Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37](C)([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[OH:31])[CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[C:37]([OH:38])(=[O:36])[CH3:40].[C:37]([OH:38])(=[O:36])[CH3:40].[C:37]([OH:38])(=[O:36])[CH3:40].[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:43]=[CH:42][C:35]([OH:36])=[C:34]([CH2:39][OH:38])[CH:33]=3)[CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)NC4CCCCC4)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1)NC1CCCCC1
Temperature: 25 °C
Yield: 295.9 %

Procedure:
A solution of N-cyclohexyl-N′-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea (0.138 g) in acetic acid (4 ml) and water (1 ml) were stirred under nitrogen at 70° C. for 45 min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (3×10 ml) to give a residue which was purified by Biotage. Elution with 50:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.126 g). LCMS RT=2.65 min, ES+ve 558 (MH)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10](O)[C:11]3[C:16]([CH2:17][O:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3.[OH-].[Na+]>ClCCl>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10]([Cl:3])[C:11]3[C:16]([CH2:17][O:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccc(Cl)cc2OCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc2c(c1)OCc1cccnc1C2Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Add thionyl chloride (2.74 mL, 4.48 g, 37.6 mmole) to 8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ol (8.48 g, 34.2 mmole) in dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere. Stir for 30 minutes at 0° C., and then stir for 60 minutes at room temperature. Add iced 1.5N NaOH (100 mL), and separate layers. Extract aqueous solution with dichloromethane (2×100 mL). Wash the combined organic solution with water and saturated NaCl, dry with MgSO4, filter, and concentrate in vacuo to give a reddish-black oil (8.82 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:10]([O:12]C=O)C>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:10]=[O:12])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: CCOC=O
Product: COc1ccc(NC=O)cn1

Procedure:
5-Amino-2-methoxy pyridine (25 g, 0.2 mol) was added to ethylformate (50 ml). This solution was refluxed for eight hours. The volatiles were removed on a rotary evaporator at 30° C. and at aspirator vacuum. The resultant product was pink solid, 30.2 g, 99% of theory, m.p. 81°-83° C. The structure was confirmed by mass spectroscopy (MS), infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:36])[F:35])[CH:16]=1.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13][C:39](=[O:41])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]5)=[C:17]([C:34]([F:37])([F:35])[F:36])[CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(Cl)cc34)cc2C(F)(F)F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of tert-butyl 4-(4-(6-chloro-3-(hydroxymethyl)quinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (407 mg, 0.75 mmol) in dichloromethane (10 mL) at 0° C. was added triphosgene (225 mg, 0.75 mmol) and Et3N (125 μL, 0.9 mmol). The resultant solution was allowed to warm up to room temperature and continued to stir for 4 h before being quenched with a satd. aqueous sodium bicarbonate (10 mL), extracted with EtOAc (3×20 mL), and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to afford the title product (57%) as colorless oil. LC-MS: (M+H)=563.26
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[F:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:37][C:31]1[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(O)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2cccc(F)c2F)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Reaction time: 6 h

Procedure:
A mixture of 2-(4-hydroxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-yl]-acetamide (45.0 mg, 0.124 mmol), 1-bromomethyl-2,3-difluoro-benzene (38.0 mg, 0.185 mmol), Cs2CO3 (60.0 mg, 0.184 mmol) in 2 mL of DMF was shaken for 6 hours after which the mixture was concentrated under reduced pressure. The residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.72 (s, 2H), 4.47 (t, 2H, J=6.78), 5.18 (s, 2H), 7.00 (m, 2H), 7.19–7.72 (m, 8H), 8.26 (s, 1H), 10.16 (s, 1H); MS (DCI/NH3) m/z 491 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][O:20][CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([O:20][CH3:21])[C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)Nc1ccccc1
Temperature: -10 °C

Procedure:
The preparation of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl O-methylhydroxylamine is described in Parts A-H of Example 1. Triethylamine (0.23 mL, 1.64 mmol) was added to a solution of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl O-methylhydroxylamine (0.45 g, 1.37 mmol) in dichloromethane (10 mL) cooled to −10° C. Phenyl isocyanate (0.15 mL, 1.37 mmol) was added to the reaction mixture and it was allowed to warm to 0° C. over 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and saturated sodium bicarbonate (40 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (30 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow material. The material was purified by HPFC (0-25% CMA in chloroform) and recrystallized from acetonitrile to afford an off-white solid. The solid was dried at 100° C. under high vacuum to afford 0.388 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxy-N′-phenylurea as an off-white powder, mp 155-156° C. Anal. calcd for C24H29N7O2: C, 64.41; H, 6.53; N, 21.91. Found: C, 64.20; H, 6.64; N, 21.93.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: CC(C)N
Product: CC(C)NS(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N-isopropyl-2,4-dichlorothiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with 65% strength aqueous isopropylamine solution.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[Li]CCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1.Br[C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1COCC1.C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:32]2[CH:37]=[N:36][C:35]([N:38]3[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]3)=[N:34][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [Pd]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of dicyclohexylamine (3.43 g, 18.94 mmol) in THF (60 mL) at −78° C. was added n-BuLi (2.5 M, 7.9 mL, 18.94 mmol) dropwise. The mixture was stirred at RT for 10 min, followed by the addition of methyl 2-(4-fluorophenyl)acetate (2.69 g, 16.02 mmol) in toluene (60 mL). After stirred at RT for another 10 min, tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.57 mmol), Pd2(dba)3 (667 mg, 0.728 mmol) and P(t-Bu)3 (10%, 1.47 g, 0.728 mmol) were added sequentially. The reaction mixture was stirred at RT for 15 h, quenched by water (150 mL) and extracted with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA=6:1) to afford the title compound (0.5 g, 8%) as an orange solid. MS (ES+) C22H27FN4O4 requires: 430. found: 431 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:24]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N3CCNC3=O)cc2C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nccc(-c2cccnc2Oc2ccc(N3CCN(c4cccc(C(F)(F)F)c4)C3=O)cc2C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)imidazolidin-2-one (0.100 g, 0.266 mmol), 1-iodo-3-(trifluoromethyl)benzene (0.050 mL, 0.35 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.012 g, 0.020 mmol), palladium (II) acetate (0.009 g, 0.013 mmol), and cesium carbonate (0.130 g, 0.399 mmol) were combined in dioxane under argon. The reaction vessel was sealed and the mixture was heated to 100 deg. C. for 48 h. The reaction was cooled to ambient temperature and diluted with dichloromethane, filtered, and concentrated in vacuo. The resulting material was adsorbed onto silica gel and purified by silica gel chromatography. The resulting material was further purified by reverse-phase HPLC using acetonitrile/water/TFA eluent to give 1-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)imidazolidin-2-one as a white solid. MS m/z=521 [M+1]+. Calc'd for C27H23F3N6O2: 520.51.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH:38]3[CH2:40][CH2:39]3)=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:33]2[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:41])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:40][CH2:39]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3C3CC3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M207) (200 mg, 0.343 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (63 mg, 39%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][CH:15]=[CH2:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O1CCOCC1.[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CC[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: CCC[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of (2S,4S)-1-Boc-2-allyl-4-aminopyrrolidine (450 mg, 1.78 mmol) prepared in Preparation Example A1-4 in dioxane (5 mL) was added Pd/C (40 mg). The reaction mixture was stirred under hydrogen condition for 24 h, filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound as an oil (390 mg, 98.5%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[CH3:27][O:28][C:29]([CH2:31]P(OC)(OC)=O)=[O:30]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:23]=[CH:31][C:29]([O:28][CH3:27])=[O:30])=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccc4ccccc4c3)oc2C)cc1

Procedure:
According to the method described for Reference Example 22, 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]cinnamate. Recrystallization from chloroform-ether gave colorless prisms, m.p.185°-186° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([Cl:20])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: Cc1cc(Cl)c(CO)c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(Cl)c(C=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
DMSO (14.2 mL, 200 mmol) was added to a stirred solution of oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at −70° C. After 15 min, alcohol (10) (6.40 g, 33.3 mmol) in dichloromethane (25 mL) was added, followed by triethylamine (56 mL). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was washed with aqueous sodium bicarbonate (75 mL), dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography (elution with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (11) as a pale yellow oil which solidified on standing: LCMS (MH+, 190), Rf 0.48 (20% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5](=[O:23])[CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CCS(=O)c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,4-Dimethyl-3,4-dihydro-2H-thiochromene-6-carbaldehyde (449 mg, 2.18 mmol, Example 5-28, Step 2) was dissolved in dichloromethane (22.0 mL) and mCPBA (751 mg, 4.35 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was then diluted with dichloromethane, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to afford the desired product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:18]I>CN(C=O)C.O>[CH3:18][O:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(C#N)cc2)CCOCC1

Procedure:
To a solution of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1 of Intermediate I, 300 mg, 1.48 mmol) in DMF (6.5 mL) was added sodium hydride (60% suspension in mineral oil, 65 mg, 1.62 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (110 μL, 1.77 mmol) was added. Stirring was continued over night at rt. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (238 mg, 74%): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, 2H), 7.51 (d, 2H), 3.89-3.82 (m, 4H), 2.99 (s, 3H), 2.03-1.98 (m, 2H), 1.94-1.91 (m, 2H); DCI(NH3)-MS m/z 235 (M+NH4)+; HPLC RT (Method I) 3.99 min.
Reaction SMILES: COC1C=CC(C([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35]([CH3:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1.C(OC([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:36][C:35]1[C:30]([C:27]2[S:26][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]([NH2:18])=[O:20])[C:29]=3[CH:28]=2)=[N:31][C:32]([NH:54][CH2:53][CH2:52][CH2:51][CH:48]2[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]2)=[N:33][CH:34]=1
Reactant: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(N)=O)cccc2s1
Temperature: 97 °C

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide (1.14 g, 2.15 mmol), 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 4.30 mmol) and diisopropylethylamine (1.12 mL, 6.45 mmol) in 1,4-dioxane (10 mL) is heated at 97° C. under a nitrogen atmosphere for 3 days. After concentration and subsequent chromatography on silica gel, eluting with MeOH in dichloromethane 0-2%, the desired product is obtained as a solid. The solid is suspended in dichloromethane (20 mL), followed by the successive addition of triethylsilane (1.5 mL) and TFA (5 mL). The resultant yellow solution is stirred for 2 hours. After concentration the solid is dissolved with stirring in MeOH (30 mL) and dichloromethane (30 mL) and the solution is treated in portions with 1.0 N LiOH (15 mL) to form a suspension. The suspension is concentrated at 45° C. under atmospheric pressure for 30 minutes, then methanol and dichloromethane are evaporated off in vacuo. The suspension is filtered and the yellow solid is dried under vacuum at 45° C. to provide the title compound (0.890 g, 100% yield). ES+(m/z) 410 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]([C:12]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)N)(C)(C)C>>[CH2:22]([N:21]1[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=[C:12]1[CH:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][CH2:2][CH2:3]1)[CH2:10][CH3:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CC(=O)N(CCN)C(CC)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(C)(C)OC(N)=O
Product: CCC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
Preparation of N-(2-amino-ethyl)—N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-acrylamide: Following the procedure of Example of 1d, 2-{acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester was converted to the title compound as a white solid: MS (ES) m/e 425.4 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[NH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])=[O:5])C.O[Li].O>C(O)C.C1COCC1>[CH3:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[C:7]([NH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])[S:8][CH:9]=1
Reactant: CCCCCCCCOC(=O)Nc1scc(C)c1C(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCOC(=O)Nc1scc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
(8.1) To a stirring solution of 4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester (254 mg, 0.74 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH—H2O (31 mg, 0.74 mmol). The reaction was stirred at RT for 5 days, and then solvent was removed under reduced pressure to give a solid. The product was taken on without further purification: 1H NMR (CDCl3) δ 6.02 (s, 1H), 4.07 (t, 2H, J=6.6 Hz), 2.32 (s, 3H), 1.60-1.40 (m, 2H), 1.27 (bs, 10H), 0.86 (t, 3H, J=6.6 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>[Pd].O1CCCC1>[NH2:22][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[NH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]2
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(N)c(O)cc2[nH]1
Reaction time: 5 h

Procedure:
A mixture of 0.67 g (2.0 mmol) of methyl 6-benzyloxy-5-nitro-indole-2-carboxylate, 60 ml of tetrahydrofuran and 0.1 g of 10% Pd/C catalyst is hydogenated for 5 h. The catalyst is filtered off and the filtrate containing the title compound is used immediately in the next step.