Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[N:5]1[NH:6][N:7]=[N:8][C:9]=1[C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1
Reactant: COc1ccc(CC(=O)Nc2sccc2-c2nn[nH]n2)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1nnc(-c2ccsc2NC(=O)Cc2ccc(OC)cc2)n1
Reaction time: 72 h

Procedure:
Chloromethyl methyl ether (0.20 ml, 2.63 mmol) was added to a heterogeneous mixture of N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide (Example 8.1., 580 mg, 1.84 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in DMF (10 ml). After stirring for 72 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was directly purified by HPLC to yield N-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide. Method [7] Retention time 6.60 min by HPLC (MH+ 360). 1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 7.47 (d, J=5.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (d, J=5.7 Hz, 1H), 5.77 (s, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: CC#N
Product: N#CCC(O)c1cc(Br)ccc1Cl

Procedure:
Alkylation of 5-bromo-2-chlorobenzaldehyde with acetonitrile following the method used in Example 114 gave 3-(5-bromo-2-chlorophenyl)-3-hydroxypropanenitrile as a pale yellow liquid. Yield (4.42 g, 75%): 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=2.8 Hz, 1H), 7.53 (dd, J=8.8, 2.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.30 (d, J=4.8 Hz, 1H), 5.13-5.09 (m, 1H), 2.96 (ABd, J=16.8, 4.8 Hz, 1H), 2.83 (ABd, J=17.0, 6.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:32]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:38][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in a yield of 82% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and diphenylmethylamine.
Reaction SMILES: O[C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:20]=2[CH:21]=1)=[N:9][C:10]1[CH:11]=[C:12]2[O:19][CH2:18][O:17][C:13]2=[CH:14][C:15]=1[CH:16]=3.C(Cl)Cl.[CH3:27][N:28]=[C:29]=[O:30]>CN(C)C1C=CN=CC=1>[CH3:27][NH:28][C:29]([C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:20]=2[CH:21]=1)=[N:9][C:10]1[CH:11]=[C:12]2[O:19][CH2:18][O:17][C:13]2=[CH:14][C:15]=1[CH:16]=3)=[O:30]
Reactant: CN=C=O
Reactant: COc1cc2c(cc1O)-c1nc3cc4c(cc3cc1C2)OCO4
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc2c(cc1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Compound 8, prepared in Example 8, (308 mg, 1 mmol), anhydrous methylene chloride (5 mL), 4-dimethylamino pyridine (489 mg, 4 mmol) and methyl isocyanate (171 mg, 0.18 mmol) are stirred at about 0° C. under a dry nitrogen atmosphere for about an hour. The reaction is allowed to cool to ambient temperature. Stirring is continued for about 16 hrs. while maintaining the nitrogen atmosphere. The solvent is then removed by reduced pressure evaporation to give a solid residue. This residue is chromatographed (silica gel eluded with ethyl acetate) to yield 7-n-Methylcarbamoyl-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:24]4[C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:30]5[C:22]([C:18]5[NH:17][CH:21]=[CH:20][N:19]=5)=[N:23]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.23 mmol), 2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridine-1-yl]acetic acid (0.050 g, 0.21 mmol) and Et3N (0.15 mL, 1.07 mmol) in DMF (0.7 mL) was added HATU (0.130 g, 0.33 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 100 mL) and sat. NaHCO3 (40 ml). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.090 g, 96%). 1H NMR (TFA salt) (400 MHz, CD3OD) δ 8.73 (dd, J=4.8, 1.6 Hz, 1H), 8.69 (dd, J=8.0, 1.6 Hz, 1H), 8.14 (s, 1H), 7.72 (s, 2H), 7.55 (m, 3H), 7.28 (dd, J=9.2, 8.4 Hz, 2H), 5.89 (s, 2H), 4.06 (m, 2H), 2.92 (t, J=6.2 Hz, 2H), 2.20 (m, 2H); MS: (ES) m/z calculated for C23H19FN8O [M+H]+ 443.1, found 443.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][O:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1Cl
Yield: 67.6 %

Procedure:
A mixture of 2-[2-hydroxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.9 g), methyl iodide (2.3 g) and potassium carbonate (2.2 g) in acetone (40 ml) was refluxed under heating for 4.5 hrs. After cooling, the reaction mixture was filtered. The filtrate was evaporated, and the oily residue was dissolved in methanol (30 ml). To the solution was added potassium hydroxide (1 g), and the mixture was refluxed under heating for 30 minutes. After cooling, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized from a mixture of benzene and n-hexane to give 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.35 g). mp 87°-92° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH2:9][CH2:10][SH:11].N1CCCCC1.C(NC(C)C)(C)C>>[O:5]=[C:4]1[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10][CH2:9][O:8]1
Reactant: OCCS
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Product: O=C(O)CC1SCCOC1=O

Procedure:
Analogously to Example 1, by reaction of maleic acid anhydride with 2-hydroxyethanethiol in the presence of piperidine (instead of diisopropylamine) and the usual working up, 2-oxo-1,4-oxathiane-3-acetic acid, m.p. = 96°-98° is obtained.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
Potassium hydroxide (6.89 g, 0.12 mol) was dissolved in methanol (30 mL). To the solution were added 7-chloroindole (4.65 g, 0.031 mol), 4-piperidone hydrochloride hydrate (9.48 g, 0.061 mol). The mixture was stirred at reflux temperature under nitrogen for about a day, and was cooled and diluted with 50 mL of water, added dropwise. The solid was collected, washed with water and vacuum dried. Yield 5.6 g (78%) as a yellow solid. mp 197°-201° C. FDMS m/e=232 (M+) .
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2].[N+:36]([O-])([OH:38])=[O:37]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (Example 5, 104 mg, 2 mmol) in dichloromethane (25 ml) was added HNO3 (6% aqueous solution, 5.6 ml, 3.8 mmol) in a drop wise fashion, followed by the addition of tetrabutyl ammonium bromide (100 mg). The reaction mixture was stirred at room temperature until the complete conversion. The reaction mixture was diluted with DCM, washed with water, brine, concentrated and purified by silica gel chromatography to give 1.2 g of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-])=O)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12.[H][H]>C(O)C.[Pd]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1

Procedure:
A room temperature solution of 1.0 g of N-[5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-pyridinyl]-2-nitrobenzamide in 100 ml of ethyl alcohol is hydrogenated over 200 mg of 10% Pd/C in a Parr apparatus under 40 psi of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with additional ethyl alcohol. The combined filtrates are concentrated in vacuo and the residue purified by crystallization from 2:1 ethyl acetate:hexane to give the desired product as pale yellow crystals: M+Na 445:M+ 423.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 26 %

Procedure:
Method as described for example 147 using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford a light brown solid (50 mg, 0.11 mmol, 26%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[CH:39]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(F)c1)N1CCN(C2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (46%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25]S(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:33][C:34]([F:39])([F:38])[CH:35](O)[CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: CC(O)C(F)(F)F
Product: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 75 mg, 0.15 mmol) and 1,1,1-trifluoro-propan-2-ol (0.026 ml, 0.2 mmol). Off white solid (10 mg, 14%). LC-MS (ESI): 472 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)[OH:4].[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([NH:1][CH:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH:3]([C:5]2[CH:9]=[CH:8][O:7][CH:6]=2)[OH:4])=[O:33])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.75 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (333 mg, 1.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (504 mg, 2.63 mmol) and 1-hydroxy-1H-benzotriazole (268 mg, 1.75 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (573 mg, 71%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:29]=[CH:28][C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([C:23]([OH:25])=O)[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH3:30])=[O:6])[CH2:3][CH2:2]1.Cl.[O:32]([NH2:34])[CH3:33]>>[CH3:33][O:32][NH:34][C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:26][CH3:27])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])=[C:9]([CH3:30])[CH:10]=1)=[O:25]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3)c2cc1C(=O)O
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(C)c3)ccnc2cc1OC
Yield: 21.74 %

Procedure:
4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid (30 mg, 0.0736 mmol) and methoxylamine hydrochloride (0.0123 ml) were used for reaction in the same manner as Example 458, and after purification by NH silica gel column chromatography (ethyl acetate:methanol=10:1), the obtained crystals were suspended in ethanol, diluted with hexane, filtered out, washed with hexane and dried by aspiration to obtain the title compound (7 mg, 0.0160 mmol, 21.74%) as light yellow crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl[CH2:23][CH2:24][N:25]([CH2:33][CH2:34]Cl)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].Cl>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[NH:18][C:17](=[O:21])[C:16]3([CH2:34][CH2:33][N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:32])[CH2:24][CH2:23]3)[C:15]2=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 2.80 mL, 2.80 mmol) was added dropwise to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 0.20 g, 0.94 mmol) in tetrahydrofuran (1.5 mL) at 0° C. The mixture was stirred for 15 minutes, then tert-butyl bis(2-chloroethyl)carbamate (0.25 g, 1.04 mmol) in THF (1 mL) was added dropwise and the mixture was warmed to room temperature. After stirring overnight, 2M aqueous hydrochloric acid was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (5:1 hexanes/ethyl acetate) gave the title compound (0.08 g, 22%) as a yellow solid.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)=[CH2:23]>C(Cl)Cl>[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Br:1])=[CH:26][CH:25]=1)=[CH2:23]
Reactant: BrBr
Reactant: C=Cc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
Bromine (16.4 g, 103 mmol) was slowly added to a solution of triphenylphosphine (28.87 g, 110.1 mmol) in CH2Cl2 (260 mL) at 0° C. After 10 minutes, 4-vinylbenzyl alcohol (12.5 g, 93.3 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was triturated with petroleum ether (3×), and the ethereal solution was concentrated in vacuo. The residue was purified by flash chromatography (hexanes) to afford 4-vinyl-benzyl bromide (6.23 g). 1H NMR (400 MHz, CDCl3) δ 7.32-7.45 (m, 4H), 6.72 (dd, 1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][OH:17])[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: COc1ccc(-c2ccc(C)c(CCO)n2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(OC)cc4)ccc3C)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of 2-[6-(4-methoxyphenyl)-3-methyl-2-pyridinyl]ethanol (Example 480, 0.15 g, 0.62 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.11 g, 51 mmol) in THF (2.50 mL) were added triphenylphosphine (0.17 g, 0.67 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.18 g, 67 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and concentrated under reduced pressure. The title compound (0.094 g, 41%) was isolated after silica gel chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.96 (d, 2H), 7.53-7.45 (m, 2H), 7.05 (d, 1H), 6.96 (d, 2H), 6.85-6.80 (m, 1H), 6.73 (dd, 1H), 4.48 (t, 2H), 4.14 (q, 2H), 3.86 (s, 3H), 3.51 (qt, 1H), 3.30 (t, 2H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.45-2.33 (m, 5H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[F:18][C:5]1[CH:4]=[C:3]([F:19])[C:2]([C:24]2[CH:25]=[N:20][CH:21]=[N:22][CH:23]=2)=[CH:7][C:6]=1[C@:8]1([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]1
Reactant: OB(O)c1cncnc1
Reactant: C[C@]1(c2cc(Br)c(F)cc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(-c3cncnc3)c(F)cc2F)N=C(N)OCC1(F)F

Procedure:
In a manner analogous to that described in Example 31, the cross-coupling reaction of (R)-4-(5-bromo-2,4-difluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.2) and pyrimidin-5-ylboronic acid yielded the title compound as a yellow solid. MS (ISP): m/z=341.1 [M+H]+.