Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:17][CH:18]1[CH2:24][C:23](=[O:25])[O:22][C:20](=[O:21])[CH2:19]1.O>C1COCC1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:23](=[O:25])[CH2:24][CH:18]([CH3:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)O)ccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-amine (4.21 g, 20 mmol) in THF (40 mL) was added 3-methylglutaric anhydride (2.56 g, 20.00 mmol), and the mixture was stirred at 90° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give 5-(9-ethyl-9H-carbazol-3-ylamino)-3-methyl-5-oxopentanoic acid (6.23 g, 18.41 mmol, 92%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.[CH3:12][CH:13]([NH2:15])[CH3:14]>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([NH:15][CH:13]([CH3:14])[CH3:12])=[O:11])[CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: CC(C)N
Product: CC(C)NC(=O)C1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from 4-(hydroxymethyl)cyclohexanecarboxylic acid and propan-2-amine as a colorless oil (57%). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.12 (m, 1H), 3.28 (t, J=7.6 Hz, 2H), 3.79 (m, 1H), 4.34 (s, 1H), 7.43 (s, 1H). MS 200 (MH+).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Decylpyrimidine-2-yl)benzoic acid (1.80 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-decylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1C(OC(C)(C)C)=O.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1CCN(C(OC(C)(C)C)=O)CC1.O1CCCC1>ClCCl>[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure described in EXAMPLE 11.5 and making non-critical variations using tert-butyl (2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate to replace tert-butyl 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate, tetrahydrofuran to replace dichloromethane, 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (89%) as a pale yellow solid: mp 83-86° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.29 (dd, J=7.8, 7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.07-6.99 (m, 2H), 6.52, 6.46 (s, 1H), 6.40 (s, 1H), 4.95, 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 3.91-3.71 (m, 2H), 3.69-3.60 (m, 1H), 3.14-2.90 (m, 5H), 1.98-1.70 (m, 3H), 1.66-1.51 (m, 1H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:15][CH:16]([CH3:19])[CH2:17][NH2:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[NH:18][CH2:17][CH:16]([CH3:19])[CH3:15])#[N:14]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1ccc(C#N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(C#N)c(NCC(C)C)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of ethyl 3-bromo-4-cyanobenzoate (500 mg, 2.08 mmol), 2-methylpropan-1-amine (250 μL, 4.16 mmol), Pd2(dba)3 (96 mg, 5 mol %), Xantphos (120 mg, 10 mol %) and potassium phosphate (959 mg, 4.16 mmol) in dioxane (10 mL) was stirred for overnight at 95° C. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated followed by column chromatography (10% ethyl acetate in hexanes) to give ethyl 4-cyano-3-[(2-methylpropylamino)]benzoate (393 mg, 76.7%) as a yellow solid. 1MS (EI) for C14H18N2O2: 247.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(#N)C>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: CC#N
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (10 gm) was dissolved in acetonitrile (100 ml) and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (2 gm) and stirred for 11 hours at room temperature, filtered. The solid obtained was dried to obtain 11 gm of crystalline form 1 of maraviroc phosphate.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(N(CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C(Cl)Cl>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH:33][C:43](=[O:44])[O:45][CH3:46])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: COC(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](N)C3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine trihydrochloride (35 mg, 0.068 mmol) was stirred in methylene chloride (1.0 mL) with triethylamine (47 μL, 0.34 mmol), followed by addition of methyl chloroformate (10 μL, 0.14 mmol). The mixture was stirred at room temperature for 30 min and concentrated. Purification by preparative LCMS using pH 10 buffer gave the title compound (24 mg, 75%). LCMS calc. for C25H27N6O4 (M+H)+: m/z=475.2. found: 475.3. 1H NMR (300 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).
Reaction SMILES: NC(N)=O.[CH2:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[CH2:6][CH3:7].[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 80.6 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2,3-dichlorophenylisocyanate (133 mg, 0.71 mmol) were coupled to form the desired urea (259 mg, 81%). LC-MS (m/z) 452.0 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1.CN(C)C=CC(C1SC=CC=1)=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:16])=[O:22])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: N#Cc1ncn2c(-c3ccsc3)ccnc12
Product: NC(=O)c1ncn2c(-c3ccsc3)ccnc12

Procedure:
3-Dimethylamino-1-(3-thienyl)-2-propen-1-one (prepared as described in Example 2) can be substituted for 3-dimethylamino-1-(2-thienyl)-2-propen-1-one in the procedure of Example 6, to produce 4-(3-thienyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].[C:19](OC(=O)C)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11]
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(=O)[nH]c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=C(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-[2-(2,4-dichloro-phenyl)-acetyl]-1H-pyridin-2-one (800 mg) in CH2Cl2 (2.8 ml) was added N,N,N′N′-tetramethyldiaminomethane (896 mg). The mixture was cooled to 0° C. and acetic acid anhydride (0.64 ml) was added. The mixture was stirred at 0° C. for 10 min and at room temperature for 4 h. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic phase was concentrated to dryness to give the title compound (857 mg) as a light brown solid that was used for the next step without further purification. MS (m/e, ISP neg. ion)=291.9 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16]O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:37]([C:44](OCC)=O)=NC(OCC)=O.OC(C)(C)C#N>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16][C:44]#[N:37])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC/C=C/C1(c2ccc(F)cc2)CCCCC1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC/C=C/C1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of (E)-3-(1-(4-fluorophenyl)cyclohexyl)prop-2-en-1-ol (Intermediate I-11A, 912 mg, 3.89 mmol) and triphenylphosphine (1531 mg, 5.84 mmol) in THF (20 mL) at −20° C. was added diethyl azodicarboxylate (0.924 mL, 5.84 mmol) dropwise and the mixture was stirred at a temperature in the range of from about 20 to about −10° C. for 20 mins. Then 2-hydroxy-2-methylpropanenitrile (0.109 mL, 1.196 mmol) was added slowly at −20° C., and the mixture was stirred for 1 hr at a temperature in the range of from about −20 to about 10° C. and for 20 hrs at room temperature. The reaction was quenched with a few drops of methanol and stirred for 20 mins. After evaporation of the solvent the residue was purified by column chromatography (80 g silica gel) eluting with 1:9 followed by 2:8 ethyl acetate-hexane to give the desired (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrile (760 mg, 80% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.30 (2H, m), 7.01 (2H, t, J=8.80 Hz), 5.85 (1H, d, J=15.63 Hz), 5.10 (1H, ddd, J=15.74, 5.72, 5.61 Hz), 3.06 (2H, dd, J=5.61, 1.65 Hz), 1.98-2.06 (2H, m), 1.77-1.86 (2H, m), 1.41-1.60 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]3[N:38]=[CH:37][C:36]4[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=4[N:30]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)cc(S(C)(=O)=O)c3)nc21
Yield: 57 %

Procedure:
Starting from morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (70 mg; 0.307 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 md; 0.205 mmol), 70 mg (0.116 mmol; 57% yield) of the desired compound were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([C:8](=[N:31][O:32][CH2:33][CH:34]=[CH2:35])[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:4]=1.[C:36](=O)([O-:38])[OH:37].[Na+:40]>>[C:36]([NH:2][C:3]1[S:7][N:6]=[C:5]([C:8](=[N:31][O:32][CH2:33][CH:34]=[CH2:35])[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:4]=1)([O-:38])=[O:37].[Na+:40]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1

Procedure:
Sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared by reacting 7-[2-(5-amino-1,2,4-thiadiazol-3yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (50 mg) and sodium hydrogencarbonate (15.6 mg) and detected according to a similar manner to that of Example 17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:11]I>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:11])[CH:7]=1
Reactant: II
Reactant: Brc1cnc2ccnn2c1
Solvent: CC#N
Product: Brc1cnc2c(I)cnn2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of compound 6-bromopyrazolo[1,5-a]pyrimidine (1 eq), ceric ammonium nitrate (0.6 eq), and I2 (0.6 eq) in acetonitrile (10 mL) was stirred over a period of 24 h at room temperature. The formed precipitate was filtered off, washed with acetonitrile, and recrystallized from acetonitrile. The filtrate was evaporated, and the product was extracted with dichloromethane. The latter was evaporated, and the residue was recrystallized from acetonitrile to give 6-bromo-3-iodopyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12](O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[CH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CC=CC(=O)O1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To 6-t-butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (0.52 parts) in dichloromethane (40 parts) was added triethylamine (0.8 parts) and the solution was cooled to -50° C. To this solution was then added a solution of methanesulphonyl chloride (0.48 parts) in dichloromethane (8 parts) during a period of one minute. The reaction mixture was then stirred for 30 minutes at -50° C. before warming to ambient temperature. After a further 3 hours the solution was washed with water, dried over magnesium sulphate and evaporated to obtain 6-t-butyldimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.4 parts).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Na+]>CO>[C:12]([C:9]1[C:10]([Cl:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:16])[N:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (prepared as described in the previous step, 2.20 g, 9.00 mmol) and 3 N aqueous NaOH (7.50 mL, 22.5 mmol) in MeOH (40 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the residue was treated with H2O (30 mL) and washed with Et2O. The aqueous layer was then acidified to pH 7 by 2 N aqueous HCl and extracted with DCM. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed in vacuo to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.41 (br s, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated for C9H13ClN2O2: 217.1 (M+H). Measured: 217.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[NH2:11][NH:12][C:13]([NH2:15])=[S:14].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][NH:12][C:13]([NH2:15])=[S:14])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: NNC(N)=S
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccnc(Cl)c1
Reaction time: 2 h

Procedure:
2-chloroisonicotinic acid 8.1.A (5000 mg, 31735 μmol) was refluxed in SOCl2 overnight under nitrogen. Another 4 mL of SOCl2 was added in the morning. After 2 hr., solution cleared up. The r×n was then concentrated and added to a thiosemicarbazide (2892 mg, 31735 μmol)/pyridine solution at 0° C. After 4 hr., LC/MS showed product MS along with many side peaks. The reaction was stopped and concentrated. Water and a small amount of EtOAc were added, precipitates were generated. Filtered and washed the precipitates with water 4 times. The solids were dried. LC/MS and the NMR of the precipitates showed to be the pure product. 4.05 g of the product 8.1.B (55%) was generated as a yellow powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl>[C:12]1([C:11]2[N:10]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:28])[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCCCN
Reactant: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
Part A. To a solution of 8-(4,5-diphenyl-1H-imidazol-2ylthio)octanoic acid (8.44 g, 0.02 mol) in methylene chloride (100 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (4.12 g, 0.02 mol), and the reaction mixture was stirred at 0° for 30 minutes. To this reaction mixture was added, dropwise, heptylamine (2.96 mL, 2.3 g, 0.02 mol) and the reaction mixture was stirred at reflux for 72 hours. The reaction mixture was cooled, and the solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue was chromatographed with a gradient of 7:3 to 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 8-(4,5-diphenyl-1H-imidazol-2-ylthio) -N-heptyloctanamide (3.28 g, 0.0067 mol) as a white solid, mp 119°-120°. 1H NMR (DMSO-d6) δ 12.5(s,1H), 7.8-7.1(m,10H), 3.2-2.9(m,4H), 2.0(t,2H,J=7 Hz), 1.75-1.0(m,21H),1.0-0.8 (m,3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([Cl:15])[CH:3]=1.O(C1C=CC([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:15][C:4]1[CH:3]=[C:2]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Reactant: Clc1cc(Br)ccc1Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(Cl)c2)OC1(C)C
Yield: 81 %

Procedure:
The title compound (472 mg, 81%) was prepared from 4-bromo-2-chloro-1-phenoxybenzene (500 mg, 1.77 mmol) in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 7.75(s, 1H), 7.60 (d, 1H), 7.42(t, 2H), 7.21(t, 1H), 7.02 (m, 3H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 15.53 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)c4ccccc4)cc3c2c1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(Cc4ccccc4)cc3c2c1C
Yield: 10.8 %

Procedure:
260 mg of 6-benzoyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is hydrogenated in 36 ml of absolute ethanol with 2 ml of glacial acetic acid and 100 mg of palladium black for 2 hours at 10 bar hydrogen pressure at 40°-45° C. After separation of the catalyst, the reaction mixture is evaporated. The residue is chromatographed over silica gel, first with toluene:glacial acetic acid:water=10:10:1 and then with toluene:ethanol:water=80:20:1, thus obtaining 27 mg (11%) of 6-benzyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester.