Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: Nc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 (0.89 g, 4.16 mmol) in 3 mL of dry methanol and 3 mL of trimethylorthoformate was added 3-aminopyridine (0.39 g, 1 eq.), and the mixture was stirred at room temperature for 1.5 hours. NaBH3CN (95%, 0.29 g, 1.05 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×30 ML). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (20 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 as a white solid (0.91 g, 75%). LRMS 292.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:40])[C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:40])[C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:9][O:10][C:11]([CH3:15])([CH3:14])[O:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#Cc3ccc(C(=O)c4ccc(F)cc4)cc3)cc2)COC(C)(C)OC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCc3ccc(C(=O)c4ccc(F)cc4)cc3)cc2)COC(C)(C)OC1
Reaction time: 16 h

Procedure:
A mixture of the product of Step E (0.06 g, 0.13 mmol) and 10% Pd/C (0.03 g) was stirred for 16 h under H2 the (balloon). The catalyst was removed by filtration through Celite pad and the filtrate evaporated to dryness to give the product (0.032 g; 53%) as pale paste. 1H-NMR (CDCl3) 1.4 (s, 3H); 1.41 (s, 3H); 1.45 (s, 9H); 1.92-1.98 (m, 2H); 2.5-2.56 (m, 2H); 2.89-2.97 (m, 4H); 3.65 (d, 2H, J=11.8 Hz); 3.86 (d, 2H, J=11.76 Hz); 4.95 (s, 1H), 7.08 (s, 4H); 7.14 (tr, 2H, J=8.64 Hz), 7.25 (d, 2H); 7.67 (d, 2H, J=8.17 Hz); 7.78-7.84 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:17])[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C@@H:53]([C@@H:71]1[CH2:75][CH2:74][CH2:73][N:72]1[C:76](=[O:95])[CH2:77][C@@H:78]([O:93][CH3:94])[C@@H:79]([N:84]([CH3:92])[C:85](=[O:91])[C@H:86]([CH:88]([CH3:90])[CH3:89])[NH2:87])[C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:56]>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([C:14]([NH:87][C@H:86]([C:85]([N:84]([CH3:92])[C@@H:79]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:78]([O:93][CH3:94])[CH2:77][C:76]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[C@H:53]([O:52][CH3:51])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:56])=[O:95])=[O:91])[CH:88]([CH3:89])[CH3:90])=[O:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To a solution of #156 (106 mg, 0.436 mmol, 1 eq.) in dichloromethane (3 mL) and N,N-dimethylformamide (0.5 mL) was added diisopropylethylamine (0.228 mL, 1.31 mmol, 3 eq.) followed by HATU (205 mg, 0.523 mmol, 1.2 eq.). The reaction was stirred for 15 minutes and #114 (276 mg, 0.436 mmol, 1 eq.) was added and stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane (10 mL) and washed with 10% citric acid (3×5 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by silica gel chromatography (Gradient: 0 to 80% acetone in heptane) afforded #160 (145 mg, 39%). LC-MS (protocol Q1): m/z 858.8 [M+H+], retention time=1.12 minutes.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([C:14]3[S:18][C:17]([CH2:19][NH:20][C:21]([C:23]4[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4]CC1>CC(C)=O.Cl.C=O>[O:29]=[C:24]1[C:23]([C:21]([NH:20][CH2:19][C:17]2[S:18][C:14]([S:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[O:22])=[CH:28][CH:27]=[CH:26][NH:25]1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)s1)c1ccc[nH]c1=O
Agent: C=O
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc[nH]c3=O)s2)CC1

Procedure:
A solution of the ketal 198a (6.0 g, 13.7 mmol) in acetone (60 ml), HCl aq. 1N (30 ml) and conc. aq. formaldehyde (8 ml) was heated to 48° C. for 15 h. The mixture was concentrated to a total weight of 46 g, whereupon an orange oil separated out, and CH2Cl2 was added (200 ml). The orange oil went in the organic phase, while water (27 ml) separated out and was removed. The CH2Cl2 layer was rinsed with a small amount of water (20 ml), dried (MgSO4), and concentrated to afforded the crude ketone as hemiaminal (5.1 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH2:33][CH:34]3[CH2:36][O:35]3)[C:24]3[C:29]([C:30]=2[CH:31]=1)=[CH:28][C:27]([Br:32])=[CH:26][CH:25]=3>CN(C=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:36][CH:34]([OH:35])[CH2:33][N:23]3[C:24]4[CH:25]=[CH:26][C:27]([Br:32])=[CH:28][C:29]=4[C:30]4[C:22]3=[CH:21][CH:20]=[C:19]([Br:18])[CH:31]=4)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2ccc(Br)cc2c2cc(Br)ccc21)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
3,6-Dibromocarbazole (0.050 g, 0.154 mmol) was dissolved in DMF (1.5 mL) and cooled to 0° C. NaH (60% dispersion in mineral oil, 0.007 g, 0.169 mmol) was added and the reaction was stirred for 45 min at 0° C. 3,6-Dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.059 g, 0.154 mmol) was added and the reaction was stirred at ambient temperature for 24 h. Upon consumption of the starting material by TLC, the reaction was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography (SiO2, 0-50% EtOAc/Hexane) to afford the desired product (37 mg, 34%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][C@H:4]([CH3:15])[N:3]1[C:16]1[O:17][C:18]2[C:19](=[C:21]([C:25]([O:27]C)=[O:26])[CH:22]=[CH:23][CH:24]=2)[N:20]=1.[I-].[Li+]>N1C=CC=CC=1>[CH3:15][C@H:4]1[CH2:5][N:6]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][C@H:2]([CH3:1])[N:3]1[C:16]1[O:17][C:18]2[C:19](=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)[N:20]=1
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(=O)N4CCCC4)C[C@@H]3C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)N2CCCC2)C[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidine-1-carbonyl)piperazin-1-yl)benzoxazole-4-carboxylate (200 mg, 0.52 mmol) in pyridine (2 mL) was added lithium iodide (550 mg, 4.11 mmol). The mixture was heated at 110° C. for 18 h and allowed to cool to ambient temperature before partitioning with 9:1 mixture of dichloromethane and isopropanol (100 mL) and 1 N HCl (50 mL). The non-homogenous organic layer was washed with brine and concentrated under reduced pressure. The residue was treated with 9:1 toluene/methanol (100 mL) and concentrated in vacuo to afford crude 2-((2S,6S)-2,6-dimethyl-4-(pyrrolidine-1-carbonyl)piperazin-1-yl)benzoxazole-4-carboxylic acid as a brown solid which was directly elaborated without purification.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:20]=[CH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>O1CCCC1>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:6]1[N:7]=[C:2]([F:1])[C:3]([CH:21]([OH:20])[CH2:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:28][CH2:29]2)=[CH:4][CH:5]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[C:12]([C:13]#[C:14][C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[N:19][CH:20]=2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=[CH:9]1.O.C(Cl)Cl>CN1C(=O)CCC1>[CH3:7][N:8]1[C:12]([C:13]2[NH:21][C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[CH:14]=2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=[CH:9]1
Reactant: Cn1cnc(-c2ccccc2)c1C#Cc1cncnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2cncnc2[nH]1
Temperature: 60 °C
Yield: 33.2 %

Procedure:
Potassium tert-butoxide (84 mg) was added to 5-[(1-methyl-4-phenyl-1H-imidazol-5-yl)ethynyl]pyrimidin-4-amine (intermediate 28) (41 mg) stirred in NMP (2 mL) and heated to 60° C. for 5 hours. After cooling to ambient temperature, water (3 mL) and then DCM (10 mL) was added. The reaction mixture was washed with water (4×10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM:MeOH (20:1 to 10:1) afforded the title compound as a white solid (13.6 mg, 33%);
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)=[O:5])C>CO.[OH-].[Na+].O>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([F:21])[CH:17]=1)[CH2:13][NH:12][C:11]1[CH:10]=[C:9]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
2.99 g of 4-[(3,5-difluorobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 30 mL of methanol, to which 12 mL of 4 mol/L sodium hydroxide in water was added at room temperature, and stirred at 80° C. for 1.5 hour. After cooling, methanol was evaporated, weakly acidified (about pH 4) by adding 6 mol/L hydrochloric acid in water under ice cooling, the deposited crystals were filtered, and washed with water and methanol. After air-drying, they were dried under reduced pressure (60-70° C., for 3 hours) to obtain 2.72 g (yield 97%) of 4-[(3,5-difluorobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid as a light reddish purple crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=1.Cl.[CH3:25][NH:26][CH3:27].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:22])[N:26]([CH3:27])[CH3:25])[CH:15]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A mixture of 3-bromo-8-(3-carboxybenzoylamino)quinoline (200 mg), dimethylamine hydrochloride (65.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (100 mg) and 1-hydroxybenzotriazole (109 mg) in dimethylformamide (3 ml) was stirred for 3 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) and recrystallized from ethanol to give 3-bromo-8-[3-(dimethylcarbamoyl)benzoylamino]quinoline (120 mg) as pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12]1>C1COCC1>[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]2)[O:13][CH2:12]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2

Procedure:
A solution of 1-fluoro-2-nitrobenzene (5.80 g, 41.1 mmol) and 4-piperidone ethylene ketal (6.68 g, 46.6 mmol) in THF (100 mL) was stirred at room temperature (2 h). The resulting mixture was washed with water and sodium bicarbonate solution. The aqueous layer was extracted with two portions of ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (10% ethyl acetate/hexane) afforded the title compound (7).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:21])[NH:15]C(OCC)=O)=O>C(O)C.[OH-].[Na+]>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)[NH:13][C:14](=[O:21])[N:15]=1
Reactant: CCOC(=O)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1nc(-c2ccccc2F)c2cc(Cl)ccc2[nH]1
Yield: 93 %

Procedure:
Ethyl 4(2-(o-fluorobenzoyl)-4-chlorophenyl)allophanate (0.2 g) was dissolved in a mixture of 6 ml of ethanol and 0.8 ml of a 20 % aqueous solution of caustic soda, and the resulting mixture was refluxed for 1 hour. After the ethanol was removed by distillation under reduced pressure, the obtained residue was acidified with concentrated hydrochloric acid and cooled overnight. Then the crystals were collected by filtration and dried to give 0.14 g of 4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone having a melting point of over 300° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:31][OH:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:31][O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: OCC1CCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and cyclobutanemethanol (44.8 mg; 0.515 mmol), example 56 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].[CH3:47][C:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:54][S:51]([C:48]6([CH3:47])[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Reactant: CC1(S(N)(=O)=O)CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) and 1-methylcyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=747 (M+H)+. 1H NMR (CDCl3): 0.79-0.92 (m, 2H), 1.20-2.03 (m, 19H), 2.20-2.32 (m, 1H), 2.35-2.48 (m, 2H), 2.52-2.64 (m, 5H), 2.85-2.93 (m, 1H), 3.04 (s, 3H), 3.05-3.14 (m, 1H), 3.35-3.46 (m, 2H), 3.97 (s, 3H), 4.60 (td, J=13.2 Hz, J=2.2 Hz, 1H), 5.04 (t, J=10.5 Hz, 1H), 5.30-5.47 (m, 1H), 5.61-5.69 (m, 1H), 6.30 (s, 1H), 6.32 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 7.30 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 10.9 (br s, 1H).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(O[C:19]([CH3:21])=[CH2:20])(=O)C.C(N(CC)CC)C>ClCCl>[CH3:12][O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[CH:20]=[C:19]([CH3:21])[O:14][N:13]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: C=C(C)OC(C)=O
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](c2cc(C)on2)CC1
Reaction time: 20 h

Procedure:
To a solution of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (5.90 g, 26.9 mmol) and isopropenyl acetate (53.8 g, 537 mmol) in dichloromethane (134 ml) was added triethylamine (5.44 g, 53.7 mmol) at 0-5° C. The cooling bath was removed 15 minutes after completed addition, and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (250 ml) and 0.1 M aqueous hydrochloric acid solution (200 ml). The organic layer was washed with one 100 ml-portion of 0.1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with one 150 ml-portion of ethyl acetate. The combined organic layers were washed with one 200 ml-portion of 2 M sodium carbonate and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (3.00 g, 50%) as off-white solid. MS m/e: 224 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[CH:19]([N:22]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:23](=[O:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:33]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:30][CH:31]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) was added n-butyl lithium (3 ml of 1.6 M solution in hexane). The reaction mixture was stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction was cooled to -30° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (1.063 g, 3.9 mmol) in THF (5 ml) was added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction mixture was poured onto 0.5N KHSO4 and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried (MgSO4). The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product. This was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from cyclohexane containing a small amount of ethyl acetate, m. pt. 158-160° C.