Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:45])[NH:12][CH:13]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:22]([NH:24][N:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:22]([NH:24][N:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])=[O:45]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)N)CC1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a solution of (1-(2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester (0.29 g, 0.46 mmol) in methylene chloride (3 ml) at 0° C. was added trifluoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol (20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.25 g of 2-amino-N-[(1R)-2-[4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide as a white amorphous powder.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][C:14](=[O:37])[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:39])[CH3:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:40]#[N:41].C([Al+]CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]([OH:37])[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:40]#[N:41])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:39])[CH3:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2=C3C(=O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)[C@@H]3C(O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A solution of 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8(14)-en-7-one (5 g, 9.4 mmole) in toluene (75 mL) at 0° C. under an argon atmosphere was treated with a solution of diethyl aluminum cyanide (1.4 M in toluene, 12.7 mL, 17 mmole). The reaction mixture was stirred at 0° C. for 0.5 hours, poured into 1N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried and concentrated to one half the volume. An equal volume of methanol was added, the mixture was placed in a cold water bath and sodium borohydride (0.75 g) was added in portions. The mixture was stirred for 0.5 hours at ambient temperature, poured into brine, the layers separated and the organic layer was dried and concentrated to give 4.5 g (85%) of 3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholestan-7-ol; mp 270°-271° C. (from CH2Cl2 ).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)(Cl)Cl.CO>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: CCc1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(O)c(Br)c1
Temperature: 25 °C

Procedure:
8.41 ml of bromine in 100 ml of CHCl3 were added dropwise within 2 hrs. to a solution, cooled to 0° C., of 20 g of 4-ethylphenol in 200 ml of CHCl3 and 100 ml of MeOH. The reaction mixture was left to warm to room temperature and was concentrated. The product was isolated by extraction. There were obtained 33.14 g of 2-bromo-4-ethyl-phenol as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([OH:20])[CH:7]=1.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=1[O:20][C:38]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N2CCCC2)c1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-(4-benzyloxy-3-hydroxy-phenyl)-propionic acid methyl ester (434 mg) was dissolved in dichloromethane (7 ml) and a solution of 1-pyrrolidinylcarbonyl chloride (200 mg) in dichloromethane (2 ml) was added. Triethylamine (0.22 ml) was added dropwise followed by a catalytic amount of DMAP. The mixture was stirred and heated at 40° C. overnight. The reaction was monitored by HPLC/MS and further portions of 1-pyrrolidinylcarbonyl chloride (400 mg) and triethylamine (0.4 ml) were added and heating continued at 55 C for 48 hours. The reaction mixture was diluted with dichloromethane and washed with dil HCl, with aq sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave the crude product. Silca gel chromatography, eluting with mixtures of ethyl acetate-hexane gave pyrrolidine-1-carboxylic acid 2-benzyloxy-5-((S)-2-benzyloxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl ester as a colourless gum, 364 mg; Rf 0.3 (ethyl acetate-hexane 1:1); HPLC/MS retention time 7.31 min, m/z 533 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=O)([O-:13])=[O:12].N>>[N+:11]([C:14]1[CH:15]=[C:16]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:20]=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: N
Product: O=[N+]([O-])c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-nitrobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CDCl3) δ 7.44-7.55 (m, 1 H), 7.82 (t, J=8.3 Hz, 1 H), 8.43-8.60 (m, 3 H), 8.80 (dd, J=4.7, 1.7 Hz, 1 H), 9.07-9.13 (m, 1 H), 9.42 (d, J=2.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 269 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1>[CH:1]1[C:14]2[CH:13]([C:20]([OH:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thioxanthene, 9.1 g, was dissolved in 100 mL of dry THF. The solution was cooled in an ice bath and n-BuLi (24 mL of 2.5M solution) was added dropwise. The red solution was stirred at room temperature for one hour. Powdered CO2 was added (ca. 150 g) causing formation of a white precipitate. After stirring an additional hour the mixture was evaporated and the residue dissolved in water. The aqueous solution was extracted with CH2Cl2, and neutralized with HCl. The precipitated product was dissolved in ether, dried and evaporated producing thioxanthene-9-carboxylic acid as a white solid (8.8 g): 1H NMR (DMSO-d6) δ 5.25 (s, 1H), 7.30 (m, 4H), 7.49 (m, 4H), 12.60 (s, 1H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[SiH4].C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:31][CH:30]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Agent: [SiH4]
Solvent: O=CO
Product: O=C(NCCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 18.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorophenethyl)-1-piperidinecarboxamide formate (0.875 g, 2.03 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane silane (0.740 g, 1.86 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.275 g, 0.35 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:2]=2[CH3:1])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccn1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccn1
Yield: 49.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-(2-pyridyl)pyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.88 g), the title compound (1.52 g) was obtained, melting point: 251° C.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38]C(F)=[CH:36][CH:35]=2)[CH2:23][CH2:22]1.[N:42]1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38][N:42]=[CH:36][CH:35]=2)[CH2:23][CH2:22]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccncc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine using 4-pyridinylboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=555, obsd.=555).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:31])[NH:29][NH2:30])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:30][NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:14]
Reactant: COC(=O)CCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.81 g (50 mmol) of sebacic acid monomethyl ester is dissolved in tetrahydrofuran and successively mixed with 8.32 ml (60 mmol) of triethylamine and 5.28 ml (55 mmol) of chloroformic acid ethyl ester [ethyl chloroformate] at -5° C. After 15 minutes 6.61 g (50 mmol) of tert-butylcarbazate in tetrahydrofuran is instilled at this temperature and then stirred at room temperature for 2 hours. The precipitate is suctioned off, the filtrate is concentrated by evaporation and taken up in ethyl acetate. The organic phase is successively washed with NaHCO3 solution, citric acid and water and dried on Na2SO4. The oil obtained after concentration by evaporation of the ethyl acetate is chromatographed on silica gel in diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:36])[CH2:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:28]([CH2:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)S(=O)(=O)CC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(CS(=O)(=O)C(C)C)no3)CN(C(=O)N3CCOCC3)C2)cc1C

Procedure:
100 mg (0.289 mmol) of the compound from Example 130A and 78 mg (0.433 mmol) of N′-hydroxy-2-(propan-2-ylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 108 mg (75% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3-hydroxypropyl)morpholine (0.623 mL, 4.5 mmol), triphenylphosphine (1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropyl azodicarboxylate (0.886 mL, 4.5 mmol). The mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the crude mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dichloromethane to give N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarbox-amide (890 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): d 10.36 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.3.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH3:14])=[N:5]1)(=[O:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][Br:22])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(C)c2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)n1nc(CBr)c2ccc(F)cc21
Temperature: 70 °C
Yield: 54.8 %

Procedure:
1-Acetyl-6-fluoro-3-methyl-1H-indazole (5.77 g, 33.1 mmol) in CCl4 (100 mL) was treated with NBS (3.64 g, 20 mmol) and benzoyl peroxide (0.388 g, 1.6 mmol) and the mixture was heated at 70° C. for 6 h. The mixture was concentrated and the residue quickly filtered through a plug of flash silica eluting with 2%→7% EtOAc in hexane to give the crude title compound (2.97 g, 65%) contaminated with traces of dibromide and starting material. This was conveniently used directly in subsequent reactions without further purification.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1CSc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCCCCCC
Product: O=C1CSc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs2CO3 (2.96 g, 9.08 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.37 g, 6.66 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 1.45 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a slightly yellow oil. Yield 1.37 g, 90.2%. Rr 0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t, 2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H). 13C NMR (CDCl3): δ 30.61, 31.81, 42.48, 42.66, 117.87, 123.78, 124.29, 127.52, 127.52, 128.78, 139.40, 165.51
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18](=[O:19])[CH2:17][CH:14]1[CH2:13][CH2:12][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:16][CH2:15]1
Reactant: O=C(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)c1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccccc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a stirred solution of this phenol (100 mg, 0.20 mmol) in acetone (10 mL) under nitrogen was added methyl bromoacetate (21 μL, 0.22 mmol) and potassium carbonate (55 mg, 0.40 mmol). The mixture was heated to reflux for 14 h., cooled to room temperature, filtered and the filtrate evaporated to afford a residue (100 mg) which was purified using preparative thin layer chromatography eluting with diethyl ether:dichloromethane:iso-hexane 1:1:5 to give the desired product (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[CH:5][CH:4]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(COCCC(O)CO)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COCCC(O)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Combine 4-(p-methoxybenzyloxy)-1,2-butandiol (42.43 g, 187.5 mmol) with DMF (700 mL) and cool in an ice bath before adding t-butyldimethylsilyl chloride (31.1 g, 206 mmol), triethylamine (31.4 mL, 225 mmol), and 4-dimethylaminopyridine (5.8 g, 47 mmol). Stir the mixture in the ice bath for 5 minutes and then allow to warm to ambient temperature and stir for sixteen hours. Filter and wash the filter cake with diethyl ether. Separate the aqueous layer and extract twice with ether. Combine the organic layers extract with water and saturated sodium chloride solution, dry over MgSO4, filter and concentrate in vacuo. Chromatograph on silica gel eluting with 2/8 ethyl acetate/hexane to give 51.4 g of the title compound the as an oil. Rf =0.25; silica gel, 2/8 ethyl acetate/hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:19][N:18]=4)[CH:12]=3)[C:6]=2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[CH3:33][N:34]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[N:8][N:7]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[N:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[CH:21][N:22]=5)[CH:12]=4)[C:6]=3[CH:32]=2)[CH:36]=[N:35]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1ccc2nnn(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc3nnn(Cc4cccc(-c5ncc(OCCN6CCOCC6)cn5)c4)c3c2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
200 mg (0.352 mmol) of 6-bromo-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-benzotriazole, 80.6 mg (0.387 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 150 mg (0.704 mmol) of tripotassium phosphate trihydrate are suspended in 6 ml of ethylene glycol dimethyl ether, degassed evacuated and flushed with nitrogen a number of times. 24.7 mg (0.035 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is again evacuated and flushed with nitrogen. The reaction mixture is stirred at 80° C. for 24 h. Water is added to the reaction mixture, which is then rendered basic using 32% NaOH and extracted with DCM. The organic phase is dried over sodium sulfate, evaporated under reduced pressure in a rotary evaporator and purified by column chromatography on silica gel; yield: 41 mg, HPLC: Rt=2.08 min (method C), LC-MS: [M+H]+=497;