Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.[C:17](Cl)(=[O:19])[CH3:18].Cl>C(Cl)Cl>[CH3:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:3]([NH:4][C:17]([CH3:18])=[O:19])[C:2]=1[CH3:1]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(N)c1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C)c1C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv.) and Et3N (1.5 mL, 1.30 equiv.) in CH2Cl2 (15 mL) at 0° C. was added acetyl chloride (0.73 mL, 1.25 equiv.) over 30 min. The reaction mixture was allowed to stir overnight at room temp., then was treated with a 2N HCl solution (10 mL) and CH2Cl2 (25 mL). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organics were washed with a 2N HCl solution (2×25 mL), water (2×25 mL), a saturated NaHCO3 solution (2×25 mL) and a saturated NaCl solution (2×25 mL), dried (Na2SO4), and concentrated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%): 1H NMR (CDCl3) δ2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 6.95 (d, 7.5 Hz, 1H) 7.02 (app t, J=7.5 Hz, 1H), 7.35 (d, J=6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl-].[NH2:16][C:17]1[CH:39]=[CH:38][C:20]([NH:21][C:22]([C:24]2[CH:37]=[CH:36][C:27]([NH:28][C:29]3[CH:34]=[CH:33][N+:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:18]=1.Cl.CO.CCOC(C)=O>CO.CCOC(C)=O>[Cl-:1].[CH3:35][N+:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]([NH:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:38]=3)=[O:23])=[CH:37][CH:36]=2)=[CH:34][CH:33]=1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-6-nitroquinoline (70 mg, 0.33 mmol) in MeOH (10 mL) was added compound D5 (100 mg, 0.28 mmol), and the mixture was stirred at 20° C. for 1 h (until a clear solution obtained). A drop of c.HCl was then added, and refluxing was continued for a further 20 h. TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) showed some D5 remained, so more 4-chloro-6-nitroquinoline (35 mg, 0.16 mmol) was added and refluxing was continued for a further 4 h. The reaction mixture was then diluted with EtOAc and the resulted precipitate was filtered and washed sequentially with EtOAc, CH2Cl2 and diisopropylether, and finally crystallized from MeOH EtOAc to give Cpd. N1 (111 mg, 75%), mp (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ14.50 (br, 1 H, N+H); 11,42, (br s, 1 H, NH), 11.10 (s, 1 H, NH), 10.58 (s, 1 H, NH), 9.82 (d, J=2.1 Hz, 1 H, ArH), 8.72 (dd, J=9.3, 2.2 Hz, 1 H, ArH), 8.60 (d, J=7.0 Hz, 1 H, ArH), 8.42 (d, J=7.4 Hz, 2 H, ArH), 8.24 (d, J=8.6 Hz, 1 H, ArH), 8.15 (d, J=8.6 Hz, 2 H, ArH), 8.04 (d, J=8.8 Hz, 2 H, ArH), 7.51 (t, J=8.3 Hz, 4 H, ArH), 7.34 (d, J=7.5 Hz, 2 H, ArH), 6.91 (d, J=7.0 Hz, 1 H, ArH), 4.01 (s, 3 H, N+CH3); LCMS 489+ve.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.[OH-].[Na+]>[C:1]([CH2:3][C:4]([NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#CCC(=O)Nc1nccs1
Reaction time: 1 h

Procedure:
4.5 g of cyanoacetic acid and 5.3 g of 2-aminothiazole, each in acetonitrile were combined, and the suspension (60 ml) was treated with a solution of 12.0 g of dicyclohexylcarbodiimide in 30 ml of acetonitrile. After exothermic reaction (and solidification) additional acetonitrile (60 ml) was added and the mixture stirred 1 hr and let stand overnight. The collected solid (20 g) was stirred with dilute (ca. 2%) NaOH solution and filtered. The filtrate was acidified with 6 N HCl and the product collected, washed with water, dried (m.p. 229°-230°) and recrystallized from acetone to give 2-(cyanoacetylamino)thiazole, m.p. 231°-2° dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CC(C)=O>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)(=[O:11])=[O:10])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) (4.3 g, 12.8 mmol) was dissolved in acetone (70 mL). Cesium carbonate (8.57 g, 25.6 mmol) and (4-fluorobenzyl bromide (1.76 mL, 14.08 mmol) were added and the mixture was stirred at room temperature overnight. The inorganic salts were filtered off and acetone was removed in vacuo. The residue was re-dissolved in ethyl acetate, washed with water and brine, then the organic layer was dried over magnesium sulfate and concentrated. The crude product was purified by re-crystallization with ethyl acetate/hexanes to afford pure Methyl 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (3.7 g, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): δ, ppm: 3.77 (s, 3H), 3.98 (s, 3H), 4.27 (s, 2H), 4.28 (s, 2H), 6.74 (d, 2H, J=8 Hz), 6.92 (m, 4H), 7.03 (m, 2H), 7.88 (d, 2H J=8 Hz), 8.16 (d, 2H, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]2=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=2)[CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[N:53]1([C:56]2[CH:57]=[CH:58][C:59]([NH:60][C:12]([C:9]3[NH:10][C:11]4[C:6]([C:7](=[O:15])[CH:8]=3)=[CH:5][C:4]([O:16][CH3:17])=[CH:3][C:2]=4[Br:1])=[O:14])=[CH:61][CH:62]=2)[CH2:52][CH2:51][O:50][CH2:55][CH2:54]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1cc(Br)c2[nH]c(C(=O)O)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a yellow suspension of 8-bromo-6-methoxyoxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27a) (3.446 g, 11.56 mmol), TBTU (9.039 g, 28.15 mmol), and HOBt (3.757 g, 27.8 mmol) in 100 mL dimethylformamide was added 4-morpholinoaniline (2.733 g, 15.3 mmol) and diisopropylethyl amine (8.2 mL, 50.2 mmol). The resulting marroon solution was stirred at room temperature under nitrogen for 16 hours during which time the reaction became greenish brown and formed a large amount of precipitate. The reaction mixture was filtered and the solids washed with dimethylformamide, water, and methanol; Drying under high vacuum afforded the desired product as a yellow solid (3.09 g, 58%). 1H NMR (300 MHz, DMSO, d6) δ 12.13 (s, 1 H, NH), 10.18 (s, 1 H, C(O)NH), 7.90 (d, 1 H, Jm=2.7 Hz, ArH5), 7.68 (d, 2 H, Jo=9.0 Hz, ArH2′ & H6′), 7.63 (s, 1 H, C═CH), 7.51 (d, 1 H, Jm=2.7 Hz, ArH7), 7.00 (d, 2 H, Jo=9.0 Hz, ArH3′ & H5′), 3.94 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N); Mass Spec.: calc. for [C21H20BrN3O4+H]+ Theor. m/z=458, 460; Obs.=458, 460.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:1]([CH:8]([CH2:12][NH:21][O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Solvent: CCOCC
Product: O=C(O)C(CNOCc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
A mixture of 2-benzyl-acrylic acid (8.0 g, 55 mmol) and O-benzylhydroxylamine (16.0 g, 130 mmol) was heated at 80° C. for 18 hours. The reaction mixture was cooled, diluted with diethyl ether (100 mL) and extracted with 1M sodium carbonate (3×100 mL). The combined aqueous extracts were acidified with 3M citric acid and then re-extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 2-(R,S)-benzyl-3-benzyloxyamino-propionic acid as a white crystalline solid (7.82 g, 53%). 1H-NMR; δ (CDCl3), 7.61-7.15 (10H, m), 4.66 (2H, d, J=1.7 Hz), 3.13-2.94 (4H, m), 2.84-2.74 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:8]1=[O:20].[Si:28]([O:35][CH2:36][CH2:37][CH2:38]Br)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH2:38][CH2:37][CH2:36][O:35][Si:28]([C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:29])[CH3:30])[C:8]1=[O:20]
Reactant: COc1cc(CN2CCC(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 17.3 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine and 3-t-butyldimethylsilyloxypropyl bromide to give the title compound: Rf=0.52 (silica gel, 1/4 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:33])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: CCCCc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CCCCc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Yield: 41.1 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-butyl-4-isocyanato-benzene (28.8 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a light yellow solid (20.3 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.28 (m, 3H), 7.13-7.10 (m, 2H), 6.36 (br s, NH), 4.30-4.26 (m, 2H), 4.08 (s, 6H), 3.61 (m, 1H), 3.17 (m, 2H), 2.57 (m, 2H), 2.17 (m, 2H), 2.02-1.98 (m, 2H), 1.34 (m, 4H), 0.94-0.80 (m, 3H); LC/MS (ESI): calcd mass 448.3, found 449.3 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)[CH:5]=1.[Li+].[OH-]>CO.C1COCC1>[C:38]([N:30]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:42])=[O:2])=[CH:13][CH:14]=2)=[O:19])[C@@H:21]([CH3:41])[CH2:22]1)(=[O:40])[CH3:39]
Reactant: COC(=O)c1cccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3cccc(C(=O)O)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-benzoic acid methyl ester (93 mg, 0.16 mmol) was dissolved in MeOH/THF (2:1, 3 mL). To this solution was added LiOH (2M in H2O, 2 mL). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to remove MeOH and THF. Then 6N HCl aqueous solution was added to acidify the reaction mixture to pH 2-3. The reaction mixture was extracted with DCM (5 mL×3). The extract was washed with water (15 mL), brine (15 mL) and dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparatory HPLC to afford the product (90 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1>C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:13]2[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1C=CCC1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
4-Bromophenylboronic acid (4 g, 19.92 mmol), Rh(acac)(C2H4)2 (acetylacetonatobis(ethylene)Rhodium (I); 103 mg, 0.4 mmol) and (R)-BINAP (249 mg, 0.4 mmol) were placed in a 100 mL 3-necked round bottomed flask and 1,4-dioxane (40 mL) was added. The reaction vessel was degassed several times before putting under a nitrogen atmosphere. Water (4 mL) was added followed by cyclopent-2-en-1-one (1.185 mL, 14.14 mmol). The reaction mixture was then heated at 100° C. overnight before cooling and washing with saturated aqueous sodium hydrogen carbonate solution (50 mL). The mixture was extracted with EtOAc (2×100 mL) and the organics dried then purified by chromatography eluting with 0-40% EtOAc/isohexane) to give the title compound (1.62 g, 48%) as an oil that crystallised upon standing; 1H NMR δ1.86-1.93 (1H, m), 2.23-2.36 (3H, m), 2.53-2.57 (1H, m), 3.34-3.43 (1H, m), 7.29-7.32 (2H, m), 7.50-7.53 (2H, m); αD=+20° (MeOH, c=1, L=1)
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>C(O)C>[CH3:11][CH:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][PH:2](=[O:4])[OH:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2][O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C[PH](=O)O)CC(C)(C)C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A 2 L 4-neck flask, equipped with thermocouple well, a dropping funnel, overhead stirrer and reflux condenser is charged with 199 grams (1.88 moles) of sodium hypophosphite monohydrate and 500 mL of 2B ethanol. Into the resultant stirred suspension is added via the dropping funnel, 52 mL (1.87 moles) of concentrated sulfuric acid. During the addition the reaction mixture temperature rises from 21° C. to 27° C. After approximately 15 minutes, 100 mL (0.624 moles) of 2,4,4-trimethyl-1-pentene is added, followed by 10.24 g (0.062 moles) of AlBN powder. The reaction mixture is heated at reflux under a nitrogen atmosphere for 20 hours. An additional 6.84 g (0.042 moles) of AlBN powder is added and the mixture is refluxed under nitrogen for another 20 hours. Solvent is removed under vacuum and the residue is partitioned between 400 mL heptane and 1 L of water. The heptane layer is concentrated under vacuum to give 98 grams (88% of theory) of 2,4,4-trimethylpentyl phosphinic acid as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[CH:22][CH:21]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[NH:7][C:6]=2[CH:19]=1>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[CH:24][CH:25]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10][CH2:11][C:12]([OH:14])=[O:13])[NH:7][C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(-c3ccc(-c4ccccc4O)cc3)c(Cl)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CSc1nc2cc(-c3ccc(-c4ccccc4O)cc3)c(Cl)cc2[nH]1

Procedure:
A solution of tert-butyl 2-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)acetate in TFA (0.9 mL) and water (0.1 mL) was stirred at room temperature for 2 h and concentrated. The resultant solid was purified with HPLC to afford the desired product. LCMS: calculated for C21H15ClN2O3S 410.05, observed m/e 411.0 (M+H)+.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)C(=O)OCC3C=CC=CC=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([NH:19][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)=[CH:17][N:18]=[C:13]2[C@:12]([CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@]1(C)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(NCc1cccc(C(F)(F)F)c1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
To a solution of 12c (0.987 g, 1.71 mmol) in 8.6 mL THF at −78° C., was added LiHMDS (1M in THF, 3.59 mL, 3.59 mmol). The red solution was stirred at −78° C. for 10 min, then a solution of t-butyl bromoacetate (0.278 mL, 1.88 mmol) was added. The reaction was allowed to slowly warm to −50° C. over 1 h, then was quenched with the addition of sat. NH4Cl. The mixture was poured into 50 mL H2O and extracted with 100 mL EtOAc. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (50% EtOAc/hexanes) to afford 432 mg (37%) of 92a. 1H NMR (300 MHz, CDCl3) δ8.94 (br s, 1H), 7.51-7.26 (m, 15H), 7.09 (t, J=7.5, 1H), 5.25-5.13 (m, 3H), 5.06 (dd, J=9.4, 6.0, 1H), 4.85 (br s, 2H), 2.89 (dd, J=13.9, 5.8, 1H), 2.80 (ABq, JAB=16.8, δνAB=91.9, 2H), 2.44 (dd, J=13.5, 9.1, 1H), 1.38 (s, 12H); MS (ESI) 713.2 (M+Na+), 689.4 (M−H+).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:50](OC(=O)C)(=[O:52])[CH3:51].C(N(CC)CC)C>ClCCl>[C:50]([NH:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:52])[CH3:51]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNC(C)=O)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate dihydrochloride (230 mg/0.28 mmol), acetic anhydride (0.2 ml/2.1 mmol) and triethylamine (0.5 ml/3.5 mmol) in dichloromethane (5.0 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (50 ml), and then washed with water (10 ml) and brine (10 ml) successively. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/200-350 mesh/20 g/dichloromethane) to give a yellow film (110 mg/53%).
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])[CH3:5].[Cl-].[NH4+].[C:15](OCC)(=O)C>O1CCCC1>[OH:6][C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:15])[CH3:5]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccnc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1

Procedure:
To methylmagnesium bromide (a 0.96 mol/L solution in tetrahydrofuran, 6.26 mL, 5.97 mmol), a solution of 3-acetylpyridine (362 mg, 2.99 mmol) in tetrahydrofuran (3.6 mL) was slowly added under a nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 1. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby 3-(1-hydroxy-1-methylethyl)pyridine (Compound DG) (415 mg, yield: quantitative) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4=[C:24]5[S:30][CH:29]=[CH:28][C:25]5=[N:26][CH:27]=[C:22]4[N:21]=[C:20]3[C@H:31]([OH:33])[CH3:32])[CH2:15][O:14]2)(=O)=O)=CC=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C.CO>[N:34]([CH2:12][C@@H:13]1[O:14][CH2:15][C@@H:16]([N:19]2[C:23]3=[C:24]4[S:30][CH:29]=[CH:28][C:25]4=[N:26][CH:27]=[C:22]3[N:21]=[C:20]2[C@H:31]([OH:33])[CH3:32])[CH2:17][CH2:18]1)=[N+:35]=[N-:36]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN=[N+]=[N-])OC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (25 mg, 0.052 mmol) and sodium azide (5.0 mg, 0.077 mmol) in DMF (0.5 mL) was stirred at 60° C. overnight. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give desired product (12 mg, 65%). LCMS calculated for C16H19N6O2S (M+H)+: m/z=359.1. Found: 359.0.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(C)CC1

Procedure:
3.4 g of methyl chloronicotinate, 5.5 g of potassium carbonate and 2.0 g of N-methylpiperazine were reacted in 50 ml of DMF analogously to Example 1a, 3.9 g (82%) of the product being obtained.