Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:27]([F:30])([F:29])[F:28])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:26].C(N(CC)CC)C>O1CCCC1>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[NH:4][C:3](=[O:26])[C:2]([C:27]([F:30])([F:28])[F:29])=[CH:11]2
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)(C(F)(F)F)C(=O)N3)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)c(C(F)(F)F)cc3cc2F)c1=O
Yield: 47.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step H of Example 1, using 3.2 grams (0.007 mole) of 3-(3-chloro-6-fluoro-3,4-dihydro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl -6-trifluoromethyluracil and 3.2 grams (0.031 mole) of triethylamine in 100 mL of tetrahydrofuran. The product was recrystallized from ethanol, yielding 1.4 grams of 3-(6-fluoro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:39][CH3:38])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Agent: COc1cccc(N)c1
Product: COc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-methoxy-phenylamine (3.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 30:70 as the eluent to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1

Procedure:
1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 1-Bromomethyl-4-fluoro-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[F-].[Cs+]>[C:1]1([NH:7][C:8](=[O:9])[O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: O=C(Nc1ccccc1)Oc1ccccc1
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
1.28 g (8.4 mmol) of cesium fluoride was weighed into a flask and dried under a reduced pressure at 130° C. for 30 minutes. 50 g (0.42 mol) of phenyl isocyanate and 39.5 g (0.42 mol) of phenol were added thereto with stirring at 105° C. for 10 minutes, followed by the removal of an unreacted raw material at a reduced pressure. Thus, 88.3 g of phenyl N-phenylcarbamate having a melting point of 123° to 124° C. was obtained at a yield of 93.1%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[C-:10]#[N:11].[K+].O>CS(C)=O>[C:10]([CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1ccnc(CCl)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(CC#N)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 1112.3 %

Procedure:
2-chloromethyl-4-methylpyridine (3.70 g, 2.17 mmol) was dissolved in dimethyl sulfoxide (9 ml) and herein potassium cyanide (1.70 g, 2.60 mmol) was added. After stirring for 17 hours at room temperature, water was added and it was extracted twice with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain the desired product (3.19 g, yield=95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]3[CH2:54][CH2:55]3)[CH:42]=2)[CH2:38][C:37]2[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=2[Cl:31])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid (1.7 g, 3.83 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.611 g, 3.83 mmol), EDC (2.205 g, 11.50 mmol), and DMAP (0.702 g, 5.75 mmol) were dissolved in DCM (60 ml); the mixture was stirred at RT for 2 days. Then it was concentrated to about half volume, diluted with EtOAc (about 200 ml) and washed with HCl 1N and NaHCO3 sat. sol. The organic layer was dried over Na2SO4, and the solvent was evaporated to dryness. The crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1); (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a white amorphous solid (2.52 g, 2.98 mmol, 78% yield, MS/ESI+ 846.0 [MH]+).
Reaction SMILES: NC(=O)[C@H:3]([NH:7][C:8]1[N:9]=[N:10][C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[CH3:24])[N:13]=1)[CH:4]([CH3:6])C.NCC1[NH:35][C:34](=[O:36])[CH2:33]C1.N[C@H](C(C)C)C(N)=O>>[CH3:24][N:19]1[C:20]2[C:16](=[C:15]([NH:14][C:12]3[N:13]=[C:8]([NH:7][CH2:3][CH:4]4[CH2:6][CH2:33][C:34](=[O:36])[NH:35]4)[N:9]=[N:10][C:11]=3[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: NCC1CCC(=O)N1
Reactant: CC(C)[C@@H](Nc1nnc(C(N)=O)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Agent: CC(C)[C@@H](N)C(N)=O
Product: Cn1ccc2c(Nc3nc(NCC4CCC(=O)N4)nnc3C(N)=O)cccc21

Procedure:
The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 5-(aminomethyl)pyrrolidin-2-one was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C18H20N8O2 as (M+H)+ 381.3. UV: λ=219, 239, 292 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.36-7.22 (3H, m), 6.60 (1H, dd, J=0.8 Hz, 2.8 Hz), 3.98 (1H, m), 3.84 (3H, s), 3.62-3.51 (2H, m), 2.40, −2.20 (3H, m), 1.90 (1H, m) ppm.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17]Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:15][O:16][CH2:17][O:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: COCCl
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1nn(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.88 g), chloromethyl methyl ether (0.835 mL), N,N-diisopropylethylamine (2.09 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with diisopropyl ether-hexane to give 3-(methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as white crystals (1.34 g, yield 58%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 106-107° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][C:6]=3[C:5](=[O:16])[N:4]1[CH2:17]CCCN1CCC(N(C3C=CC=CC=3)C(=O)CC)CC1)[CH:9]=[CH:10][CH:11]=2.[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]CBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:17][N:4]1[C:5](=[O:16])[C:6]2[CH:15]=[CH:14][CH:13]=[C:8]3[C:7]=2[C:12](=[CH:11][CH:10]=[CH:9]3)[C:3]1=[O:2]
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Reactant: BrCCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 31 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.O.[OH-].[Na+]>CN(C=O)C>[Br:21][C:12]1[S:11][C:10]([N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][O:16][CH2:17]3)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(-c2csc(N3C4CCC3COC4)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(N3C4CCC3COC4)sc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 8-(4-(4-chlorophenyl)thiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step-2 of compound 56, 0.27 g, 0.88 mmol) in DMF (5 ml) at 0° C. was added N-bromosuccinimide (0.19 g, 1.06 mmol) in a portion wise manner. The resulting mixture was stirred at room temperature for 30 min. The progress of reaction was monitored by TLC. To the reaction mixture water (20 ml) and 1M NaOH solution (5 ml) were added slowly and aqueous layer was extracted with ethyl acetate (2×30 ml). The reaction mixture was washed with water (1×20 ml). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.26 g, 78.0%). MS: m/z 386 (M+1).
Reaction SMILES: C(N[C:6](=[O:37])[C@@H:7]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH2:34])[CH2:8][NH:9][CH2:10]C1C=CC(Br)=CC=1C)(C)(C)C.[CH2:38]([C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1)[CH3:39]>>[CH2:38]([C:40]1[CH:41]=[CH:42][C:43]([CH2:10][NH:9][CH2:8][C@H:7]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=2[NH:34][C:20]([NH:19][CH:7]([CH3:8])[CH3:6])=[O:36])[C@@H:6]([OH:37])[CH2:23][CH2:24][CH3:25])=[CH:46][CH:47]=1)[CH3:39]
Reactant: CCc1ccc(C=O)cc1
Reactant: Cc1cc(Br)ccc1CNC[C@H](NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1N)C(=O)NC(C)(C)C
Product: CCC[C@H](O)[C@H](CNCc1ccc(CC)cc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NC(C)C

Procedure:
The compound 1.2 (Z=—C(O)—, R2=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H; cf. procedure (65a); 0.93 g, 2.67 mmol) and (2S, 3S)-11.5 (l=m=0, PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 1.0 g, 2.76 mmol) were combined in procedure (1c). A portion (52 mg, 0.11 mmol) of the resultant product was combined with 4-ethylbenzaldehyde (0.015 mL, 0.11 mmol) and taken through procedure (1d). The crude product was purified by RP-HPLC to afford the title compound (1S, 2S)-1.5 (l=m=0, R1=4-ethylphenyl, R3=—CH(OH)n-propyl, Z=—C(O)—, R2=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H; 20 mg). Exact MS calcd for C29H41F3N5O4, the formula for (M+H)+=580.3111. Found: 580.3131.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]2([CH3:23])[CH3:22])=C(N)C=1.C(OC1C=CC(CC(Cl)=O)=CC=1)C1C=CC=CC=1.[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][C:59]2C=C(OC)C=[CH:61][C:60]=2C2CCC3C(=CC=C(OC)C=3)C2(C)C)=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][CH2:59][C:60]2[CH:61]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]2([CH3:23])[CH3:22])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2(C)C
Agent: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(CNCCc2ccc(OCc3ccccc3)cc2)c1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-benzyloxyphenylacetyl chloride according to an analogous synthetic method to Example 152, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (89 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (61 mg). This compound (60 mg) was used according to an analogous synthetic method to Example 22 to provide 4-{2-{[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol (50 mg). Synthesized from 4-{2-{[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol and 1-(2-chloroethyl)azepane according to an analogous synthetic method to Example 383 described below, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (42 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (27 mg).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[O:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:45][CH2:44]1
Reactant: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (0.6 g), phosphorus oxychloride (5 ml), N,N-dimethylaniline (0.14 ml), 1-methylpiperazine (10 ml) and fumaric acid (260 mg), 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine fumarate (575 mg) was obtained.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:14])=[CH:11][C:12]=1[I:13]>O.CCO>[Cl:6][C:7]1[C:12]([I:13])=[CH:11][C:10]2[NH:14][C:3](=[S:5])[NH:15][C:9]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(I)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1

Procedure:
KOH (15.7 g, 238 mmol) in water (50 mL), followed by carbon disulfide (14.4 mL, 238 mmol), was added to a solution of 4-chloro-5-iodobenzene-1,2-diamine (50 g, 198 mmol) in EtOH (300 mL). The mixture was heated at reflux for 3 h, cooled and filtered. To the filtrate was added water (300 mL) and then AcOH (25 mL) in water (50 mL). The precipitate was collected, washed with water and a small amount of EtOH and dried to afford the desired product as a brown powder, which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)=[C:9]([Cl:10])[C:5]=2[CH:4]=1.Cl.[C:30]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:30]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)=[C:9]([Cl:10])[C:5]=2[CH:4]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: FC(F)(F)c1cc(-c2sc3ccc(CBr)cc3c2Cl)ccc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromomethyl-3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (50 mg, 0.104 mmol) in DMF (1 mL) are added β-alanine tert-butyl ester hydrochloride (19 mg, 1 eq.) and K2CO3 (68 mg, 5 eq.). The mixture is stirred at 50° C. overnight. The mixture is diluted with EtOAc (40 mL), washed with 10% aqueous Na2S2O3, brine, dried over MgSO4, filtered, and concentrated. The mixture is purified by column chromatography (EtOAc/Hexane, gradient) to give 43 mg of 3-{[3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester in 76% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.Cl[C:42]1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)([O-])[O-])=CC=2OC)[N:43]=1.NC1C=CC(C#N)=CC=1C(NC)=O>>[C:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1)#[N:43]
Reactant: COc1cc(CP(=O)([O-])[O-])ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CNC(=O)c1cc(C#N)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-amino-5-cyano-N-methylbenzamide (Compound 150A). MS (ES+): m/z 593.19 (100) [MH+]; HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: Br[CH2:2][CH2:3][C@@H:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:5][N:6]([CH3:23])[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.Cl.[NH:32]1[CH2:37][CH2:36][C:35]2([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[S:39][CH2:38]2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C@@H:4]([CH2:5][N:6]([CH3:23])[C:7](=[O:22])[C:8]2[CH:9]=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=2)[CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][C:35]3([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[S:39][CH2:38]3)[CH2:34][CH2:33]2)=[CH:29][CH:28]=1
Reactant: CN(C[C@@H](CCBr)c1ccc(Cl)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CCC2(CC1)CSc1ccccc12)c1ccc(Cl)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as in Example 21 from 4-bromo-2-(S)-(4-chlorophenyl)-1-(N-(3,5-bistrifluoromethylbenzoyl)-methylamino)butane and spiro(2,3-dihydrobenzothiophene-3,4'-piperidine) hydrochloride except that 3 eq. of diisopropylethylamine were used.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[F:17][C:18]([F:25])([F:24])[C:19]([NH:21][CH2:22]O)=[O:20]>>[CH3:1][C:2]1[C:10]([CH2:22][NH:21][C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of 2,6-dimethyl benzoic acid (2.0 g, 13.33 mmol) in cone. H2SO4 (4 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (2.1 g, 13.33 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration and dried to afford 3.2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.92 (m, 2H), 7.15-7.04 (m, 2H), 4.36 (s, 2H), 2.18 (m, 6H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li][C:17]([CH3:20])([CH3:19])[CH3:18].CCCCC.C(Br)C(=C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH2:19][C:17]([CH3:20])=[CH2:18])([CH3:7])([CH3:6])[CH3:5]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1
Agent: C=C(C)CBr
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C(C)Cc1cc(F)ccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A solution of N-Boc-4-fluoroaniline (9.02 g, 42.7 mmol) in THF (112 mL) was cooled to −60° C. using a cryocool instrument. The solution was treated with 1.7 M t-BuLi in pentane (63 mL, 106.7 mmol) dropwise. After the first equivalent of base was consumed, a yellow solution formed. The reaction was allowed to warm to −20° C. and was stirred at that temperature for 2.5 hours. The reaction was then treated with a solution of methallyl bromide (5.67 g, 42.7 mmol) in THF (35 mL) dropwise and stirred for an additional 1.5 hours at −20° C. The reaction was then quenched by addition of water. After coming to room temperature, the reaction was treated with ethyl acetate and extracted with water and brine, dried over MgSO4 and filtered. The solvent was then removed and the residue was purified on silica gel using a gradient of 0-25% ethyl acetate in hexane to afford 11.3 g (80% yield) of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H), 1.72 (s, 3H), 3.28 (s, 2H), 4.71 (s, 1H), 4.92 (s, 1H), 6.32-6.50 (m, 1H), 6.86 (dd, 1H, J1=3.0, J2=9.1), 6.93 (ddd, 1H, J1=3.0, J2=8.5, J3=11.5), 7.65-7.82 (m, 1H); HPLC-MS calcd. for C15H20FNO2 (M+H+-tBu) 210.1, found 210.3.