Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:31])([CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2C(=O)O

Procedure:
A mixture of 5.0 g. 5-benzyloxy-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran-4-carboxylic acid (prepared by the method of Example 88, Part A), 500 mg. 5% palladium-on-carbon catalyst and 150 ml. ethyl acetate is hydrogenated for 18 hours by the procedure of Example 86. After removal of catalyst and evaporation of solvent 4.25 g. of foam is obtained. Purification by silica gel chromatography, eluting with 2:1 hexane/ethyl ether affords 1.84 g. of product, M.P. 147°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=5[F:30])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CO
Product: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 165 °C
Yield: 57.2 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2-(propyloxy)aniline (0.137 g, 0.433 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (3 drops) was added. The vial was sealed and heated in the microwave at 165° C. for 30 min. The reaction was cooled to rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel, and flash chromatographed. Product was then triturated with diethyl ether to give the title compound (0.184 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 9.18-9.41 (m, 1H), 8.24-8.47 (m, 2H), 8.18 (d, J=4.9 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.26-7.48 (m, 3H), 7.17 (t, J=8.1 Hz, 2H), 6.83-7.01 (m, 1H), 6.63 (br. s., 1H), 6.43 (d, J=5.1 Hz, 2H), 3.91 (t, J=6.0 Hz, 2H), 3.69 (d, J=11.4 Hz, 2H), 2.60 (t, J=11.6 Hz, 2H), 2.36-2.52 (m, 4H), 2.22-2.36 (m, 1H), 1.75 (d, J=11.0 Hz, 2H), 1.14-1.66 (m, 10H), 0.66-0.88 (m, 3H). MS (M+H) 743.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>CCO>[NH:13]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[NH2:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1NN
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro-3-methyl-5-nitropyridine (35 g, 200 mmol) in EtOH (400 mL) was added hydrazine hydrate (30.0 g, 600 mmol) and the resulting reaction mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled down with an ice bath, the resulting precipitate was filtrated off, washed with cold H2O and Et2O and dried at 50° C. under reduced pressure to afford the title product (25.40 g, 113 mmol, 98%) as a yellow solid. tR: 0.43 min (LC-MS 2); ESI-MS: 169 [M+H]+; ESI-MS: 167 [M−H]− (LC-MS 2).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=2)[C:18]([O:20]C)=[O:19])=[O:11])[S:2]1.[OH-].[Na+]>C1COCC1.O>[S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=2)[C:18]([OH:20])=[O:19])=[O:11])[S:2]1
Reactant: COC(=O)c1cc(NC(=O)CCCC[C@H]2CCSS2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCC[C@H]1CCSS1)Nc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-methyl 5-(5-(1,2-dithiolan-3-yl)pentanamido)-2-hydroxybenzoate (650 mg, 1.83 mmol) was taken up in 6 mL of THF and NaOH (220 mg, 5.5 mmol) was added as a solution in 6 mL of H2O. The resulting reaction mixture was stirred at room temperature for 8 h and then concentrated under reduced pressure. Enough 1 N HCl was added to the aqueous layer to adjust the pH to 2 and the resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford (S)-5-(5-(1,2-dithiolan-3-yl)pentanamido)-2-hydroxybenzoic acid. Mass calculated for C15H19NO4S2: 341.08. found: [M+H]+=342.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[O:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].C(N(CC)C(C)C)(C)C>CO>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH:28]3[O:33][CH2:32][CH2:31][N:30]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CC3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)C(=O)CN1CCOC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Reaction time: 17 h
Yield: 51.9 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.18 mmol) in MeOH (1.5 mL) was added 2-chloro-N,N-dimethylacetamide (24 mg, 0.20 mmol) and N,N-diisopropylethylamine (95 μL, 0.55 mmol). The reaction was stirred at 60° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 49 mg (52%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.51-8.57 (m, 1H), 7.86-7.93 (m, 1 H), 7.76-7.84 (m, 1 H), 7.55-7.62 (m, 1 H), 7.26-7.41 (m, 5 H), 7.09-7.18 (m, 1 H), 6.58-6.66 (m, 1 H), 5.71-5.77 (m, 1 H), 5.62-5.68 (m, 2 H), 3.79-3.91 (m, 1 H), 3.68-3.79 (m, 1 H), 3.39-3.53 (m, 1 H), 2.90-3.20 (m, 7H), 2.69-2.82 (m, 4 H), 2.62 (d, 1 H), 2.11-2.24 (m, 1 H), 1.96-2.09 (m, 1 H); ES-MS m/z 525.38 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Reactant: NOCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Yield: 84.5 %

Procedure:
After a solution of 10.22 g (34.38 mmol) of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in dehydrated acetonitrile (113 mL) was cooled from −30 to −40° C. under argon atmosphere, 4.4 mL (37.78 mmol) of 2,6-lutidine was added, and then 5.92 mL (36.09 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise over 10 minutes, followed by further allowing to react at −30° C. for 15 minutes. To this reaction mixture was added 8.46 g (68.73 mmol) of benzyloxyamine (washed with acetonitrile (5 mL)), followed by raising the temperature to 0° C. within 30 minutes, and further 4.4 mL (37.78 mmol) of 2,6-lutidine was added, followed by allowing to react at 0 to 5° C. for 3.5 days. This reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (200 mL) and washed sequentially with water (200 mL), 10% aqueous citric acid solution (200 mL×3 times), 6.5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL). Each aqueous layer was back-extracted with ethyl acetate (100 mL), the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1) to afford 11.69 g of the title compound as a colorless oil (yield 85%). Enantiomeric excess: 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=9/1, flow rate 1 mL/min., retention time 4.5 min.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Nc1ccc(Sc2ccccn2)c(Cl)c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 642.1 mg (2.81 mmol) of 3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 4-[3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile as a yellow solid, mp 225-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.CN(C)C=O.C1C(=O)N([Br:27])C(=O)C1>CC(=O)OCC>[Br:27][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1sc(Br)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (3.6 g, 16.02 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL). This was followed by the addition of NBS (2.85 g, 16.01 mmol, 1.00 equiv) portions at −5° C. The resulting solution was stirred for 2 h at room temperature (20 degree C.). The resulting solution was diluted with 100 mL of EA. The resulting mixture was washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 4.8 g (99%) of [5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methanol as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:36][CH3:37])([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:35])[CH:21]=3)[CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH2:36][CH3:37])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:35])[CH:21]=3)[CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCCC2)c(C)c1
Yield: 66.8 %

Procedure:
10% palladium carbon (13.0 mg) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 147-(1); 29.7 mg, 0.058 mmol) in methanol (0.3 mL), and the mixture was stirred in a hydrogen atmosphere for 19 hours. The reaction solution was filtered and concentrated under reduced pressure to give the title compound (19.9 mg, 66%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:17]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)c1c[nH]c2ccccc12

Procedure:
Using indole (5.00 g) and 6-bromohexanoyl chloride (9.95 ml) according to the same method as that of Reference Example 1, the title compound (9.65 g) was obtained as colorless crystals having a melting point of 150 to 151° C.
Reaction SMILES: Br[CH2:2][C:3]([C@:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:28]([O-:34])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[C:28]([O:34][CH2:2][C:3]([C@:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CC[C@](O)(C(=O)CBr)C3
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O

Procedure:
A mixture of 9(R)-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.00 g) obtained in Reference Example 4-(1), sodium valerate (1.44 g) and acetone (50 ml) was stirred under reflux for 2 hours. After removing insoluble matters by filtration, the reaction mixture was concentrated under reduced pressure. The residue was treated with ether (15 ml) and precipitated crystals were collected by filtration to give orange crystals of 9(R)-valeryloxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 149°-152° C.
Reaction SMILES: [Na].FC1C=C(C=CC=1F)C[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.CS([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C:28]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[C:27](S(C)(=O)=O)[N:26]=1)(=O)=O>>[F:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[CH2:8][O:7][C:25]1[N:26]=[C:27]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C:28]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:30]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: Fc1ccc(COCc2ccc(F)c(F)c2)cc1F
Agent: [Na]
Product: Fc1ccc(COc2nc(OCc3ccc(F)c(F)c3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
In Examples 17-19, the procedure described in Example 16 was followed but with substitution of the appropriate sodium alkoxide (2 eq) for sodium-3,4-difluorobenzyloxide in the reaction with 2,4-bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) to afford the following compounds:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[C:4]([C:26](=O)[CH3:27])[CH:3]=1.C([O-])(=O)C.[NH4+:33]>CO.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=2)=[C:4]([CH:26]([NH2:33])[CH3:27])[CH:3]=1
Reactant: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CO
Product: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Yield: 31.5 %

Procedure:
A solution of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanone (190 mg, 0.47 mmol), ammonium acetate (360 mg, 4.7 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65° C. for 3 hours. The reaction mixture was quenched with acetic acid (˜100 uL) and poured into sodium bicarbonate (50 mL). This mixture was extracted with dichloromethane (3×60 mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (60 mg, 32%). LCMS for C21H23ClF2N3O (M+H)+: m/z=406.1. Found: 406.1.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O-:25])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19](=[O:22])[CH2:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O:25][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19](=[O:22])[CH2:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 1.5 h

Procedure:
Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (75.8 mg) was dissolved in 7 ml of DMF. Sodium hydrogencarbonate (4.9 mg) and 0.038 ml of pivaloyloxymethyl iodide were added to the solution in an argon atmosphere at −30° C. The mixture was stirred for 1.5 hr. Ethyl acetate (50 ml) was added to the reaction solution. The mixture was washed three times with 30 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to 5 ml under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to give 62.3 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH:20]=O)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][CH2:20][CH2:19][NH:18][C:17](=[O:22])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-Bromo-2,3-dihydro-1H-inden-2-amine (0.21 g, 1.0 mmol) in 16 mL of DCM/MeOH (7/1, v/v) was added tert-Butyl(2-oxoethyl)carbamate (160 mg, 1.0 mmol) and NaBH(OAc)3 (297 mg, 1.4 mmol), and the mixture was stirred at RT for 3 hours. DCM was added to the mixture, and then washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(SCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
79.7 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 303.1 mg of 4-acetamidothiophenol in 6 ml of dimethylformamide at room temperature, followed by the addition of a solution of 454.8 mg of 2-bromomethyl-benzothiazole in 1 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 462.7 mg (yield 81%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[NH4+]>S(=O)(=O)(O)O>[C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:17])=[O:18])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: N#Cc1cnn2c(-c3ccccc3)ccnc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 4.0 g of 7-phenylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Example 7 of U.S. Pat. No. 4,236,005) and 40 ml of concentrated sulfuric acid was stirred at room temperature for 16 hours. The solution was then carefully poured into ice with stirring and the mixture was carefully made just basic with concentrated ammonium hydroxide. The solid was collected by filtration and recrystallized from dichloromethane to give pale yellow needles m.p. 236°-238.5° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
2-[4-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.23 g, 77%) as pale yellow crystals.