Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:9]([O:11]C)=[O:10])[CH2:3][CH3:4].[OH-].[Na+]>C1COCC1>[CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=1)[C:9]([OH:11])=[O:10])[CH2:3][CH3:4]
Reactant: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 80.8 %

Procedure:
Methyl 3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoate (14.87 g, 47.36 mmol) was vigorously stirred in a mixture of aqueous 1M sodium hydroxide (120 mL) and THF at approximately 45° C. for 4 hours. The bulk of the THF was removed under reduced pressure and the resultant solution partitioned between water and diethyl ether. The aqueous phase was acidified with 2M hydrochloric acid and then extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated in vacuo gave a white solid (11.5 g). 1H NMR δ (CDCl3): 0.90 (t, 3H), 1.20 (d, 3H), 1.49-1.69 (m, 2H), 4.33-4.46 (m, 1H), 5.12 (s, 2H), 6.75-6.79 (m, 1H), 6.99-7.03 (m, 1H), 7.06-7.11 (m, 1H), 7.26-7.47 (m, 5H)
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=4)[N:17]=3)[N:12]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C)C=O.C(OCC)(=O)C>[OH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:24]([C:22]2[S:23][C:19]([C:16]3[N:17]=[C:18]4[C:10]([C:8]([C:2]5([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[O:9])=[CH:11][N:12]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:13]4=[N:14][CH:15]=3)=[CH:20][CH:21]=2)=[O:25])[CH2:65][CH2:64]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)O)s4)nc23)CCCCC1
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Yield: 34.3 %

Procedure:
A solution of 5-[7-(1-methyl-cyclohexanecarbonyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.080 g, 0.16 mmol), BOP (0.071 g, 0.16 mmol) and 4-hydroxypiperidine (0.162 g, 1.6 mmol) in 2 mL of N,N-dimethylformamide was stirred overnight. The resulting black mixture was taken up in 30 mL of ethyl acetate and washed with three 20 mL portions of a sat. aq. NH4Cl solution, dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->50% EtOAc/hexanes afforded 0.032 g (34%) of [2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone as a tan oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F
Solvent: O
Product: Cc1cc(-c2c(-c3ccc(S(N)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F

Procedure:
The title compound was prepared according to the method of procedure Example 384, substituting 2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 mg, 27%). mp 243-245° C. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3H), 7.01 (m, 2H), 7.25 (m, 1H), 7.45 (s, 1H), 7.47 (bs, 2H), 7.6 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI/NH3) m/z 472 (M+H)+, 489 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.5 H2O: C, 58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:49])[NH:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)([CH3:42])[CH3:41])[CH:33]=4)=[CH:22][C:17]=3[C:18]=2[C:19]([OH:21])=O)=[CH:10][CH:9]=1.[CH3:50][N:51](C=O)C.CCN(C(C)C)C(C)C.CN>ClCCCl.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:49])[NH:39][C:40]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([CH3:41])[CH3:42])[CH:33]=4)=[CH:22][C:17]=3[C:18]=2[C:19]([NH:51][CH3:50])=[O:21])=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1cccc(C(=O)NC(C)(C)c2ccccc2)c1)S(C)(=O)=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
Oxalyl chloride (22 μL, 0.250 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylic acid (50 mg, 0.083 mmol) in DCE (832 μL) at rt. DMF (3 μL, 0.042 mmol) was added. The mixture was allowed to stir for 30 min, concentrated and diluted with THF. DIEA (59 μL, 0.333 mmol) and methanamine (208 μL, 0.416 mmol, 2M in THF) was added. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46-8.56 (1H, m), 8.36 (1H, s), 7.97-8.05 (3H, m), 7.94 (1H, s), 7.86 (1H, d, J=7.78 Hz), 7.59-7.67 (2H, m), 7.53 (1H, t, J=7.65 Hz), 7.35-7.42 (4H, m), 7.29 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.28 Hz), 3.06 (3H, s), 3.01 (3H, s), 2.82 (3H, d, J=4.52 Hz), 1.69 (6H, s). LC-MS retention time: 1.51 min; m/z (MH+): 614. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.89 min, purity=92%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=12.11 min, purity=91%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: Cc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: Cc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 23.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl) amine (1.40 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:7])=[CH:4][CH:3]=1.[I:10]C1C=CC=CC=1C>>[I:10][C:8]1[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][Br:7]
Reactant: Cc1ccccc1I
Reactant: BrCc1ccc(I)cc1
Product: BrCc1ccccc1I

Procedure:
o-Iodobenzyl bromide was prepared by the procedure described by H. A. Sloviter, J. Am. Chem. Soc. 71, p.3360 (1949) for p-iodobenzyl bromide by starting with o-iodotoluene. The crude product was distilled at reduced pressure to yield a liquid product, bp. 85°-92°/0.5 mm Hg, which crystallized spontaneously to yield a solid product having a mp of 42°-49°.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])(=O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][CH:9]([O:12][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CON(C)C(=O)C1(C(F)(F)F)CCC(O)CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CON(C)C(=O)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 16 h

Procedure:
6.00 g (23.5 mmol) of 4-Hydroxy-1-trifluoromethyl-cyclohexanecarboxylic acid methoxy-methyl-amide (69) were dissolved in 20 ml of CH2Cl2 and 6.8 ml of 2,6-lutidine were added. Afterwards, 6.48 ml (28.2 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate were added at 0° C. and the mixture allowed to stand at ambient temperature for 16 h. The mixture was then diluted using 30 ml of CH2Cl2 and washed successively twice using 30 ml of water, twice using 30 ml of a 0.1; N aqueous HCl-solution and once using 30 ml of a saturated aqueous NaHCO3-solution respectively. The organic layer was then dried over MgSO4 and evaporated to yield 8.40 g. Rt=0.99 min (Method Q).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CCO>[OH:16][NH:15][C:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C@@H:2]([OH:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)=[NH:13]
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CCC[C@H]2O
Temperature: 70 °C
Yield: 29 %

Procedure:
Prepared using General Procedure 1. To a stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (79.1 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (34.9 mg, 0.50 mmol) and sodium bicarbonate (42.2 mg, 0.50 mmol). The mixture was heated at 70° C. for 18 h. The product was purified by chromatography (MeOH/DCM) to provide 27.3 mg (29%) (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 as a white solid. LCMS-ESI (m/z) calculated for C11H11NO: 173.2; found 174.1 [M+H]+, 156.1 [M−NH4]+, tR=2.60 min.(S)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-5 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:11])=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10](=[O:11])[NH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCC(=O)c1ccc(Cl)s1)NCc1ccccc1F
Agent: Cl
Solvent: CO
Product: O=c1[nH]cc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1300 mg (ca. 4.0 mmol) of 1-[2-(5-chloro-2-thienyl)-2-oxoethyl]-3-(2-fluorobenzyl)-urea (Example 235A) are suspended in 15 ml of concentrated hydrochloric acid, diluted with 15 ml of methanol diluted and stirred at RT for 2 hrs. The suspension is filtered, the filtrate concentrated in vacuo and the residue purified by preparative HPLC [Method 10]. 220 mg (18% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: Cn1nnc2cc(C(=O)O)ccc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1nnc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc21
Yield: 53 %

Procedure:
The title compound is prepared from 1-methyl-1H-benzotriazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 53% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:24][C:23]([NH2:25])=[N:22][N:21]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=[O:9].CN(C)C=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:24][C:23]([NH2:25])=[N:22][N:21]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])(=[O:29])=[O:9]
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Reactant: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Yield: 84 %

Procedure:
In the same manner as in Example 140 and using 5-[3-[3-chloro-4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine instead of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole and using N,N-dimethylformamide instead of dichloromethane, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([NH2:20])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Ca+2].[C:28](Cl)(Cl)=[S:29].C(=O)=O>ClCCl.O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([N:20]=[C:28]=[S:29])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N)S1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N=C=S)S1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.8 g of the 5-amino-2-chloro-4-fluoro-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P2 in 100 ml of dichloromethane is added dropwise at 25°-30° C. to a suspension of 6 g of calcium carbonate, 4 ml of thiophosgene, 20 ml of dichloromethane and 20 ml of water. After the evolution of carbon dioxide has ceased, the mixture is stirred for 18 hours at room temperature. After filtration and washing with water, the organic phase is separated off, dried over sodium sulfate and then concentrated by evaporation, yielding 4.8 g of 2-chloro-4-fluoro-5-isothiocyanato-thiolbenzoic acid (methoxycarbonylmethyl) ester in the form of an oil which is used in the next reaction step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[NH:25]1>C(O)(C)C>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[N:25]1[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5]
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: CC1CCCC(C)N1
Solvent: CC(C)O
Product: CC1CCCC(C)N1CCC(=O)N1c2ccccc2C(=O)N(C)c2ccccc21

Procedure:
6.3 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 8.4 (0.075 mol) of 2,6-dimethyl piperidine were refluxed in 100 ml of isopropanol for 6 hours. The reaction mixture was worked up as described in Example 13. After recrystallization from ethyl acetate by addition of a little ether, 4.2 gm (54% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28].CCCCCC>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:11]([C:12]([NH:28][CH2:27][C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1cccs1
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
A solution of 2.1 g (10.0 mmol) 2-chloroquinoline-3-carboxylic acid in thionyl chloride (60 ml) was heated for 2 h at 85° C. Then excess thionyl chloride was removed under vacuum. The residue was taken up with DCM (60 ml) and the solution was cooled to 0° C. and then mixed with 4.0 ml (30.0 mmol) NEt3 and 1.03 ml (10.0 mmol) thiophene-2-methylamine. After stirring for 90 min at RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 1.44 g (4.8 mmol, 48%) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22]C(=O)C2C=CC=CC=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(OP(O[C:48]2[C@H:49]([CH3:65])[C@@H:50]3[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22][C:48]2[C@H:49]([CH3:65])[C@@H:50]3[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cn2c(Cl)ncc2s1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(Cl)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 58.9 %

Procedure:
The procedure of Example 23-a) is repeated, except that 303.0 mg of (3S,5S)-1-allyloxycarbonyl-3-benzoylthio-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 23 is used. Thus, 261.0 mg of a mercaptan compound is prepared as a yellow oil. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (186.7 mg) is prepared as a colorless amorphous material from this mercaptan and 260.9 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([CH:32]=[O:33])[CH:24]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]3[CH:32]([OH:33])[C:25]4[C:26]([C:2]=23)=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C(O)c1cc(OC)ccc1-3
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([CH:18]([OH:20])[CH3:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[O-2].[Mn+4].[O-2]>[C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)(=[O:20])[CH3:19]
Reactant: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Yield: 60.3 %

Procedure:
To a solution of 2-benzyl-6-bromo-3-(1-hydroxyethyl)-4-phenyl-2H-isoquinolin-1-one (250 mg) in THF (5 ml) was added manganese(IV) oxide (500 mg), and the mixture was heated under reflux for 1 hr. To the reaction mixture was add manganese(IV) oxide (500 mg) and the mixture was heated under reflux for 1 hr, manganese(IV) oxide (500 mg) was added and the mixture was heated under reflux for 1 hr, and manganese(IV) oxide (500 mg) was added and the mixture was heated under reflux for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=8:1) and recrystallized (ethyl acetate-hexane) to give the title compound (150 mg).