Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Yield: 80 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.56 mmol) in DMF (5 mL) was added 2-chlorobenzothiazole (263 mg, 1.56 mmol) and Cs2CO3 (590 mg, 1.87 mmol). The resultant suspension was warmed (50° C., 18 h). The reaction mixture was concentrated under a stream of nitrogen. The resultant residue was purified by silica gel flash chromatography using EtOAc:hexane (10-30%) to provide the title compound (406 mg, 80%). MS (ESI): mass calcd for C17H11NO4S, 325.0; m/z found, 326.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.76-7.72 (m, 2H), 7.70 (d, J=8.0, 1H), 7.67 (d, J=9.0, 1H), 7.57 (s, 1H), 7.49-7.44 (m, 1H), 7.43-7.38 (m, 1H), 7.32-7.27 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:11][N:10]3[CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:29][O:30][CH2:31][C:32]([N:13]1[CH:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][N:10]2[CH:28]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C@@H:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:33]
Reactant: c1ccc(C[C@@H]2NC(c3ccccc3)Cn3cc(-c4ccccc4)nc32)cc1
Reactant: COCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COCC(=O)N1C(c2ccccc2)Cn2cc(-c3ccccc3)nc2[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinomethylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2 eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C. chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom, H), 6.6 (m, 1H, H1), 5.3 (m, 1H, H1), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.P(Cl)(Cl)Cl.C([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(C)C>ClC1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:1][CH:2]([CH3:10])[CH3:3])=[CH:33][CH:32]=1)=[O:6]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CC(C)Oc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2O)cc1
Yield: 149.4 %

Procedure:
Chlorobenzene (2.0 mL) was added to 2-hydroxy-5-(piperidin-1-ylsulfonyl)benzoic acid (470 mg), and under stirring, phosphorus trichloride (0.072 mL) was added thereto and kept stirred at 130° C. for 1 hour. 4-Isopropylaniline (249 mg) was added to it, and stirred at 130° C. for 16 hours. The solvent was evaporated off under reduced pressure, then ethyl acetate was added thereto, washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the intended product (515 mg, 75%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 197 mg (0.85 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. 325 mg (89%) of the title compound were obtained as pale beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:37]1([C:35]2[NH:34][C:33]3[CH:40]=[C:29]([O:28][C:24]4[N:25]=[CH:26][N:27]=[C:22]([N:17]5[CH2:18][CH2:19][CH:14]([N:10]6[CH2:9][CH2:8][C:7]7[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=7[NH:12][C:11]6=[O:13])[CH2:15][CH2:16]5)[CH:23]=4)[CH:30]=[C:31]([CH3:41])[C:32]=3[N:36]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C6CC6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]imidazole and 0.06 mL (0.32 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:40][CH:39]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: COc1ccc([C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: COc1ccc([C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)cc1
Yield: 30 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methoxyphenyl)pyrrolidine-2-carboxamide, gave Compound 62, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methoxyphenyl)pyrrolidine-2-carboxamide (7 mg, 30%). 1H-NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.00 (s, 1H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 7H), 5.00 (dd, 2H), 4.20 (m, 2H), 3.80 (m, 1H), 3.7 (s, 3H), 3.20 (m, 1H), 3.20-3.00 (m, 2H). MS (EI) for C28H26FN5O4 found 516 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1[C:12](=[O:27])[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:14]=[C:15]([Cl:17])[N:16]=1>>[Br:8][C:7]1[C:2]([NH:1][C:11]2[C:12](=[O:27])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:14]=[C:15]([Cl:17])[N:16]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Reactant: Nc1ncc(Cl)cc1Br
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(Cl)cc3Br)c2=O)cc1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-amino-3-bromo-5-chloropyridine and 3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one in a manner analogous to that for the preparation of example 26. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.51 (d, 1H, J=2.4 Hz), 8.40 (d, 1H, J=2.4 Hz), 7.51 (s, 1H), 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.8 Hz), 5.00 (s, 2H), 3.73 (s, 3H). MS (ES) [m+H] calc'd for C17H13BrCl2N4O2, 455, 457, 459; found 455, 457, 459.
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.[BH3-]C#N.[Na+]>>[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH2:50][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:47]=[N:48][CH:49]=2)[O:38]1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: C1COCCN1
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1(C)OB(c2cncc(CN3CCOCC3)c2)OC1(C)C
Yield: 71.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl)-dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])[N:4]=1.C(Cl)(Cl)(Cl)[Cl:23]>>[Cl:23][C:11]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(c1ccccc1)c1nc(OC)cc(OC)n1
Reactant: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Cl)(c1ccccc1)c1nc(OC)cc(OC)n1

Procedure:
Methyl 2-(4,6-dimethoxypyrimidin-2-yl)-2-phenylacetate (2.0 g) and N-chlorosuccimimide (2.0 g) were stirred at reflux in carbon tetrachloride (25 ml) under a bright light for 18 hours. The reaction mixture was filtered and evaporated to dryness, and the residue was purified by column chromatography on silica eluting with ether:hexane (1:1), yielding the desired product (2.16 g) as a pale yellow oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:24])[N:19]([CH2:21][CH2:22][OH:23])[CH3:20])([CH3:16])([CH3:15])[CH3:14].O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18](=[O:24])[N:19]([CH2:21][CH2:22][O:23][N:26]1[C:30](=[O:31])[C:29]2[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:36])[CH3:20])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.7 %

Procedure:
Diethylazodicarboxylate was added dropwise over 45 min to a stirring solution of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (7.10 g, 40.5 mmol), N-hydroxyphthalimide (7.17 g, 44.0 mmol) and triphenylphosphine (11.5 g, 43.8 mmol) in tetrahydrofuran (150 mL). The resultant reaction mixture was stirred 22 h at ambient temperature and was concentrated in vacuo to a thick oil. Chloroform (200 mL) was added and the resultant solution was chilled to affect crystallization of diethyl 1,2-hydrazaine dicarboxylate. The precipitate was filtered and the filtrate was concentrated and further diluted with hexanes. A single crystal of triphenylphosphine oxide was added. The resultant crystals of triphenylphoshine oxide were removed by filtration and the filtrate was concentrated in vacuo and chromatographed on silica gel to afford [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (12.8 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, DMSO-d6) δ 7.86 (bs, 4 H), 8.55 (bs, H), 4.24 (t, J=5.5 Hz, 2 H), 3.50 br t, J=5.4 Hz, 2 H), 2.92 and 2.88 (br s, 3 H), 1.39 and 1.36 (br s, 9 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCl
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ClCCCOCc1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
In a 2 l flask, a mixture of 3-chloropropanol (56.7 g), benzyl bromide (102.6 g) and dry THF (600 ml) is stirred and cooled with ice/salt mixture. Potassium tert-butoxide (70 g) is added in portions (5-10 g), maintaining the internal temperature at about 0° C. After the mixture is stirred for 3 more hours at room temperature, the solvent is evaporated. Addition of 1N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum to give 1-chloro-3-benzyloxypropane (108.4 g) b.p.0.01 60°-80° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-]>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])([CH3:21])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(C)O)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol) in DCM (5.2 mL), cooled to 0° C. (water/ice bath) under N2, was added 3M MeMgBr (1.4 mL, 4.21 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated to (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol, 92% yield) afford as a colorless oil which slowly crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (274 mg, 69%).
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH2:47]([O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH2:48][CH3:49].[BH3-]C#N.[Na+]>>[CH2:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH2:48][CH3:49]
Reactant: CCCOCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCOCCCNCc1ccc(B(O)O)s1
Yield: 36.5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexaness/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%).
Reaction SMILES: [C@H:1]12[CH2:49][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:42])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:49][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:42])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 59.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (99 mg, 0.148 mmol) in THF (2 mL) and MeOH (0.5 mL) was added 3N lithium hydroxide (0.197 mL, 0.592 mmol). The reaction mixture was stirred at 75° C. After 3.5 h, the reaction was cooled to rt and concentrated to a white paste which was purified by reverse phase prep-HPLC using prep method 6 and dried under vacuum to give the title compound (81.4 mg, 0.088 mmol, 59.2% yield) as a white solid. LC/MS: m/e 655.5 (M+H)+, 3.76 min (method 8). 1H NMR (400 MHz, 1:1 CHLOROFORM-d:METHANOL-d4) δ 7.90 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 5.35-5.23 (m, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.58 (br. s., 1H), 4.08 (d, J=9.0 Hz, 1H), 4.02 (br. s., 1H), 3.76 (dd, J=9.3, 1.5 Hz, 1H), 3.30-3.21 (m, 2H), 3.16 (d, J=10.3 Hz, 2H), 3.00 (br. s., 1H), 2.74 (td, J=11.1, 5.5 Hz, 1H), 2.18-1.94 (m, 7H), 1.91-1.84 (m, 1H), 1.82-1.75 (m, 1H), 1.71 (s, 3H), 1.70-1.63 (m, 2H), 1.63-1.30 (m, 11H), 1.28-1.17 (m, 2H), 1.14 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.93 (s, 3H), 0.92 (br. s., 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C(O)C>[CH2:26]([O:33][N:34]=[C:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)Oc1ccc(Oc2ccc(CCC(=O)C(C)C)cc2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2ccc(CCC(=NOCc3ccccc3)C(C)C)cc2)cn1

Procedure:
1-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-4-methylpentan-3-one (310 mg, 0.947 mmol) was stirred with O-benzylhydroxylamine hydrochloride (181 mg, 1.14 mmol) and pyridine (0.92 ml, 1.14 mmol) in 5 ml of ethanol at room temperature for 18 h. The reaction mixture was concentrated and further reacted without purification. Yield: 310 mg, M+H+: 433.26.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:24][CH2:25][C@@H:26]([NH:29][CH2:2][CH2:3][OH:4])[CH2:27][CH2:28]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: BrCCOC1CCCCO1
Reactant: N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1
Agent: Cl
Product: OCCN[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 23 to obtain the title compound.