Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[N:21]([CH2:25][CH3:26])[N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].C1COCC1.C(O)(C)C>O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[N:21]([CH2:25][CH3:26])[N:20]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:41])([CH3:40])[CH3:42]
Reactant: CCn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
A mixture of 118c (80 mg, 0.13 mmol), lithium hydroxide (13 mg, 0.53 mmol), THF (6 mL), i-propanol (4 mL) and water (2 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and diluted with water (5 mL). It was then extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 118 (20 mg, 26%) as a white solid. MS-ESI: [M+H]+ 558.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.50 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 5.88 (s, 1H), 4.92 (t, J=5.0 Hz 1H), 4.46-4.45 (m, 2H), 3.91 (q, J=7.5 Hz, 2H), 3.59 (s, 3H), 2.19 (s, 3H), 1.40 (s, 9H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:29]=[C:30]=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:30](=[O:31])[NH:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) is added dropwise under a nitrogen atmosphere to a solution of 2-phenylphenol (5.0 g, 29.3 mmol) and octyl isocyanate (5.5 g, 35.5 mmol) in 75 mL of methylene chloride. After the addition, the solution is stirred overnight at room temperature. The solution is washed with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.09 g of a tan solid. Recrystallization from diisopropyl ether-hexane gives the title compound as a white crystalline solid (6.88 g, 72%), mp 59°-60° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[O:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13]1)[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enol (3.00 g, 6.95 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (100 mL) is added followed by dry pyridine (1.10 g, 13.90 mmol). Ethyl chloroformate (3.02 g, 27.80 mmol) is added slowly and the reaction mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 mL) and 10% citric acid (200 mL). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 2:1). 1H nmr (CDCl3, 400 MHz); 7.70 (br s, 1H), 7.35-7.15 (m, 10H), 6.35 (m, 1H), 6.15 (m, 1H), 5.80 (m, 1H), 5.65 (m, 2H), 4.35 (t, 1H), 4.25 (m, 2H), 4.20 (q, 2H), 3.10 (m, 1H), 1.95 (d, 1H), 1.30 (t, 3H), MS (ES+) m/e 504 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1([CH3:22])[CH2:15][C:14]2[NH:13][CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:10]=2[CH2:9][CH2:8]1.[OH-].[K+].CN(C)[CH:27]=[O:28]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][C:11]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:22])([CH3:6])[CH2:15][C:14]=2[NH:13][C:12]=1[CH:27]=[O:28]
Reactant: CN(C)CCCc1c[nH]c2c1CCC(C)(C)C2
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.5 mL, 5.1 mmol) was added dropwise to ice-cooled dimethylformamide (1.1 mL, 14.1 mmol) and then stirred at room temperature for 30 minutes. A solution of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-dimethyl-amine (1.1 g, 4.6 mmol) in dimethylformamide (2 mL) was added dropwise at −5° C. The mixture was stirred at room temperature overnight. Ice cubes were added to the reaction mixture followed by the addition of 10 N potassium hydroxide to pH 11–12 and stirring for one hour. The mixture was extracted with ethyl acetate and the extract washed with brine and concentrated. The residue was chromatographed (5%-10% methanol in dichloromethane) to give 650 mg of 3-(3-dimethylamino-propyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a brown solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.25 (br s, 1H, NH), 9.41 (s, 1H, CHO), 2.62 (t, 2H, CH2), 2.36 (t, 2H, CH2), 2.30 (s, 2H, CH2), 2.21 (t, 2H, CH2), 2.12 (s, 6H, 2×CH3), 1.60 (m, 2H, CH2), 1.46 (t, 2H, CH2), 0.93 (s, 6H, 2×CH3). MS m/z 262 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH:42]([N:45]([CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47][NH2:48])([CH3:44])[CH3:43]>C(Cl)(Cl)Cl.O>[CH:42]([N:45]([CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47][NH:48][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[O:40])([CH3:44])[CH3:43]
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (74 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 33%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1)[CH3:2].[S:11]1[CH2:17][C:15](=[O:16])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[C:12]1=[S:13].[Cl-].[NH4+].N>C(O)C>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=[C:17]2[S:11][C:12](=[S:13])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15]2=[O:16])[N:8]=1)[CH3:2]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCNc1nc(C=O)cs1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCNc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Yield: 84.8 %

Procedure:
The reaction described in Example 1 was repeated, but using 1.27 g of 2-ethylaminothiazole-4-carbaldehyde, 1.3 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 30 ml of ethanol, giving 1.9 g of the title compound as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.O1CCCC1.Cl[CH2:43][CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>O>[CH3:22][C:21]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:24]4[CH2:28][CH2:27][O:26][C:25]4=[O:29])=[CH:3][C:2]=3[N:1]3[CH2:43][CH2:44][CH2:45][S:46]3(=[O:48])=[O:47])=[O:9])[CH2:15][CH2:14]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N)CC2)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-{3-amino-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (93.1 mg) described in Example 133, triethylamine (63 μL) and tetrahydrofuran (1 mL) was added 3-chloropropanesulfonyl chloride (38 μL), and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the residue were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (42 μL) and DMF (1 mL), and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the residue was added a mixed solvent of isopropyl ether and ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (62.1 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:29](O)(=[O:32])[CH:30]=[O:31]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]2[O:11][C:30](=[O:31])[CH:29]([OH:32])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)ccc1O
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)cc2c1OC(=O)C2O
Yield: 99.6 %

Procedure:
18.7 g of 4-tert-butyl-2-(1 -methylpentadecyl)phenol, 5.06 g of glyoxylic acid monohydrate and 0.05 g of p-toluenesulfonic acid are heated for 7 h under a water separator in 40 ml of 1,2-dichloroethane. The reaction solution is then cooled down, washed 3 times with 80 ml of water each time and freed of solvent in a rotary evaporator to leave 21.4 g of 5-tert-butyl-3-hydroxy-7-(1-methylpentadecyl)-3H-benzofuran-2one as a yellowish oil. This yellowish oil is introduced in 25 ml of toluene as initial charge together with 8 ml of thionyl chloride and 3 drops of DMF and then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively, but still controllable. The reaction mixture is then stirred at 100° C. for a further 1 h. About 25 ml of liquid are subsequently distilled off to remove excess thionyl chloride. The residue is diluted with 80 ml of toluene and admixed at room temperature with 7 ml of triethylamine added dropwise. The thick red reaction mixture is then refluxed for 30 min. The precipitated triethylamine hydrochloride is filtered off after cooling down to room temperature, and the filtrate is concentrated to an oily consistency in a rotary evaporator. The residue is chromatographed over silica gel (hexane:ethyl acetate 99:1) to isolate the isoxindigo as a waxy red material, obtaining 4.1 g (20% of theory, based on 4-tert-butyl-2-(1-methylpentadecyl)phenol) of 5,5′-di-tert-butyl-7,7′-bis(1-methylpentadecyl)-[3,3′]bibenzofuranylidene-2,2′-dione of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:12]1[O:22][C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH:10][CH:18]1[CH2:19][CH2:20][C:15]2([O:22][CH2:12][CH2:13][O:14]2)[CH2:16][CH2:17]1)=[O:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)c1sc(Br)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.4 %

Procedure:
A suspension of 3-Amino-5-bromo-thiophene-2-carboxylic acid methyl ester (1.03 g, 4.38 mmol) in dry THF (1.1 ml) was treated with 1,4-cyclohexanedione monoethylene ketal (684 mg, 4.38 mmol), followed by dibutyltin dichloride (133 mg, 0.44 mmol). After 5 min, phenyl silane (877 μL, 4.8 mmol) was added and the reaction mixture was stirred at room temperature for 2 days when a clear solution resulted. The solution was then concentrated and the residue purified by silica gel column chromatography using EtOAc:hexanes as eluent to furnished 5-Bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (1.11 g, 68% yield). 1H NMR (CDCl3, 400 MHz): 6.90 (br s, 1H), 6.65 (s, 1H), 3.95 (s, 4H), 3.78 (s, 3H), 3.35 (m, 1H), 2.00 (m, 2H), 1.80 (m, 2H), 1.65 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.CCN(CC)CC.[CH3:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:33]([O:32][CH3:31])=[O:34])[CH2:15][C:13]=2[N:14]=1
Reactant: COC(=O)Cl
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) (2.16 g, 2.0 mmol) in DMF (10 ml), was added Et3N (560 uL, 4.0 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of methylchloroformate (186 uL, 2.4 mmol) followed by stirring at room temperature overnight. The reaction mixture was basified (with 2M NaOH) before partitioning between water (25 ml) and DCM (50 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo, affording the title compound as a brown solid used without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH3:24]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:24])=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Product: NC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12

Procedure:
Following standard procedure C, the acetate salt of methyl 2-(3′-trifluoromethylphenyl)-1-H-benzimidazole-4-carboxylate (134.8 mg, 0.358 mmol) was treated with excess liquid ammonia in a sealed vessel. The product was purified by recrystallisation from methanol, to yield off-white needles. (78 mg, 72%). mp 268-270° C.; Found C 57.68 H 3.82 N 12.96 C15H10F3N3O.0.6CH3OH Requires C 57.74 H 3.82 N 12.95; vmax(cm−1) 3488.83, 3348.86, 3176.45, 1667.66, 1600.93, 1329.63; δH 7.44-7.52 (1H, t), 7.88-8.04 (5H, m), 8.66-8.70 (1H, d), 8.70 (1H, s, 2′ H), 9.3 (1H, br s, NH), 13.6 (1H, br s, NH); m/z (EI) 305 (M+), 288, 260, 145.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][NH:51][CH2:52][C:53]1[CH:64]=[CH:63][C:56]([CH2:57][N:58]2[CH2:61][CH:60]([OH:62])[CH2:59]2)=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:51]([CH2:52][C:53]3[CH:54]=[CH:55][C:56]([CH2:57][N:58]4[CH2:61][CH:60]([OH:62])[CH2:59]4)=[CH:63][CH:64]=3)[CH3:50])=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (35 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([O:11][CH3:12])[CH:4]=1)[CH3:15]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(N)c(OC)c1

Procedure:
To a solution of 3.343 g (20 mmole) of 4-amino-3-methoxybenzoic acid in 200 mL EtOH is bubbled a stream of HCl gas for three minutes. The HCl saturated solution is stirred at room temperature for two days. Solvent is evaporated under vacuum and the resulting residue is dissolved in 100 mL water. The water layer is basified with K2CO3 and extracted with CH2Cl2 (3×200 mL). The combined CH2Cl2 layer is washed with saturated NaHCO3 (200 mL), brine and then dried over MgSO4, filtered and evaporated under reduced pressure to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:32]([O:34]CC)=[O:33])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:32]([OH:34])=[O:33])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C(=O)O)(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (200 mg, 0.37 mmol) and lithium hydroxide monohydrate (88 mg, 3.7 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid in 67% yield (150 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88 (m, 2H); 1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([C:15]([NH:14][C:12]2[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]3[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6][C:7]=3[CH:13]=2)=[S:16])[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reactant: CC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(C(=S)Nc2cc3sc(C(C)(C)C)nc3cc2N2CCC(C)CC2)CC1

Procedure:
A solution of 2.0 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole and 0.78 g of 1-acetyl-piperazine in 30 ml of chloroform is stirred for 30 minutes and the product triturated with petroleum ether to obtain 6-[(4-acetyl-piperazin-1-yl)thiocarbonylamino]-2-tert-butyl-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 187°-190°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1.[CH:42]([NH2:45])([CH3:44])[CH3:43]>CS(C)=O>[CH:42]([NH:45][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:9]=2)[N:3]=1)([CH3:44])[CH3:43]
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: CC(C)N
Solvent: CS(C)=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a solution of 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.85 mmol) in DMSO (5 mL) was added isopropylamine (60 mg, 1.02 mmol). The mixture was stirred at 110° C. for 12 h. The reaction was quenched with ice cold H2O and was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with flash chromatography (basic alumina, eluting with 30-40% EtOAc in Hex) to give 5-(3-(4-(isopropylamino)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (220 mg, 52%). MS (ESI, pos. ion) m/z: 609.6 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H), 8.39 (s, 1H), 8.23 (m, 1H), 8.12 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.79-7.57 (m, 5H), 7.43 (d, J=8 Hz, 2H), 7.312 (d, J=8 Hz, 3H), 6.90 (d, J=8 Hz, 2H), 4.38 (m, 3H), 3.72 (s, 3H), 2.32 (s, 3H), 1.17 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]C)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17].C(OCC)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[NH:17][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(-c2ccc(F)cc2)n[nH]1

Procedure:
A mixture of methyl 3-(4-fluorophenyl)-3-oxopropanoate (10.0 g, 0.051 mol) and hydrazine hydrate (1.1 eq, 2.8 g, 0.056 mol) in 20 mL glacial acetic acid is heated 3 h under reflux. The resulting suspension is cooled down and 10 mL diethyl ether is added. The precipitate is filtered off, dried in vacuo and 9 g (100%) of 3-(4-fluorophenyl)-1H-pyrazol-5-ol are obtained as white solid.