Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[S:14][CH:13]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)[C:15]=2[S:14][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCNCC4)ncnc23)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4F)csc23)CC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
30 mg (0.0736 mmol) of 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine was dissolved in 1 ml of dimethylchloride, and 20 (0.147 mmol) of acetyl chloride and 19 μl (0.110 mmol) of diisopropylethylamine were added thereto. The mixture was stirred at room temperature for 13 hr. The resulting mixture was dissolved in ethylacetate and washed with sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain 17 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (46.7 mg, 0.212 mmol) and THF (1.2 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (212 μl, 0.212 mmol, 1M in THF) was added drop wise to give a light yellow solution. The mixture was stirred for 15 min. Then, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.177 mmol) in THF (1.2 mL) was added drop wise. After 1.5 h, more LHMDS (450 μL, 1M in THF) was added at −78° C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride at −78° C. The reaction was warmed to RT. The product was extracted with EtOAc and the organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 20 to 50% EtOAc/Heptane) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (40 mg, 38% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.68 (s, 3H), 3.80 (s, 3H), 5.06 (s, 2H), 6.81 (m, J=8.66 Hz, 2H), 7.21 (m, J=8.66 Hz, 2H), 7.45-7.54 (m, 4H), 7.62 (d, J=7.69 Hz, 1H), 8.13 (dd, J=8.60, 2.08 Hz, 1H), 8.53 (d, J=1.82 Hz, 1H), 13.24 (s, 1H). m/z (ESI) 603.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30]([C:32]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(C2(C(O)=O)CCCC2)=CC=1.S(=O)(=O)(O)O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Li+].[OH-]>CC(C)=O.CO.C(Cl)(Cl)(Cl)Cl.C1COCC1.O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:43][C:40]2[CH:39]=[CH:38][C:37]([C:32]3([C:30]([OH:31])=[O:29])[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:42][CH:41]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CCCC1
Reactant: Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Agent: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccc(COc3cccc(-c4c5cccc(C(F)(F)F)c5nn4Cc4ccccc4)c3)cc2)CCCC1

Procedure:
This compound was prepared similarly to that of Example 525 by treating 3-(2-benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (20 mg, 1 eq) with 1-(4-bromomethyl-phenyl)-cyclopentanecarboxylic acid methyl ester (48 mg, 3 eq) and potassium carbonate (37 mg, 5 eq) in acetone (1.5 mL). The latter reagent was obtained by heating 1-p-tolyl-cyclopentanecarboxylic acid in methanol and a catalytic amount of sulphuric acid. Subsequent α-bromination was accomplished by refluxing the ester (100 mg, 1 eq) with NBS (82 mg, 1 eq) and benzoyl peroxide (5 mg, 3%) in carbon tetrachloride (2 mL) for one hour. The reaction mixture was cooled, water was added and product extracted with dichloromethane. The residue was purified by flash chromatography (ethyl acetate/n-heptane, 1:9, as an eluent). Then the resulting compound was hydrolyzed with aq LiOH (1M, 40 eq)/THF 1:1 and purified by preparative HPLC, affording the desired product in 48% yleld.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[NH2:25]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[NH:25][C:24]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[N:18]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Nc1ccncc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: CCn1c2ccccc2c2cc(-c3nc4cnccc4[nH]3)ccc21
Temperature: 145 °C
Yield: 15.1 %

Procedure:
A mixture of 9-ethyl-9H-carbazole-3-carbaldehyde (444 mg, 1.99 mmol) and 3,4-diaminopyridine (217 mg, 1.99 mmol) in nitrobenzene (1.5 ml) was heated at 145° C. for 24 hours. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (0.1% ammonium hydroxide/5% methanol/dichloromethane) to afford the title compound 5A (94 mg):
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].CS([C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O>O1CCCC1>[OH:4][CH2:3][CH2:2][S:1][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1N[C@H](SCCO)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Under ice-cooling, 2.58 g of 2-mercaptoethanol and 33 ml of 1N sodium hydroxide are added to a solution of 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 150 ml of tetrahydrofuran, and the mixture is stirred for 30 minutes. The solvent is then distilled off under reduced pressure and 150 ml of ethyl acetate is added. The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate-n-hexane (1:2). The earlier eluate fractions are combined and concentrated under reduced pressure to give 5.6 g of (3R,4R)-4-[[2-(hydroxy)ethyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH:11]([OH:13])[CH3:12])[CH:5]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1
Reactant: CC(O)c1cc(OC(F)(F)F)ccc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(OC(F)(F)F)ccc1O
Yield: 85.4 %

Procedure:
In 20 ml of dichloromethane was dissolved 0.85 g (3.83 mmole) of the compound obtained in step 1; and, a suitable amount of Cellite and 1.73 g (4.6 mmole) of pyridinium dichromate were added thereto. The resultant mixture was stirred for 30 minutes at room temperature and filtered by a Cellite layer to obtain precipitates, which were purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate of 6:1 and then concentrated under reduced pressure at 0° C. to obtain 0.72 g (yield 85%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][NH:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][NH:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CNCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 60 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylamino-ethyl)-amide (28 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N-methyl-ethylendiamine (25 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 466. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (br, 1H), 8.20 (br, 1H), 7.95 (s, 1H), 7.88 (m, 1H), 7.69 (m, 2H), 7.56 (d, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 3.59 (s, 3H), 3.44 (m, 2H), 2.98 (m, 2H), and 2.70 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:28]=[CH:27][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:22][C:23]([F:26])([F:25])[F:24])[N:16]=[C:17]([CH2:19][O:20]C)[N:18]=1)[N:7]=3.[OH-].[K+]>Br>[Cl:1][C:2]1[N:28]=[CH:27][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:15]([CH2:22][C:23]([F:26])([F:25])[F:24])[N:16]=[C:17]([CH2:19][OH:20])[N:18]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: COCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Agent: Br
Agent: [K+]
Agent: [OH-]
Product: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 100 °C
Yield: 3.5 %

Procedure:
A suspension of 8-Chloro-2-[5-methoxymethyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (500 mg, 1.20 mmol) in 48% aqueous HBr (2.1 mL) was sealed and heated at 100° C. for 3 h while carefully monitoring by LCMS. The mixture was cooled to room temperature and poured over a cold solution of 10% KOH. The solid was collect by filtration (˜90% purity by LCMS and 1H NMR analysis). The solid was used in subsequent steps without purification. A small amount was purified by HPLC to give 17 mg of 387. LCMS: 401.0. 1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.11 (s, 1H), 7.24 (s, 1H), 5.81 (q, J=8.9 Hz, 2H), 5.34 (t, J=6.0 Hz, 1H), 4.71-4.57 (m, 4H), 4.46 (d, J=6.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[N:42]1(C(Cl)=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:25])[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)N3CCOCC3)CC2)cc1

Procedure:
The title compound, MS: m/e=613.2 (M+H+), [α]58920=−10.99 (c=0.4369, chloroform), was prepared in accordance with the general method of example 102 (part1) and example 38 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and 4-morpholine carbonyl chloride.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20](N)[CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CCCCO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc([C@H](C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 160 °C
Yield: 64.6 %

Procedure:
To phthalimide (1.3 g, 0.0088 mol) in a 2-5 mL microwave vial was added (S)-1-(4-methoxyphenyl)ethan-1-amine (2.20 mL, 0.015 mol) and K2CO3 (1.2 g, 0.0087 mol). The reaction mixture capped and heated at 160° C. for 2 minutes. The resulting crude solid was suspended in n-BuOH and was filtered. The filtrate was put aside. The solid was washed with H2O and the filtrate was discarded. The solid was washed with CH2Cl2 and the resulting filtrate was partitioned with H2O. The organics (n-BuOH and CH2Cl2 layer) were combined and concentrated. The crude residue was purified by silica gel column chromatography using CH2Cl2 as eluent to yield 1.6 g (64%) of the title compound. LC/MS: m/z (ES+) 282 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (106 mg, 90%), MS (ISP) m/z=471.4 [(M+H)+], mp 122.5° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20]C)=O.[CH3:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29](OCC)=[O:30])[N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[C:28]([N:25]3[CH:26]=[CH:27][C:23]([CH3:22])=[N:24]3)[C:29](=[O:30])[NH:1]2)=[CH:4][C:5]=1[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)Cn1ccc(C)n1
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccn(-c2c(O)c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
To a solution of methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate, (Intermediate 47) (416 mg, 1.365 mmol) and ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (Alinda Chemical Ltd, 275 mg, 1.638 mmol) in THF (8.4 mL) stirred under nitrogen at room temperature was added KHMDS 1M/THF (4.09 mL, 4.09 mmol) The reaction mixture was stirred at room temperature for 20 min before being quenched with MeOH, evaporated in vacuo and taken up in water (10 mL). The aqueous layer was acidified to pH=6-7 and filtered. The precipitate obtained was washed with acetonitrile, then with diisopropyl ether and filtered to give the title compound 7-chloro-6-(4-(dimethylamino)phenyl)-4-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)quinolin-2(1H)-one (415 mg, 73.2% yield) as a light yellow powder. LCMS: (M+H)+=395; Rt=2.68 min. HRMS: calculated for C21H20ClN4O2 (M+H)+: 395.1275. found: 395.1283.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:22])[CH2:15][O:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][CH2:11]1>C(Cl)(Cl)(Cl)Cl>[C:13]([O:12][CH2:11][C:10]([CH3:9])([CH3:22])[CH2:15][Br:1])(=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)COC(c2ccccc2)OC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CBr)COC(=O)c1ccccc1
Temperature: 24 °C
Yield: 91.6 %

Procedure:
N-Bromosuccinimide (20.7 g) was added to a stirred solution of 5,5-dimethyl-2-phenyl-1,3-dioxane (19.2 g) in 200 mL of CCl4 containing 8.5 g of BaCO3 in suspension. The mixture was heated to reflux under Ar for 2.2 h, then cooled to 24° C. over 15 h, filtered and concentrated. The residue was partitioned between ether and water, and the ethereal solution was washed with brine, dried (MgSO4), filtered and concentrated to give 24.8 g of a yellow oil which was stored in the dark at 0° C. under Ar.
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:41])[CH2:9][CH2:10][C@@H:11]([C:27](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+]>C1COCC1>[CH:1]1([O:7][C:8](=[O:41])[CH2:9][CH2:10][C@@H:11]([CH2:27][OH:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[N:14]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCC(=O)OC2CCCCC2)C(=O)N2C(=O)OC[C@H]2c2ccccc2)COC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H](CO)CCC(=O)OC2CCCCC2)COC1(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (8.12 g, 13.9 mmol, 1.0 equiv) was dissolved in a 4:1 mixture of THF:MeOH (150 mL) and the solution cooled to 0° C. Solid NaBH4 (1.05 g, 27.8 mmol, 2.0 equiv) was added in ca 200 mg portions over a 20 min period. The solution was stirred at 0° C. for 4 h. During this time two additional 500 mg portions of NaBH4 were added. After this time LC/MS analysis showed consumption of the starting material. The excess hydride reagent was quenched by the addition of 10,% citric acid. The mixture was diluted with ca 100 mL of EtOAc and the organic layer separated. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The alcohol was purified by flash chromatography on silica, (120 g), eluting with 0-41% EtOAc in hexanes. This afforded 5.2 g (90% yield) of (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a clear syrup. MS ESI +ve m/z 436 (M+Na).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:11]1[C:12]([F:22])=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[N:17]=[CH:16][CH:15]=[CH:14]2)C(OCC)=O)C.[OH-].[Na+].Cl>C(O)C>[F:22][C:12]1[C:11]([CH2:5][C:4]([OH:23])=[O:3])=[C:20]([F:21])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc2ncccc2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1c(F)cc2ncccc2c1F
Yield: 70 %

Procedure:
To a round-bottom flask containing 2-(5,7-difluoro-quinolin-6-yl)-malonic acid diethyl ester (2.48 g, 7.68 mmol) were added ethanol (77 mL) and 10% aqueous NaOH (103.2 mL). The solution was refluxed for 3 h. After such time the ethanol was removed under reduced pressure to form a yellow suspension and tetrahydrofuran (50 mL) was added to give a clear yellow solution which was placed in an ice bath and stirred. 6N Hydrochloric acid (50 ml) was slowly added to the solution to reach pH 1. The light orange solution was refluxed for another hour, at which time two layers formed. The top tetrahydrofuran layer was collected and the aqueous solution was extracted with dichloromethane. The organic layers were brined and dried with anhydrous sodium sulfate. The solution was then filtered and the filtrate was concentrated to obtain the title compound (1.20 g, 70.1%). 1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.98˜9.00 (m, 1H), 8.47˜8.50 (d, 1H), 7.61˜7.74 (m, 2H), 3.86 (s, 2H). ES-MS m/z: 224.2 (M++1).
Reaction SMILES: [O:1]([C:8]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH:9]([O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=1)[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[O:1]([C:8]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:25])[CH:9]([O:14][C:15]1[N:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[N:20]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(Oc2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
1.3 g of methyl 3-phenoxy-3-phenyl-2-(4,6-dimethoxy-2-pyrimidinyl)oxybutyrate (Example 6 change to 42) are dissolved in 20 ml of MeOH and 40 ml of THF, and 3.7 g of 10% NaOH solution are added. The mixture is stirred at 60° C. for 6 hours and at room temperature for 12 hours, the solvent is removed by distillation under reduced pressure, and the residue is taken up in 100 ml of water. Unreacted ester is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. Drying over magnesium sulfate and removal of the solvent by distillation result in 1.0 g of a white powder.