Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Cl:22][CH2:23][C:24]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:7][CH:8]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Solvent: C1CCOC1
Product: CN(C(=O)CCl)c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 1.25 h
Yield: 52.5 %

Procedure:
To a mixture of (4-methylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.6 g, 2.1 mmol) and TEA (0.6 ml, 4.19 mmol) in dry THF (40 ml) was added dropwise chloroacetyl chloride (0.25 ml, 3.14 mmol). The mixture was stirred for 75 min. and evaporated in vacuo followed by addition of water 75 (ml). The aqueous phase was extracted with EtOAc (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on column chromatography (silicagel) using EtOAc-Heptane 1:1 as eluent. Pure fractions were collected; the solvent evaporated in vacuo affording 400 mg (53%) of 2-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([CH3:16])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:15][Br:36])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)c(OC(C)=O)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)c(OC(C)=O)c(CBr)c1
Temperature: 25 °C

Procedure:
A solution of methyl 4-acetoxy-3,5-dimethylbenzoate (2.4 g) in carbon tetrachloride (35 mL) was treated with AIBN (azobisisobutrylnitrile, 0.177 g, 0.1 equivalent) and NBS (N-bromosuccinimide, 2.117 g, 1.1 equivalents). The reaction was heated at reflux under a nitrogen atmosphere for 6 h. The reaction was cooled to room temperature and diluted with chloroform (30 mL). This solution was washed with water (4×50 mL) and then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. An off-white, waxy solid was recovered. Yield=4.63 g. The crude bromide was used as such for the following reaction.
Reaction SMILES: [F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.Cl>O1CCOCC1>[F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: FC1(c2nccs2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(F)(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of the product of Example 27B (3.55 g, 14.59 mmol) in dioxane (40 mL) was added 1M HCl (100 mL). The reaction mixture was stirred overnight at ambient temperature, quenched with 10M NaOH (10 mL) and extracted with three portions of 1:1 ethyl acetate-hexanes. The combined organic layers were concentrated. The resulting residue was chromatographed on silica gel eluting with 0%-20% ethyl acetate-hexane to obtain the title compound (2.15 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.95 (m, 2H), 2.61-2.72 (m, 6H), 2.24-2.42 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1
Reactant: NC(=O)C1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(C(N)=O)CC1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalents of piperidine-4-carboxamide as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [O:1]([CH2:19][C@H:20]1[C@@H:27]2[C@@H:23]([O:24][C:25](=[O:28])[CH2:26]2)[CH2:22][C@@H:21]1[F:29])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:1]([CH2:19][C@H:20]1[C@@H:27]2[C@@H:23]([O:24][CH:25]([OH:28])[CH2:26]2)[CH2:22][C@@H:21]1[F:29])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](OC[C@H]1[C@H]2CC(=O)O[C@H]2C[C@@H]1F)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC[C@H]1[C@H]2CC(O)O[C@H]2C[C@@H]1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 5 (989 mg, 2.40 mmol) in toluene (15 mL) at −78° C. (bath temperature) was added dropwise a 1.5 M solution of diisobutylaluminum hydride in toluene (2.4 mL, 3.6 mmol). After 1 h, methanol (2 mL) and ethyl acetate (2 mL) were added, the solution was warmed to room temperature, added to saturated sodium potassium tartarate (30 mL), and stirred for 30 min. The layers were separated, the aqueous phase was extracted with ethyl acetate (3×30 mL), dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 10 cm tall×26 mm diameter silica gel column eluting with 40% ethyl acetate in hexane to afford 6 (832 mg, 84%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[C:6]([Cl:37])[C:5]=1[OH:38].[OH-].[Na+].Cl>C(O)C>[Cl:37][C:6]1[C:5]([OH:38])=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=1)[C:3]([OH:39])=[O:2]
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc(Cl)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Reaction time: 15 h
Yield: 103.5 %

Procedure:
320 mg (0.57 mmol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester was dissolved in 20 mL of hot ethanol. 5 mL (14 mmol) of 7 M aqueous sodium hydroxide was added and the mixture was left at ambient temperature for 15 h. The resulting solution was acidified to pH 1 by addition of concentrated aqueous hydrochloric acid. The resulting precipitate was filtered off and dried by suction to afford 232 mg (0.59 mmol, 103%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.45 (d, 1H), 8.21 (d, 1H), 8.11 (d, 1H), 8.03 (d, 1H), 7.77 (d, 1H), 7.62 (dd, 1H), 7.31 (t, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 3.83 (s, 3H). MS: m/z 395.0 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cc2ccccc2cn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(C3OCCO3)ncc2c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of 3-isoquinolinecarboxaldehyde (7 g, 44.5 mmol), 5.5 g (88 mmol) of ethylene glycol, 400 ml of toluene and 1.1 g (4.4 mmol) of p-toluenesulfonic acid was refluxed for 16 h while separating the water formed. The mixture was cooled to room temperature and washed with sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate, and concentrated in vacuo to afford 8 g (89.9%) of 3-(1,3-dioxolan-2-yl)isoquinoline (Formula XII: R2 =R7 =H).
Reaction SMILES: [CH3:1][C:2](=CC)[CH3:3].CSC.C#CC.Br[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:16]=[N:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(CC)CC>C1COCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)CC>[CH:1](/[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:16]=[N:17][CH:18]=1)=[CH:2]\[CH3:3]
Reactant: CC=C(C)C
Reactant: COC(=O)C(C)c1ccc(-c2cncc(Br)c2)cc1
Agent: [Pd]
Agent: C#CC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCO
Solvent: O
Solvent: C1CCOC1
Product: C/C=C/c1cncc(-c2ccc(C(C)C(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a 0° C. solution of 2-methyl-2-butene (2M in THF, 14 mL, 28 mmol) in THF (20 mL) was added BH3.DMS (10 M in DMS, 1.4 mL, 14 mmol). After 30 min, the solution was allowed to warm to room temperature for 1 h, then cooled to -40° C. A stream of propyne (large excess) was passed through the solution, and the solution was allowed to warm to 0° C., then concentrated. 14b (100 mg, 0.31 mmol), Pd2 (dba)3)(14 mg, 0.014 mmol) and triphenylphosphine (18 mg, 0.068 mmol) were added, and the mixture was dissolved in 20 mL of 3:1:1 toluene:nPrOH:water. Et2NH (0.5 mL, 4.8 mmol) was added, the solution was degassed, and heated to reflux for 3 h. The mixture was cooled and partitioned between EtOAc and saturated aqueous NH4Cl. The organic phase was washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatography (20% EtOAc/hexanes to 40% EtOAc/hexanes) provided 38 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:17]1([CH2:16][S:23][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1SCc1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
85 g of 2-chloro-3-cyanopyridine, 98.2 g potassium carbonate anhydrous powder and 600 g of dimethyl formamide were mixed to obtain a suspension. To this suspension, a solution of 79.2 g benzyl mercaptan in 250 ml dimethyl formamide was added dropwise over a period of approx. 3 hours at 80-90° C. The reaction mass was agitated for 2 hours at the same temperature. The temperature was slowly raised to 120° C. Then, the reaction mixture was reacted at 120-130° C. for about 1.5 hours. Afterwards, heating was stopped and reaction mass was allowed to attain the room temperature. Inorganic cake was separated by filtration. Dimethyl formamide was distilled under reduced pressure, and the residue left at bottom was 2-(phenyl methyl thio)-3-cyano pyridine 150 g, sufficiently pure to be used in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([N:78]2[CH2:83][CH2:82][O:81][CH2:80][CH2:79]2)=[CH:8][C:6]=1[NH2:7]
Reactant: Nc1cc(Br)ccc1Cl
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCOCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-bromo-2-chloroaniline (1.09 g, 5.29 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (202 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (0) (198 mg, 0.22 mmol), and morpholine (2.3 mL, 26.4 mmol) in dry THF (12 mL) was degassed by nitrogen. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0M in THF (25.0 mL, 25.0 mmol) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% EtOAc in hexanes) to yield 2-chloro-5-morpholinoaniline. 1H NMR (400 MHz, CDCl3) δ ppm 7.12 (1H, d, J=8.6 Hz), 6.42 (2H, m), 4.00 (2H, br. s.), 3.93 (4H, m), 3.22 (4H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH2:19])=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C(O)(=O)C>CO>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][N:19]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH3:10])=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: NOCc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NOCc1ccc(Cl)c(C(F)(F)F)c1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentrated, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 358.1 (M+1)+].
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:26])[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1>C(OC(=O)C)(=O)C>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:26])[C:14]2[C:15](=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc([N+](=O)[O-])ccc32)c2ccccc21
Temperature: 90 °C
Yield: 76.2 %

Procedure:
A mixture of 3.68 g (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid, prepared as described in part A above, and 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 10.0 ml of acetic anhydride was heated at 90° C. for one hour and then allowed to cool to 25° C. The solid which separated was collected by filtration, washed with diethylether and dried to obtain 3.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-nitrophthalide (Formula III: R°=R1 =R3 =Y1 =H; R2 =NO2 ; R=R5 =CH3 ; R4 =N(CH3)2; R6 =CH2CH3) as an orange solid which melted over the range 185°-187° C. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A benzene solution of this product developed a black-purple color when spotted on silica gel.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][CH2:35][CH2:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH2:36][CH2:35][OH:34])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: OCCC1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(CCO)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-(2-hydroxyethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.69 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 3H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 446 [M+H]
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:26]1([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C(c2ccccc2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester (100 mg, 0.24 mmol) (from Example 5b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 60° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6,8-diphenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a light brown solid. (Yield 61.2 mg, 66.2%). HRMS m/z Calcd for C25H20N4O [(M+H)+]: 393.1710. Found: 393.1714.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][C:30]([CH3:33])([CH3:32])[O:29][C:27](=[O:28])[NH:22][CH2:23][C:24](=[O:25])[NH:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of L-Lys(Z)OMe 40 (1.05 g, 2.6 mmol) in dry DMF (40 mL) was added Boc-GlyOH (494 mg, 2.8 mmol), HATU (977 mg, 2.57 mmol), and DIEA (2.03 mL, 11.7 mmol). The mixture was stirred at rt overnight. The solvent was then removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (960 mg, yield 90%). Intermediate 41 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.12 (t, 1H), 7.98 (t, 1H), 7.47-7.38 (m, 5H), 6.98 (t, 1H), 5.13 (s, 2H), 4.56 (m, 1H), 4.05 (d, 2H), 3.65 (s, 3H), 3.02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[NH:23])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccccc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of benzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19]N>C(O)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[NH:19][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][C:3]2=1
Reactant: NNc1ccccc1Cl
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1CCc2[nH]c3c(Cl)cccc3c2C1
Yield: 83.1 %

Procedure:
A mixture of 4-oxo-cyclohexanecarboxylic acid (3.1 g, 21.7 mmol) and 2-chlorophenylhydrazine hydrochloride (4.0 g, 21.7 mmol) in glacial acetic acid (740 ml) is stirred at reflux for 3 h. The solvent is evaporated and water is added to the residue. The resulting precipitate is filtered off and dried under high vacuum to give the subtitle compound as a brownish solid (4.5 g) in 83% yield. tR (LC-5) 0.88 min; ESI-MS (positive ion): m/z 250.14 [M+H]+ (calcd 249.70 for C13H12NO2Cl). 1H-NMR (DMSO-d6): 1.75 (m, 1H); 2.14 (m, 1H); 2.62 (m, 5H); 6.90 (t, J=7.9 Hz, 1H); 7.02 (d, J=7.3 Hz, 1H); 7.30 (d, J=7.6 Hz, 1H); 7.92 (br s, 1H); 10.9 (br s, 1H).