Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(C)C.P(Cl)(Cl)([Cl:17])=O>C(#N)C>[Cl:17][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1nccc2ccccc12
Solvent: CC#N
Product: Clc1nccc2ccccc12

Procedure:
Methyl ester 104 is coupled with compound 7, which is synthesized as described in Reaction Scheme 1, in the presence of palladium acetate coupling catalyst, tetrabutylammonium fluoride, sodium bicarbonate in dimethyl formamide at 100° C., to produce compound 105. Compound 105 is converted to isopropoxy isoquinoline compound 107 by one of two methods. In the first method, compound 105 is treated with phosphoryl chloride in refluxing acetonitrile to produce the 1-chloro isoquinoline compound 106, which is then reacted with isopropyl alcohol in the presence of sodium hydride base to product compound 107. Alternatively, compound 105 is converted directly to compound 107 by reaction with isopropyl bromide, in dimethylformamide at 80° C., in the presence of potassium tert-butoxide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]([CH:34]=[O:35])[CH3:33]>CC(C)=O>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:4][CH:5]1[CH2:10][CH2:31][N:32]([CH3:33])[C:34](=[O:35])[CH2:6]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)C(=O)C1
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 0.87 mmol), (prepared as described in Example 49), potassium carbonate (370 mg, 2.68 mmol) and 4-(1-methyl-2-oxopiperidin-4-yOmethyl-4-toluene sulphonate (260 mg, 0.87 mmol) in DMF (8 ml) was stirred at 95° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture was diluted with acetone, filtered and the filtrate evaporated ‘in vacuo’ to give a residue which was purified by column chromatography, eluting with dichloromethane/methanol/0.88 ammonia (100/8/1). The relevant fractions were combined and evaporated ‘in vacuo’ to give an oil which crystallised on trituration with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methyl-2-oxopiperidin-4-ylmethoxy)quinazoline (66 mg, 17%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]([OH:27])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CCOCC>[CH2:28]([NH:35][C:25](=[O:27])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Yield: 89.3 %

Procedure:
5 g (13.14 mmol) of Nα-benzyloxycarbonyl-Nε-tert.-butoxycarbonyl-L-lysine in 30 cm3 of dry DMF and 1.41 g (13.14 mmol) of benzylamine are condensed in the presence of 2.01 g (13.14 mmol) of hydroxybenzotriazole in 10 cm3 of dry DMF and 2.98 g (14.54 mmol) of dicyclohexylcarbodiimide in 10 cm3 of dry DMF. A pasty solid is obtained after treatment under the same conditions as for the preparation of the compound (5). This solid is covered with ether to give a precipitate of N-benzyl-Nα-benzyloxycarbonyl-Nε-tert.-butoxycarbonyl-L-lysinamide (5.51 g; 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]1[CH:81]=[CH:80][C:78]([NH2:79])=[CH:77][CH:76]=1>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:79][C:78]3[CH:80]=[CH:81][C:75]([F:74])=[CH:76][CH:77]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26.4 mg, 72%). LC-MS m/z 667 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Agent: Cl
Product: O=C(NC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[N:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=NCc2ccccc2)CC1
Reaction time: 120 h

Procedure:
A mixture of (4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (3.80 g, 16.7 mmol), benzylamine (1.82 g, 16.7 mmol), acetic acid (0.01 g, 16.7 mmol) and anhydrous magnesium sulfate (4.01 g, 33.3 mmol) in methylene chloride (20 mL) was stirred for 5 days. The mixture was filtered through Celite and concentrated under reduced pressure to give trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.10 g, 97%) as a 97:3 trans:cis mixture.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.I[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:11]=1
Reactant: Ic1cnccn1
Reactant: COc1cc(OC)c(C2OCCO2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)c(C2OCCO2)cc1-c1cnccn1
Yield: 59 %

Procedure:
Ex-46C: 2-(5-[1.3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolved in DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2M aqueous Na2CO3 (17.8 mL, 35.6 mmol) was added and the mixture was purged with nitrogen for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h. After cooling, water (50 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The organic phase was washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the resulting yellow-orange solids via silica chromatography (50–80% EtOAc/hexanes) provided 1.02 g of 2-(5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid (59% yield). 1H-NMR (CDCl3) δ 9.10 (d, J=2 Hz, 1H), 8.61 (m, 1H), 8.39 (d, J=3 Hz, 1H), 8.07 (s, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 4.13–4.18 (m, 2H), 4.01–4.05 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[F:26])[CH:6]=[C:5]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:4]=1>O1CCOCC1.CO>[F:26][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[C:7]1[CH:6]=[C:5]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:4]=[C:3]([NH2:2])[N:8]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.[ClH:1]
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)OC(C)(C)C)C4)nc(N)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.0 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.050 g, 0.11 mmol) in methanol (1 mL). The reaction mixture was stirred at r.t. for 30 min The volatiles were removed under reduced pressure to afford the desired product as an HCl salt. Analytic LCMS (M+H)+: m/z=343.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[OH-].[NH4+:17]>>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:17])[CH:11]=[CH:10]2
Reactant: [NH4+]
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Agent: [OH-]
Product: Nc1ccc2cc(C(F)(F)F)ccc2n1
Yield: 38 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)quinoline (1 g, 4.3 mmol) in ammonium hydroxide (50 ml) was stirred overnight at 130° C. The resulting mixture was then concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%˜2% methanol in dichloromethane to afford 6-(trifluoromethyl)quinolin-2-amine as an off-white solid (350 mg, 38%). (ES, m/z): [M+H]+ 212; 1H NMR (300 MHz, CDCl3): δ 7.97-7.86 (m, 2H), 7.71 (s, 2H), 6.85 (d, J=9.0 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1/[CH:7]=[CH:15]/[CH:13]=[O:14]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(C=O)sc2ccccc12
Solvent: Cc1ccccc1
Product: Cc1c(/C=C/C=O)sc2ccccc12
Temperature: 80 °C
Yield: 52 %

Procedure:
3-Methylbenzo[b]thiophene-2-carboxaldehyde (4.2 g, 23.8 mmol) was dissolved in dry toluene (100 ml) and treated with (formylmethylene)triphenylphosphorane (7.35 g, 24.2 mmol). The reaction mixture was heated to 80° C. for 10 hours, allowed to cool and the residue was washed with 200 ml of hexane/Et2O 1/1 and then triturated with isopropyl ether to give pure title compound (2.5 g, 12.38 mmol, yield 52.0%), m.p.=90-92+ C.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[N:13]1([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)C>[N:13]1([C:18]2[CH:19]=[C:20]([N:21]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])[CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=[CH:17]1
Reactant: Nc1cccc(-n2cccc2)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2cccc(-n3cccc3)c2)C1=O
Yield: 78.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 3-(1H-pyrrol-1-yl)aniline (0.697 g; 4.41 mmol) in ethanol (3 mL). 1-(3-(1H-pyrrol-1-yl)phenyl)-2-oxopyrrolidine-3-carboxylic acid 0.313 g (80%) was obtained as a brown oil.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[Li]CCCC.[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1.Cl>C1COCC1.O>[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]([C:11]3[NH:10][C:18]4[C:13]([CH:12]=3)=[CH:14][CH:15]=[CH:16][N:17]=4)[OH:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a cold solution of 1-phenylsulfonyl-7-azaindole (1.29 g, 5 mmol) in 250 ml of THF was added at -30° C. n-BuLi (2.5M in hexane, 4 ml, 10 mmol). The mixture was stirred at -30°-40° C. for 1 h and then cooled to -50° C. To the above mixture was added dropwise at -50° C. a solution of 4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]butyraldehyde (1.37 g, 5 mmol) in 25 ml of THF, and the mixture was stirred at -40°-50° C. for 1 h and then allowed to warm to -5° C. for 2 h. Water was added to the mixture, and the resulting reaction mixture was acidified with 1N HCl solution, and then re-basified with an aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; then methylene chloride/acetone 2/1-1/1) followed by recrystallization from methylene chloride/methanol to afford 501 mg (25%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-7-azaindole, as a white crystalline solid, m.p.166°-169° C.
Reaction SMILES: [OH:1][CH2:2][C@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[Cl:26][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Temperature: 60 °C
Yield: 23 %

Procedure:
In a 50 mL pear flask was added (S)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (92 mg, 0.27 mmol) in DMF (2 ml) to give a solution. At room temperature 1-chloropyrrolidine-2,5-dione (36 mg, 0.27 mmol) was added, and the mixture was heated to 60° C. for 4 hours, at which point the reaction seemed to have stalled. An additional 0.2 equivalence of 1-chloropyrrolidine-2,5-dione was added, and the mixture was heated to 60° C. for another hour. The mixture was then cooled, and partitioned between brine and EtOAc. The aqueous layer was further extracted with EtOAc, and the organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The residue was then triturated with hot EtOAc, and the resulting precipitate was collected on a fritted-glass funnel. The collected solid was then recrystallized from EtOH to give the product (S)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (23 mg, 0.062 mmol, 22% yield) as a pink solid. 1H NMR (DMSO-d6) δ 10.68 (s, 1 H), 8.60 (s, 1 H), 8.37 (s, 1 H), 8.02 (s, 2 H), 7.69 (s, 1 H), 7.59 (s, 2 H), 5.05 (s, 1 H), 4.76 (t, J=5.8 Hz, 1 H), 4.19 (q, J=7.1 Hz, 2 H), 3.40-3.50 (m, 2 H), 1.34-1.45 (m, 6 H); m.p. 223.0-223.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:20][CH2:21][C:22]#[CH:23].[Li+].CC([N-]C(C)C)C.[Si:32](Cl)([CH3:35])([CH3:34])[CH3:33]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:20][CH2:21][C:22]#[C:23][Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: CCc1ccc(Cc2cc(Br)c(COCCC#C[Si](C)(C)C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
To a cooled solution (−78° C.) of 1-bromo-2-((but-3-ynyloxy)methyl)-4-chloro-5-(4-ethylbenzyl)benzene (BT) (96 mg, 0.245 mmol) was added LDA (2M in THF, 0.18 mL, 0.36 mmol). After stirring for 20 min, TMS-Cl (50 μL, 0.393 mmol) was added. After stirring for another 2.5 h, additional TMS-Cl (30 μL, 0.236 mmol) was added. The reaction solution was stirred at −78° C. for 70 min and then warmed to room temperature with stirring for 1.5 h. Water was added and the mixture was extracted with ethyl acetate and the extracts were washed with brine, and dried over Na2SO4. The solution was concentrated and the resulting residue was purified by preparative TLC to afford 72 mg of title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:32][NH:33][C@H:34]([CH3:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[N:33]([CH3:32])[C@@H:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:41])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CN[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 98, Step 1, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (R)-(+)-N,α-dimethylbenzylamine.
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1>CCOC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[O:17])[NH:7][N:6]=[N:5]2)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1
Reactant: CC(C)Oc1cc(F)ccc1N=C=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 81 %

Procedure:
This reaction with TMS-N3 was performed behind a blast shield. The crude 4-fluoro-1-isocyanato-2-isopropoxybenzene was placed under argon and trimethylsilylazide (16 mL, 118.2 mmol, 2 equiv) was added. The reaction mixture was heated to refluxed for ON under argon. After cooling to RT, the reaction mixture was concentrated under vacuum, and the residue was charged with saturated NaHCO3 (100 mL) and stirred vigorously for 5-10 min, then the basic reaction mixture was diluted with EtOAc. The layers were separated, and the organic layer was monitored by TLC to confirm that all the product had been extracted by the saturated NaHCO3 solution. EtOAc was added to the combined basic aqueous extracts, and the pH was adjusted to <3 using 6N HCl. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc 3×. The combined organic layers were dried over Na2SO4, filtered, and the solvent removed under vacuum to provide 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (11.4 g, 81%) as a brown oil that was used without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[SH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC1C=CC(S(O[CH2:30][C:31]([F:34])([F:33])[F:32])(=O)=O)=CC=1>O>[F:32][C:31]([F:34])([F:33])[CH2:30][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.7 g of sodium hydride was added to 30 ml of dry dimethylformamide, and then 7.5 g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4 g of light yellow oily liquid, yield 53.8%.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:14]([Cl:27])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:27][C:14]1[CH:13]=[N:12][C:11]2[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:5]=3)[CH2:3][CH2:2][O:26][C:22]3[CH:21]=[C:20]([CH2:19][CH2:18][NH:17][C:15]=1[N:16]=2)[CH:25]=[CH:24][CH:23]=3
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCCc1cccc(c1)OCCc1cccc(c1)N2
Yield: 20.7 %

Procedure:
To a solution of 3-{2-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was added a solution of sodium hydroxide in water (0.893 mL, 0.50 M). The resultant solution was stirred at rt for 2 days until the reaction was complete. The reaction was neutralized with HCl (3 M, aqueous solution) to pH 7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product as a white powder (8.5 mg, 21%). LCMS for C20H20ClN4O (M+H)+: m/z=367.0. 1H NMR (400 MHz, CD3OD): δ 7.81 (s, 1H), 7.70 (s, 1H), 7.57 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.08 (m, 2H), 6.69 (s, 1H), 6.67 (m, 2H), 5.73 (dd, J=6.8, 0.8 Hz, 2H), 5.14 (dd, J=7.2, 1.2 Hz, 2H), 3.72 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H).