Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:22])=[CH2:24]
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (200 mg, 0.63 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μL, 0.69 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (139 mg, 55%). LCMS (Method B): RT=3.35 min, M+H+=403.
Reaction SMILES: [CH2:1]([C:5]1([N:20]([CH3:22])[CH3:21])[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Si]([Cl:27])(C)(C)C>C(OCC)(=O)C>[ClH:27].[CH2:1]([C:5]1([N:20]([CH3:22])[CH3:21])[CH2:6][CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2c[nH]c3ncccc23)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
1-Butyl-N,N-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)cyclohexanamine (425 mg, 1.42 mmol) was dissolved in ethyl acetate (100 ml). Me3SiCl (358 μl, 2.84 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×10 ml) and then dried. Example 238 (435 mg, 91%) was a colourless solid
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:4][C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>ClCCl.O>[C:28]([NH:1][C:2]1[C:3]([S:15]([F:20])([F:16])([F:17])([F:18])[F:19])=[CH:4][C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])(=[O:30])[CH3:29]
Reactant: CON(C)C(=O)c1cc(N)c(S(F)(F)(F)(F)F)cc1C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(NC(C)=O)c(S(F)(F)(F)(F)F)cc1C
Reaction time: 2 h

Procedure:
5-Amino-N-methoxy-2,N-dimethyl-4-(pentafluorosulfanyl)benzamide (200 mg) was dissolved in dichloromethane (10 ml) and then triethylamine (100 μl) and acetyl chloride (50 μl) were added while stirring. After 2 h, further acetyl chloride was added (50 μl) and the mixture was stirred for 4 h. Then the reaction mixture was admixed with water and saturated sodium hydrogencarbonate solution, and the organic phase was removed and washed three times with water. After drying over magnesium sulfate, the organic phase was filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 170 mg of the desired compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccccc1Cl)CCNCC2
Yield: 49.9 %

Procedure:
The title compound (90 mg) was prepared according to Example 189 using 266 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 292 mg of 2-chlorophenylboronic acid. MS (ESI): exact mass calculated for C16H20ClN3, 289.13. found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.63 (m, 1H), 7.58-7.49 (m, 2H), 7.41-7.39 (m, 1H), 4.66 (br s, 2H), 4.16 (m, 1H), 4.00-3.44 (m, 2H), 3.0-2.6 (m, 2H), 1.47-1.38 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][C:8]([N:10]([CH2:16][C@:17]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:52])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]2[CH:51]=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][CH:40]=2)=[CH:25][CH2:24]3)[CH2:21][CH2:20]1)[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:6]([CH2:7][C:8]([N:10]([CH2:16][C@:17]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:52])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]2[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:50][CH:51]=2)=[CH:25][CH2:24]3)[CH2:21][CH2:20]1)[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])([OH:59])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-tert-butoxy-N-(2-(dimethylamino)ethyl)-3-oxopropanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (31 mg, 0.038 mmol) in dichloromethane (1 ml) was added TFA (0.25 ml, 3.24 mmol). The mixture was stirred at rt for 3 h then was concentrated under reduced pressure. The residue was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxy-N-(2-(dimethylamino)ethyl)acetamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as a white solid (15 mg, 0.021 mmol, 56.1% yield). LCMS: m/e 701.5 (M+H)+, 2.11 min (method 6). 1H NMR (500 MHz, Acetic acid-d3 acid-d) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.31 (d, J=8.24 Hz, 2H), 5.38 (d, J=5.19 Hz, 1H), 4.85 (d, J=16.17 Hz, 1H), 4.69 (d, J=15.56 Hz, 1H), 3.86-4.13 (m, 2H), 2.97-3.82 (m, 6H), 2.62-2.73 (m, 1H), 2.13-2.24 (m, 2H), 1.06-1.92 (m, 38H), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:16]1(=[O:23])O[C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1.C(N(CC)CC)C>[NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:16]1(=[O:23])[NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC(=O)O1
Agent: Nc1cc2cccnc2c2ncccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)N1

Procedure:
5-Amino-1,10-phenanthroline (350 mg, 1.8 mmol) was refluxed with glutaric anhydride (2.0g, 17.5 mmol) in pyridine (3 mL) and triethylamine (3 mL) for 2 hours. The reaction mixture was reduced to a viscous oil by rotary evaporation. Column purification on silica with 10% methanol in methylene chloride (product produced bright red spots with Fe(II) on TLC) gave the crude product (320 mg 1.1 mmol). Further purification of the crude product was by recrystallization once from 30 mL boiling water to give the title compound (250 mg, 0.85 mmol) as centimeter long transparent needles.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:15](Br)[CH3:16].[CH:18](N(CC)C(C)C)(C)[CH3:19].O>CN(C)C=O>[Br:1][C:2]1[C:9]([O:10][CH2:18][CH3:19])=[C:8]([O:11][CH2:15][CH3:16])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1cc([N+](=O)[O-])c(O)c(O)c1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c([N+](=O)[O-])cc(C=O)c(Br)c1OCC

Procedure:
2-Bromo-3,4-dihydroxy-5-nitrobenzaldehyde (5.2 g), ethylbromide (4.5 ml) and N,N-diisopropylethylamine (10.5 ml) in N,N-dimethylformamide (50 ml) were stirred at 70° C. for 2 days. The mixture was poured into water and extracted with ether. The organic phase was washed with NaOH-solution, dried with Na2SO4 and evaporated to dryness.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(Cl)Cl.[C:31]([O:35][CH2:36]C)(=[O:34])[CH:32]=[CH2:33].CN1CCCN2CCCN=C12>CO>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Agent: CN1CCCN2CCCN=C12
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (75 mg, 0.203 mmol) was dissolved in methanol (2.0 mL) and DCM (1 mL) before ethyl acrylate (27.1 μL, 0.244 mmol) and 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (1.457 μL, 10.15 μmol) were added and stirred at ambient temperature for 16 h. Methyl 3-(5-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)propanoate was obtained after purification via flash chromatography. MS (ESI) m/z: Calculated: 455.2; Observed: 456.4 (M++H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](O)=O.C=O.[ClH:15]>>[ClH:15].[ClH:15].[CH3:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCN1CCNCC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A total of 100 g (0.77 mol) of 1-(2-hydroxyethyl)piperazine was added dropwise to a stirred solution of 78.6 g (1.54 mol) of 90% formic acid at 0° C. To the resulting solution, 63.2 g (0.77 mol) of 37% formaldehyde was added dropwise. The solution was stirred at 0° C. for 15 minutes and heated on a steam bath for 3 hours. The solution was acidified with 150 ml of concentrated hydrochloric acid. The water was removed and the resulting residue dissolved in 200 ml of 25% NaOH, and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and the solvent removed. The resulting residue was distilled to give 84.7 g (76%) (b.p. 96-97° C./3 Torr) of the alcohol as a colorless liquid. The dihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@H:14](O)[CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][C@H:14]1[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]1
Reactant: CN1CC[C@H](O)C1
Reactant: COc1ccc(Br)cc1O
Product: COc1ccc(Br)cc1O[C@H]1CCN(C)C1
Yield: 30.5 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (1.00 g, 4.93 mmol) and (S)-1-methyl-pyrrolidin-3-ol (593 mg, 5.86 mmol) to afford titled compound as a colorless solid (430 mg, 30%). LC/MS (Method B) 1.17 min, [M+1]+ 286/288.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:42](Cl)[O:43][CH3:44]>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][O:43][CH3:44])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added i-Pr2NEt (47 μl, 0.27 mmol) and MOMCl (35 μl, 0.45 mmol). The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.ClC1C=CC=CC=1COCCN([C@H]1CC[C@H](C)CC1)[C:24](=[O:39])[NH:25][C:26]1[S:27][C:28]([S:31]CC(C)(C)C(O)=O)=[CH:29][N:30]=1.C([O:53][C:54](=[O:56])[CH3:55])C>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:24](=[O:39])[NH:25][C:26]2[S:27][C:28]([S:31][CH2:55][C:54]([OH:53])=[O:56])=[CH:29][N:30]=2)[CH2:4][CH2:3]1
Reactant: CC1CCC(NCc2ccncc2)CC1
Reactant: CCOC(C)=O
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Product: C[C@H]1CC[C@H](N(Cc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
A mixture of 4-formylpyridine (0.88 g, 8.25 mmol), trans-4-methyl-cyclohexylamine hydrochloride (0.93 g, 8.25 mmol) and NaBH3CN (1.3 g, 20.6 mmol) in MeOH (50 mL) and AcOH (1.5 mL) was refluxed for 1.5 h. The heating was discontinued and the reaction mixture was left at rt for 2 days. The volatiles were removed in vacuo and the residue was divided between aqueous NaHCO3 and DCM. The DCM phase was concentrated in vacuo. Purification on preparative HPLC gave the TFA salt of (4-methyl-cyclohexyl)-pyridin-4-ylmethyl-amine. The amine was coupled and hydrolyses using the procedure described in the procedure for the preparation of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH:11]([O-:16])([O-])[O:12][CH2:13][CH3:14].CN1[CH2:22][CH2:21]N(C)C1=O>>[CH2:21]([O:16][CH:11]([O:12][CH2:13][CH3:14])[N:6]1[CH2:7][CH2:8][CH2:9][NH:10][C:5]1=[N:4][N+:1]([O-:3])=[O:2])[CH3:22]
Reactant: CN1CCN(C)C1=O
Reactant: CCOC([O-])[O-]
Reactant: O=[N+]([O-])N=C1NCCCN1
Product: CCOC(OCC)N1CCCNC1=N[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 10 g of 2-nitroiminohexahydropyrimidine, 12.4 g of ethyl orthoformate, 10 ml of 1,3-dimethyl-2-imidazolidinone was heated under reflux for 2.0 hours while removing the resultant distillate by means of the Dean-Stark trap. After cooling to room temperature, the mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oil was purified by column chromatography [silica gel, eluent: hexane/ethyl acetate (1:2)] to obtain 2.3 g of 1-diethoxymethyl-2-nitroiminohexahydropyrimidine. Typical examples of the compounds of the formula (2) which could be prepared according to the procedures similar to those of Examples 9 to 14 are shown in Table 3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH2:10]
Reactant: [H][H]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C)c1N
Yield: 100.6 %

Procedure:
Palladium charcoal (1.0 g of 10%) was added to a solution of 3-methyl-2-nitroanisole (16.8 g, 0.1 mol) in ethanol (150 mL) and the solution was hydrogenated (50 lb initial hydrogen pressure) until hydrogen uptake ceased (2 hours). The solution was filtered and evaporated to give 13.8 g of 2-methoxy-6-methylbenzenamine (compound XLIV) as an oil. The product was dissolved in acetic anhydride (100 mL) and the resulting solution was refluxed for 1 hour. Part of the solvent (50 mL) was slowly removed over a 1-hour period, after which time the solution was cooled and the remainder of the solvent was removed under reduced pressure. The residual oil was crystallized from ethyl acetate:hexane (200 mL of 1:2) to give 20.5 g of N-acetyl-N-(2-methoxy-6-methylphenyl)-acetamide, mp 116°-119° C. Anal Calcd for C12H15NO3 : C, 65.14; H, 6.83; N, 6.33. Found: C, 65.44; H, 7.04; N, 6.39.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:16]([O:20][CH2:21][O:22][C:23]([C:25]1[N:26]2[CH:29]([S:30][CH2:31][C:32]=1[CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH:28]([NH2:38])[C:27]2=[O:39])=[O:24])(=[O:19])[CH2:17][CH3:18]>C(Cl)Cl.C(O)CC>[C:16]([O:20][CH2:21][O:22][C:23]([C:25]1[N:26]2[CH:29]([S:30][CH2:31][C:32]=1[CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH:28]([NH:38][C:13](=[O:15])[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][Cl:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11])[C:27]2=[O:39])=[O:24])(=[O:19])[CH2:17][CH3:18]
Reactant: O=C(O)C(C(=O)O)c1ccc(CCl)cc1
Reactant: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Solvent: ClCCl
Solvent: CCCO
Product: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(NC(=O)C(C(=O)O)c3ccc(CCl)cc3)C(=O)N12

Procedure:
α-Carboxy-p-chloromethylphenylacetylnitrophenyl polymer prepared as in the procedure of Example 22, carrying four m. mole of p-chloromethylphenylmalonic acid was suspended for about 8 hours in 20 ml of dry methylene chloride solution containing 1 millimole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid propionyloxymethyl ester. After only traces of the 7-amino-cephalosporanic acid ester derivative remain in solution, which is determined by thin layer chromatography on cellulose in 70% aqueous propanol, the polymer is filtered off and washed with portions of 50 ml each of methylene chloride. The combined filtrates are evaporated and the residue is dissolved in 20 ml of distilled water. The solution is acidified to a pH of 2 by adding 0.2 normal hydrochloric acid and extracted twice with ethylacetate. The organic solution is dried over sodium sulfate and evaporated at room temperature. The remaining solid is dried overnight over phosphorus pentoxide under vacuum to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid propionyloxymethyl ester.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24](C4C=CC=CC=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH3:38][NH:39][CH3:40].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:39]([CH3:40])[CH3:38])=[O:9])=[O:4]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNC
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 4, 35 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of dimethylamine-HCl (11.36 mg, 0.139 mmol), 4-methylmorpholine (0.046 mL, 0.418 mmol), and BOP (61.6 mg, 0.139 mmol). This was stirred for 1 h and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=33.5 min) to give 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,N-dimethylpropanamide (16.1 mg, 0.030 mmol, 42.8% yield) as a single enantiomer. LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.69 (4 H, d, J=8.14 Hz), 7.49-7.65 (3 H, m), 5.11 (1 H, s), 3.51 (2 H, t, J=6.49 Hz), 2.98 (3 H, s), 2.92 (3 H, s), 2.60 (2 H, t, J=6.60 Hz). HPLC Peak RT=9.6 min (Analytical Method D).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH:20](O)[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].P(Br)(Br)[Br:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Br:24][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]2[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)O)cccc32)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 282 (400 mg, 1.27 mmol) in dry DCM (2 mL) and dry Et2O (2 mL) at 0° C. under Argon was added PBr3 (515 mg, 1.91 mmol) and the mixture was stirred at RT overnight. The mixture was poured into cold NaHCO3 (aq.) and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 450 mg (92%) of 4-(1-bromoethyl)-1-tosyl-1H-indole (284) give as a yellow oil, which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.65 (d, J=2.8 Hz, 1H), 7.35-7.23 (m, 4H), 6.89 (d, J=2.8 Hz, 1H), 5.53-5.50 (m, 1H), 2.36 (s, 3H), 2.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30]>>[OH:31][C:29]([C:28]([F:33])([F:32])[F:27])=[O:30].[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)CC1
Product: O=C(O)C(F)(F)F
Product: O=C(c1csc(-c2ccccc2)n1)N1CCNCC1

Procedure:
This compound was synthesized from tert-butyl 4-(2-phenylthiazole-4-carbonyl)piperazine-1-carboxylate as described for example 46 step 4 (300 mg, crude) as trifluoroacetate salt and it was taken as such for the next step. MS (ESI) m/z: Calculated for C14H15N3OS: 273.09. found: 274.0 (M+H)+