Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(Cl)c1
Product: Nc1cc2ncnc(Nc3cccc(Cl)c3)c2cn1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (208 mg, 1.08 mmol) and 3-chloroaniline (1.21 g, 9.48 mmol) is stirred at 150° C. for 20 min. The resulting product is chromatographed over alumina (5-10% MeOH/CH2Cl2) to give 7-amino-4-(3-chloroanilino)pyrido[4,3-d]pyrimidine (177 mg, 60%) as a white solid. 1H NMR (DMSO) δ 9.92 (1H, brs), 9.35 (1H, s), 8.45 (1H, s), 8.08 (1H, brs), 7.79 (1H, brd, J=8.0 Hz), 7.40 (1H, t, J=8.1 Hz), 7.16 (1H, dd, J=7.9, 1.3 Hz), 6.68 (2H, brs), 6.46 (1H, s).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:33][CH:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc(C2Cc3ccccc3N2)cc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1c1ccccc1
Yield: 53.9 %

Procedure:
(±)-6-(Morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is prepared by following the procedure described in example 1d, step 3d, using 0.50 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.42 g of 2-phenylindoline (which can be prepared according to Santangelo, E. M. et al. Eur. J. Org. Chem. 2008, 5915), and 0.48 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.31 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 50 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.43 g of (±)-6-(morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is obtained in the form of a cream-colored solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH:33]=O)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.O1CCCC1.[CH3:40][NH:41][CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][N:41]([CH3:42])[CH3:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(C=O)c2c(=O)[nH]ncc21
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To 133 mg (0.270 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(a) and 112 mg of Molecular sieve (3A) was added 5 ml of tetrahydrofuran solution containing 2M dimethylamine at room temperature, and the mixture was stirred for 10 minutes. Then, 156 mg (0.740 mmol) of sodium triacetoxyborohydride was added to the mixture, and the mixture was stirred for further 17 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; ethyl acetate→chloroform:methanol=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 74 mg of the title compound as a pale yellowish solid. (Yield: 53%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:31]=4)=[CH:24][C:23]=3[CH:36]=1)[CH:13]=[C:12]2[CH2:37][C:38]([OH:40])=[O:39])C1C=CC=CC=1.[CH:41]([O-])=O.[NH4+].C(O)C>O>[C:32]([C:30]1[N:31]=[C:27]([C:25]2[O:26][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:14]4[C:15]5[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=5)[C:12]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:13]4)=[CH:36][C:23]=3[CH:24]=2)[S:28][CH:29]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: O=C[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5cc(OCc6ccccc6)ccc54)ccc3o2)n1
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Reaction time: 48 h
Yield: 68.1 %

Procedure:
A mixture of 5-benzyloxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetic acid (3.0 g), 10% Pd--C (0.6 g) and ammonium formate (2.0 g) in a mixed solvents of ethanol (60 ml) and water (6 ml) was stirred under reflux for 18 hours. After removal of the catalysts by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% hydrogen chloride in methanol (200 ml) and the mixture was stored in refrigerator for 2 days. The resulting solution was concentrated under reduced pressure and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (1.76 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][N:17]([O:18][CH3:19])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CONCc1ccc(F)cc1Cl
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (97% yield): mp 127-128° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.95 (2H, s, NCH2), 6.41 (1H, s, CH), 6.96 (1H, m, aromatic), 7.13 (1H, dd, J=2.5 Hz and J=8.7 Hz, aromatic), 7.38 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C, 52.49; H, 4.15; N, 3.76.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CNCCOC
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: COCCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine are reacted together by general method E. 22.1 mg (35.1% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1>>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 27 %

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 3-amino-6-bromo-picolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (27%). LCMS (m/z): 621.2 (MH+); LC Rt=4.41 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O>C(OCC)C>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(C2CCNCC2)cn1
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
A solution of 2-fluoro-5-bromopyridine (7.69 g) in diethyl ether (160 ml) was cooled to −78° C., and into which n-butyl lithium (1,56M-hexane solution, 30 ml) was added dropwise at a temperature not higher than −70° C. After 15 minutes' stirring, tert-butyl 4-oxo-1-piperidinecarboxylate (8.7 g) was added. Temperature of the reaction liquid was raised to −35° C. and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure and isopropyl ether was added to the resulting residue. Whereupon precipitated crystals were recovered by filtration to provide the title compound (4.15 g). The filtrate was purified on column chromatography (hexane/ethyl acetate=3/1-2/1) to provide tert-butyl 4-(6-fluoro-3-pyridinyl)-4-hydroxy-tetrahydro-1(2H)-pyridinecarboxylate (1.25 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][C:22]([CH3:28])([CH2:25][O:26][CH3:27])[C:23]#[CH:24]>CN(C=O)C.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:23][C:22]([O:21][CH3:20])([CH3:28])[CH2:25][O:26][CH3:27])[N:5]=2
Reactant: C#CC(C)(COC)OC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(COC)OC)nc21

Procedure:
A suspension of 1.5 g (5.34 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 30 ml of a DMF/Et3N (v/v; 2/1) mixture is placed in an 80 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 1.37 g of (±)-3,4-dimethoxy-3-methylbut-1-yne (10.69 mmol), 0.101 g of CuI (0.53 mmol) and 0.187 g of bis(triphenylphosphine)palladium(II) dichloride (0.27 mmol) are successively added.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 50 (407 mg, 0.51 mmol) and Pd/C (10% wt., 50 mg) in THF (5.0 mL) and MeOH (2.5 mL) was stirred at room temperature under an atmosphere of H2 for 24 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E021 (65 mg, 27%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[CH:4]1)[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([C:5]=1[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2
Reactant: CCn1cc(C#N)c2ccc(C(F)(F)F)cc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(Cl)c(C#N)c2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at −78° C. was added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture was continued for 0.5 hr after the addition, followed by the addition of hexachloroethane and the mixture was then brought to room temperature slowly and stirred for 0.5 hr. The solvent was then evaporated and the residue was treated with water. The organics were extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent was chromatographed (silica gel, dichloromethane/hexanes, 3 /2) to provide 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH:25]=O)=[C:15]1[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH3:57])=[CH:52][CH:51]=1>>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([N:56]([CH2:25][CH2:24][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:44])([CH3:46])[CH3:45])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:57])=[CH:52][CH:51]=1
Reactant: CC(C)(C)[Si](OCCc1c(CC=O)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(N(C)CCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 73 %

Procedure:
Crude {1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehyde from step 7, example 142 was treated with 4-Methylamino-benzoic acid methyl ester according to the procedure in Example 142 step 8 to yield the desired 4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoic acid methyl ester in 73% yield.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]2[O:11][CH2:12][O:10][C:8]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)c(O)cc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2c(cc1F)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrClCH2 (24.8 g, 190 mmol) in dry DMF (50 mL) was added Cs2CO3 (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60° C. overnight and then poured into water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.23 (d, J=5.6, 1H), 6.63 (d, J=9.6, 1H), 6.08 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)SSC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of (R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-Cys(StBu)-OH) (Compound SP639) (280 mg, 0.708 mmol) in methylene chloride (1.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (371 μL, 2.12 mmol) and acetic anhydride (66.8 μL, 0.708 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-Cys(StBu)-OH) (Compound SP640) (270 mg, 0.617 mmol, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([NH:58][C:59]([C@@H:61]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]2)=[O:60])[CH2:57][CH2:56]1>CN(C=O)C.C(Cl)Cl>[CH:55]1([NH:58][C:59]([C@@H:61]2[CH2:66][CH2:65][CH2:64][N:63]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:32])[CH2:62]2)=[O:60])[CH2:57][CH2:56]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](C(=O)NC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (65 mg), EDAC (191 mg), (R)-piperidine-3-carboxylic acid cyclopropylamide (250 mg) and TEA (7 drops) in DMF (3 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water, 10% sodium carbonate, dried and concentrated. The residue was purified on a silica gel column to give 200 mg of the titled compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Ca+2].[OH-].S(=O)(=O)(O)[OH:17]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Reaction time: 6 h

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene and 1.56 kg (21-mol) of calcium hydroxide are heated to 70° C. in 5 l of water and the mixture is well stirred. The reaction is finished after about 6 h, as can be detected by gas chromatography. The mixture is acidified to pH 1.5 with 70% strength sulfuric acid and worked up as described in Examples 1 and 2 (the alkaline solution can also be filtered from inorganic salts at 60° C. before acidification). 1.40 kg of yellow 2,3-difluoro-6-nitrophenol are isolated; a residual content of 2,3-difluoro-4-nitrophenol cannot be detected. The yield corresponds to 80% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[C@@H:4]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CO.CNC.CO>C1COCC1>[NH2:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:3]([N:2]([CH3:31])[CH3:1])=[O:30]
Reactant: CN(C)C(=O)[C@H](Cc1ccccn1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
To a solution of 1.47 g of the compound obtained in Step 84-1 in a mixed solution of MeOH and THF (25 ml 4:1; v/v) was added a solution of 2 mol/L dimethylamine MeOH (5.8 ml) and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under vacuum and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; v/v) to obtain 0.60 g of the title compound (brown oil).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:42][CH2:43][OH:44].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:42][CH2:43][OH:44])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: OCCCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(CCO)C1
Yield: 10.8 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (100 mg, 0.19 mmol Example 74), diisopropylethylamine (100 μl, 0.58 mmol), 2-chloroethanol (60 μl, 0.58 mmol) and potassium iodide (32 mg, 0.19 mmol) in acetonitrile (1.5 ml) was heated in a microwave at 160° C. for 20 minutes. Purification of the resulting product on preparative HPLC (standard basic condition) gave the title product (10 mg, 11%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.75 (t, 2H), 3.47 (s, 2H), 3.61 (t, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 3.93 (s, 2H), 5.41 (brs, 1H), 6.79 (brs, 1H), 7.18 (m, 2H), 7.21 (s, 1H), 7.75 (brs, 1H), 7.86 (s, 1H), 8.52 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 489.