Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27]([OH:29])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CCCCCCC.CCOC(C)=O>[C:16]([O:20][C:21](=[O:22])[NH:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:26]([C:27](=[O:29])[N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:25]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-tert-butoxycarbonylamino-5-trifluoromethyl-benzoic acid and using a gradient of n-heptane:EtOAc (100:0 to 0:60) for the chromatographic purification. Light brown solid (4%). MS (ESI): m/z=486.20 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]CC(C)C)=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O-:23].[Na+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)COC(=O)C(C)(C)CCCCl
Reactant: Cc1ccc(C)c([O-])c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1
Yield: 80 %

Procedure:
subsequently reacting said 2-methylpropyl 5-chloro-2,2-dimethylpentanoate with sodium 2,5-dimethylphenolate under reflux in a solvent comprising a mixture of from 10 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide to 5 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide, hydrolyzing the resulting ester, and thereafter acidifying the mixture and isolating 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid;
Reaction SMILES: [SH-:1].[Na+].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=1>CN(C)C=O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[S:1])=[C:15]([CH3:21])[CH:14]=1
Reactant: [SH-]
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)ccc1C(N)=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.1 %

Procedure:
To a slurry solution of sodium hydrosulphide (2.80 g, 50 mmol) and magnesium chloride hexahydrate (5.05 g, 25 mmol) in dimethylformamide (50 ml) is added 4-bromo-2-methyl benzonitrile (4.90 g, 50 mmol) in one portion and the resulting green slurry is stirred at room temp for 90 minutes. The reaction mixture is poured onto water (200 ml) and the resultant precipitate filtered and washed with water. This yellow solid is then suspended in 2N HCl (200 ml) and stirred for 1 hour, then filtered, washed with water and hexane and dried in vacuo to give 4-bromo-2-methyl-thiobenzamide (820 mg).
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5](F)[CH:4]=1.C(C1C=CC(C(N)=O)=CC=1)#[N:17]>>[NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: N#Cc1ccc(C(N)=O)cc1
Product: NC(=O)c1ccc(C(N)=NO)cc1
Yield: 94 %

Procedure:
The title compound was obtained following procedure described for Intermediate 1 step 2 but starting from 4-cyanobenzamide (396.1 mg, 2.71 mmol) (60° C. for 24 h). Solvents were removed under vacuum, solid residue was triturated in water, filtered and dried under vacuum to give the title compound as a white solid (460 mg, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 9.78 (bs, 1H), 7.98 (bs, 1H), 7.87-7.84 (m, 2H), 7.74-7.72 (m, 2H), 7.38 (bs, 1H), 5.88 (bs, 2H).
Reaction SMILES: [S:1]1[C:12]2[C:11]3[NH:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15].[C:19](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14]([NH:13][C:2]1[S:1][C:12]2[C:11]3[N:10]([CH3:19])[CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:15])[CH3:18]
Reactant: CCNC(=O)Nc1nc2c(s1)-c1[nH]ccc1CC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2c(s1)-c1c(ccn1C)CC2
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(5,8-dihydro-4H-[1,3]thiazolo[4,5-g]indol-2-yl)-N′-ethylurea in toluene is added DDQ (1.1 eq.). The reaction mixture is stirred at about 45° C. for about 4 hrs. The reaction mixture is pumped down and the crude material is purified by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.C1OC1C>CN(C)P(=O)(N(C)C)N(C)C>[CH2:17]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Reactant: CCCCCCBr
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-8-nitroquinoline (22 g, 0.1 mole), n-hexyl bromide (18.5 g, 0.11 mole), triethylamine (1 g) and hexamethylphosphoric triamide (16 ml) was maintained at a bath temperature of 120°-130° while 10 g of propylene oxide was added during 0.5 hr. The mixture was heated at a bath temperature of 130°-145° for 3 hr and 5 more grams of propylene oxide was added. After 8 hr at 110°-120°, a low-boiling fraction was distilled off at 100° (1 atm) and the residue was cooled and poured into 3 liters of ice water. The resulting dull red solid was filtered and extracted with diethyl ether (2.5 g of 5-hydroxy compound was recovered as a diethyl ether-insoluble red solid). The ether extract was washed with dilute sodium hydroxide and water, dried (sodium sulfate) and concentrated to leave a thick oil. Trituration with petroleum ether (bp 20°-40°) gave 19.5 g (65%) of the required 5-hexoxy-quinoline derivative as a tan solid, mp 46°-49°. Crystallization from aqueous methanol (carbon) provided an analytical sample as yellow needles, mp 53°-55°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[O:29][C:30]2[C:31](=[C:33]([C:37](O)=[O:38])[CH:34]=[CH:35][CH:36]=2)[CH:32]=1.[OH-].[Na+]>O.CO>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:30]3[O:29][C:28]([CH3:27])=[CH:32][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cc2c(C(=O)O)cccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3oc(C)cc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-benzofuran-4-carboxylic acid which was synthesised by saponification of the corresponding methyl ester derivative (Ishikawa T. et al. Heterocycles 1994, 39, 1, 371-380) with NaOH in a mixture water/MeOH.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][CH2:6][CH2:7][O:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38][CH3:39])[CH2:12][CH2:11][CH2:10]1>C(O)C>[CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38][CH3:39])[CH2:12][CH2:11][CH2:10]1)=[S:4]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2OC)c2ccc(Cl)cc21

Procedure:
0.13 ml of methyl isothiocyanate was added to 20 ml of a suspension of 0.5 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol. The mixture was refluxed for 3 hours. The reaction mixture was subjected to vacuum distillation to remove ethanol. The residue was mixed with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol =50/1) to obtain 0.46 g of 5-(2-methylaminothiocarbonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:19]([CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)#[N:20]
Reactant: N#CCBr
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 2.11 g (10 mmol) 3,3-diphenylpropylamine (Aldrich), (0.54 g, 4.54 mmol) bromoacetonitrile (Aldrich), and 2.5 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 1.24 g (yield 50%) N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR (CDCl3, 300 MHz) 7.45–7.10 (m, 10 H), 4.05 (t, 1 H), 3.50 (s, 2 H), 2.67 (t, 2 H), 2.23 (dt, 2H); 13C NMR (CDCl3, 75 MHz) 144.25, 128.53, 127.68, 126.33, 117.72, 48.58, 47.13, 37.19, 35.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=O)[C:5]2[CH:6]=[C:7]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[N:8]=[CH:9][C:10]=2[CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][CH2:55][CH2:56][OH:57]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:20]([NH:54][CH2:55][CH2:56][OH:57])=[O:22])[C:5]2[CH:6]=[C:7]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: NCCO
Reactant: O=C(O)c1cc(F)cc2cnc(N[C@H]3CC[C@H](O)CC3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(NCCO)c1cc(F)cc2cnc(N[C@H]3CC[C@H](O)CC3)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7-fluoro-3-[(trans-4-hydroxycyclohexyl)amino]isoquinoline-5-carboxylic acid (23.0 mg, 0.076 mmol) in 5 ml DMA was treated with HATU (62.1 mg, 0.16 mmol) and triethylamine (49.5 mg, 0.49 mmol). After 1 hour, 2-aminoethanol (15.0 mg, 0.25 mmol) was added and the solution was heated to 50° C. for 2 hours. The reaction was monitored by LC/MS to show no start acid left. The solvent was removed under vacuum and the crude was dissolved in CH2Cl2 and washed with 1 M NaHCO3 aqueous. The organic layers were dried over MgSO4. The crude material after removal of the solvent was purified by prepHPLC to give 5.8 mg (yield 19.3%). 1H NMR (400 MHz, MeOD) ppm 1.21-1.56 (m, 4H), 1.87-2.20 (m, 4H), 3.48-3.67 (m, 4H), 3.77 (m, 2H), 7.02 (s, 1H), 7.46-7.69 (m, 2H), 8.78 (s, 1H). HRMS: m/z 348.17226[M+H]+), calc. 348.17180. MS m/z, (APCI); 348.2 ([M+H]+).
Reaction SMILES: [CH3:1][SH:2].[OH-].[K+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1>CN(C)C=O.C(O)C>[CH3:1][S:2][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
28.3 g of methylmercaptan are dissolved in 500 ml of dimethylformamide at 0° C., under nitrogen. 37.4 g of potassium hydroxide, dissolved in 150 ml of ethanol, are then added dropwise at -10° C., after which 94.5 g of 4-chloronitrobenzene are added. The reaction mixture is warmed to 100° C. and stirred at this temperature for 8 hours. It is then stirred into 5 kg of ice water. The precipitate is filtered off with suction, washed, dried and recrystallised from methanol. Yield: 86.2 g of yellow crystals of melting point 71°-73.5° C.
Reaction SMILES: [C:1]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[O-]CC.[Na+].[C:32]1([CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:41][CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: ICCCCc1ccccc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CCCCc1ccccc1)(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Ethyl 2-carboethoxy-4[4'-(4"-chlorophenyl)phenyl]-4-oxobutanoate (0.40 g, 1.02 mmol) was added in one portion at rt to a solution of sodium ethoxide (0.08 g, 1.12 mmol) in DME (1 mL). After 15 min, 4-phenyl-1-iodobutane (0.24 g, 0.93 mmol) in DME (3 mL) was added. The resulting solution was stirred for 18 h. The solvent was concentrated in vacuo and the resulting oil dissolved in CH2Cl2 (100 mL) and washed with water (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (10% to 25% ethyl acetate) as the eluent to afford a crystalline solid which was recrystallized with hexane and ethyl acetate to afford 1-[4'-(4"-chlorophenyl)phenyl]-3,3-dicarboethoxy-1-oxo-7-phenylheptane (0.272 g, 28%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:33]([S:35][CH2:36][CH2:37][NH2:38])[CH3:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][NH:38][CH2:37][CH2:36][S:35][CH2:33][CH3:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCSCCN
Reactant: O=Cc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCSCCNCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carbaldehyde (0.31 g), 2-(ethylsulfanyl)ethanamine (0.14 g), acetic acid (1 drop) and tetrahydrofuran (2 mL) was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (4 mL), and sodium borohydride (28 mg) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.37 g, quantitatively) was obtained as a yellow oil from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH2:12](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][CH:7]1[CH:4]2[CH2:3][CH2:2][CH:1]1[CH2:6][CH2:5]2
Reactant: CCOCC
Reactant: O=C(O)CC1C2CCC1CC2
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask was placed bicyclo[2.2.1]hept-7-yl-acetic acid (554 mg, 3.95 mmol), diethyl ether (20 mL) and methanol (5 mL) and cooled to 0° C. in an ice bath. The mixture was then treated with a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (3.95 mL, 7.9 mmol) dropwise. After the addition was complete, the mixture was warmed to 25° C. and stirred for 1 h. The mixture was concentrated in vacuo to afford bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (theoretical yield 3.95 mmol) which was used on crude. Bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (3.95 mmol) in diethyl ether (10 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (224 mg, 5.9 mmol) in diethyl ether (20 mL) cooled to 0° C. The mixture was stirred for an additional 3 h at 0° C. and quenched with a saturated sodium sulfate solution (15 mL), extracted with diethyl ether (3×20 mL). The combined organics were dried over sodium sulfate, concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) to afford bicyclo[2.2.1]hept-7-yl-methanol (180 mg, 36%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[CH:7]2.[O:13]1CCOCC1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[N:8]=[CH:7]2
Reactant: Cc1ncc2cccc(O)c2n1
Reactant: C1COCCO1
Product: O=Cc1ncc2cccc(O)c2n1
Temperature: 80 °C

Procedure:
A solution of 8-hydroxy-2-methyl-quinazoline (A3) (5 mmol) in dioxane (10 mL) was added dropwise over 3 h into a stirred mixture of SeO2 (8.8 mmol) in dioxane (30 mL) at 50° C. The resulting mixture was then heated at 80° C. for 16 h, allowed to cool, and the solids filtered off. The filtrate was concentrated and purified via column chromatography on silica (dichloromethane/MeOH, 40:1). This afforded 8-hydroxy-quinazoline-2-carboxaldehyde (2) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>ClCCl>[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22]([N:23]2[CH2:24][CH2:25][N:26]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:27][CH2:28]2)=[O:29])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(S(=O)(=O)c2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
2-Chlorobenzenesulfonyl chloride (35.4 mg, 0.17 mmol) was added at 0° C. to a stirred solution of N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (60 mg, 0.17 mmol) and DIEA (24.6 mg, 0.19 mmol) in dichloromethane (2 mL). the resulting mixture was stirred for 2 hrs then the product was extracted with dichloromethane. The organics was separated and washed with saturated sodium bicarbonate solution, followed by brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography using silica gel 60-120 mesh with 60% ethyl acetate in hexane as eluant to afford 30 mg (36%) of N-Biphenyl-4-yl-3-[4-(2-chloro-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.12 (M+1)+ 96.7%. 1H NMR: (CDCl3): δ 9.6 (s, 1H), 8.06 (d, 1H), 7.56 (m, 8H), 7.42 (t, 3H), 7.34 (t, 1H), 3.78 (t, 2H), 3.7 (t, 2H), 3.48 (s, 2H), 3.38 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:7]CC)=O)C.[CH3:11][N:12]([C:14]([NH2:16])=[S:15])[NH2:13].C[O-].[Na+].CO>C(Cl)Cl>[CH3:11][N:12]1[C:14](=[S:15])[NH:16][C:4](=[O:3])[C:5](=[O:7])[NH:13]1
Reactant: CN(N)C(N)=S
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1[nH]c(=O)c(=O)[nH]c1=S
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
Under anhydrous condition, 35 g of diethyloxalate is added, dropwise, to a vigorously stirred solution of 21 g of 2-methyl-3-thiosemicarbazide, 32.4 g of fresh sodium methoxide, and 750 ml of methyl alcohol. The resulting suspension is heated at 60° C. for 4 hours, stirred overnight at room teperature, and heated at 70° C. for 15 hours. The white suspension is cooled to room temperature, 200 ml of ice water is added andthe reaction concentrated in vacuo. The residue is cooled to 0° C. and made acidic with 2N hydrochloric acid. The reaction mixture is concentrated, ethyl alcohol is added and the suspension is heated to boiling. The white precipitate is collected, washed with hexane and dried to give 11 g of the crude product. Eight grams of the crude product is heated in methylene chloride and filtered while hot. The collected solid is resuspended in methyl alcohol and a solution of 4N potassium-2-ethyl hexanoate is added. The mixture is cooled to 0° C. and the precipitate collected. The solid is dissolvd in water, filtered, and 2N hydrochloric acid is added to the clear 0° C. solution. The resulting precipitate is collected and dried to give 4.1 g of the pure product. 13C NMR(CDCl3):δ 44,145, 150.115, 152.559, 169.786.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=O.[OH:24][C:25]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:26]=1[NH2:27]>ClCCl.O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH:27][C:26]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=1[OH:24])=[O:23]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Nc1cc(Cl)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1Cl)Nc1cc(Cl)ccc1O
Reaction time: 1.5 h

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (66.5 g, 0.41 mol) and dichloromethane (300 ml) was added 2-chlorophenylacetic acid (67.0 g, 0.39 mol) dissolved in dichloromethane (200 ml). The mixture was stirred for 1.5 hours and 2-hydroxy-5-chloroaniline (56.4 g, 0.39 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and the mixture was filtered to give the desired amide. The dichloromethane was separated and washed with water. Evaporation of the dichloromethane under reduced pressure afforded additional product which was triturated with a small amount of dichloromethane and combined with the material collected previously to give 108.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)[C:5]([O:7][CH3:8])=[O:6].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[O:22])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1C=O
Yield: 58.1 %

Procedure:
20 g (0.070 mol) of methyl 2-(bromomethyl)phenylglyoxylate O-methyloxime, 32 g (0.237 mol) of N-methylmorpholine N-oxide monohydrate and 300 ml of CCl4 are mixed and heated to reflux. After refluxing for 9 hours, the mixture is filtered, and the organic phase is washed with water and with 2 N hydrochloric acid, dried and concentrated. The residue is recrystallized from pentane. 9.0 g of product (58%) are obtained as colorless crystals.