Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10](NC(CC3SC=CC=3)=O)[C:11](=O)[N:8]2[C:7]=1C([O-])=O)=O.[Na+].C(=O)(O)[O-:29].[Na+].[N-]=[N+]=[N-].[Na+]>O>[N:8]12[CH2:11][CH2:10][CH:9]1[S:22][CH2:23][C:6]([C:5]([OH:4])=[O:29])=[CH:7]2
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C([O-])O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=CN2CCC2SC1
Temperature: 50 °C

Procedure:
A solution of commercial cephalothin sodium salt (5.0 g), sodium bicarbonate (1.06 g), sodium azide (0.82 g) and water. (75 ml) is heated at approximately 50° C. (122° F.) until TLC (thin layer chromatography) shows the starting material is consumed. The reaction is cooled to approximately 3° C. (37° F.), covered with ethyl acetate and acidified with 1N HCl . The ethyl acetate extract is dried over Na2SO4, filtered and the filtrate is concentrated to dryness to give [6R[6a,7B]]-3-(azidomethyl)-8-oxo-7-](2-thienylacetyl) amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-carboxylic acid. A mixture of this azido intermediate (1.0 g), 10% Pd/C (1.0 g), NaHCO3 (1.54 g) and 75% methanol/H2O is subjected to hydrogenation at room temperature until TLC shows the disappearance of starting azide. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is dissolved in water, acidified with 1N HCl and the solution is washed with CHCl3. The aqueous phase is concentrated to dryness and the crude product is purified using 50W-X4 cation exchange resin to give product (II).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:60])=[C:49]([C:51]23[CH2:58][CH:57]2[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]3)[CH:50]=1>ClCCl>[F:60][C:48]1[CH:47]=[CH:46][C:45]([NH:44][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:50][C:49]=1[C:51]12[CH2:58][CH:57]1[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]2
Reactant: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1
Reaction time: 0.25 h
Yield: 198.5 %

Procedure:
To a solution of 5-chloro-2-pyridinecarboxylic acid (60 mg, 0.38 mmol) and diisopropylethylamine (0.17 ml, 0.99 mmol) in dichloromethane (20 ml) at 23° C. was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (174 mg, 0.46 mmol), the mixture was stirred for 15 min, then (1SR,7RS)-1-(5-amino-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13A) (91 mg, 0.36 mmol) was added and the resulting light yellow solution was stirred for 1 h at 23° C. The reaction mixture was poured on ice cold sat. NaHCO3-solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a brown solid (280 mg, 168%), which was purified by silica gel column chromatography with dichloromethane/ethyl acetate to give the title compound as a light yellow solid (147 mg, 88%). MS (ISP): m/z=392.1 [(M+H)+] and 394 [(M+2+H)+].
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:29])[NH:27][CH:24]([CH3:26])[CH3:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 87.8 %

Procedure:
L-Proline benzyl ester hydrochloride (500 mg, 2.073 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 mg, 6.0 mmol) and isopropylisocyanate (210 mg, 2.48 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 3% methanol, 97% chloroform) to give a colourless oil identified as the title compound (528 mg, 1.82 mmol, 88%).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand., 2, 34–41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) was added dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g, 102.0 mmol) was gradually added to the ice-cold solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure to yield crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-cold solution of 2-amino-2-methylpropanol (8.40 g, 94.2 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3 mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloride in methylene chloride (200 mL). After the mixture was stirred at room temperature for 10 minutes, the mixture was washed successively with water, 8.0 M hydrochloric acid, a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0 mmol) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ice water and a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized form diethyl ether-hexane to yield 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless fine needles (melting point: 172.5–174.5° C.) (20.9 g, yield: 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])=[CH:3][CH:2]=1.[H][H].O>C(O)(=O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(O)CN1C(=O)CC(c2ccncc2)C1=O
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)CC(C2CCNCC2)C1=O

Procedure:
2.8 g of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid are suspended in 160 ml of acetic acid and hydrogenated in an autoclave at 100° C. and a hydrogen pressure of 150 bar for 24 h using 100 mg of 5% rhodium on carbon as a catalyst. The catalyst is then filtered off and the filtrate is concentrated to dryness in vacuo. The product thus obtained is taken up in a little water and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)Nc4ccc(O)cc4)cc3)cc12

Procedure:
4-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 4-aminophenol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (28%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.44 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.24 (d, 2H), 7.10 (d, 2H), 6.76 (d, 2H), 4.72 (m, 1H) 3.27 (t, 2H), 3.12 (t, 2H), 2.50 (s, 3H), 2.06 (d, 3H). LRMS [M+H]=449.2
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccc(I)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.00 g (12.1 mmol) 4-iodophenethylamine and 0.37 g (3.03 mmol) DMAP in 50 mL THF are cooled down to 0° C. 4.95 g (48.5 mmol) acetic anhydride are added and, after removing of the cooling bath, the reaction mixture is stirred for 5 h at r.t. The reaction mixture is quenched in ice cold water and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 98.5/1.5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47]Cl>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCCl
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
Potassium carbonate (410 mg, 2.97 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature for 30 min. 2-Dimethylaminoethyl chloride hydrochloride (85.6 mg, 0.59 mmol) was then added. The mixture was heated at 80° C. for 1 h. The resulting reaction mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (350 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C31H35N3O5S2 [M+H]+ 594.77, observed 594.2.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)CC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CC(C)Cc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-3-methyl-butyramidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.76 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH2:37]Cl)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH:35]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27](I)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(C)cc1)=CCC2c1ccccc1OC
Yield: 95 %

Procedure:
A solution of 0.41 g (2.99 mmol) of 4-methylphenylboronic acid in 13 cm3 of methanol and 30 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 1.37 g (2.7 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 0.15 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for two hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with 100 cm3 of ethyl acetate, washed with two times 50 cm3 of distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The brown residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture. 1.2 g (93%) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-(4-methylphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([OH:13])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)OCC
Product: CCOC(=O)c1sc(N)nc1O

Procedure:
Prepared according to literature procedure (Baldwin, J. J., et al. J. Med. Chem. 1980, 23, 65-70.) from thiourea and diethyl bromomalonate. MS m/z 189 (m+1).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[O:13][CH3:14].CO>CCOCC>[Br:12][C:8]1[C:7]([O:13][CH3:14])=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: COc1c(Br)cccc1CO
Reaction time: 0.08 h

Procedure:
LiBH4 (5.00 g, 0.23 mmol) was added to a solution of 3-bromo-2-methoxy-benzoic acid methyl ester (10.50 g, 42.80 mmol) in Et2O at 0° C. The reaction mixture was stirred for 5 minutes, MeOH (8.70 mL, 0.22 mmol) was added in a dropwise fashion. The reaction mixture was then stirred for 30 minutes, and was quenched into 1N NaOH. The resulting solution was extracted with Et2O (3×200 mL) and the combined organic phases were washed with brine (1×150 mL), dried over MgSO4 and concentrated to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 1.68 (t, J=5.86 Hz, 1H), 3.90 (s, 3H), 4.61 (d, J=5.86 Hz, 2H), 6.89 (d, J=8.50 Hz, 1H), 7.25-7.30 (m, J=2.00 Hz, 1H), 7.57 (d, J=2.05 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:3][CH:4]=3)[CH:10]=[CH:11][C:12]=2[CH3:25])=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Yield: 76.6 %

Procedure:
In the same manner as in Reference Example 4 and using N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.61 g, 7.75 mmol), p-toluenesulfonyl chloride (1.77 g, 9.31 mmol) and pyridine (15 mL) as starting materials, the title compound (2.92 g, 77%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].[O:11]=[C:12]([CH3:18])[CH2:13][CH2:14][CH2:15][C:16]#[N:17].Cl>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:11][C:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:18])[CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: Clc1cc(Cl)cc(I)c1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC(O)(CCCC#N)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
The Grignard reagent of 3,5-dichlorophenyl iodide was prepared by the reaction of 20.0 grams (0.073 mole) of 3,5-dichlorophenyl iodide and 1.8 grams (0.073 mole) of magnesium turnings in 350 mL of diethyl ether. The reaction mixture was heated at reflux for about three hours and then allowed to cool to ambient temperature. To the Grignard reagent, with stirring, was added dropwise during a 15 minute period a solution of 8.4 mL (0.073 mole) of 5-oxohexanenitrile in 25 mL of diethyl ether. The exothermic reaction caused the reaction mixture temperature to rise to about 30 ° C. Upon completion of addition, the reaction mixture was stirred for one hour and then was poured into 400 mL of water. The mixture was made acidic with about 80 mL of aqueous 2N hydrochloric acid and extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chroma-tography on silica gel, using 5% diethyl ether in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.4 grams of 5-hydroxy-5-(3,5-dichlorophenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].Cl.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])=[CH:23][CH:24]=1
Reactant: NCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccccn1
Yield: 75.2 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 2-pyridylsulfonyl chloride (see Heterocycles, 28, 1115 (1989)) (220 mg, 1.24 mmol) in place of 3-pyridylsulfonyl chloride, and using 4-(thiazol-2-yl)benzylamine hydrochloride (300 mg, 1.14 mmol) obtained in Reference Example 4-(d) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (284 mg) as a white solid. (Yield: 75%)
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26](O)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>>[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with Biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.34 min; [M+H]+=457.0.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: C=CCI
Reactant: O=c1cnc2ncc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)cnc2ncc(Br)cc21
Yield: 64.2 %

Procedure:
7-Bromopyrido[2,3-b]pyrazin-2(1H)-one (368 mg, 1.628 mmol) was suspended in dry DMF (10 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (741 mg, 5.372 mmol) and allyl iodide (331 μL, 3.581 mmol). It was then stirred for 2 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid which was purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a light brown solid (278 mg, 64%).