Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40](=[O:41])[N:15]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1)([CH3:28])[CH3:29]
Reactant: CCCCCCCCc1ccc(NCc2ccc(C(=O)OC)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(C(=O)OC)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 6.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using methyl 4-[(4-octylphenyl)aminomethyl]benzoate (2.65 g) and 2,6-diisopropylphenyl isocyanate (1.68 g) as starting materials, methyl 4-{[3-(2,6-diisopropylphenyl)-1-(4-octylphenyl)ureido]methyl}benzoate (0.29 g) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=O)(C)(C)C.C1C=C[C:33]2N(O)N=[N:36][C:34]=2C=1.C(N)C.N=C=N.[N-]=C=O.C(=O)([O-])[O-]>CN(C=O)C>[CH2:34]([NH:36][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:12]([C:10](=[O:11])[CH2:9][NH2:8])[CH3:13])[CH:16]=2)=[CH:26][CH:25]=1)=[O:29])[CH3:33]
Reactant: CN(Cc1cccc(-c2ccc(C(=O)O)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2cccc(CN(C)C(=O)CN)c2)cc1
Reaction time: 8 h
Yield: 319.7 %

Procedure:
To a solution of 3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-carboxylic acid (9 mg) in DMF (1 ml) was added HOBt (2 mg) and ethylamine (2 mg), and PS-Carbodiimide (manufactured by Biotage AB) (100 mg) was added thereto, followed by shaking overnight. Thereafter, PS-Isocyanate (manufactured by Biotage AB) and MP-Carbonate (manufactured by Biotage AB) were added in an amount of 50 mg, and DMF (0.5 ml) was further added thereto, followed by shaking for 2 hours. The insoluble material was filtered and the filtrate was concentrated. To the obtained residue was added MeOH (0.5 ml), and a 4 M hydrogen chloride/EtOAc solution (0.5 ml) was added thereto, followed by shaking for 1 hour. Thereafter, the reaction mixture was concentrated to obtain N-ethyl-3′-{[glycyl(methyl)amino]methyl}biphenyl-4-carboxamide (15.4 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2([CH:11]=[CH2:12])[CH2:10][CH2:9]2)[CH:7]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>O1CCOCC1.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]>[CH:11]([C:8]1([C:6]2[CH:7]=[C:2]([B:13]([OH:17])[OH:14])[CH:3]=[N:4][CH:5]=2)[CH2:10][CH2:9]1)=[CH2:12]
Reactant: C=CC1(c2cncc(Br)c2)CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C=CC1(c2cncc(B(O)O)c2)CC1
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 73 Step C (0.036 g, 0.161 mmol), bis(pinacolato)diboron (0.082 g, 0.321 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.029 g, 0.032 mmol), tricyclohexylphosphine (0.018 g, 0.064 mmol) and potassium acetate (0.047 g, 0.48 mmol) in dioxane (0.80 mL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then passed through a syringe filter and concentrated under reduced pressure to provide the title compound: LCMS m/z 189.12 [M]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:20][CH2:21][C:22](=O)[CH2:23][CH3:24].[BH4-].[Na+].CO>ClCCl.C(O)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:20][CH2:21][CH:22]([N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[CH2:23][CH3:24]
Reactant: CCC(=O)CC
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCC(CC)N1CCC2(CC[C@H](NC(C)=O)c3ccccc32)CC1
Reaction time: 5 h

Procedure:
A solution of the piperidine (B5) (20 mg, 0.077 mmol) and 3-pentanone (27 mg, 0.31 mmol) in dichloromethane (2 ml) was stirred in a vial for 90 minutes and treated with titanium (IV) isopropoxide (60 μl, 0.21 mmol) for 24 hours. To the reaction mixture was added sodium borohydride (10 mg, 0.27 mmol) and stirred for 5 hours, then treated with methanol (1 ml) and acetic acid (1 drop) for 1 hour. The solvents were evaporated and the residue was dissolved in methanol (1 ml) and acidified with TFA and purified by HPLC to give the title compound no. 56. LC-MS: m/e=329.28 (M+H). Rt=1.42 min. 1H-NMR (500 MHz, DMSO-d6): 8.65 (br.s, 1H), 8.18 (d, 1H), 7.42 (d, 1H), 7.31 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (m, 1H), 3.45 (m, 1H), 3.35 (m, 1H), 3.28-3.17 (m, 2H), 3.10 (m, 1H), 2.28 (m, 2H), 2.05 (m, 1H), 1.86 (s, 3H), 1.84 (m, 4H), 1.72 (t, 1H), 1.68-1.59 (m, 2H), 1.51 (m, 1H), 1.37 (m, 1H), 0.99 (t, 5H), 0.91 (t, 1H).
Reaction SMILES: [C:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12

Procedure:
A mixture of 3-heptanoylindole (1.0 g) obtained in Pre. Ex. 1, ethyl 4-bromobutyrate (0.86 g) and potassium carbonate (1.0 g) in dimethyl formamide (DMF) (25 ml) was stirred at room temperature for 16 hours. The mixture was poured into a mixture of hydrochloric acid (100 ml) and ethyl acetate (AcOEt) (50 ml). The organic layer was washed with water, dried over MgSO 4 and evaporated. The residue was chromatographed on a silica gel column with a mixture of n-hexane and AcOEt (3:1) as eluent to give ethyl 4-(3-heptanoyl-1-indolyl)butyrate as a colorless oil. (1.53 g)
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[NH:4][CH:3]1[CH3:20].Br[C:22]1[CH2:26][O:25][C:24](=[O:27])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+].N#N.O>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:22]2[CH2:26][O:25][C:24](=[O:27])[CH:23]=2)[CH:3]1[CH3:20]
Reactant: O=C1C=C(Br)CO1
Reactant: CC1NC(=O)C2(CCN(C(=O)OC(C)(C)C)CC2)C1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: CC1C(O)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Temperature: 90 °C

Procedure:
To a round bottom flask was charged tert-butyl 4-hydroxy-3-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1000 mg, 3.52 mmol), 4-bromofuran-2(5H)-one (860 mg, 5.28 mmol), Pd(OAc)2 (79 mg, 0.352 mmol), Xantphos (305 mg, 0.528 mmol), and K2CO3 (972 mg, 7.03 mmol). The flask was sealed, vacuumed and back filled with N2 and filled with dioxane (14 mL) and water (190 μL, 10.6 mmol). The reaction mixture was heated at 90° C. overnight, and filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM, came out at 6% MeOH/DCM, followed by another column with 0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1)]+=367
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([C:34]1[O:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:37]5[O:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(C=O)o5)cc34)c2)no1
Temperature: 55 °C
Yield: 87 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from the previous step (0.21 g, 0.4 mmol), 5-formylfuran-2-ylboronic acid (0.07 g, 0.51 mmol), bis(triphenylphosphine)palladium(II)dichloride (0.035 g, 0.05 mmol), and 1.0 M Na2CO3 solution (3 mL) in EtOH (2 mL) and 1,2-dimethoxyethane (3 mL) was heated at 55° C. for 1 hour. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 30-60% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea as solid (0.172 g, 87%). 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.53 (br, 1H), 8.80 (d, 1H), 8.78 (s, 1H), 7.32 (dd, 1H), 8.07 (d, 1H), 7.67 (m, 2H), 7.34-7.54 (m, 3H), 7.07 (d, 1H), 7.01 (d, 1H), 5.94 (s, 1H), 1.32 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15].C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:28])(=[O:29])[NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15]
Reactant: COCCNC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1Cl
Reactant: O=C(O)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCNC(=O)c1cc(S(=O)(=O)NC(=O)c2ccccc2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
At room temperature, 1.0 g (6.1 mmol) of 2-chlorobenzoic acid are dissolved in 120 ml of tetrahydrofuran and mixed with 1.0 g (6.1 mmol) of N,N′-carbonyldiimidazole. After 30 minutes at room temperature and a further 30 minutes at reflux temperature, 2.0 g (6.1 mmol) of 2,4-dichloro-N-(2-methoxyethyl)-5-sulfamoylbenzamide are added at reflux temperature. After 10 minutes, 0.9 g (6.1 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene are added and the mixture is kept at reflux temperature for a further 3 hours. The mixture is subsequently evaporated to dryness, the residue is taken up in 60 ml of acetonitrile and the solution is poured into 60 ml of water. The solution is acidified to pH 1 using 2N HCI and the precipitate is separated off, washed with water and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)COc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(CO)cc1)OCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
182 g of 4-hydroxymethylphenoxyacetic acid and 199 g of α-bromoacetophenone are dissolved in 600 ml of dry DMF, and then, at 0° C., 138 ml of triethylamine are rapidly added dropwise. The mixture is allowed to reach room temperature, and is stirred overnight. The DMF solution is poured into 3.5 1 of water, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated. The product precipitates out on evaporation. It is filtered off with suction, washed with ethyl acetate/n-hexane 1:1 and dried under high vacuum.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C[C@@H](CO)NC(=O)CCl
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride, 25.64 g (0.227 mol), in 57 ml of acetone is added dropwise with stirring to a solution of L-leucinol, 26.63 g (0.227 mol), and sodium acetate, 37.24 g (0.454 mol), in a mixture of 340 ml of acetone and 170 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 250 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (S)-2-chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 28 g; [α]D25 -32.6° (c 0.52, methanol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:8][N:7]=1)=O)C.C(O)C.[BH4-].[Na+]>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:8][N:7]=1
Reactant: CCOC(=O)c1cc(-c2ncccn2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-ethoxycarbonyl-isoxazol-5-yl)-pyrimidine (35 gm) in 2:1 v/v ethanol:THF mixture (525 ml) was added sodium borohydride (7.5 gm) in lots at 0° C. It was stirred at 30° C. temperature over a period of 4 h. The reaction mixture was evaporated under vacuum to provide a residue and to the residue, (150 ml) was added. The suspension was extracted with ethyl acetate (4.5 ltr). Combined organic layers was washed with water and concentrated under vacuum to provide crude mass in 23 gm quantity, which was recrystallized from ethanol to provide the title compound in 15.1 gm quantity (53%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Product: CC(C)Cc1ccc(-c2ccnc(Cl)n2)cc1

Procedure:
2,4 dichloropyrimidine was coupled with 4-isobutylphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 247:
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2]>CCO.[Pd]>[CH2:1]([N:3]([CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH2:21][CH3:22])[CH3:2]
Reactant: CCN(CC)CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c(N)cc21
Reaction time: 20 h
Yield: 0 %

Procedure:
A mixture of N,N-diethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1 H-indol-1-yl]-2-oxoethanamine (0.68 g, 2.2 mol) and 10% Pd on carbon (0.06 g) in EtOH (150 mL) was stirred under 1 atm of H2 for 20 h, then filtered through a pad of Celite. The filtrate was concentrated, the residue dissolved in CH2Cl2 and purified by silica gel chromatography using 0-10% MeOH (containing 0.2% NH3)/CH2Cl2to obtain 1-[(diethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a brown solid (281 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, J=7.14 Hz, 6H), 2.57 (q, J=7.02 Hz 4H), 2.97 (t, J=8.24 Hz 2H), 3.28 (s, 2H), 3.71 (s, 3H),4.12 (t, J=8.24 Hz, 2H), 4.62 (s, 2H), 6.70 (s, 1H), 7.54 (s, 1H); ESIMS (M+H)+=278.19.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.[OH:27][N:28]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([NH:28][OH:27])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of 0.125 g (0.347 mmol) of the product of Step 2 in 4.4 mL of N,N-dimethylformamide (DMF) is added 0.056 g (0.417 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) followed by 0.089 g (0.462 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The resulting mixture is stirred for 1 h at room temperature and then 0.095 mL of a 50% aqueous solution of hydroxylamine is added and the reaction mixture is stirred overnight. The reaction mixture is then diluted with ethyl acetate and washed with water and brine. The organics are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel eluting with a gradient of ethyl acetate-hexanes (1:1 to 2:1) to provide 0.065 g (50%) of 2-[(hydroxyamino)carbonyl]-6-methylphenyl 4-(2-butynyloxy)benzenesulfonate as a white solid. Electrospray Mass Spec: 376.0 (M+H)+
Reaction SMILES: N[C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1.[ClH:20].N([O-])=O.[Na+].NC(N)=O>C(O)(=O)C.O>[Cl:20][C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1
Reactant: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Reactant: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCn1ccnc1-c1nc(Cl)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-amino-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 5; 0.55 g, 2.2 mmol) was suspended in glacial acetic acid (20 ml) and concentrated HCl (30 ml). The solution was cooled to 0° C. and to this a solution of sodium nitrite in water (15 ml) was added dropwise. After stirring at 0° C. for 10 mins, the reaction was slowly warmed to room temperature and stirred for 1 hour. Once complete by LCMS, a solution of urea (0.25 g) in water (10 ml) was added dropwise. After stirring at room temperature for 30 mins, solvent was removed under reduced pressure. The residue was partitioned with sat. NaHCO3 (aq) and EtOAc. Extraction with EtOAc (×3), drying with MgSO4 and concentrating yielded an orange oil which was used without purification (0.20 g). MS (ES) (M+H)+: 302 for C11H12ClN3O3S; NMR: 3.34 (s, 3H), 3.62 (m, 2H), 3.81 (s, 3H), 4.22 (m, 2H), 7.24 (s, 2H).
Reaction SMILES: [CH3:1][Mg]I.Cl[C:5]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1>C1COCC1>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:12]3[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10]([O:24][CH3:25])[CH:11]=3)[N:6]=[C:5]([CH3:1])[N:14]=2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: C[Mg]I
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nc(C)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Reaction time: 1 h

Procedure:
To 166 mg (1.16 mmol) CuBr in 4 ml THF are added dropwise at −78° C. 773 μl (2.32 mmol) of a 3M solution of methylmagnesium iodide. After stirring for 20 minutes 50 mg (0.145 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline are added at the same temperature. After stirring for 1 h the reaction mixture is allowed to reach rt and stirring is continued overnight. After dilution with 50 ml ethyl acetate and filtration the reaction mixture is extracted with brine. Evaporation of the organic phase yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:12]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[C:18]=2[CH:17]=[CH:16][C:15]([OH:19])=[CH:14]3)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[S:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[CH2:37][O:19][C:15]1[CH:16]=[CH:17][C:18]2[N:13]([C:12]([C:20](=[O:25])[C:21]([CH3:23])([CH3:24])[CH3:22])=[C:11]([CH2:26][C:27]([CH3:33])([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])[CH:14]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cn2c1C(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn2c1C(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A suspension of ethyl 3-{1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)-6-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (85.0 mg, 0.176 mmol), 2-(chloromethyl)-1,3-benzothiazole-HCl (60.1 mg, 0.263 mmol), and potassium carbonate (97.1, 0.703 mmol) in DMF (3.0 mL) is stirred at 50° C. for 1 h. The mixture is cooled to 23° C. then filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, hexanes to 1:1 hexanes:EtOAc) to yield ethyl 3-[6-(1,3-benzothiazol-2-ylmethoxy)-1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)indolizin-2-yl]-2,2-dimethylpropanoate (74 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]=4[CH3:26])[C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCCc2ccc(-c3ccc(F)cc3)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(-c3ccc(F)cc3)cc2C1=O
Yield: 10.9 %

Procedure:
Using analogous reaction conditions as described in example 1, 7-(4-fluoro-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 0.4132 mmol) was reacted with 3-iodo-4-methyl-pyridine (108.5 mg, 0.4958 mmol), 1,4-dioxane (25 mL), copper iodide (2.8 mg, 0.01432 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (14.2 mg, 0.1239 mmol) and potassium phosphate (219.2 mg, 1.0330 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 15 mg of the product (11.1% yield).