Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1.O[CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1O
Reactant: OCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
Diethyl azodicarboxylate (0.182 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-6-methoxyquinazoline (0.2 g), N-(2-hydroxyethyl)pyrrolidine (0.086 g), triphenylphosphine (0.303 g) and methylene chloride (3 ml) and the reaction mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using a 45:4:1 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.033 g) as a white solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9 (m, 2H), 2.1 (m, 2H), 3.2 (m, 2H), 3.7 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.6 (m, 2H),6.2 (s, 2H), 7.1 (d, 1H), 7.5 (s, 1H), 8.2 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M−H− 441 and 443.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([CH3:39])[C:36]([OH:40])=[C:35]([CH3:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([CH3:41])[C:36]([OH:40])=[C:37]([CH3:39])[CH:38]=3)[C:42]([N:5]3[CH2:6][CH2:7][C:2]([CH3:1])([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)[CH2:3][CH2:4]3)=[O:43])=[O:29])[CH2:26][CH2:27]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: CC1(N2CCOCC2)CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C)(N3CCOCC3)CC2)cc(C)c1O
Reaction time: 20 h

Procedure:
55 mg (0.22 mmol) 4-(4-methyl-piperidin-4-yl)-morpholine (used as the hydrochloride salt, purity 90%) were added at RT to a solution of 90 mg (0.19 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h), 70 mg (0.22 mmol) TBTU and 70 μL (0.50 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 20 h. The reaction solution was poured onto saturated NaHCO3 solution, the precipitate formed was filtered off and dried. Further purification was carried out by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][Br:27])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Yield: 32.3 %

Procedure:
A mixture of 3-[(6-bromo-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (3.39 g, 9.95 mmol), NBS (1.949 g, 10.95 mmol) and AIBN (0.082 g, 0.498 mmol) in carbon tetrachloride (45 ml) was heated at reflux overnight. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. Chromatography of the residue (EtOAc:hexane) gave 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.35 g, 32.3% yield) as a colorless oil which crystallized to a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.44 (dd, 1H), 7.34 (s, 1H), 7.19-7.27 (m, 1H), 7.10-7.15 (m, 1H), 6.97 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]([C:11]1([OH:14])[CH2:13][CH2:12]1)=[O:10])[CH3:7].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C(Cl)Cl>[Cl:23][C:21]([O:14][C:11]1([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:13][CH2:12]1)=[O:22]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1(O)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(OC(=O)Cl)CC1

Procedure:
Step 81) A THF solution (50 mL) of 1-hydroxy-cyclopropanecarboxylic acid ethyl ester (5 g, 38.4 mmol) and pyridine (3.3 mL, 41 mmol) was added dropwise a phosgen/toleune solution (25 mL, 47.5 mmol) at 0° C. in 5-10 min. the reaction mixture was allowed slowly warm up overnite. The solid was filtered off and the filtration was concentrated in vacuo. The residue was dissolved in hexane, refiltered, and concentrated in vacuo to afford.7.4 g (100%) the product. The product was dissolved in CH2Cl2 (100 mL) as a stack solution: 1H NMR (300 MHz, CHLOROFORM-D) □ ppm 1.25 (t, J=7.14 Hz, 3H), 1.37 (m, 2H), 1.57 (m, 2H), 4.21 (q, J=6.95 Hz, 2H); (ppm) 13.97, 15.75, 62.07, 62.13, 150.54, 168.71.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[C:31]4[C:27](=[CH:28][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=4)[CH:26]=[C:25]([C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:44]([Li])(C)(C)C.IC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:44][C:28]1[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:30]=[C:31]2[C:27]=1[CH:26]=[C:25]([C:40]([F:41])([F:43])[F:42])[CH:24]=[C:23]2[CH2:22][O:21][CH2:20][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2nn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-phenyl-4-(((5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (97 mg, 0.16 mmol) was dissolved in dry tetrahydrofuran (3 mL) and stirred at room temperature for 15 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium (1.7 M in pentane, 190 μL, 0.33 mmol). The reaction was gradually warmed to −20° C. over 1 h, cooled to −78° C. and treated with iodomethane (10 μL, 0.19 mmol). The reaction was warmed to 0° C. over several hours then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, filtered and concentrated to afford 100 mg (quant.) as a clear oil. LC/MS (HPLC method 1): tR=3.70 min, 634.26(MH)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[CH:33]=[CH:32][NH:31][N:30]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[CH:33]=[CH:32][N:31]([C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)[N:30]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COC(C(=O)O)c1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(-c2cc[nH]n2)cc1OC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccn(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc1OC
Reaction time: 24 h
Yield: 489.8 %

Procedure:
To a solution of 2-methoxy-2-(4-morpholinophenyl)acetic acid (0.1 g, 0.42 mmol) and 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.86 g, 0.42 mmol) in anhydrous DMF (4 mL) at room temperature was added diisopropylethylamine (0.22 ml, 1.26 mmol) then bromotripyrrolidinophosphonium hexafluorophosphate (0.23 g, 0.50 mmol). After 24 hrs, saturated aqueous NaHCO3 was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-60% EtOAc-hexanes) gave 1-(3-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a white solid (0.90 g, 50% yield). MS: m/z 438.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24][CH3:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:25][S:24][CH2:23][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10]
Reactant: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Reactant: OB(O)c1ccncc1
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: CCO
Solvent: COCCOC
Product: CSCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 66.8 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methylsulfanylmethyl-phenyl)-amide (0.23 g) and 4-pyridineboronic acid (0.092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.058 g) to obtain the title compound (0.153 g) as a brownish foam (0.153 g). MS (ISN): 457.2 (M−H)−
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>CO>[CH3:11][C:10]1([CH3:12])[S:13][CH:1]([C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[NH:8][C@H:9]1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccco1
Solvent: CO
Product: CC1(C)SC(c2ccco2)N[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
A solution containing 2.48 ml of furfural and 4.27 g of D-penicillamine in 90 ml of 30% methanol is stirred for 8 hours, then evaporated to dryness. The partly crystalline residue is rubbed with ether to give the title compound, m.p.: 141°-143° C., [α]D20 =+103° (c=0.602, dimethylsulphoxide).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:21][CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:23][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:11][C:6]1=2
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CCCO)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CCCO)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol (1000 mg, 4.0983 mmol) in DMF (10 mL) was portionwise added sodium hydride (491.8 mg, 12.25 mmol). After stirring at RT for 5 min, 4-(oxiran-2-yl)pyridine (620 mg, 4.92 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. Ice water was added into the reaction mixture and the solid mass filtered, washed with water (2×10 mL) and hexane (2×50 mL). The residue was purified by reverse phase HPLC to yield 3-(3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol. 1H NMR (CD3OD, formate salt) δ (ppm): 8.43 (bs, 2H), 7.39 (d, 2H), 7.23 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 5.07 (t, 1H), 4.48 (bs, 2H), 4.23 (m, 2H), 3.7 (t, 2H), 3.6 (bs, 2H), 3.4 (t, 2H), 3.2 (m, 1H), 2.95-3.03 (m, 1H), 2.4 (s, 3H), 2.03 (bs, 2H). Separation by chiral HPLC provides enantiomers II-75a-b.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:26]=[CH:25][C:18]3[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[C:42]([O:44]C)=[O:43].[Li+].[OH-]>O1CCOCC1.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].C(O)=O>[Cl:28][C:4]1[CH:3]=[C:2]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[C:36]([F:35])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([C:15]1[CH:26]=[CH:25][C:18]2[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:17]=2[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=CO
Solvent: C1COCCO1
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (7 mg), Cs2CO3 (82 mg) and 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. No. 505083-04-5, 33 mg) in dioxane (2 ml) was heated at 80° C. for 20 min in a sealed tube. 1N aqueous LiOH solution (1 ml) was added and stirred for 20 min at room temperature. The mixture was acidified with HCOOH and then purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=537.2[M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19](=[O:21])[NH2:20])[CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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.C(O)C.C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19](=[O:21])[NH2:20])[CH2:15][CH2:14]1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(Br)c2n1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, 8-bromo-2-methyl-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)quinoline (4.7 g), 2,4-dichlorophenylboric acid (2.9 g) and sodium carbonate (4.5 g) were suspended in a mixed solvent of deaerated water (14 mL), toluene (7 mL) and ethanol (7 mL), followed by adding thereto tetrakis(triphenylphosphine)palladium (0.81 g), and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and stirred at room temperature for 3 hours. The solid precipitated was collected by filtration and washed with a water-ethanol (2:1) mixed solvent (30 mL) and then ethanol (30 mL) to obtain the title compound (4.7 g).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:26][CH2:27][S:28][CH3:29].[I-].[K+]>CN(C=O)C>[CH3:29][S:28][CH2:27][CH2:26][N:5]1[C:6]2[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CSCCCl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCSC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.025 g, 0.099 mmol), Cs2CO3 (0.129 g, 0.396 mmol), (2-chloroethyl)(methyl)sulfane (0.039 mL, 0.396 mmol) and potassium iodide (0.0165 g, 0.099 mmol) in DMF (2 mL) was heated at 80° C. After ˜1 h, additional Cs2CO3 (0.129 g, 0.396 mmol), (2-chloroethyl)(methyl)sulfane (0.039 mL, 0.396 mmol) and potassium iodide (0.0165 g, 0.099 mmol) were added, and heating was continued for 1 h. Upon cooling, the mixture was partitioned between EtOAc (25 mL) and water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna column; gradient: 10-90% MeCN-water with 0.1% TFA). The fractions with product were concentrated down to the aqueous phase and then partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(2-(methylthio)ethyl)-2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile: MS (ESI): m/z 327 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13]O)=[CH:11][S:10][C:9]1=[N:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C=O)C.O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13][N:40]=[N+:41]=[N-:42])=[CH:11][S:10][C:9]1=[N:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)N=c2scc(CO)n2CCCNC(C)=O)c(OC)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)N=c2scc(CN=[N+]=[N-])n2CCCNC(C)=O)c(OC)c1
Reaction time: 2 h

Procedure:
The compound (3.45 g) obtained in the above (2) and triethylamine (976 mg) were dissolved in DMF (35 ml), and thereto was added dropwise methanesulfonyl chloride (0.75 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours, and thereto was added sodium azide (627 mg), and the mixture was further stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol (98:2)] to give the title compound (3.48 g) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CN.C1COCC1.[CH3:28][N:29](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=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH3:28])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (50 mg, 0.18 mmol) was reacted with methyl amine 2M in THF (0.18 mL, 0.35 mmol), HATU (103 mg, 0.6 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-methylbenzamide 20. LC/MS (ESI+): m/z 280 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.59 (dd, J=10.4, 6.2 Hz, 2H), 8.49 (d, J=8.9 Hz, 1H), 8.43 (d, J=5.3 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.07 (d, J=17.7 Hz, 2H), 7.96 (d, J=7.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 2.83 (t, J=24.6 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28]([OH:30])=O)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([Cl:27])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1.C([O-])(O)=O.[Na+]>C1COCC1>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([Cl:27])[CH:21]=3)[C:28]([N:74]3[CH2:73][CH2:72][CH:71]([N:68]4[CH2:67][CH2:66][N:65]([CH3:64])[CH2:70][CH2:69]4)[CH2:76][CH2:75]3)=[O:30])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1
Reactant: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1Cl
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.21 mmol) of (R)-1-carboxy-2-(3-chloro-4-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 70.0 mg (0.22 mmol) TBTU and 35 μL (0.27 mmol) triethylamine in 10 mL THF was stirred for 1 h at RT. Then 40 mg (0.22 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added and the reaction mixture was then stirred overnight at RT. The reaction solution was stirred with 20 mL semisaturated NaHCO3 solution, extracted twice with 20 mL EtOAc and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (Alox, activity stage II-III DCM/MeOH 40:1).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[CH3:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:41])(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:21]([CH3:35])=[CH:22][C:23]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][C:25]=1[CH3:26])[CH2:16][CH:17]=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: C=CCC(Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1C[C@H](CC=O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 418.3 %

Procedure:
Treat a solution of (R)-4-Benzyl-3-[2-(4-benzyloxy-2,6-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (7.5 g, 16 mmol) in THF (120 mL) and water (40 mL) with 2.5% OsO4 in tBuOH (16 g, 1.6 mmol). Add Sodium periodate (10 g, 47 mmol) to the solution and stir the reaction for 3 hr at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with 1N sodium thiosulfate and brine. Separate the organic, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 3.25 g (43%) of desired product. MS (m/e): 486 (M+1).