc1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1N(Cc1ccccc1)C(=O)C2
Reaction time: 24 h
Yield: 36.5 %

Procedure:
A solution of 1-benzyl-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (50 mg, 0.18 mmol) and acetohydrazide (40 mg, 0.53 mmol) in 20 mL of n-butanol was heated to reflux, and stirred for 24 h under N2 atmosphere. The solvent was evaporated in vacuo and the residue was purified by prep-TLC (DCM:MeOH=25:1) to give 6-benzyl-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (20 mg, 38%). 1H NMR (300 MHz, CD3OD): δ 2.36 (s, 3H), 3.77 (d, J=14.1 Hz, 1H), 3.98 (d, J=14.1 Hz, 1H), 4.69 (d, J=15 Hz, 1H), 5.64 (d, J=15 Hz, 1H), 6.77-6.80 (m, 2H), 7.13-7.16 (m, 3H), 7.49-7.62 (m, 3H), 7.82-7.85 (m, 1H). LRMS (M+H)+: 304 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:14])[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:14])[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2c(F)cccc2N1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(F)c2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoroindoline-2(R/S)-carboxylic acid methyl ester (0.43 g, 2.205 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (0.47 g, 2.33 mmol) dissolved in dried dichloromethane(10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.36 ml, 2.33 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 10:1 dichloromethane: diethyl ether as eluent. An off-white foam was obtained which was the mixture of the two diastereomers.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:27])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[C:23]([C:24]([OH:26])=O)[C:16]=23)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH:1]1([NH:6][C:7](=[O:27])[C@H:8]([N:13]2[C:24](=[O:26])[C:23]3=[CH:22][NH:21][C:17]4[C:16]3=[C:15]([CH:20]=[CH:19][N:18]=4)[CH2:14]2)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H](C)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@H](C(=O)NC1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 37 %

Procedure:
In a manner similar to Step C of Example 19, 4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was cyclized in a mixture of THF (2 mL), HATU (112 mg, 0.296 mmol) and 4-methylmorpholine (37.4 mg, 0.370 mmol) and the resulting product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (32 mg, 37% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 0.61-0.72 (m, 2 H) 0.90-1.06 (m, 5 H) 1.37-1.66 (m, 7 H) 1.66-1.77 (m, 2 H) 1.77-1.99 (m, 4 H) 3.98-4.22 (m, 1 H) 4.85-4.97 (m, 2 H) 5.21 (d, J=9.35 Hz, 1 H). [M+H] calc'd for C20H26N4O2, 355; found, 355.5.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:21]2[CH:3]=[CH:2][CH:24]=[C:23]([F:25])[CH:22]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1cccc(F)c1
Yield: 173.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-chlorobenezeneboronic acid (29 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) at 90° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid (45 mg, 84%). LC-MS m/e 441.24 (M+H+)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([F:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH3:21]>C1COCC1>[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:21])=[O:16])=[C:13]([F:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(F)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(N)=O)c(F)c1
Reaction time: 1 h

Procedure:
Oxalyl chloride was added to a THF solution of 4-tert-butyl-2-fluorobenzoic acid and stirred for 1 hour, and aqueous ammonia was added to this. By post-treating the reaction liquid, 4-tert-butyl-2-fluorobenzamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[NH:4][N:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Br.[OH-].[Na+]>C(O)(C)C.O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[NH:4][N:3]=1
Reactant: CCOC(=O)c1cccc(Sc2cc(N)n[nH]2)c1
Reactant: Clc1ccccn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Temperature: 175 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A stirred solution of ethyl 3-(3-amino-1H-pyrazol-5-ylthio)benzoate (0.150 g, 0.57 mmol), 2-chloropyridine (0.130 g, 1.14 mmol) in isopropanol (2 mL) was treated with hydrobromic acid (0.150 mL) and heated at 175° C. in a microwave oven for 30 minutes. The mixture was then diluted with water (1.5 mL) and treated with sodium hydroxide (1 pellet). The reaction was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in methanol, acidified with conc. hydrochloric acid and purified on Prep HPLC (MeCN/H2O/5 mM NH4OAc) to give the title material (0.113 g, 62%) as a solid. The compound was used as such in the next reaction.