Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:34])[CH3:33]
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and acetyl chloride (0.023 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-acetylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (84 mg, 75%) as an oil. Rf: 0.15 (EtOAc) LC/MS (APCI) tr=3.78 min, m/z 409.31 (67), 407.36 (M++H, 100). HPLC tr=2.69 min (96.74%) 1H NMR (270 MHz, CDCl3) δ 1.38 (2H, m, CH2), 2.00 (2H, m, CH2), 2.08 (3H, s, CH3), 2.84 (1H, m, ½CH2), 3.74 (1H, m, ½CH2), 4.18 (1H, m, CH), 4.41 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.88 (1H, d, J=8.6 Hz, ArH), 7.22 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.26 (1H, m, ArH), 7.37 (1H, br s, NH), 7.41 (1H, m, ArH), 7.51 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][Br:11]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1cccc(Cl)c1
Solvent: CC#N
Product: Clc1cccc(CCBr)c1
Yield: 92.5 %

Procedure:
According to Scheme 11, a solution of 3-chlorophenethyl alcohol (5 g, 32 mmol) in 50 mL of dry MeCN was treated with dibromotriphenylphosphorane (13.54 g, 32 mmol) for 24 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was triturated with hexane and filtered. Evaporation of the solvent provided 6.5 g of 3-chlorophenethyl bromide. A solution of the bromide (6.5 g, 29.6 mmol) in 50 mL of dry DMSO containing NaCN (2.17 g, 44 mmol) was heated to 100° C. overnight. The reaction mixture was diluted with water and extracted with ether. The ether layer was washed with water, dried and the solvent was removed in vacuo. Chromatography (silica gel, hexane:ethyl acetate, 4:1) provided 3.7 g of nitrile 89.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][CH3:26])=[O:24])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2nc(Cl)ncc2F)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (1 g, 5.98 mmol) in isopropanol (18 mL, 3 mL/mmol) was added DIPEA (1.6 mL, 8.9 mmol) and 3-amino-N-methylbenzamide (900 mg, 5.98 mmol) and the mixture was heated at 80° C. for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL) and water (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-N-methylbenzamide (800 mg, 50%) as a solid. Observed mass (M+1): 281.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9].O.O.[I-:13].[Na+]>[Cu]I.CNCCNC.O1CCOCC1>[I:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9]
Reactant: C[C@H](O)c1ccccc1Br
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)c1ccccc1I
Temperature: 150 °C
Reaction time: 16 h
Yield: 240.4 %

Procedure:
To each of three identical Emrys microwave reaction vessels was added (S)-1-(2-bromophenyl)ethanol (1.67 g, 8.3 mmol), CuI (189 mg, 1.0 mmol), 1,4-dioxane (12.4 ml), N,N′-dimethylethylenediamine (0.18 ml, 1.7 mmol) and sodium iodide dihydrate (3.1 g, 16.6 mmol). Each vessel was sealed and heated in an Emrys microwave reactor to 150° C. for 2 h. On cooling, the mixtures were combined and partitioned between water (20 ml) and EtOAc (20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was taken up in isohexane (50 ml) and the solution held at −15° C. for 16 h to afford (S)-1-(2-iodophenyl)ethanol as a white crystalline solid (4.95 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Ic1ccccc1
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert iodobenzene and 4-methoxybenzenethiol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (410 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.27 (dt, J=8.85, 2H; Ha, Ha′), 7.12–6.96 (m, 5H; HC, Hc′, Hd, Hd′, He), 6.75 (dt, 2H; Hb, Hb′), 3.67 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 159.76 (C4), 138.56 (C8), 135.32 (C2, C6), 128.86 (C9, C13), 128.10 (C10, C12), 125.68 (C11), 124.19 (C1), 114.92 (C3, C5), 55.27 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.26; H, 5.59; S, 14.65.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:22](/[S:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:26])([F:11])[F:25])=[CH:18][CH:17]=2)(=[O:21])=[O:20])\[C:23]#[N:24])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 4-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[4-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([CH2:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])=[O:30]
Reactant: CCc1cccc(CC)c1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The dimethyl acetal of 2-(2,6-diethylanilino)acetaldehyde (13.0 grams), sodium carbonate (5.8 grams) dissolved in water (50 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (6.2 ml) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2,6-diethylanilino)acetaldehyde.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25](O)=[O:26])[C@H:22]([C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C@:39]1([C:44]([O:46][CH3:47])=[O:45])[CH2:41][C@H:40]1[CH:42]=[CH2:43].[Si](O[C@H]1C[C@@H](C(OC(C)(C)C)=O)[C@H](C(=O)N(CCCCC=C)C)CC1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([NH:38][C@:39]2([C:44]([O:46][CH3:47])=[O:45])[CH2:41][C@H:40]2[CH:42]=[CH2:43])=[O:26])[C@H:22]([C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Agent: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C

Procedure:
Compound 41 was synthesized from compound 40 and (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate as described for compound 39 to yield compound 41 as a yellow oil in 76% yield. MS (ESI, EI+): m/z=645 (MH+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:22](=[O:23])([O:9][C:8]([C:7]1[CH:6]=[N:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=1)=[O:10])[O:24][CH2:25][CH3:26]
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC(=O)c1cncc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of 5-(trifluoromethyl)nicotinic acid (10.0 g, 52.3 mmol) in THF (250 mL) was added triethyl amine (7.18 mL, 52.3 mmol) at room temperature, then ethyl chloroformate (4.98 mL, 52.3 mmol) was added dropwise at 5° C. slowly. The reaction was stirred for 1 hour to give ethyl [5-(trifluoromethyl)pyridin-3-yl]carbonyl carbonate. NaBH4 (1.702 g, 45.0 mmol) was added to the mixture portionwise at −78° C. followed by addition of MeOH (100 mL) over 30 minutes. The reaction was warmed to 0° C. and stirred overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate=2/1 to give the title compound (5.7 g, 62% yield) as a yellow oil. MS: 178.0 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.92 (d, J=0.4 Hz, 1H), 4.77 (s, 2H), 2.34 (brs, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])C.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Cl)cc1=O
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.925 g, 4.29 mmol) in a 4:1 mixture of THF:MeOH (20 mL) was added a 1 M solution of LiOH (8.6 mL). After stirring for 30 minutes, the reaction mixture was acidified to pH 1 with 10% HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 0.732 g t91%) clean desired product.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:25]4[CH:30]=[CH:29][N:28]=[C:27]5[N:31]([CH2:35][C:36]6[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=6)[N:32]=[C:33]([I:34])[C:26]=45)=[C:18]([F:23])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(CC2CCCCC2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(CC6CCCCC6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Reaction time: 96 h
Yield: 86 %

Procedure:
A mixture of 2-(cyclohexylmethyl)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (0.026 g, 0.082 mmol), 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.033 g, 0.083 mmol; prepared according to the procedure of Example 84, Step D), and DMAP (0.020 g, 0.165 mmol) in bromobenzene (1 mL) under N2 was stirred at 150° C. for 4 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The desired product (0.048 g, 86%) was obtained as a pale yellow solid. LRMS (APCI pos) m/e 680 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[NH2:11][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH2:13][OH:12])[CH:15]=[CH:16][CH:17]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Nc1cc(Cl)n2nccc2n1
Product: Nc1cc(-c2cccc(CO)c2)n2nccc2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, MeOD) δ ppm 4.72 (s, 2H) 6.27-6.31 (m, 1H) 6.47 (s, 1H) 7.56 (t, J=7.58 Hz, 1H) 7.62 (d, J=7.58 Hz, 1H) 7.84 (d, J=7.33 Hz, 1H) 7.91-7.97 (m, 2H).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.Cl.[C:15]1([CH:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[C:15]1([CH:21]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[CH:5]=[CH:4]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: ClC(c1ccccc1)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=Cc1ccc2ccn(C(c3ccccc3)c3cccc(/C=C/c4ccc5ccccc5n4)c3)c2c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Powdered potassium hydroxide (0.50 g, 8.93 mmol) was added to a stirred solution of indole-6-carboxaldehyde (Example 29a) (0.54 g, 3.70 mmol) in dimethyl-sulphoxide (10 ml). The solution was stirred under nitrogen for 10 minutes then solid a-phenyl-3-[2(E)-(quinolin-2-yl)ethenyl]benzyl chloride hydrochloride (Example 16a) (1.75 g, 4.46 mmol) was added and then stirred mixture was heated at 60° C. for 4 hours. The mixture was poured onto ammonium chloride solution and extracted with dichloromethane and the extract was dried and evaporated. The residue was chromatographed on silica in ethyl acetatehexane (1:3) to give a gummy solid which was recrystallised from ether-hexane, m.p. 75° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38].C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[CH3:46][S:47]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 90.7 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (178 mg, 0.280 mmol) was dissolved in dichloromethane (6 mL), and the solution was treated with triethylamine (0.156 mL, 1.12 mmol) and methanesulfonyl chloride (0.043 mL, 0.56 mmol), followed by purification by slurry using hexane to obtain 4-methanesulfonyloxy-5-methyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (152 mg, yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]Cl)[CH:19]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:24][C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH:13]4[CH2:15][CH2:14]4)[CH:23]=[CH:22][N:21]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1cc(OCC2CC2)ccn1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Yield: 82.5 %

Procedure:
To 5-fluoro-2-mercapto-1H-benzimidazole (0.88 g, 0.0051 mol) in methanol (25 ml) NaOH (0.2 g, 0.0051 mol) dissolved in H2O (1 ml) and 4-cyclopropylmethoxy-2-chloromethylpyridine hydrochloride (0.91 g, 0.0046 mol) dissolved in methanol (10 ml) were added in the given order. The mixture was heated to boiling and NaOH (0.2 g, 0.005 mol) dissolved in H2O (1 ml) was added and the mixture was refluxed for 1 hour. After evaporation of methanol, CH2Cl2 (75 ml) and H2O (50 ml) were added and pH adjusted to 10. The mixture was vigorously stirred, the phases were separated, the organic phase was dried over Na2SO4 and evaporated giving the desired product (1.25 g, 72%). NMR data for the product is given below.
Reaction SMILES: [P:1]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH:11]([F:13])[F:12])=[O:2].[Br:20]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[P:1]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:20])=[CH:6][C:5]=1[CH:11]([F:13])[F:12])=[O:2]
Reactant: CCOP(=O)(OCC)Oc1ccc(C)cc1C(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)Oc1ccc(CBr)cc1C(F)F
Temperature: 80 °C
Yield: 69.8 %

Procedure:
200 mg of 2-(difluoromethyl)-4-methylphenyl diethyl phosphate (4C) was added to a solution of N-bromosuccinimide (254 mg) in benzene (10 mL), followed by the addition of benzoyl peroxide (3.2 mg). The reaction mixture was refluxed at 80° C. for about 48 hours and then cooled to room temperature and the succinimide residue removed by filtration. The filtrate was then washed successively with an aqueous solution of sodium bicarbonate, water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Subsequent flash column chromatography afforded a light yellow oily liquid (177 mg, 70%): 1H-NMR (CDCl3, 500 MHz) δ 7.7 (s, 1H), 7.6 (d, J=8.4 Hz, 1H), 7.3 (d, J=8.4 Hz, 1H), 6.8-6.9 (t, J=5.6 Hz, 1H), 4.5 (s, 2H), 4.2 (q, 4H), 1.3 (t, J=7.1 Hz, 6H) (FIG. 11). 13C-NMR (CDCl3, 50 MHz) δ 138.8, 130.4, 124.9, 120.4, 110.6, 65.1, 38.5, 15.9 (FIG. 12). 31P-NMR (CDCl3, 81 MHz) δ −6.57. 19F-NMR (CDCl3, 188.3 MHz) δ −116.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH:29]=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[C:33]1=[O:47].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:34]4[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:32]([CH3:31])[C:33]4=[O:47])[CH2:42][CH2:43]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
To a stirred solution of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6 mmol) in CH2Cl2 (20 mL) were added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirred for 20 min. NaBH(OAc)3 (0.65 g, 30.6 mmol) was added and stirred under nitrogen for 2 h. Saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C34H41F3N6O3, 638.32. m/z found, 639.3 [M+H]+, 661.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][S:6]([NH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=[O:13])(=[O:8])=[O:7].[OH-].[K+].Cl>C(O)C.O>[OH:13][CH:12]([C:11]1[CH:14]=[C:15]([CH:16]=[CH:17][C:10]=1[NH:9][S:6]([CH3:5])(=[O:8])=[O:7])[C:18]([O:20][CH3:21])=[O:19])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C(O)C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Nitromethane (1.22 g, 0.02 mol) was added to an ice-cooled mixture of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde (2.57 g, 0.01 mol) in ethanol and the mixture stirred for 10 min. To this mixture was added potassium hydroxide (1.23 g, 0.022 mol in 20 mL 90% ethanol) at 0° C. over a period of 20 min. The reaction mixture was further stirred at 0° C. for 0.5 h and then at room temperature for 4 h. The mixture was neutralized with 2N HCl and poured in water (100 mL). The mixture was extracted with chloroform, dried over sodium sulfate, filtered, and concentrated. The residue was passed through a column of silica gel eluting with chloroform:methanol (99:1 to 95:5). The desired pure fractions were combined, concentrated, recrystallized from ethyl acetate-hexane, and dried to give 0.8 g (25%) of methyl 3-[1-(R,S)-hydroxy-2-nitroethyl]-4-[(methylsulfonyl)amino]benzoate as off-white crystals, mp 148° C.