Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 3-(1,1′-biphenyl-4-yloxy)azetidine hydrochloride (100 mg, 382 μmol) in dichloromethane (2.5 mL) was added triethylamine (63 μL, 48 mg, 478 μmol) followed by phenyl isocyanate (35 μL, 38 mg, 320 μmol) and the reaction stirred at room temperature for 2.5 hours. The mixture was loaded directly onto a 2 g pre-packed SCX-2 cartridge and the product eluted with 1:1 dichloromethane:methanol (15 mL). The solvents were evaporated to give the urea (113 mg, 100%) as a white powder; LCMS retention time 2.57 minutes, m/z 345.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ8.54 (s, 1H), 7.62 (d, 4H, J=7.6 Hz), 7.50 (d, 2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.23 (t, 2H, J=7.8 Hz), 7.98-7.91 (m, 3H), 5.09 (m, 1H), 4.46-4.42 (m, 2H) and 3.95-3.91 (m, 2H).
Reaction SMILES: CC(C)(C)C(=O)CC(OCC)=[O:6].[CH2:13]([C:16]1([C:32]([CH3:35])([CH3:34])[CH3:33])[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1)[CH:14]=[CH2:15]>>[CH2:13]([C:16]1([C:32]([CH3:33])([CH3:35])[CH3:34])[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1)[CH:14]=[CH2:15].[Br:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]2[CH2:18][CH2:17][C:16]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH2:13][CH2:14][CH2:15][OH:6])[O:21][C:20]2=[O:22])[CH3:24])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Agent: C=CCC1(C(C)(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC(CCCO)(C(C)(C)C)OC1=O

Procedure:
6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-tert-butyl-1,3-oxazinan-2-one was prepared from ethyl 4,4-dimethyl-3-oxopentanoate following procedures analogous to those described in Example 207 Steps 1 to 8. The title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-tert-butyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 78. Two isomers were isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:3]=12.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(Cl)nc[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A solution of 2.35 g (12.9 mmol) of 4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 60 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 2.20 g (12.9 mmol) of benzylbromide and 0.31 g (12.9 mmol) of sodium hydride in 20 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 20 mL of 2 M sodium hydrogen sulfate and then extracted with 70 mL of ethyl acetate. The organic phase was dried with sodium sulfate and concentrated to 4.0 g of off-white solid. The solid was purified by flash chromatography using (100 g of silica gel, methylene chloride) to provide 1.53 g (43%) of 4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.32 (t, J=7.4 Hz, 3H), 2.67 (q, J=7.4 Hz, 2H), 5.49 (s, 2H), 6.40 (s, 1H), 7.04 (d, J=7.0 Hz, 2H), 7.28 (m, 3H), 8.60 (s, 1H)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34]([C:38](=[N:40]O)[NH2:39])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([C:38]2[N:40]=[C:28]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:30][N:39]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Product: Cc1cc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.22 mmol) of the compound from Example 170A and 51 mg (0.33 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 60 mg (50% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:39](=[O:41])=[O:40].Cl>O1CCCC1.C1CCCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:39]([OH:41])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1ncn2Cc1ccccc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Reaction time: 1 h
Yield: 26 %

Procedure:
Compound 35a (3.95 g, 9.90 mmol) obtained in Example 35 was dissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50 mol/L solution (9.9 mL) of lithium diisopropylamide (14.9 mmol, 1.5 equivalents) in cyclohexane at −78° C., and then the mixture was stirred for 1 hour. Into the reaction solution was poured carbon dioxide generated from dry ice and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1 mol/L aqueous hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5 to 10:1). To the residue were added acetone and diethyl ether, and the deposited crystals were collected by filtration to obtain (R)-1,8-dibenzyl-2-carboxy-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 47a, 1.13 g, 26%). To Compound 47a (740 mg, 1.67 mmol) was added thionyl chloride (10.0 mL, 137 mmol, 82 equivalents) and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and then to the reaction residue was added methanol (3 mL). The mixture was concentrated and the residue was directly purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound (211 mg, 28%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(/C=C/c1ccc2c(c1)C(=NOCc1ccccc1)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH2Ph (94 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was cooled down to RT and evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-benzyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (55 mg) as a 70/30 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.CO[CH:14](OC)[CH2:15][CH:16](OC)OC>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:16]=[CH:15][CH:14]=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of (4-methoxyphenyl)hydrazine hydrochloride (8.0 g, 0.046 mol) and 1,1,3,3-tetramethoxypropane (8.3 g, 0.05 mol) in ethanol (120 mL) was heated to reflux for 1 hour. The reaction was then cooled to room temperature and concentrated. The residue was diluted with saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-(4-methoxyphenyl)-1H-pyrazole (7.7 g, 97%) as a yellow oil. 1H NMR (400 MHz, CDCl3, δ): 7.82 (m, 1H), 7.69 (m, 1H), 7.59 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 6.43 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([CH3:15])[CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([C:30]2[N:31]=[C:32]([NH2:35])[S:33][CH:34]=2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.ClCCCl>[F:19][C:20]1[CH:21]=[C:22]([C:30]2[N:31]=[C:32]([NH:35][C:12](=[O:14])[CH2:11][C:10]3[C:6]4[C:5](=[O:16])[N:4]([CH3:17])[C:3](=[O:18])[N:2]([CH3:1])[C:7]=4[N:8]([CH3:15])[CH:9]=3)[S:33][CH:34]=2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cn1c(=O)c2c(CC(=O)O)cn(C)c2n(C)c1=O
Reactant: Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4)cs3)cn(C)c2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7 (80 mg, 0.318 mmol) with 4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (84 mg, 0.318 mmol) in the presence of EDCI hydrochloride (74 mg, 0.381 mmol), HOBt (13 mg, 0.096 mmol) and DMAP (4 mg, 0.032 mmol) in 1,2-dichloroethane (4 mL) to give 52 mg of the product as an off white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 3.21 (s, 3H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95 (s, 2H), 6.35 (s, 1H), 7.82-8.02 (m, 4H), 12.62 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 496.26 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:16]([O:18]CCN(CC)CC)=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:12]([CH3:14])=[O:13])[C:9]([CH3:11])=[O:10].[NH:26](C(OC(C)(C)C)=O)[C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38](ON1C(=O)CCC1=O)=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32].C(OCC)(=O)C>C([O-])(O)=O.[Na+].CC(C)=O>[NH2:26][C@H:27]([C:34]([N:36]1[CH2:50][CH2:49][CH2:48][C@H:37]1[C:38]([NH:1][C@H:2]([C:16]([OH:18])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:15])[N:8]([C:9]([CH3:11])=[O:10])[C:12]([CH3:14])=[O:13])=[O:39])=[O:35])[CH2:28][C:29](=[O:33])[O:30][CH2:31][CH3:32]
Reactant: CCN(CC)CCOC(=O)[C@@H](N)CCCNC(=N)N(C(C)=O)C(C)=O
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N(C(C)=O)C(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 121.8 %

Procedure:
22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2 was dissolved in 300 ml of 5% NaHCO3. 24 g of Boc-Asp(OEt)-Pro-OSu in 150 ml of acetone was added into the reaction mixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetate was added into the mixture. The ethyl acetate solution was washed with water (3×100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid was added into the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to yield 32 g of H-Asp(OEt)-Pro-Arg(diAc)*OCH2CH2N(CH2CH3)2.2TFA.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH:16]=2)[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 53 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 467.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@H:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1.ClCl>O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@H]1Cc2c(-c3ccon3)ccc3c2[C@@H](CN3)C1
Agent: O=[Mn]=O
Agent: ClCl
Product: CCCN(CCC)[C@@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Yield: 30.9 %

Procedure:
A mixture of (+)(2aS,4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (180 mg, 0.5 mmol) and 1 g of MnO2 in 40 mL of CH2 Cl2 was sonicated at 50-55 KHz for 2 hr. The reaction mixture warmed to reflux during the time period. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, ethyl acetate) to provide 50 mg of the isoxazole indole product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH3:25][O:26][N:27]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 13.3 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone in 40 ml of ethanol is treated with 10 g of sodium carbonate and 8.3 g of O-methylhydroxylamine hydrochloride; the mixture is subsequently heated at reflux temperature while stirring. After 4 hours, the mixture is poured onto ice and extracted with ethyl acetate. The organic phase is washed, dried over sodium sulfate and concentrated under reduced pressure to yield 2',4'-dichloro-2-(3-pyridyl)-acetophenone O-methyl oxime as the E,Z-isomer mixture in the form of a yellowish oil. Chromatographic separation on silica gel with n-hexane/ethyl acetate (4:1) as the eluant yields firstly the E-isomer (nD20 =1.5845) and then the Z-isomer (nD20 =1.5745).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].BrBr.BrO.S(=O)(O)[O-:26].[Na+].Cl>[OH-].[Na+].O.O1CCOCC1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:26])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: O=S([O-])O
Agent: BrBr
Agent: Cl
Agent: OBr
Solvent: C1COCCO1
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 84 %

Procedure:
883 Gram of 4'-n-pentyl-4-acetylbiphenyl was introduced into a 30 l stainless steel reactor (provided with a stirrer, a reflux condenser and a funnel for dropwise adding), added 3.75 l of p-dioxane and dissolved with stirring. On the other hand, 1.8 kg of bromine was dropwise added to and dissolved in a solution of 2 kg of sodium hydroxide dissolved in 7.5 l of water, cooled to 10°-15° C. The resulting hypobromous acid solution was maintained at about 10° C. This solution was dropwise added to the above-mentioned p-dioxane solution over 50 minutes, followed by stirring at 35°-40° C for 3 hours, allowing to stand over one night, adding 250 g of sodium bisulfite, stirring, neutralizing with 2.8 l of conc. hydrochloric acid, separating the resulting solid by filtration, water-washing, drying and recrystallizing from 6 l of acetic acid, to give 747 g of 4'-n-pentyl-4-biphenylcarboxylic acid of m.p. 177° C (smectic liquid crystal being formed) (Yield 84%).
Reaction SMILES: [CH3:1][Si:2]([O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH2:9][N:8]([CH2:7][CH2:6][O:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)OCCNCCO[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)OCCN(CCO[Si](C)(C)C)S(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
To a mixture of 4.97 g of bis(2-trimethylsilyloxylethyl)amine, 3.03 g of triethylamine and 50 ml of benzene, 3.21 g of benzenesulfonyl chloride was added at 0° C. under stirring. After the addition, the mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, and the filtrate was subjected to vacuum distillation. The residue was passed through a silica gel column with the eluent varying from benzene to benzen-acetic acid (9:1). As a result, 6.23 g of the title compound was obtained as a colorless oily substance. NMRδ: 7.83 (2H,d,J=8.0 Hz),7.52 (3H,m), 3.72, 3.31 (each 4H,t,J=6.5 Hz), 0.09 (18H,s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14](Cl)(=O)=O)[CH:12]=[CH:13][C:7]=2[O:6]1.COC(=O)CC1CC2C=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C=CC=2O1>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([SH:14])[CH:12]=[CH:13][C:7]=2[O:6]1
Reactant: COC(=O)CC1Cc2cc(S(=O)(=O)Cl)ccc2O1
Agent: COC(=O)CC1Cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2O1
Product: COC(=O)CC1Cc2cc(S)ccc2O1

Procedure:
Compound 4D was prepared according to the method of Example 1 utilizing compound 4C. Compound 4D was prepared in 44% yield for 2 steps. MS: 223 (M−1)+. Preparation of {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic acid methyl ester (Compound 4E)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([CH:15]2[C:24]3[C:23](=[O:25])[CH2:22][CH:21]([CH2:26][CH2:27][CH3:28])[CH2:20][C:19]=3[NH:18][C:17]([CH3:29])=[C:16]2[C:30]#[N:31])[CH:12]=[C:11]([O:32][CH2:33][CH3:34])[C:3]=1[O:4][CH2:5][CH:6]=[CH:7][C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:68][O:69][CH2:70][CH2:71][NH2:72]>ClCCl.O>[CH3:68][O:69][CH2:70][CH2:71][NH:72][C:8](=[O:9])[CH:7]=[CH:6][CH2:5][O:4][C:3]1[C:11]([O:32][CH2:33][CH3:34])=[CH:12][C:13]([CH:15]2[C:24]3[C:23](=[O:25])[CH2:22][CH:21]([CH2:26][CH2:27][CH3:28])[CH2:20][C:19]=3[NH:18][C:17]([CH3:29])=[C:16]2[C:30]#[N:31])=[CH:14][C:2]=1[Br:1]
Reactant: COCCN
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)O)c(OCC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)NCCOC)c(OCC)c1
Reaction time: 2 h

Procedure:
A mixture of 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid (0.1 g), HATU (0.108 g), DiPEA (165 μl) and 2-methoxyethylamine (25 μl) in dichloromethane was stirred for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 65.5 mg. MS-ESI: [M+H]+=586.4/588.4; HPLC: Rt=16.39 min. (method 1). Diast. ratio: 5:1
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)[CH2:2][CH3:3].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Ethyl 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylate (8 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (4.5 g). M.p. 202°-204° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][C:5]=1[Cl:11]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cnc1Cl
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4 (5 mL). The mixture was heated to 60° C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2 (200 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].O[CH2:12][CH:13]([CH2:15]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[CH:1]([C:4]1[CH:5]=[C:6]2[C:8]([CH:12]=[CH:13][CH:15]=[N:7]2)=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: OCC(O)CO
Reactant: CC(C)c1cccc(N)c1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: CC(C)c1ccc2cccnc2c1
Yield: 102.6 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-isopropylaniline (1 g, 7.4 mmol), glycerol (2.11 g, 22.9 mmol) and 3-nitro benzenesulfonic acid sodium salt (2.2 g, 9.61 mmol) gave the title compound (1.3 g, 100%) which was used in the next step without purification.