Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH:11]([CH3:13])[CH3:12].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:10]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])=[CH:7][C:2]=1[F:1])[CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CC(C)CN(CC(C)C)c1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N(CC(C)C)CC(C)C)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 2-fluoro-N1,N1-diisobutylbenzene-1,4-diamine (0.40 g, 1.68 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (8.4 mL, 8.4 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (290 mg, 1.85 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as pale yellow oil (280 mg, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=O)=CC=1)([O-])=O.[H][H]>O1CCCC1.C(O)C.[C].[Pd]>[CH3:23][NH:22][C:20]([CH2:19][CH2:18][C@@H:13]1[CH2:14][C@@H:15]([OH:17])[CH2:16][NH:12]1)=[O:21]
Reactant: [H][H]
Reactant: CNC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)CC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine (1.52 g) in tetrahydrofuran (15 ml) and ethanol (15 ml), 10 palladium-carbon (228 mg) was added. The mixture was stirred at room temperature for 3.5 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated, and the residue was combined with water, washed with dichloromethane and lyophilized to give (2R,4R)-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][NH:34][CH2:31][CH2:32][CH3:33])=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CCCN
Product: CCCNCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and propylamine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.25-3.8 (m, 12H), 3.05 (t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 394 (+H)+;
Reaction SMILES: F[C:2]1[CH:7]=CC(N2C(I)=C(N)C=N2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([C:41]([F:44])([F:43])[F:42])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[C:31]=3[I:32])[C:23]2=[O:40])[C:20]=1[CH3:21].C/C(/[B-](F)(F)F)=C\C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[C:17]([C:41]([F:43])([F:42])[F:44])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[C:31]=3[I:32])[C:23]2=[O:40])[C:20]=1[CH3:21].[Cl:15][C:16]1[C:17]([C:41]([F:44])([F:43])[F:42])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[C:31]=3/[C:2](/[CH3:7])=[CH:3]/[CH3:4])[C:23]2=[O:40])[C:20]=1[CH3:21]
Reactant: Nc1cnn(-c2ccc(F)cc2)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C/C=C(\C)[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: C/C=C(\C)c1c(N2CCC(n3nc(C(F)(F)F)c(Cl)c3C)C2=O)cnn1-c1ccc(F)cc1
Temperature: 80 °C

Procedure:
The starting material 3-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one was prepared from a procedure analogous to Example 2, substituting 1-(4-fluorophenyl)-5-methyl-pyrazol-4-amine for 1-(4-fluorophenyl)-5-iodo-pyrazol-4-amine in step 2a. A solution containing 3-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one (90 mg, 0.16 mmol), potassium (2Z)-2-butene-2-yltrifluoroborate (32 mg, 0.20 mmol), PdCl2(dppf) (6.0 mg, 0.0080 mmol), and aqueous 2 M sodium carbonate (0.25 mL, 0.49 mmol) in dioxane (5 mL) was heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (SiO2, 20-50% EtOAc/hexanes) afforded the titled compound (33 mg, 0.070 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.45 (dd, J=8.9, 4.8 Hz, 2H), 7.11 (dd, J=8.0, 8.0 Hz, 2H), 5.73 (dddd, J=8.4, 6.8, 6.8, 1.6 Hz, 1H), 5.02 (dd, J=9.2, 6.9 Hz, 1H), 3.94 (ddd, J=9.6, 8.8, 4.8 Hz, 1H), 3.76 (ddd, J=9.6, 7.9, 6.2 Hz, 1H), 2.92 (dddd, J=13.6, 13.6, 8.8, 6.4 Hz, 1H), 2.67 (dddd, J=13.6, 9.2, 8.0, 4.4 Hz, 1H), 2.41 (s, 3H), 1.69 (dd, 6.8, 1.2 Hz, 3H), 1.60 (dd, J=1.2, 1.2 Hz, 3H); MS: (ES) m/z calculated for C22H20ClF4N5O [M+H]+482.1. found 482.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[CH:20]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)c1
Yield: 57.6 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (7-04) (24.0 g, 57.60%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) and 3-methyl-benzenesulfonyl chloride (6-04) (24.67 g, 129.87 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[CH:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[C:23](B5OC(C)(C)C(C)(C)O5)=[CH:22][C:16]=4[C:17]=3[C:18]([NH:20][CH3:21])=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:44]1[CH:45]=[CH:46][C:47]2[O:60][CH2:59][N:50]3[C:51]4[CH:52]=[CH:53][CH:54]=[C:55]([F:58])[C:56]=4[CH:57]=[C:49]3[C:48]=2[N:61]=1.C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:58][C:55]1[C:56]2[CH:57]=[C:49]3[C:48]4[N:61]=[C:44]([C:23]5[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:15]6[O:14][C:13]([C:10]7[CH:11]=[N:12][C:7]([O:6][C:5]8[CH:41]=[CH:42][C:2]([F:1])=[CH:3][CH:4]=8)=[CH:8][CH:9]=7)=[C:17]([C:18]([NH:20][CH3:21])=[O:19])[C:16]=6[CH:22]=5)[CH:45]=[CH:46][C:47]=4[O:60][CH2:59][N:50]3[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a stirring mixture of 2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.09 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (28 mg, 0.10 mmol) and Na2CO3 (18 mg, 0.17 mmol) in dioxane (0.8 mL) was added X-Phos (5 mg) and Pd2(dba)3 (5 mg) under N2 protection. The mixture was stirred at a pre-heated oil-bath 100° C. for 3 h. The mixture was concentrated and the residue was extracted with EA. The residue was washed with H2O, brine and dried over Na2SO4. After concentrated, the crude product was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.70 (d, J=2.0 Hz, 1H), 8.31˜8.34 (m, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 7.44 (s, 2H), 7.15 (s, 2H), 7.04˜7.10 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 6.76˜6.81 (m, 1H), 5.94 (s, 2H), 5.90 (d, J=8.8 Hz, 1H), 3.30 (s, 3H), 2.96 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 708.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]=2[CH2:22]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)CC3)cc1

Procedure:
Compound ey was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with acetyl chloride. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:13]([C:11]2[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:12]2[C:1](=[CH:2][CH:15]=[CH:16][CH:11]=2)[O:3]1)[CH3:8]
Reactant: CCOC(=O)CN(C)C
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Product: CN(C)CC1CC(c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2O1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using 5-bromo-2-chlorobenzotrifluoride in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[CH:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2NC(=O)CCl)[CH2:14][CH2:13][CH:12]=[CH:11]1>>[CH:10]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:9])[CH2:7][Cl:8])[CH2:14][CH2:13][CH:12]=[CH:11]1
Reactant: COCCNC(=O)CCl
Reactant: O=C(CCl)Nc1ccccc1C1C=CCC1
Product: COCCN(C(=O)CCl)c1ccccc1C1C=CCC1

Procedure:
The preparation of N-[2-(cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide was conducted in a fashion analogous to example 2. Reaction of 30.00 g (188.4 mmol) of 2-(cyclopent-2-enyl)aniline, 75.75 g (750 mmol}of triethylamine, and 70.91 g (750 mmol) of 2-chloroethyl methyl ether at 100° C. in a closed, 500 mL flask for 56 hr. afforded ca. 40 g of a crude product consisting of, in part, 90.05 wt % of N-(2-methoxyethyl)-2-(cyclopent-2-enyl)aniline and 7.24 wt % of 2-(cyclopent-2-enyl)aniline. Acylation of this material with 2-chloroacetyl chloride provided ca. 50 g of a product consisting of, in part, 89.35 wt % of N-[2- cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide and 8.84 wt % of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide. This material was purified by column chromatograph then bulb-to-bulb distillation (bp 165-175°C/1 mm/Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=Cc1ccncc1
Product: O=C(O)c1cc(F)ccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-5-fluorobenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 168.9, 152.4, 149.6, 148.8, 147.2, 121.9, 121.6, 116.6, 113.0, 110.7, 44.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[N:21]3[CH:20]=1)=O>>[CH3:31][C:22]1([CH3:32])[CH2:23][CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]13)[CH:28]=[CH:27][CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: CC1(C)CCc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (indol-3-yl)acetamide and (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[O:43]>ClCCl.C1(C)C=CC=CC=1>[C:27]([C:24]1[N:23]=[C:22]([O:31][CH2:32][CH3:33])[C:21]([C:10]2[N:11]([C:42]([Cl:44])=[O:43])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[CH:26][N:25]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reaction time: 0.5 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyrimidine (850 mg, 1.71 mmol) and triethylamine (600 uL, 4.28 mmol) in 10 mL of dichloromethane at 0° C. was added 1.88 mL solution of 20% phosgene in toluene (Fluka). After stirring for 30 min the mixture was concentrated to dryness under reduced pressure. Purification by flash column chromatography on silica gel, eluting with 10-20% of ethyl acetate in hexane provided 861 mg of rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Si](=O)=O>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)c2ccccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed dichloromethane (150 mL), (4-bromonaphthalen-1-yl)methanol (6.3 g, 26.57 mmol, 1.00 equiv), PCC (11.4 g, 183.72 mmol, 2.00 equiv) and 20 g Silicon dioxide. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and washed with ethyl acetate/petroleum ether (1/10-1/5). This resulted in 5.3 g (85%) of 4-bromonaphthalene-1-carbaldehyde as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:33])([CH3:32])[CH2:22][N:23]4[C:26](=[O:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:19][CH:18]=3)[C:10]2=[O:34])[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][N:28]([CH3:30])[CH2:27][C:26]([N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:11]3[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:7]=4)[C:10]3=[O:34])[CH:25]=2)[C:21]([CH3:33])([CH3:32])[CH2:22]1)=[O:31]
Reactant: Nc1cccnc1
Reactant: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Nc5cccnc5)c4)C(C)(C)C3=O)cc21
Temperature: 140 °C
Yield: 27.7 %

Procedure:
To a solution of 242 mg of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N,N-dimethylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) below in 2 mL of N-methylpyrrolidinone are successively added, under argon, 70 mg of 3-aminopyridine, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 11 mg of palladium acetate and 652 mg of caesium carbonate. The reaction mixture is heated at 140° C. for 1 hour by microwave, cooled to room temperature, diluted with 10 mL of dichloromethane and filtered, and the filtrate is concentrated under reduced pressure. The residue is taken up in 30 mL of water and the precipitate formed is filtered off and purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (93/7 by volume) to give 75 mg of 3-[1-(N,N-dimethylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:38]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])=[CH:32][CH:33]=1)(=[O:40])[CH3:39]
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(NC(C)=O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (Preparation 56)(42 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/DMF/water (5 mL/2 drops/1 mL, dissolved with warming, added water and then cooled to 0° C. overnight) gave the title compound (58 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2cccc(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2cccc(OC)c2)cc1
Temperature: 50 °C
Yield: 102.9 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.16 g). To the solution was added 1N sodium hydroxide solution (2.8 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.O.[OH-].[Li+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of 10.0 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 1.80 g of lithium hydroxide monohydrate, 30 ml of water and 90 ml of methanol was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the obtained residue was added water, and washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 9.10 g of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid.