Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([NH:50][CH3:51])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[N:37]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH:36]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.[Cl-].[Na+].O.C(Cl)Cl>[Br:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([N:50]([CH3:51])[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:9])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[N:37]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH:36]=1
Reactant: O=C(O)c1ccncc1
Reactant: CNC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccncc1)C1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
4-pyridinecarboxylic acid (30.3 mg, 0.247 mmol) was dissolve in N,N-Dimethylformamide (DMF) (3 mL) under argon flow. HATU (86 mg, 0.226 mmol) was added. After 30 minutes of stirring, 1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-methyl-4-piperidinamine D25 (100 mg) was added. After 20 minutes of stirring, DIPEA (0.144 mL, 0.822 mmol) was added. The mixture was stirred at room temperature under argon flow for all the night. DCM (10 mL) has been added to the mixture. The work-up has been done with 2×10 mL of Na2CO3, 10 mL of brine. The organic layer was filtrated by a phase separator and put under vacuo to remove the solvent. The crude material was purified by silica chromatography eluting by a gradiant of solvent: 0-5% of MeOH in DCM. The fractions were collected and the solvent has been evaporated to give the product D26 in 41 mg. LCMS [M+H]+555.01/557.03 g 2.64 min (5 min run)
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(C)[nH]1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
Ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 20, 12.3 g, 0.803 mmol) was dissolved in anhydrous DCM and cooled to −5° C. N-bromosuccinimide (14.23 g; 0.0803 mmol) was added and the reaction stirred for 10 min and then poured into ice-cold 2 N sodium hydroxide (500 ml). The brown solution was extracted with EtOAc (2×150 ml), the combined organic extracts were washed with water, brine and dried over Na2SO4, then concentrated in vacuo to give a brown solid which was dried under vacuum. (16.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21]([O:23]C)=O)[CH:3]=1.[CH3:25][NH2:26].CO>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][C:21]([NH:26][CH3:25])=[O:23])[CH:3]=1
Reactant: CN
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)NC
Reaction time: 16 h
Yield: 76 %

Procedure:
To a suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxy-2-oxoethoxy)benzamide (1.074 g, 3 mmoles) (prepared in Example 15), in a 1N solution of methylamine in toluene (10 ml) was added 3 ml of methanol and the mixture stirred for 16 hours. This was concentrated in vacuo and the residue crystallized from methanol-ether to give 815 mg (76%) of the title compound as white solid; mp. 149°-151° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[N:2]=1.B.C1COCC1.CO>C1COCC1>[OH:12][CH2:11][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=C(O)c1cc2ccccc2cn1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2ccccc2cn1
Temperature: 75 °C
Reaction time: 17 h
Yield: 12.3 %

Procedure:
To a stirred solution of isoquinoline-3-carboxylic acid (0.3179 g, 1.84 mmol) in dry THF (10 mL) at room temperature was added BH3—THF (1.0 M, 7.5 mL, 7.5 mmol). The mixture was stirred for 17 hrs, dry CH3OH (10 mL) was added, and the reaction was heated to 75° C. with stirring for a further 24 hrs. The mixture was concentrated and the residue was treated with dry CH3OH (3×10 mL), removing the solvent by evaporation each time. The crude product was purified by column chromatography (12 g silica gel, 19:1 CH2Cl2:CH3OH) to give 0.0359 g of 3-(hydroxymethyl)isoquinoline as a white film. The solid was dissolved in dry CH2Cl2 (5 mL) and treated with MnO2 (˜85%, 0.2978 g, 2.91 mmol) with stirring for 19 hrs then filtered through celite. Concentration of the filtrate afforded 0.0252 g (9%) of isoquinoline-3-carboxaldehyde as yellow oil. 1H NMR (CDCl3) d 7.73-7.82 (m, 2H), 7.97-8.07 (m, 2H), 8.37 (s, 1H), 9.36 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1>ClCCl>[OH:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1)=[O:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: O[C@@H]1CCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 757.2 %

Procedure:
A mixture of 4.86 g (26 mmol, 1 eq) of 3-nitrosalicylic acid and 12.16 g (26 mmol, 1 eq) of bromotripyrrolidinophosphonium hexafluorophosphate in 65 ml of dichloromethane and in the presence of 13.7 ml (78 mmol, 3 eq) of N,N-diisopropylethylamine was stirred at ambient temperature for 30 minutes. 4.52 g (4.10 mmol, 2 eq) of (R)-(+)-3-pyrrolidinol in solution in 10 ml of dichloromethane were added dropwise and the reaction medium was stirred at ambient temperature overnight. The reaction medium was extracted with a 1 N sodium hydroxide solution and separated by settling out. The aqueous phase was acidified with a 1N hydrochloric acid solution and extracted with ethyl acetate (5×150 ml). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 7.83 g of (2-hydroxy-3-nitrophenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone were obtained in the form of a golden yellow amorphous solid. Crude yield>100%. HPLC: 93% [252].
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:33]=O>CO.[Pd]>[CH3:33][N:8]1[CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]([NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])[C:2](=[O:1])[CH:6]2[CH2:7]1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CN(C)CCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O

Procedure:
A solution of 0.361 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide (prepared as described in Example 63) in 10 ml of methanol was treated with 1 ml of 40% aqueous formaldehyde solution and then hydrogenated for 1 hour in the presence of 0.03 g of 10% palladium-on-carbon. The catalyst was removed by filtration and evaporation gave 0.395 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-7-methyl-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a clear oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CCN(CC)CC>C(O)C>[Cl:1][CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](O)CCl
Yield: 75.8 %

Procedure:
In a 200 ml autoclave were charged 40.0 g (0.24 mol) of ethyl 4-chloro-3-oxobutyrate, 20 mg of Ru2Cl4((S)-Tol-BINAP)2.NEt3, and 40 ml of ethanol, and reaction was conducted at 100° C. under a hydrogen pressure of 300 KPa for 5 hours. After the solvent was removed, the reaction mixture was distilled (60° C./200 Pa.) to give 30.3 g of the title compound. Optical purity: 95%e.e.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH:11][S:26]([C:18]1[O:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1)(=[O:27])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ccccc1)c1cc2ccccc2o1
Yield: 26.6 %

Procedure:
Following General Procedure B, the title compound (235 mg) was prepared from 2-(benzylthio)-5-chloroaniline (509 mg, 2.052 mmol) and benzofuran-2-sulfonyl chloride (443 mg, 2.052 mmol) in pyridine (5 ml).
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][CH3:11])=[N:4][C:5]([OH:9])=[C:6]([Br:8])[CH:7]=1.[Li]CCCC>C1COCC1>[Br:8][C:6]1[C:5]([OH:9])=[N:4][C:3]([CH2:10][CH3:11])=[CH:2][CH:7]=1
Reactant: CCc1nc(O)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Br)c(O)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
step 5—To a suspension of 30 (320 mg) in THF (10 mL) at −78° C. was added dropwise a solution of n-BuLi (2.0M in cyclohexane, 1.25 mL). The reaction was stirred at −78° C. for 2 h then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 45 mg of 3-bromo-6-ethyl-2-hydroxy-pyridine (32) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:28])[NH:22]2>>[Cl:27][C:26]1[C:18]([CH3:17])=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:28])[C:20]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(6-methoxybiphenyl-3-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[S:3][C:2]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])=[N:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCN(CCC)c1nc(C)c(-c2c(C)nc3c(C(CC)CC)cc(C)nn23)s1
Temperature: 100 °C

Procedure:
35 mg of 3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.09 mmol) and 45 mg of di-n-propylamine (0.44 mmol) and 57 mg of cesium carbonate (0.18 mmol) are place into 4 ml reaction vial with 3 ml of dry THF and the vial is capped with a Teflon cap. The reaction vial is heated at 100° C. for 4 h. The reaction mixture is transferred into microwave reaction vessel and sealed. The reaction mixture is heated at 160° C. for 30 min by microwave. The mixture is concentrated and applied onto silica-gel chromatography column (Hexane:AcOEt=3:1) to give the title compound. 5.3 mg (14%); mass spectrum (m/e): 414; 1H-NMR (CDCl3): 5.59 (s, 1H), 3.45 (m, 4H), 3.36 (m, 1H), 2.57 (s, 3H), 2.47 (s, 3H), 2.17 (s, 3H), 1.80 (m, 8H), 0.99 (t, 6H, J=7.5 Hz), 0.89 (t, 6H, J=9.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH:10]([N:15]([CH3:17])[CH3:16])[CH2:9]2)[C:5]([F:18])=[C:4]([NH:19][NH2:20])[N:3]=1.[CH:21]1([CH2:26][C@H:27]([CH2:31][N:32]([CH:41]=[O:42])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][NH:20][C:28](=[O:29])[C@H:27]([CH2:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:31][N:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:41]=[O:42])[C:5]([F:18])=[C:6]([N:8]2[CH2:9][CH:10]([N:15]([CH3:16])[CH3:17])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NN)c2F)CC1(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOCC
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)CC1(C)C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,4,4-tetramethyl-3-pyrrolidinamine (7.37 g, 24.34 mmol, prepared according to the procedures of Example 133) in DMF (77 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (7.08 g, 23.18 mmol), N-methylmorpholine (12.75 mL, 116.0 mmol), 1-hydroxy-7-azabenzotriazole (3.79 g, 27.85 mmol), and EDC (5.33 g, 27.80 mmol). The solution was stirred overnight and was then diluted with Et2O (100 mL) and washed with water (3×100 mL). The combined aqueous phase was extracted with a fresh portion of Et2O (100 mL), and this organic phase was washed with a fresh portion of water (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was diluted with EtOAc (200 mL), and the resulting solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (12.52 g, 92% yield, mixture of diastereomers). LCMS: (M+H)+: 590.2.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1)=[O:5].CC([O-])(C)C.[K+].CC(O)(C)C>C1COCC1>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[NH:25][C:10]1[C:9]2[C:14](=[CH:15][C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:7]([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:23]#[N:24]
Reactant: N#Cc1cnc2cc(N3CCOCC3)c(NC(=O)CCCl)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1N1CCOCC1
Yield: 101.6 %

Procedure:
To a stirred solution of 3-chloro-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-(4-morpholinyl)-6-quinolinyl]propanamide (0.30 g, 0.61 mmol) in 1.2 ml of THF at 0° was added 1.2 ml of 1.0 M KOtBu/tBuOH dropwise during 1 m. After 2 h at 0° the reaction was quenched with solid CO2 and partitioned with DCM-water. The organic layer was washed with water, dried, and evaporated to give 0.28 g of the title compound as a white amorphous solid; ms 452.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[N+](C)([O-])=O.Cl>CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(N)nc(O)c3c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Reaction time: 1 h
Yield: 96 %

Procedure:
Thirty-four milligrams of 2-amino-4-hydroxy6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 15 ml of nitromethane which has been saturated with hydrogen chloride gas at 0° C. The mixture is stirred for 1 hour. Anhydrous ether is added and the solid filtered to give 27.6 mg (62%) of 2-amino4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish solid: m.p. >260° C.; NMR (DMSO-d6, 80 MHz) delta 7.71 (d, 2H, J=8.4 Hz), 8.00 (d, 2H, J=8 4 Hz), 8.40 (d, 1H, J=2.3 Hz), 8.75 (d, 1H, J=2.3 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53](O)=[O:54].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>CS(C)=O.O>[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:4](=[O:42])[C@@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:41])=[CH:17][CH:16]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][CH:23]=1)=[O:29])=[O:54]
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N(C)C)cc2)c2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
The product from Example 10A (15 mg, 0.022 mmol) was combined with (R)-2-(dimethylamino)-2-phenylacetic acid (4.82 mg, 0.027 mmol), HATU (9.38 mg, 0.025 mmol) and Hunig's base (0.014 mL, 0.078 mmol) in DMSO (0.5 mL) and the mixture was stirred at room temperature for 45 min. Diluted with water and collected the solid by filtration. The product was purified by chromatography on silica gel, eluting with 0-4% MeOH in CH2Cl2 to give the title compound (8 mg, 43% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02 (s, 9 H) 1.65-1.73 (m, 1 H) 1.86-1.95 (m, 2 H) 1.99-2.08 (m, 1 H) 2.13-2.20 (m, 2 H) 2.26 (s, 6 H) 2.49 (dd, J=12.21, 6.56 Hz, 1 H) 2.53-2.60 (m, 1 H) 3.32-3.39 (m, 1 H) 3.65-3.68 (m, 1 H) 3.69 (s, 3 H) 3.74-3.80 (m, 1 H) 3.81-3.87 (m, 1 H) 4.01 (s, 1 H) 4.38 (d, J=9.77 Hz, 1 H) 4.56 (s, 4 H) 4.76 (d, J=7.17 Hz, 1 H) 4.80 (dd, J=8.01, 2.52 Hz, 1 H) 5.39 (d, J=9.61 Hz, 1 H) 6.70 (t, J=7.25 Hz, 1 H) 6.73 (d, J=7.93 Hz, 2 H) 7.12-7.19 (m, 6 H) 7.36-7.43 (m, 5 H) 7.47-7.51 (m, 4 H) 9.30 (s, 1 H) 9.71 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[N:12]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.CC([O-])(C)C.[Na+].C1(C)C=CC=CC=1>C(Cl)Cl.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CCN(c2ccccn2)CC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A flask was charged with 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (Example 37) (100 mg, 0.24 mmol), 2-bromopyridine (0.55 mg, 0.22 mmol), Pd2(dba)3 (38 mg, 0.24 mmol), BINAP (1.18 mg, 0.0019 mmol), NaOtBu (33.6 mg, 0.35 mmol), and toluene (2 mL). The reaction mixture was heated at reflux overnight, cooled to rt, and diluted with CH2Cl2. The solid was filtered off. The solvent was evaporated. The residue was purified by flash chromatography (33% EtOAc in hexane) to give the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-4-carboxamide (55 mg, 47% yield): LC-MS m/z 492.1 (MH+), retention time 2.47 min (method 1); Rf=0.33 (50% EtOAc in hexane).
Reaction SMILES: O=O.[CH3:3]C(C)([O-])C.[K+].[C:9]([CH2:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.IC>N#N.O>[C:10]1([C:9](=[O:16])[CH:17]([CH3:3])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: N#N
Agent: O=O
Agent: [K+]
Solvent: CI
Solvent: O
Product: CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a three-neck flask in N2 atmosphere free of water and oxygen were successively added 0.066 mol potassium tert-butoxide and 150 mlTHF. Then to the resulting mixture was slowly added dropwise 0.06 mol dibenzoylmethane with stirring while cooling the mixture with ice-bath. The reaction was allowed to continue at room temperature for 1 hour, then 0.07 mol iodomethane was added dropwise at room temperature. Next, the reaction was allowed to continue at room temperature for further 48 hours. After the reaction was finished, the solvent was removed by distillation. To the solid mixture was added saturated saline until the solid mixture was just completely dissolved. The solution was extracted with suitable amount of anhydrous ethyl ether for three times. The organic phase was combined and dried over anhydrous sodium sulfate. The solvent was removed to give 12 g product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CC(CC(=O)O)c1ccc2c(c1)OCO2
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc3c(c2)OCO3)CC(=O)O1
Yield: 97.9 %

Procedure:
3-(1,3-benzodioxol-5-yl)glutaric acid (3.2 g) was treated with acetyl chloride (15 mL) and the resulting mixture heated at reflux for 5 hours. The cooled reaction mixture was then azeotroped with toluene (2×100 mL) and concentrated under reduced pressure. The residue was slurried with diethyl ether and filtered to afford the title compound (2.91 g).