Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].I[CH:37]([CH3:39])[CH3:38]>CN(C=O)C.CC(C)=O>[CH3:38][CH:37]([N:27]1[N:28]=[N:29][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)=[N:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:26]1)[CH3:39]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4nnn[nH]4)CC3)cn2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
A solution of 2-[4-(methylsulfonyl)phenyl]-5-({[1-(1H-tetrazol-5-yl)-4-piperidinyl]methyl}oxy)pyridine (157 mg, 0.38 mmol) in DMF (2 mL) and acetone (3 mL) was added potassium carbonate (105 mg, 0.76 mmol) at room temperature. After stirring for 15 min, 2-iodopropane (193 mg, 1.14 mmol) was added by syringe and the mixture was heated at 50° C. for 16 h. The salt was removed by filtration and washed with MeOH/CH2Cl2. After concentration, a small amount of MeOH/CH2Cl2 was added and the resulting precipitate was collected and washed with a small amount of MeOH. The material was dried in vacuo to give the title compound (130 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.34-8.25 (m, 2H), 8.07 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.7 Hz) 7.55 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.88 (septet, 1H, J=6.7 Hz), 4.03 (d, 2H, J=6.6 Hz), 3.98 (d, 2H, J=12.6 Hz), 3.25 (s, 3H), 3.01-2.86 (m, 2H), 2.11-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.50 (d, 6H, J=6.7 Hz), 1.46-1.30 (m, 2H); LRMS (ESI), m/z 457 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:13]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:14]=3[N:15]=[C:16](Cl)[N:17]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[OH-].[NH4+].[CH3:34][CH:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([O:50][CH3:51])[CH:44]=2)[CH2:39][CH2:38]1)[CH3:36]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:13]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:14]=3[N:15]=[C:16]([NH:47][C:46]3[CH:48]=[CH:49][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH:35]([CH3:34])[CH3:36])[CH2:38][CH2:39]4)=[CH:44][C:45]=3[O:50][CH3:51])[N:17]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Br)cc4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2ccc(Br)cc2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Yield: 73.1 %

Procedure:
According to General Protocol III/Step A & B, 5-bromo-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.5 g, 3.69 mmol), 27% aqueous ammonium hydroxide, and 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (0.550 g, 3.32 mmol) were combined to afford 5-bromo-2-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide as a pale yellow solid (1.78 g). An aliquot of 5-bromo-2-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (0.340 g) was detosylated according to the General Protocol III/Step C to afford 5-bromo-2-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.204 g, 58% yield, 3 steps); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.41 Hz, 6H), 2.56 (s, 4H), 2.63 (d, J=6.23 Hz, 1H), 3.07 (s, 4H), 3.26 (s, 3H), 6.19 (dd, J=3.30, 1.83 Hz, 1H), 6.45 (d, J=8.97 Hz, 1H), 6.59 (d, J=2.01 Hz, 1H), 6.91 (d, J=2.20 Hz, 1H), 7.41 (s, 1H), 7.51 (dd, J=9.06, 2.29 Hz, 1H), 7.75-7.84 (m, 2H), 7.96 (d, J=2.20 Hz, 1H), 8.35 (s, 1H), 8.88 (d, J=8.97 Hz, 1H), 11.26 (s, 1H), 11.85 (s, 1H). ESIMS (M+H)+=580.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][CH:9]([CH3:26])[CH2:10][C@@H:11]([NH3+:25])[B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1.[C:27]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C@H:35]([C:39](=[O:40])[NH:25][C@H:11]([B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1)[CH2:10][CH:9]([CH3:26])[CH3:8])[CH:36]([CH3:37])[CH3:38])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H]([NH3+])B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described in step B of example 1 but using (S)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylammonium trifluoroacetate ((C) in Synthetic Scheme 1) (for preparation see Kettner, C. A. and Shenvi, A. B. J. Biol. Chem. 1984, 259, p. 15106-15114 and Matteson, D. S. and Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, p. 5241-5242) (2.395 g, 6.32 mMol), Boc-L-valine (1.373 g, 6.32 mMol), TBTU (2.23 g, 6.95 mMol, 1.1 equiv), DIEA (3.3 mL, 18.95 mMol, 3.0 equiv) and DMF (24 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCc1ccc(F)cc1
Reaction time: 24 h
Yield: 86.8 %

Procedure:
3-(para-Fluorophenyl)propionic acid (25.00 g, 150.0 mmol, 1 eq.) was dissolved in methylene chloride (100 mL) at 25° C. under N2 and thionyl chloride (54.2 mL, 740.0 mmol, 5 eq.) added dropwise via an addition funnel. Worked up after 24 hours by stripping off the solvent then rerotovaping 2 times from toluene (25 mL) to obtain 24.3 g of a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])C.[Li+].[OH-].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[F:47]>CO.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:4]([C:6]2[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:11]=2)=[O:5])=[CH:42][C:41]=1[F:47]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c(=O)n(CC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(=O)c(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cn(-c2ccc(F)cc2)c1=O

Procedure:
3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester was hydrolyzed with 1N LiOH in MeOH and THF at 65° C. The acid was coupled with 4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine using the method for example 1 to give 3-ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide mp 140-142° C.; LCMS m/z=575 (M+1); 1H NMR (DMSO) δ: 11.18 (s, 1H), 8.49 (d, 1H, J=2.5 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=3 Hz, J=13 Hz), 7.65-7.39 (m, 6H), 7.55 (s, 1H), 7.41 (s, 1H), 6.49 (d, 1H, J=5.0 Hz), 4.00 (q, 2H, J=7.4 Hz), 3.95 (s, 6H), 1.23 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([CH3:17])([NH:15][CH3:16])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([N:15]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=2)[CH3:16])([CH3:17])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methyl-5-methylaminohexanamide (0.31 g-see Preparation 13), 4-fluorophenethyl bromide (0.2 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9](Br)[Br:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.O>[Br:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(C=C(Br)Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C#CBr)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a solution of 1-chloro-4-(2,2-dibromovinyl)benzene (9.60 g, 32.7 mmol) in toluene was added potassium tertbutoxide (7.35 g, 65.6 mmol) at RT. The reaction mixture was heated at 80° C. for 3 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over sodium sulfate and concentrated under reduced pressure to give the desired product (5.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-4-fluorophenol (2.18 g, 11.4 mmol) in DMF (15 mL) was added potassium carbonate (3.15 g, 22.8 mmol) portion wise at room temperature. The mixture was stirred at room temperature for 10 minutes then 4-methoxybenzyl chloride (1.55 mL, 11.4 mmol) was added drop wise. On completion of the addition the reaction was heated at 60° C. under nitrogen for 15 hours. The cooled reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1M aqueous NaOH solution (50 mL) and brine (50 mL), then dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude title compound as an off-white solid in quantitative yield, 3.62 g.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[F:11][C:12]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([CH:20]([OH:21])[C:17]2[CH:18]=[CH:19][C:12]([F:11])=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:8]=[C:7]([F:9])[CH:6]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Temperature: -10 °C
Yield: 67.1 %

Procedure:
To a stirred suspension of magnesium turnings (2.6 g, 109 mmol) in anhydrous tetrahydrofuran under argon (10 mL), a solution of 1-bromo-3,5-difluoro-benzene (21 g, 109 mmol) in dry tetrahydrofuran (90 mL) was slowly added. The reaction mixture was stirred and heated at 90° C. until all magnesium was consumed (1 hour). Thereafter, the reaction was cooled at −10° C. and a solution of 2-fluoro-5-formyl-benzonitrile (13.5 g, 90.6 mmol) in 100 mL of anhydrous tetrahydrofuran was added during 30 min After 1 hour, the reaction mixture was quenched by adding dropwise 200 mL of 20% ammonium chloride solution. Ethyl acetate was added, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. Organic layers were collected, washed with brine, dried and evaporated. Crude was triturated with isopropyl ether/hexane 1:1 (100 mL), filtered and washed with the same mixture (50 mL) to afford 16 gr of final product. Purification of the resulting organic phase by chromatography over silica gel (hexane/EtOAc 4:1) afforded 4.5 g of the title compound (total amount 20.5 g, 87% yield).
Reaction SMILES: [C:1]([S:4][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:15]([O:19][C:20](=[O:28])[CH2:21][NH:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[CH2:21][N:22]([C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:5]=1[S:4][C:1](=[O:3])[CH3:2])[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)Sc1c(Cl)cccc1C(=O)O
Solvent: ClCCl
Product: CC(=O)Sc1c(Cl)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Acetylthio-3-chlorobenzoic acid (11.5 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (350 ml) were cooled to 0°-5° C., and N,N1 -dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (50 ml) was added. The mixture was stirred overnight. The DCC-urea was filtered and washed with CH2Cl2. The filtrate was then washed 2×125 ml 1 N HCl, 2×125 ml saturated NaHCO3, 2×125 ml brine, dried (MgSO4), filtered and concentrated to give 20.6 g of an oil. The crude product was used without further purification in the next step.
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(C)C)=CC=1.[OH:18]C1C=CC(CC2C=CC(O)=CC=2)=CC=1>>[OH:17][C:14]1[C:15]([OH:18])=[CH:16][C:11]2[C:12]([CH:13]=1)=[CH:7][CH:6]=[CH:5][CH:8]=2
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Product: Oc1cc2ccccc2cc1O

Procedure:
bis-phenols such as 2,2-bis(p-hydroxyphenyl)propane and bis-(p-hydroxyphenyl)methane
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[C:22]1([CH:28]([CH3:32])[CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:6])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:30][CH2:29][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:32])=[O:9])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reactant: CC(CCO)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCC(C)c1ccccc1
Reaction time: 2 h

Procedure:
At 0° C. to a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 42 mg 3-phenyl-1-butanol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 2 h and again after 4 h at room temperature 36 mg of triphenylphosphine and 25 mg of diisopropylazodicarboxylate were added. After additional 12 h the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 110 mg of 2-methyl-2-{[1-(3-phenyl-butoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][CH2:31][CH:32]1[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:33]1>ClCCl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH:32]2[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:33]2)=[O:8])=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-2-ethoxybenzoic acid (2.9 g) in dichloromethane (50 ml), triethylamine (1.6 g) is added at 25° C. The resulting mixture is cooled to -10° C., and isobutyl chloroformate (2.0 g) is added slowly. After the mixture is stirred at the same temperature for 1 hour, a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (3.0 g) in dichloromethane (10 ml) is added. The reaction mixture is stirred for 1 hour at a temperature of between -10° C. and -5° C. and then at 25° C. overnight. The mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recyrstallized from ethanol to give the title compound (4.1 g), mp 151°-153° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([OH:27])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg+]
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde (2.11 g, 5.62 mmol) in THF (30 mL) cooled to −78° C. and under a nitrogen atmosphere, was added 3.0M MeMgBr in diethyl ether (2.6 mL). The mixture was stirred at 0° C. for 30 min and then additional 3.0M MeMgBr in diethyl ether (0.3 mL) was added. After 15 min stirring, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The crude material was combined with a second portion of crude reaction mixture obtained following the same method (starting from 140 mg, 3.73 mmol of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde) and the combined batches were purified by column chromatography (Si—PCC, gradient 20-100% DCM in pentane) affording the title compound as a gum which then solidified on standing (2.02 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.07 (1H, d, J=8.35), 7.80-7.75 (2H, m), 7.51-7.38 (5H, m), 7.33-7.26 (2H, m), 7.20-7.14 (3H, m), 5.25-5.15 (1H, m), 4.06 (1H, d, J=11.01 Hz), 2.31 (3H, s), 1.70 (3H, d, J=6.88 Hz).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])C=C.Cl.CN(C)[C:16]1[CH:21]=CC=C[CH:17]=1>>[CH2:21]([C:10]1[C:9]([F:11])=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[OH:4])[CH:16]=[CH2:17]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(F)ccc1F
Agent: Cl
Product: C=CCc1c(F)ccc(F)c1O
Temperature: 170 °C
Reaction time: 5 h

Procedure:
The 2,5-difluorophenol allyl ether (13 g) was dissolved in N,N-dimethylaniline (90 ml) and the resulting solution was stirred under a nitrogen gas stream at 170° C. for 5 hr. Then the liquid reaction mixture was poured into a 10% aqueous solution of hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: 7% ethyl acetate/n-hexane) to give 2-allyl-3,6-difluorophenol (7.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:4][CH:3]=1>O>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]2[NH:21][C:15]3[C:16]([C:18](=[O:20])[C:23]=2[CH:24]=1)=[CH:17][C:9]1[NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:11](=[O:13])[C:10]=1[CH:14]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Yield: 91.7 %

Procedure:
2,5-Bis{(4-methylphenyl)amino}terephthalic acid (3.76 gm; 10 mmol) and polyphosphoric acid (40 gm) were heated at 150° C. for 2.5 hours under a nitrogen atmosphere. The mixture was allowed to cool and then poured into iced water (100 ml) when a magenta solid precipitated out. This was filtered off, washed with water and then methanol, then dried under vacuum over phosphorous pentoxide to give 3.12 gm (92%) of 2,9-dimethylquinacridone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[N:5]3[N:20]=[CH:21][N:22]=[C:4]3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3ncnn23)nc1
Temperature: 150 °C

Procedure:
50 mg (0.16 mmol) of 6-({2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}amino)-nicotinonitrile (Example 54A), 29.5 mg (0.16 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and 18 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 3.3 ml of dioxane and 1.1 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 6.5 mg (10% of theory) of the product as a solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCCCCCC(=O)O
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and heptanoic acid