Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][NH:6][CH2:7][CH3:8])[CH3:4].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.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.CC([O-])(C)C.[Na+].C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]([N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:6][CH2:7][CH3:8])[CH3:4]
Reactant: CCNNCC
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)NC(C)C
Product: CCNN(CC)c1ccccc1
Temperature: 80 °C
Yield: 32 %

Procedure:
1,2-Diethylhydrazine dihydrochloride (1.2 equiv., 0.6 mmol, 97 mg), bromobenzene (1.0 equiv., 0.5 mmol, 0.05 mL), Pd(OAc)2 (0.05 equiv, 0.025 mmol, 6 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), and NaOtBu (3.8 equiv., 1.9 mmol, 183 mg) and diisopropylamine (2 mL) were added to a flame dried test tube which was capped with a septum and purged briefly with argon (˜1 min.) and then heated to 80° C. for 4 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (2% EtOAc/Hex) to give the title product as a viscous yellow oil (27 mg, 0.16 mmol, 33% yield).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)C1
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (30%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1cc(C)cc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)cc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 36-4 (750 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][CH:16]=2)[CH:9]=1.C([NH2:25])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[S:19][C:18]([C:20]([NH2:25])=[O:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: O=C(O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Reactant: NC=O
Product: NC(=O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
5-[6-(2-Chlorophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]thiophene-2-carboxylic acid (100 mg, 0.30 mmol) was suspended in 1 mL of formamide. The reaction mixture was stirred for 30 minutes at 200° C. After cooling, the precipitate was filtered, dissolved in 1 mL dimethylformamide and purified by reverse phase HPLC. 30 mg of product were isolated.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][CH:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Si:20]([O:21][CH:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:3][C:4]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[CH:5][N:6]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: N#Cc1cc(-c2cnc(Br)s2)ccc1F
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
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 85 °C
Yield: 32 %

Procedure:
Prepared using General Procedure 1. To 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy) silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1 mmol) in dioxane (1.8 mL) and H2O (0.2 mL) was added tetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). The solution was degassed with N2 and the reaction mixture heated at 85° C. for 6 h. Upon cooling, the reaction mixture was diluted with brine and washed with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (30% EA/Hexanes) to produce 0.05 g (32%) of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzo-nitrile as a white solid. LCMS-ESI (m/z) calculated for C25H27FN2OSSi: 450.6; found 451.1 [M+H] +, tR=4.84 min (Method 3).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].[C:22]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35](OC)=[O:36])[CH:34]=1)[C:29]([OH:31])=[O:30])([CH3:25])([CH3:24])[CH3:23].[Li+].[OH-].CO>CN(C=O)C.C(O)(C(F)(F)F)=O.O>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:35]([C:33]3[CH:32]=[C:28]([CH:27]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:34]=3)[C:29]([OH:31])=[O:30])=[O:36])[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]
Reactant: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cc(C(=O)O)cc(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Following the method described in Example 2c, Step 4, (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (223 mg) was coupled with 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (165 mg, see Preparation H6, Step 1) in 8 mL of DMF. After 14 h, 2 mL of this reaction mixture was removed and purified to provide Example 2ba. The remaining portion of the reaction mixture was charged successively with aq. LiOH (48 mg in 2 mL water) and MeOH (1 mL) before being stirred at RT for 14 h. The mixture was diluted with 2.0% TFA/water, filtered, and purified directly by RP-HPLC to afford the titled compound. MS found: (M+H)+=500.4.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)(Cl)Cl>[S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[N+:5]([O-:19])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)cnc1ccsc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2ccccc2c2sccc21
Yield: 65.8 %

Procedure:
Thieno[3,2-c]isoquinoline (13 g, 71 mmol) and 3-Chloroperoxybenzoic acid (57-86%, 21 g, 71 mmol) were combined in chloroform (300 mL) at 23° C. After 3 days the mixture was diluted with chloroform (750 mL), washed with 10% aqueous sodium hydroxide (2×500 mL) and brine (500 mL), dried (MgSO4), and concentrated in vacuo to give the crude product (13 g) as a yellow-brown solid. Recrystallization from hot ethanol (ca. 75 mL) provided the title compound (9.4 g, 66%, m.p. 190-95° C.) as dense brown needles.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:17])=[O:4]
Reactant: CC(C)(Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(Cc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2,2-dimethyl-3-phenylpropanoic acid (0.856 g, 4.8 mmol) in chloroform (6 mL) at 0° C. was treated with oxalyl chloride (3.05 g, 24 mmol) and 1 drop of dimethylformamide. The reaction solution was stirred for 1 h at 0° C. The ice bath was removed and the reaction mixture stirred at room temperature over night. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 2,2-dimethyl-3-phenylpropanoyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][N:4]=1
Reactant: Oc1ncc(I)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(I)cnc1Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A 100 ml 3-necked round bottom flask, fitted with a condenser topped with a N2 inlet, a mechanical stirrer and a thermometer, was charged with 17.2 g (0.0673 mole) of 3-chloro-2-hydroxy-5-iodopyridine, 14.85 g (0.0713 mole) of PCl5, and 1 ml (1.68 g; 0.0109 mole) of POCl3. The reaction mixture, containing solids, was slowly stirred and slowly heated to 130° C. The reaction mixture was stirred under N2 for 5 hours after which it was cooled to room temperature and allowed to stand overnight. The reaction mixture was cautiously poured into crushed ice and allowed to stand for 1 hour. Methylene chloride (200 ml) was added to the reaction mixture to dissolve the solids present in it. The layers was separated and the organic phase was washed with dilute base, water and saturated NaCl. After drying over anhydrous MgSO4 and filtration, the solvent was evaporated leaving 11.8 g of a yellow solid. The solid was recrystallized from methanol resulting in 6.60 g of solid that had spectral and physical properties identical to the product obtained in Example 1, STEP D.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:3][CH:4]=3)[N:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:9]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
(±)-7-Chloro-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.13 g; 0.33 mmol) (from Example 1e supra) was combined with aniline (100 μL; 1.10 mmol) (Aldrich). The mixture was heated to 110° C. A clear solution resulted upon heating and then a new solid precipitated out of solution. Reaction mixture was cooled to room temperature after 45 minutes. The residue was triturated with hexanes and then purified by flash chromatography (Biotage, 40M, 40:60 to 50:50 ethyl acetate-hexanes gradient) to give (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid, after crystallization from ethyl acetate-hexanes. (Yield 21.6 mg; 14.8%). A substantial amount of (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one adhered to the silica and was eluted with 50:50 ethyl acetate-methanol. (Yield 88 mg; 60%). Melting Point: 222–234° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 90.1 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with K2CO3 (7.30 g, 52.8 mmol) followed by 1-bromopropane (3.90 g, 31.7 mmol) and the mixture was heated to about 50° C. under nitrogen for 12 h. The solvent was distilled out completely, and the residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulphate and evaporated to afford 5.50 g (90%) of the title compound as pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[F:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:61]=1B(O)O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:61]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)=[O:29]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (4.51 g, 8.4 mmol) in acetonitrile (140 mL). Add Pd(OAc)2 (0.28 g, 1.3 mmol), tricyclohexylphosphine (0.59 g, 2.1 mmol), cesium fluoride (11.4 g, 75.6 mmol) and 2,5-difluorobenzeneboronic acid (2.56 g, 16.2 mmol). Flush the flask with nitrogen then heat the reaction mixture to 90° C. Heat the reaction mixture for one hour and then cool it to room temperature. Add water (400 mL) and extract the aqueous layer with methylene chloride (3×400 mL). Combine the organic layers and dry with sodium sulfate, filter, concentrate and purify by flash column chromatography (0-4% MeOH—NOH (10/1, v/v)/CH2Cl2) to give 2.42 g (68%) of the title compound: mass spectrum (ion spray) m/z=502.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6](C)=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[CH:35]=[CH:34][NH:33][C:30]3=[N:31][CH:32]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[C:29]4[CH:35]=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[CH:6]=[N:7]1)([CH3:12])[CH3:13]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in the same manner as described for example 35 (step a) from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (1 g, 3.36 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.98 g, 4.04 mmol) wherein the reaction mixture was stirred at 100° C. for 5 h. The product was collected as an off white solid (600 mg, 53%). LCMS (ES−) m/z: 333.08.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)C=O.[C:29]([CH2:32][C:33]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([OH:40])=[O:39])=[O:34])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:32]/[C:33]([NH:35][C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38]([OH:40])=[O:39])=[O:34])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1OCc1ccc2ccccc2c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1ccc2ccccc2c1

Procedure:
Piperidine (0.27 mL, 2.7 mmol) was added to a suspension of 3-methoxy-4-(naphth-2-ylmethoxy)benzaldehyde (0.80 g, 2.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.55 g, 2.5 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH providing (E)-2-[[3-(3-methoxy-4-(naphth-2-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic (0.74 g, 66%) as a yellow crystalline solid; mp 197-200° C.; δH (400 MHz, DMSO-d6) 3.86 (s, 3H, OCH3), 5.30 (s, 2H, OCH2), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (1, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.37 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.50-7.63 (m, 5H, CH═CHCO, H5, Naphth-H), 7.91-8.01 (m, 5H, H3, Naphth-H), 8.63 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.7, 70.1, 110.8, 113.4, 116.6, 120.1, 120.3, 122.5, 122.7, 125.9, 126.2, 126.4, 126.6, 127.6, 127.7, 127.8, 128.1, 131.2, 132.6, 132.7, 134.0, 134.5, 141.1, 141.6, 149.3, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C28H23NO5 [M−H]− 452.1493. found 452.1495; vmax 1135, 1260, 1511, 1584, 1668, 3055 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])([CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (170 mg, 0.687 mmol) in THF (5 mL) at 0° C. was added 3.0 M methylmagnesium bromide in ether (688 mL, 2.1 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water (2 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and the solvent was removed in vacuo to give an oil that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 7:3) to afford 120 mg (66%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline: 1H NMR (400 MHz, DMSO-d6) 7.54 (d, J=7.7, 1H), 7.50 (dd, J=7.7, 1.5, 1H), 7.14 (ddd, J=7.3, 7.3, 1.7, 1H), 7.04 (ddd, J=7.9, 7.9, 1.0, 1H), 5.14 (s, 1H), 3.69 (m, 2H), 1.87 (t, J=6.5, 2H), 1.46 (s, 9H), 1.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]CN)=[CH:34][CH:33]=1)[CH3:30])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:38][C:35]4[CH:36]=[CH:37][C:32]([CH2:31][N:29]([CH3:30])[C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:33][CH:34]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(Cc1ccc(CCN)cc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(N-tert-butyloxycarbonyl-N-methylaminomethyl)phenyl]ethanamine (0.19 g) and ethanol (4 ml) were stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (160 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]Br)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][N:11]2[CH:12]=[N:13][C:9]([C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)([OH:8])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: OC(c1ccccc1)(c1nc[nH]n1)C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1
Yield: 47 %

Procedure:
The title compound was prepared from cyclohexyl(phenyl)1H-1,2,4-triazol-3-ylmethanol (Preparation 18, 500 mg, 1.94 mmol) and tert-butyl4-(bromomethyl)piperidine-1-carboxylate (649 mg, 2.33 mmol) using the same method as described in preparation 3, to give a clear oil, in 47% yield, 415 mg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:22][O:23][C:24]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:30])=[CH:27][CH:26]=1)=[O:34]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1

Procedure:
1.6 g of acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound F1) are dissolved in 30 ml of dichloromethane. 982 mg (5.45 mmol) of terephthalic acid monomethyl ester and 1.25 g (6.74 mmol) of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are added successively under stirring. After 3 h further 18 mg (0.1 mmol) of terephthalic acid monomethyl ester are added. After 15 h the reaction is treated with aqueous hydrochloric acid and extracted several times with dichloromethane. After evaporation of the combined organic phases, the crude product is crystallized from ethyl acetate/cyclohexane to give 1.87 g (73% of theory) of the title compound as colourless solid.