Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CC(C)=O>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 16.3 g of 2-aminobenzamide, 82 ml of saturated aqueous sodium acetate solution and 82 ml of acetic acid was added a solution of 21 g of 4-chlorobenzoyl chloride in 14 ml of acetone. The mixture was stirred at room temperature for one hour after addition was complete. The tan precipitate was collected by filtration and recrystallized from ethanol to give 24.1 g of light tan 2-(4-chlorobenzamido)benzamide, m.p. 205°-207°, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][Cl:25])[N:19]=1>C1COCC1>[Cl:25][CH2:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: c1ccc(CNCc2ccccn2)nc1
Solvent: C1CCOC1
Product: ClCc1cccc(CN(Cc2ccccn2)Cc2ccccn2)n1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
In a 250 ml three-necked flask 1 equivalent of bis(2-pyridylmethyl)amine was dissolved in 100 ml of THF and the solution was admixed with 1 equivalent of 2,6-bis(chloromethyl)pyridine and 4 equivalents of N,N-diisopropylethylamide. The solution was stirred at room temperature for 7 days. The solution was filtered and the filtrate was purified by column chromatography.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH:27]=[O:28])([CH3:23])([CH3:22])[CH3:21].O[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH:27]=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.8 %

Procedure:
Triphenylphosphine (5.89 g, 22.44 mmol) was added to a solution of 3-tert-butyl-4-hydroxybenzaldehyde (4 g, 22.44 mmol) in tetrahydrofuran (40 ml), followed by addition of 2-hydroxyethylmorpholine (2.94 g, 22.44 mmol) and then the dropwise addition of diethylazodicarboxylate (3.91 g, 22.44 mmol). The mixture was allowed to stir at room temperature for 3 days. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (2×150 ml), basified to pH 9 with solid sodium bicarbonate, saturated with solid sodium chloride and extracted with ethyl acetate (3×150 ml). The combined organic layers were dried over magnesium sulfate and concentrated to afford 2.8 g (44%) of 3-tert-butyl-4-(2-morpholin-4-ylethoxy)benzaldehyde as a yellowish oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:21].[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[CH:30][CH:29]=2)[C:25]([CH2:31][C:32]([NH:35][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[O:16][CH2:17][CH:18]([CH3:19])[CH3:20])([CH3:33])[CH3:34])=[CH:26]1
Reactant: CC(C)COc1cc(F)ccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)COc1cc(F)ccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[4-fluoro-2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2-[4-fluoro-2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 155°-156° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)=[N:32][CH:33]=2)O1>>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:31]2[N:32]=[CH:33][C:28]([C:2]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=3)=[CH:29][CH:30]=2)=[CH:35][N:36]=1
Reactant: Nc1nccc(Oc2cc(C(F)(F)F)ccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidin-2-amine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H14F3N7O, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 2H), 8.67 (dd, J=2.3, 0.8, 1H), 7.99 (d, J=5.6, 1H), 7.95 (dd, J=8.3, 2.3, 1H), 7.81 (dd, J=8.2, 0.9, 1H), 7.76-7.69 (m, 2H), 7.59 (s, 1H), 6.18 (d, J=5.8, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:8]=2[N:9]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][N:16]([CH2:31][C:27]4[S:26][CH:30]=[CH:29][N:28]=4)[CH2:17][CH2:18]3)=[CH:10][C:8]=2[N:9]=1
Reactant: O=Cc1nccs1
Reactant: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN(Cc2nccs2)CC1

Procedure:
4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-ol dihydrochloride salt (250 mg) and 2-thiazole-carboxaldehyde (0.08 ml) were stirred together in 1,2-dichloroethane (3 ml) and triethylamine (0.18 ml) with sodium triacetoxyborohydride (187 mg) at room temperature overnight. Dichloromethane/brine extraction and purification on silica yielded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-thiazol-2-ylmethyl-piperidin-4-ol (119 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([C:17]1[CH:57]=[CH:56][C:20]([O:21][C@@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[OH:13][C:14]([C:17]1[CH:57]=[CH:56][C:20]([O:21][C@@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[NH:3][C:4](=[O:7])[O:5][N:49]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogen carbonate (0.58 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-[(4-{cis-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.060 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.055 mL) were added, and the mixture was stirred at room temperature for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 46%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Cl[C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[CH:10]=1.Cl>O.O1CCCC1>[C:3]([CH:2]([C:1]#[N:5])[C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[CH:10]=1)#[N:4]
Reactant: N#CCC#N
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(C#N)C#N)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
To 100 ml of tetrahydrofuran solution containing 6.6 g (0.1 mol) of malononitrile was added 4.0 g (0.1 mol) of 60 wt % sodium hydride under cooling with ice, then 17 g (0.1 mol) of 6-chloro-1,3-dimethyluracil was added thereto and the mixture was stirred for 5 hours at room temperature. The reaction mixture was mixed with 100 ml of water, neutralized with concentrated hydrochloric acid, and thereafter extracted with 200 ml of ethyl acetate. The extract was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crystals thus-deposited were collected by filtration to obtain 12.9 g (63%) of 6-dicyanomethyl-1,3-dimethyluracil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[C:22]=1[CH:23]=[O:24])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[C:22]=1[CH2:23][OH:24])[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cncc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cncc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
To a suspension of 109b (95 mg, 0.106 mmol) at 0° C. in methanol (5 mL) was added sodium borohydride (24 mg, 0.636 mmol) and the mixture was stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 109 (13.5 mg, 18.7%). LCMS: [M+H]+ 681.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
7-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.0 g, 8.62 mmol) and 0.5 g of platinum oxide were added to 100 mL of ethanol and the mixture was shaken under about 50 psi hydrogen at about ambient temperature for about a day. The mixture was filtered and the filtrate concentrated to yield a solid comprising the desired product. Yield 1.64 g (81%) as a yellow solid. FDMS m/e=234 (M+).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:17]([CH:21]=1)[C:18]([NH2:20])=[O:19].C(N(CC)C(C)C)(C)C.CCOCC>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:17]([CH:21]=2)[C:18]([NH2:20])=[O:19])=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: NC(=O)c1cc(N)ccc1N1CCOCC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: NC(=O)c1cc(Nc2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Yield: 64.8 %

Procedure:
In the same way as described in the general procedure for amine displacement using 5,8-dibromo-imidazo[1,2-a]pyrazine (0.131 g, 0.47 mmol), 5-amino-2-morpholin-4-yl benzamide (157 mg, 0.71 mmol), N,N-diisopropylethylamine (0.120 mL, 0.71 mmol) in iso-propanol (3.7 mL). Trituration with tPrOH and Et2O affords the title compound (127 mg, 67%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)=O.CO>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:13][CH3:14])[CH3:11])[N:5]=1)[CH3:2])[CH3:14]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CCc1ccccc1N
Solvent: CO
Solvent: O=CO
Product: CCc1ccccc1N=C(C)c1cccc(C(C)=Nc2ccccc2CC)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of 2-ethylaniline were added to a round-bottom flask with 30 ml of methanol. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 24 hours at 50° C. The flask was then cooled to room temperature and placed in a freezer at −30° C. After 1 day, yellow crystals had formed. The crystals were isolated by filtration and identified by 1H NMR as the desired product (1.25 g, 55.2%). 1H NMR (CDCl3): δ 8.38 (d, 2, Hpyr), 7.86 (t, 1, Hpyr) 7.20 (m, 4, Haryl), 7.07 (t, 2, Haryl), 6.65 (d, 2, Haryl) 2.49 (q, 4, Hbenzyl), 2.35 (s, 6, N—C—CH3), 1.14 (t, 6, CH2CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:23][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:7]([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:8])=[CH:22][C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: Cc1ccoc1C(=O)Cl
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccoc1C(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Reaction time: 3 h
Yield: 47.1 %

Procedure:
A solution of 3-methyl-2-furancarbonyl chloride (9.5 g, 0.066 mole) in toluene (20 ml) was added to 1-methylethyl 5-amino-2-chlorobenzoate (14 g, 0.066 mole) and triethylamine (10 g) in toluene (20 ml). After about three hours at ambient temperature, the mixture was washed with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate and finally water. With cooling, the product (m.p. 99°-100° C., 10 g, 47% yield) was crystallized from toluene.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)[CH2:22][CH2:21]3)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)C.[Li+].[OH-].FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>C1COCC1.CO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:7]2[C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:10][S:9][C:8]=2[C:11]=1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: CCOC(=O)Cc1csc2c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(OC)ccc12
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(CC(=O)O)csc2c1S(=O)(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Compound from step 4 (22 mg, 0.041 mmol) was dissolved in 2 mL of THF/MeOH (3:1), followed by addition of 1N LiOH (5.0 eqv). The resulting mixture were stirred at 40° C. for 3 hours. The organic solvent was evaporated under N2 and residues were diluted with water (2 mL). The aqueous layers were partitioned with ether (2 mL). After removal of organic layers, the aqueous layers were neutralized by 1N HCl (5.0 eqv) and then extracted with ethyl acetate (5 mL). The organic layers were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated in vacuo to afford {6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.38 (s, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.22 (s, 1H), 6.60 (m, 1H), 4.01 (s, 2H), 3.98 (s, 3H), 3.77 (m, 4H), 3.22 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>O>[CH:11]([NH:18][CH2:2][CH2:3][OH:4])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNC(c1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 59 %

Procedure:
In a 500 mL round bottom flask equipped with a condenser and a thermometer, 2-choroethan-1-ol (23.3 grams, 0.39 mol, Kodak), α-aminodiphenylmethane (82.0 grams, 0.45 mol, Fluka), and water (17 mL) were placed. The mixture was heated on a steam bath (ca. 90° C.) for six hours. After cooling to ambient temperature, NaOH (15 grams, 0.37 mol) was added and the mixture heated on a steam bath for 45 minutes at ca. 90° C. Water (50 mL) was then added to the solution. The resulting two-layered mixture was extracted with two 50 mL portions of toluene. The combined toluene extracts were dried over sodium hydroxide pellets and the toluene then removed by rotary evaporation at reduced pressure. The residue was fractionally distilled using a 7.5 inch Vigreux column. The fraction boiling at 175-177° C./2 mm pressure was collected and then recrystallized from hexane. Yield 39.0 g (59% yield). 1H NMR (δ, 360 MHz, CDCl3) 2.32 (bs, 2H, --OH & --NH), 2.74 (m, 2H, --NCH2CH2O--), 3.64 (m, 2H, --NCH2CH2O--) 4.84 (s, 1H, CHPh2) and 7.30 (m, 10H, aromatic H); 13C NMR (δ, 90 MHz, {1H}, CDCl3); 49.5 (--NCH2CH2O--), 61.5 (--NCH2CH2O--) 67.0 (CHPh2), 127.2, 127.3, 128.3 and 147.5 (CHPh2) mp 69-70° C. uncorrected.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC1C=C(O)C=CC=1C.[C:20]1([CH:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[C:29](=[O:37])[C:28]2=[O:38])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[C:39]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[C:29]([OH:37])([C:8]3[C:7]([OH:10])=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)[C:28]2=[O:38])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3,4-dimethylphenol, and 1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (84%): mp 147-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.44-7.20 (m, 11H), 6.90 (s, 1H), 6.79-6.72 (m, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 6.20-6.17 (m, 1H); MS (ES+) m/z 450.1 (M−17).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.C1COCC1.O.Cl>C(OCC)(=O)C.O>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]([OH:23])=[O:4])=[CH:15]1
Reactant: COC(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
LiOH (1.6 g, 67.3 mmol) is added to [2-(1H-indol-3-ylsulfanyl)-phenyl]-acetic acid methyl ester (2 g, 6.73 mmol) in 27 mL mixture of THF/water (20:7). The reaction mixture is stirred for 10 minutes at 150° C. in a Emrys Optimizer EXP microwave reactor under microwave heating and cooled to room temperature. The reaction mixture is poured into water and acidified with concentrated HCl. Ethyl acetate is added and the organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:17])=[O:6]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1OC
Reaction time: 3 h

Procedure:
A 7.00 g portion of 2,4-dimethoxy-5-nitrobenzoic acid was dissolved in 2-butanone, and 9.90 g of potassium carbonate and 3.6 ml of dimethyl sulfate were added, followed by 3 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 5.45 g of methyl 2,4-dimethoxy-5-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 65.8 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.8 g (24.5 mmol) of 2-amino4-methylthiazole to give 4.8 g of title compound as an off- white solid (95% yield, m.p. 188° C.).