Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])#[N:22]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccc(C#N)c2)c1
Yield: 49.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (193 mg, yield: 49.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1Cl)=[O:5])[CH3:2].[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C([O-])([O-])=O.[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]#[N:13])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scnc1Cl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1Oc1cccc(C#N)c1
Temperature: 80 °C
Yield: 39.1 %

Procedure:
A stirred of 665 mg (3.5 mmol) 4-chloro-thiazole-5-carboxylic acid ethyl ester, 416 mg (3.5 mmol) 3-cyanophenol, 2.4 g (7.3 mmol) Cs2CO3 and 60 mL dimethylformamide was warmed to 80° C. in an oil bath for 72 hours. The mixture was then cooled, poured into 70 mL water, and extracted with ethyl acetate (3×40 mL). The combined extracts were washed with water (2×50 mL), brine (1×50 mL), dried over Na2SO4, and concentrated via rotary evaporation. The resulting oil was chromatographed on a Biotage Flash 40S® silica column, loaded with methylene chloride and eluted with 20% ethyl acetate/80% hexanes to give 375 mg of a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[N:3]1.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl.[OH-].[K+]>C(O)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[C:20]2[CH2:21][CH2:22][NH:17][CH2:18][CH:19]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc3[nH]ccc3c2)n1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nnc(-c2ccc3[nH]cc(C4=CCNCC4)c3c2)n1
Temperature: 25 °C

Procedure:
A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][CH2:3][CH:23]([C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(C)=O
Reactant: CCCSc1ncc(CCCl)n1Cc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCCSc1ncc(CCC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 71 %

Procedure:
The procedure of Example 3(iv) was followed using 5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazole hydrochloride in place of 5-chloromethyl-1-[(2chlorophenyl)methyl]2-propylthio-1H-imidazole hydrochloride. The title compound was obtained in 71% yield after chromatography over silica gel with a gradient of ethyl acetate in methylene chloride.
Reaction SMILES: N1CCC[CH2:2]1.C([Li])CCC.[CH3:11][CH2:12][C@@H:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CI>C1COCC1>[CH3:11][CH2:12][C:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])([CH3:2])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C1CCNC1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: [Li]CCCC
Agent: [O-]B([O-])c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: -57.5 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
A 2L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyllithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at a temperature between −20 and −25° C. over a period of 1 hour. The solution was maintained at this temperature for 30 minutes and then cooled to −55 to −60° C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to a temperature of −50° C. and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between −50 and −55° C. during the addition. The reaction was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below −55°C. The reaction was stirred for 13 hours at −15 to −20° C. and then quenched with 500 mL of 2M HCl at a temperature below 0° C. After warming to 20° C., the layers were separated and the aqueuous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110° C. for 3 hours and then cooled to −5 to −10° C. for 1 hour. The product was filtered and washed with 25 mL of −5° C. acetonitrile and dried under vacuum to provide 43.7 g of simvastatin phenylboronate at >99% purity by HPLC.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1>ClS(O)(=O)=O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Following the general procedure of Example 6 but making non-critical variations, 9α-hydroxyandrostenedione (20.00 g.) is reacted with chlorosulfonic acid (10 ml.) at a reaction temperature of 1°-11°. Upon workup the reaction gives androsta-4,9(11)-diene-3,17-dione, 17.94 g., (89.7% weight yield, 95.2% chemical yield); m.p. 201°-204.5°; [α]D +217° (chloroform); UV (methanol) λmax = 240 nm (ε = 16,300).
Reaction SMILES: [CH:1]1([C:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CNC(=O)C1.[Br:24][Br-]Br.CCOCC>O1CCCC1>[Br:24][CH2:9][C:8](=[O:10])[C:7]([OH:17])([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CBr)C(O)(c1ccccc1)C1CCCCC1
Yield: 1158.9 %

Procedure:
1-Cyclohexyl-1-hydroxy-1-phenyl-2-propanone (2.83 g, 12.2 mmole) was added to 50 mL of dry tetrahydrofuran (THF). The solution was stirred and a solution of pyrrolidone hydrotribromide (6.08 g, 12.3 mmole) in 125 mL of dry THF was added dropwise over a period of 2 hours. After being refluxed for 4 hours, the reaction mixture was cooled. Ether was added and the solution washed twice with water and dried over magnesium sulfate. Upon evaporation of the solution to dryness, an orange oil was isolated. The product was purified by flash column chromatography (silica, hexane/ethyl acetate (99:1 followed by 95:5) to afford 3-bromo-1-hydroxy-1-cyclohexyl-1-phenyl-2-propanone (1 44 g, 37.7%). NMR (CDCl3) 1.0-2.0 (m, 10 H), 2.4 (m, 1 H), 3.5 (s, 1 H), 4.1 (s, 1 H), 7.2-7.6 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([O:10]C)=O)[C:5](=O)[CH2:4][CH2:3]1.Cl.[Cl:15][CH2:16][C:17](=[NH:19])[NH2:18].C[O-].[Na+]>CO>[Cl:15][CH2:16][C:17]1[N:19]=[C:8]([OH:10])[C:6]2[CH2:7][C:2]([CH3:1])([CH3:13])[CH2:3][CH2:4][C:5]=2[N:18]=1
Reactant: COC(=O)C1CC(C)(C)CCC1=O
Reactant: N=C(N)CCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCc2nc(CCl)nc(O)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate (6.0 g, 33 mmol) and 2-chloroacetimidamide hydrochloride (4.6 g, 36 mmol) in methanol (30 mL) was added sodium methoxide (4.4 M in MeOH, 9.0 mL, 40 mmol). The reaction mixture was stirred at ambient temperature for three hours and then concentrated. The resulting residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by silica gel chromatography provided 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (4.2 g, 57% yield) as a white solid. MS (ES) for C11H15ClN2O: 227 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]([NH:23][CH3:24])=[O:22]>>[CH3:26][C:25]([CH3:28])([CH3:27])[C@H:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:21](=[O:22])[NH:23][CH3:24]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0) as starting materials and isolated (115 mg, 52%) as a white solid; MS (ESI, m/z): 388.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1c2ccccc2oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.54 mL, 3.21 mmol) was added slowly to a solution of, 1,3-dihydroxyxanthen-9-one (689 mg, 3.02 mmol) and pyridine (7.3 mL) in CH2Cl2 (30 mL) at 0° C. The reaction then was allowed to slowly warm to RT and stirred for 16 h. The orange mixture then was dissolved in CH2Cl2 (100 mL), and washed with 10% citric acid (2×25 mL) and brine (1×25 mL). The organics were dried (Na2SO4), concentrated, and purified by Biotage chromatography using 10% EtOAc/hexanes as eluent to yield 702 mg (65%) of trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9H-xanthen-3-yl ester as a light yellow solid. Rf=0.65 (50% EtOAc/hexanes). See R. Pillai et al., J. Org. Chem., 51, pages 717-723 (1986). 1H NMR (DMSO-d6, 400 MHz) δ: 12.90 (s, 1H), 8.20 (d, 1H), 7.96 (dd, 1H), 7.70 (d, 1H), 7.56 (dd, 1H), 7.37 (m, 1H), 7.05 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CCN(CC)CC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])#[N:9]
Reactant: Cc1nsc(N)c1C#N
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1snc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (5.31 g, 38.2 mmol) in DCM (200 mL) at 0° C., NEt3 (5 g, 50 mmol) was added followed by the dropwise addition of a solution of the butyryl chloride (4.88 g, 45.8 mmol) in DCM (50 mL). After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was washed with water (100 mL), 1N HCl (100 mL), brine (200 mL) and dried over Na2SO4. Concentration of the DCM layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate the pure N-(4-cyano-3-methyl-isothiazol-5-yl)-butyramide (7.57 g, 95%) as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC(=O)[NH:35][C:36]1([CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][CH:44]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([CH2:41][O:42][C:43]2[CH:44]=[CH:45][C:46]([CH2:49][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC3(N)CCCC3)cc2)c1
Yield: 61 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:12][C:13]([N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][O:27][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:16][CH2:17]1)=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)c(CN(C(=O)OC(C)(C)C)C3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
Et3N (2.56 mL, 18.4 mmol) and DMAP (153 mg, 1.23 mmol) were added to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (4.00 g, 12.3 mmol) in CH2Cl2 (110 mL) at 0° C. A sol. of p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) in CH2Cl2 (18 mL) was added dropwise, and the mixture was stirred for 3 days while warming up to rt. The mixture was partitioned between CH2Cl2 and water, and the aq. layer was extracted with CH2Cl2 (3×). The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 8:2) yielded the title compound (4.90 g, 83%). LC-MS: tR=1.13 min; ES+: 480.53.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([SH:22])[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([S:22][CH2:20][CH3:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: CCS
Product: CCCCOC(=O)c1nc(SCC)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
52 mg of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, Example D-20c, was dissolved in 2 ml of ethanethiol and heated in a sealed tube at 70° C. for 24 h, and 1000 C for 48 h. The resultant solution was concentrated under vacuum and the residue (54 mg) was purified by chromatography on silica gel using a gradient of 0 to 20 percent ethyl acetate in hexanes to elute the product. 25 mg of product was obtained; MS (+): m/z 306.06 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:47])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C@@H:17]([NH:39]C(OC(C)(C)C)=O)[CH2:18][S:19]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C(O)=O)(F)(F)F.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:47])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C@@H:17]([NH2:39])[CH2:18][SH:19]
Reactant: Cc1cccc(NC(=O)[C@@H]2CCCN2C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)c1C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)[C@@H]2CCCN2C[C@@H](N)CS)c1C
Reaction time: 2 h

Procedure:
N-[2(R)-t-butoxycarbonylamino-3-triphenylmethylmercapto-propyl]-L-proline-2,3-dimethylphenyl amide (0.124 g, 0.19 mmol) was dissolved in CH2Cl2 (3 mL) and CF3CO2H (1 mL) at ambient temperature, treated with triethylsilane (0.121 mL, 0.76 mmol) and stirred for 2 h. Thereaction mixture was concentrated, triturated with 0.1% aq TFA soln, the solid precipitate filtered off, and the filtrate lyophilized to provide the title compound. 1H NMR (CD3OD) δ 7.10 (s, 3H), 3.55-3.68 (m, 1H), 3.32-3.45 (m, 2H), 2.75-3.19 (m, 5H), 2.5-2.65 (m, 1H),2.31 (s, 3H), 2.15 (s, 3H), 1.9-2.15 (m, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1COCC1>[CH:11]1([NH:16][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC2CCCC2)nc1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
6-Fluoronicotinic acid (300 mg, 2.13 mmol) and cyclopentylamine (0.84 mL, 8.50 mmol) were combined in anhydrous THF (5 mL) and triethylamine (0.59 mL, 4.25 mmol). The mixture was heated at 60° C. for 3 days. The mixture was concentrated under reduced pressure, and the residue was suspended in water. The aqueous mixture was brought to pH 3 with phosphoric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried in a vacuum oven for 1 h at 50° C. to give the title compound as a solid (63 mg, 14%): HPLC MS RT=1.14 min, MH+=207.2; 1H NMR (DMSO-d6) δ: 12.29 (1H, broad s), 8.50 (1H, d), 7.73 (1H, dd), 7.29 (1H, d), 6.42 (1H, d), 4.16 (1H, broad s), 1.90 (2H, m), 1.67 (2H, m), 1.53 (2H, m), 1.43 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-(1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chlorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (64 mg, 54%).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2nc3ccc4c(OCc5ccccc5)cccc4c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (80 mg), sodium hydroxide (34 mg) and benzyl bromide (100 μL) in ethanol (2 mL) was heated to reflux for 4 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with dilute acid, dried (MgSO4) and the solvent removed in vacuo to yield the crude title compound as a brown solid (50 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(C2OCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a tetrahydrofuran (200 mL) solution of 4-[1,3]dioxolane-2-ylbenzaldehyde (6.32 g, 35.5 mmol) described in Manufacturing Example 73-1-1, aniline (2.08 mL, 35.5 mmol) and acetic acid (10.2 mL, 178 mmol) was added sodium triacetoxyborohydride (15 g, 71 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.16 g, 46%).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>COC(C)(C)C>[CH3:9][S:10]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: C#CC(O)(CF)CF
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: C#CC(CF)(CF)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and methanesulfonyl chloride (0.85 ml) were dissolved in tert-butyl methyl ether (15 ml); to the solution under cooling with ice, triethylamine (1.5 ml) was added dropwise in a nitrogen atmosphere. After the end of the dropwise addition, the solution was stirred for 1.5 hours under cooling with ice. To the reaction mixture, tert-butyl methyl ether was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.9 g).