Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:40]=O)=[C:35]([CH:39]=1)[C:36]([OH:38])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O1CCCC1>[C:26]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([CH3:29])=[C:2]([NH:1][CH2:40][C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:39][C:35]=4[C:36]([OH:38])=[O:37])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:15]=3)(=[O:27])[NH2:28]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: O=Cc1ccc(F)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(F)cc4C(=O)O)c3C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (60.0 mg, 0.154 mmol), 5-fluoro-2-formylbenzoic acid (64.6 mg, 0.384 mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid (0.022 mL, 0.384 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr and then quenched with water (3 mL). The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to dryness. The residue was dissolved with minimum amount of DMF, diluted with MeOH (3 mL), divided into 2 portions, and purified by reverse phase HPLC. The correct fractions were combined, concentrated under vacuum, and lyophilized to afford the desired product (TFA salt) (31.6 mg, 0.048 mmol, 31.3% yield) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C@H:23]([OH:27])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH2:5]1.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>N1C=CC=CC=1>[C:30]([OH:35])(=[O:36])[CH2:31][CH2:32][C:33]([OH:1])=[O:34].[O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C@H:23]([OH:27])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH2:5]1
Reactant: O=C1CCC(=O)O1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
After 5 g of 7-ketocholesterol was dissolved in 50 ml pyridine, 1.8 g of succinic anhydride was added thereto, the mixture was heated to react for 8 hours at 90° C. and allowed to stand at room temperature overnight. Then, the resulting liquid was poured into 500 ml ice-cold water. The crystals precipitated by acidification with hydrochloric acid were collected by filtration and then dissolved in ethanol, active carbon was added thereto for decoloration and filtered off, water was added to the filtrate, and the precipitated crystals were recovered by filtration. Upon recrystallization thereof from aqueous ethanol, 5.4 g of 7-ketocholesterol succinic acid half ester was obtained as flaky crystals, m.p. 187.5°-189.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][P:59]([CH3:62])(=O)[OH:60].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:58][P:59]([CH3:62])(=[O:60])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:30])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CO)cc1
Reactant: CP(C)(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(COP(C)(C)=O)cc1
Reaction time: 24 h

Procedure:
1,1-dimethylethyl [2-({[4-(hydroxymethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (650 mg, 1.531 mmol), BOP (1016 mg, 2.297 mmol), dimethylphosphinic acid (216 mg, 2.297 mmol), DMAP (10 mg, 0.082 mmol) and DIPEA (0.401 mL, 2.297 mmol) were stirred in DMF (8 mL) at room temperature overnight. Additional BOP (2370 mg, 5.36 mmol), DIPEA (0.936 mL, 5.36 mmol), dimethylphosphinic acid (504 mg, 5.36 mmol) and DMAP (20 mg, 0.164 mmol) were added and stirring continued for 24 hours. Additional BOP (1016 mg, 2.297 mmol), DIPEA (0.401 mL, 2.297 mmol) and dimethylphosphinic acid (216 mg, 2.297 mmol) were added and stirring continued for 6 hours. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-20% MeOH-EtOAc) gave [4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate as a yellow gum. 1H-NMR (600 mHz, DMSO-d6) δ 9.90 (s, 1H), 8.72 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.90 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.49 (m, 2H), 7.43 (dd, J=3.6 and 1.2 Hz, 1H), 7.10 (dd, J=4.8 and 3.6 Hz, 1H), 5.02 (d, J=8.4 Hz, 2H), 1.46 (d, J=13.8 Hz, 6H), 1.42 (s, 9H). MS: cal'd 401 (MH+-Boc), exp 401 (MH+-Boc).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:19]=[CH:18][C:11]2[C:12]([CH2:16]O)=[CH:13][CH2:14][O:15][C:10]=2[CH:9]=1.S(Cl)([Cl:22])=O>C(OCC)C>[F:7][C:8]1[CH:19]=[CH:18][C:11]2[C:12]([CH2:16][Cl:22])=[CH:13][CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: OCC1=CCOc2cc(F)ccc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1ccc2c(c1)OCC=C2CCl
Reaction time: 2 h

Procedure:
1.22 g of pyridine are added to 28 g of 7-fluoro-4-hydroxymethyl-2H-1-benzopyrane in 50 ml of diethylether. The mixture is cooled to 5° and 2 g of thionylchloride in 10 ml diethylether slowly added dropwise. The reaction is continued for 30 minutes at 5°-10° and 2 hours at room temperature. The resulting mixture is poured onto ice-water, the organic phase separated and the aqueous phase extracted with a further 20 ml of diethyl ether. The combined ether solutions are dried over MgSO4 and concentrated by evaporation.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][C:16]([C:18]3([NH:24][S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Br:34])(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:6]1)[CH2:12]2)=[O:4].O1CCCC1.CO.[OH-].[Li+]>O>[Br:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:25]([NH:24][C:18]1([C:16]([NH:15][CH:8]2[CH:7]3[CH2:6][C:5]4([C:3]([OH:4])=[O:2])[CH2:12][CH:11]([CH2:10][CH:9]2[CH2:14]4)[CH2:13]3)=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:27])=[O:26]
Reactant: COC(=O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
In a 25-mL flask, 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid methylester (140 mg, 0.253 mmol) was charged, and dissolved through addition of tetrahydrofuran (5 mL), and methanol (5 mL). Lithium hydroxide dissolved in purified water (5 mL) was added thereto, followed by stirring for 12 hours at room temperature. After the reaction was completed, the resultant solution was vacuum-evaporated, acidified with 2N hydrochloric acid aqueous solution to pH 1-2, and extracted with addition of ethyl acetate (20 ml). The organic layer was added with magnesium sulfate so as to remove remaining moisture. Through filtering and vacuum distillation, the solvent was removed so as to obtain 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid (106 mg, 79%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(N(CC)CC)C.[CH2:12]([CH:17]1[C:21](O)([CH3:22])[CH:20]=[CH:19][C:18]1=[O:24])[CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:12]([C:17]1[C:18](=[O:24])[CH2:19][CH:20]([S:3][C:1](=[O:4])[CH3:2])[C:21]=1[CH3:22])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)=S
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC1=C(C)C(SC(C)=O)CC1=O
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Into the same flask as used in Example 1, thioacetic acid (35 g) and triethylamine (7 g) were charged, and 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) was dropwise added thereto at a temperature of 20° to 35° C. for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 40° to 60° C. for 3 hours. After completion of the reaction, the mixture was diluted with toluene (50 ml) and treated in the same manner as in Example 50 to obtain 2-n-pentyl-3-methyl-4-acetylthio-2-cyclopentenone (24.1 g). Yield, 94%. nD20 1.5146.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[CH3:10])[C:5]([Cl:29])=[CH:4][N:3]=1.O.[NH3:31]>>[NH2:31][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[CH3:10])[C:5]([Cl:29])=[CH:4][N:3]=1
Reactant: Cc1cccc2cc([C@H](C)Nc3nc(Cl)ncc3Cl)n(-c3ccccc3)c(=O)c12
Reactant: N
Solvent: O
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)ncc3Cl)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A mixture of (S)-3-(1-(2,5-dichloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5101) (85 mg, 0.20 mmol) in ammonia water (15 mL) in a sealed tube was stirred at 150° C. for 16 h. The solution was allowed to cool to room temperature and then partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product, (S)-3-(1-(2-amino-5-chloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (5102, compound 249 in Table 4) (40 mg, 49.6% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:15]=[C:16]1[C:20]([CH3:22])([CH3:21])[O:19][C:18]([CH3:24])([CH3:23])[C:17]1=[O:25].[OH:26]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH:15]1[C:16]2([C:17](=[O:25])[C:18]([CH3:24])([CH3:23])[O:19][C:20]2([CH3:21])[CH3:22])[O:26]1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
To a solution of 4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (3.40 g, 9.03 mmol) in methanol (140 ml) at 35° C. is added 50% aqueous hydrogen peroxide (1.04 ml, 15.60 mmol), immediately followed by 2M aqueous lithium hydroxide (1.15 ml, 2.30 mmol). The reaction mixture is stirred for a further 45 minutes at 35° C., then allowed to cool to room temperature and quenched with saturated sodium metabisulfite. After extracting the product into diethyl ether (×3) the organic phase is separated, washed with additional water, then dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 2-(4-bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (3.0 g) as a yellow solid. This material was of sufficient purity to use directly in the next step.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:16]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)cc(C(F)(F)F)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 3-fluoro-5-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 60 mg (45.3% yield) of biphenyl-4-carboxylicacid {2-[4-(3-fluoro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.64%, 1H NMR: (DMSO) δ 8.7-8.62 (t, 1H), 8.02-7.94 (d, 2H), 7.86-7.66 (m, 7H), 7.54-7.46 (m, 2H), 7.44-7.38 (m, 1H), 4.26-4.12 (bs, 2H), 3.74-3.44 (m, 6H), 3.42-3.34 (m, 2H).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[N:14]=[C:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1nccc(OC2COC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a suspension of oxetan-3-ol (100 mg, 1.35 mmol) in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL) was added 60% sodium hydride in mineral oil (81 mg, 2.03 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction was then cooled to 0° C. and a solution of 2,4-dichloropyrimidine (300 mg, 2.03 mmol) in tetrahydrofuran (1 mL) and N,N′-dimethylformamide (1 mL) was added. The mixture was warmed to room temperature and stirred for 24 h. The reaction was then diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Chromatography on silica gel (10-60% ethyl acetate in hexanes) to afford 2-chloro-4-(oxetan-3-yloxy)pyrimidine (91 mg, 0.49 mmol, 36% yield) as a white solid. MS ESI: [M+H]+ m/z 186.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](I)[C:27]([CH3:31])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[C:27]([CH3:31])=[CH:26][N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cnc(F)cc1I
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1cnc(F)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-4-iodo-5-picoline (CAS RN: [153034-94-7]) was prepared the title compound as a light yellow oil, MS (ESI−): m/z=410.0558 ([M−H]−, 1Br).
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[C:13]=2[C:24]=1[CH3:25])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:25][C:24]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:15][O:16][C:12]=2[C:11]([CH3:26])=[C:10]([CH3:27])[C:9]=1[NH2:8]
Reactant: Cc1ccc(C2COc3c(C)c(C)c(NCc4ccccc4)c(C)c32)nc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)nc1
Yield: 85 %

Procedure:
Using N-benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 278, the title compound was synthesized in the same manner as in Reference Example 30. Yield 85%. Melting point: 125-127° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][C@@H:4]([OH:20])[C@@H:3]2[OH:21].N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[Si:31]([O:20][C@@H:4]1[CH2:5][C@H:6]2[C@H:7]3[C@H:16]([CH2:17][CH2:18][C@:2]2([CH3:1])[C@H:3]1[OH:21])[C:15]1[CH:14]=[CH:13][C:12]([OH:19])=[CH:11][C:10]=1[CH2:9][CH2:8]3)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 11.52 g of 1,3,5(10)-estratriene-3,16α,17β-triol in 200 ml of dimethylformamide, cooled to -20° C., is combined, after adding 6.52 g of imidazole, dropwise with a solution of 13.24 g of tertbutyldimethylsilyl chloride in 100 ml of dimethylformamide. This reaction mixture is stirred for one hour with continued cooling and then poured into ice water. The resultant precipitate is filtered off, washed with water and dissolved in dichloromethane. The solution is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@H:47]([CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[CH2:48][OH:49].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@H:47]([CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[CH2:48][OH:49])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H](CO)C1CCCCC1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H](Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1)C1CCCCC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then (R)-2-amino-2-cyclohexylethanol (209 mg, 1.46 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol (18 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.38 (m, 1H), 8.09 (dd, J=1.0, 8.0 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.18-7.32 (m, 3H), 5.48 (s, 2H), 4.70 (br s, 1H), 3.72 (m, 1H), 3.50 (m, 2H), 1.54-1.77 (m, 6H), 0.94-1.23 (m, 5H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3(C)C)cn2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3(C)C)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
To a solution of tert-butyl 4-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino) pyridin-3-yl)-3,3-dimethylpiperazine-1-carboxylate 190c (1.19 g, 1.9 mmol) in dichloromethane (20 mL) was added 3M HCl in diethyl ether (15 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure to afford 190d (900 mg, 95%). LCMS: [M+H]+ 392.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[CH3:15][N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([C:18](=[O:19])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[CH3:15])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H]1CCCN1C)CC2
Yield: 95.1 %

Procedure:
A solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.7 g, 11.71 mmol), 1-methyl-L-proline (Acros, 1.739 g, 13.46 mmol), HATU (5.79 g, 15.22 mmol), and DIPEA (6.13 mL, 35.1 mmol) in N,N-Dimethylformamide (DMF) (25 mL) was stirred at room temperature overnight. The next morning the solution had completely solidified. The solids were diluted with ethyl acetate/THF and washed with saturated sodium bicarbonate until all solids had dissolved. The organic layer was dried over sodium sulfate, filtered, concentrated onto celite, and purified by column chromatography to afford 5-(methyloxy)-1-(1-methyl-L-prolyl)-6-nitro-2,3-dihydro-1H-indole (3.4 g, 95% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1 H), 7.35 (s, 1 H), 4.20-4.31 (m, 1 H), 4.10-4.20 (m, 1 H), 3.88 (s, 3 H), 3.56-3.70 (m, 1 H), 3.25 (t, J=8.43 Hz, 2 H), 3.15-3.21 (m, 1 H), 2.52-.64 (m, 1H), 2.45 (s, 3 H), 2.21-2.35 (m, 1 H), 1.75-1.93 (m, 3 H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1

Procedure:
Meanwhile, the 3-methylbenzoyl chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of m-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (3.84 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.