Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[CH:35]=[CH:34]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][N:33]2[CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc2ccn(CC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4 g, 0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93 mmol) and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as a yellow solid: mp: 138° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)[CH2:8]1.[NH2:22][C:23]1[C:24]([C:30]([OH:32])=O)=[N:25][C:26](Br)=[CH:27][CH:28]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:21])[C:6]=2[N:7]2[CH2:11][CH2:10][C@@H:9]([CH2:12][NH2:13])[CH2:8]2)=[O:32])=[N:25][C:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[CH:27][CH:28]=1
Reactant: Cn1ncc(N)c1N1CC[C@@H](CNC(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: OB(O)c1ccccc1F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1N1CC[C@@H](CN)C1
Yield: 48 %

Procedure:
Following the procedures for Example 141, (S)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate and 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 134 as a white solid (76 mg, 48%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.05 (t, J=7.9, 1H), 7.73 (dd, J=8.7, 2.0, 1H), 7.57 (s, 1H), 7.49-7.22 (m, 4H), 7.07 (s, 2H), 3.65 (s, 3H), 3.33-3.18 (m, 4H), 3.00 (dd, J=8.8, 6.3, 2H), 2.23 (dt, J=13.9, 7.0, 1H), 1.97 (td, J=12.5, 7.1, 1H), 1.68-1.55 (m, 1H). ESIMS m/z=410.1 (M+1)
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.Cl.[OH:15][CH:16]1[O:24][C@@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@@H:19]([OH:20])[C@@H:17]1[NH2:18]>CO.C([O-])(O)=O.[Na+]>[CH:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]2[C:10](=[N:9][O:8][N:7]=2)[C:2]=1[NH:18][C@@H:17]([C@H:19]([OH:20])[C@@H:21]([OH:22])[C@@H:23]([OH:24])[CH2:25][OH:26])[CH:16]=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: N[C@@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C[C@@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a brown flask, 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) (483 mg) was placed and dissolved in methanol (14.0 ml). Under an argon atmosphere, a solution in which L-glucosamine hydrochloride (283 mg) was dissolved in 0.3 M NaHCO3 solution (5.57 ml) was added thereto, and the resulting mixture was stirred at room temperature. After 24 hours, methanol was removed by concentration under reduced pressure, and the resulting precipitates (unnecessary substances derived from NBD-Cl) were removed by filtration. The precipitates were washed with water, and the filtrate and the washing solution were combined, followed by purification by HPLC. A target fraction was collected and lyophilized, whereby a target product was obtained (yield: 102 mg, yield ratio: 23%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][C:53](C)(C)C)=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:3])[CH3:2].Cl.C(N(C(C)C)CC)(C)C.ClC(OC)=O>O1CCOCC1.O>[C:1]([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][CH3:53])=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:32][CH:33]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:24])([CH3:23])[CH3:25])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Agent: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)COC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of the product of Example 174F (0.030 g, 0.037 mmol) in dioxane (0.50 mL) at 0° C. was added a solution of HCl in dioxane (3.0 mL, 4 N), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (0.40 mL) and diisopropylethylamine (0.030 mL, 0.172 mmol) and methyl chloroformate (0.0032 mL, 0.041 mmol) were added at room temperature. After 1 hour water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.019 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80-0.82 (m, 15 H), 1.41-1.58 (m, 2 H), 2.00 (s, 3 H), 2.54-2.57 (m, 1 H), 2.71-2.79 (m, 3 H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.61-3.73 (m, 2 H), 3.78-3.84 (m, 1 H), 4.03-4.24 (m, 3 H), 4.90 (d, J=5.5 Hz, 1 H), 6.62 (d, J=9.6 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 7.10-7.21 (m, 7 H), 7.29-7.31 (m, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.80 (d, J=9.9 Hz, 1 H), 7.85-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Yield: 32.7 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 326 mg; 1.0 mmol) and 2-aminothiazole (231 mg; 2.23 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40M column, eluent: 5% to 30% gradient of ethyl acetate/hexanes) 132 mg of (S)-3-Cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22ClN3O2S (M++Na+) 426.1013, found 426.1016; and 91 mg of regioisomeric (S)-3-Cyclohexyl-2-(7-Chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22ClN3O2SNa (M++Na+) 426.1013, found 426.1017.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]([NH:15][S:25]([C:18]3[C:19]([CH3:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[Cl:16])(=[O:27])=[O:26])[S:13][CH:14]=2)=[CH:2]1
Reactant: Nc1nc(-c2csc3ccccc23)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2csc3ccccc23)cs1

Procedure:
The title compound was prepared from 4-(1-benzothien-3-yl)-1,3-thiazol-2-amine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (47.0 mg) with purity >90%. MS (pos) m/z 455.0, 457.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]2[CH2:27][CH2:26][C@@:25]3([CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])[NH:24]2)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]3[CH2:27][CH2:26][C@@:25]4([CH2:31][CH2:30][N:29]([CH3:32])[C:28]4=[O:33])[NH:24]3)[CH:16]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CCc1cnc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)cc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2cc([C@H]3CC[C@@]4(CCN(C)C4=O)N3)ncc2CC)c1
Temperature: 140 °C
Yield: 73.3 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (54.39 mg, 0.3000 mmol) in MeCN (1 mL) and water (0.2000 mL) was added (2R,5S)-2-(4-bromo-5-ethyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 122) (80 mg, 0.2400 mmol), sodium carbonate (50.12 mg, 0.4700 mmol) and bis(triphenylphosphine)palladium (II) dichloride (8.2 mg, 0.0100 mmol). The microwave vial was sealed and heated at 140° C. for 15 minutes. The reaction was concentrated in vacuo and loaded onto a silica column (10 g, Biotage SNAP cartridge). The silica column was then eluted with a gradient of (80:20:2 EtOAc:MeOH:0.88M NH3):EtOAc from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give (2R,5S)-2-[4-(5-ethoxy-2-fluoro-phenyl)-5-ethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (69.9 mg, 0.1759 mmol, 74.4% yield) as a colourless oil;
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)(=[O:3])[CH3:2].[OH:19]O.[OH-].[Na+]>CO>[C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][C:8]12[O:19][CH:12]1[CH2:11][CH2:10][C:9]2=[O:13])(=[O:3])[CH3:2]
Reactant: OO
Reactant: CCCCCC(CCC1=CCCC1=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CCC12OC1CCC2=O)OC(C)=O
Reaction time: 18 h

Procedure:
A stirred solution of 2-(3-acetoxyoctyl)cyclopent-2-enone (31.8 g.) [prepared as described in (f) above] in methanol (700 ml.) was treated slowly with aqueous hydrogen peroxide solution (45 ml. of "100 vol." solution) and aqueous 4N sodium hydroxide solution (15 ml.) at 5° to 10° C. and allowed to stand at room temperature for 18 hours. The solution was concentrated in vacuo (to about 100 ml. volume), and water (100 ml.) was added to the residue. The mixture was extracted with chloroform and the chloroform extract was washed with water and dried over magnesium sulphate. The solvent was removed in vacuo to give 2-(3-acetoxyoctyl)-2,3-epoxycyclopentanone (26.4 g.) which was used as starting material in the following preparation (h) of 5-acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCC(CN)CC1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CNC(=O)c2cc(F)cc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (60 mg, 0.21 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (54 mg, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-((1-methylpiperidin-4-yl)methyl)benzamide 10. LC/MS (ESI+): m/z 395 (M+H). 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=8.8 Hz, 1H), 8.48 (d, J=10.6 Hz, 1H), 8.46-8.38 (m, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 2.90 (d, J=7.8 Hz, 2H), 2.84-2.63 (m, 4H), 2.19 (s, 1H), 2.03 (s, 3H), 1.82 (s, 2H), 1.66 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]\[CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](\[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC/C(=C/C=O)c1cccc(F)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)OC)c1cccc(F)c1

Procedure:
As described in Example 99, (Z)-3-(3-fluorophenyl)-2-octenal (6.2 g) was treated with (carbomethoxymethylene)triphenylphosphorane (10.5 g) in dichloromethane (50 mL) for 4 days at room temperature. The ester was isolated in the usual way and furnished 6.6 g of (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[Na].[CH3:14][C:15](N(C)C)=O.[OH2:20]>C(O)C.[Cu]>[Cl:8][C:5]1[CH:4]=[C:3]([S:9]([OH:12])(=[O:11])=[O:10])[C:2]([C:2]2[C:3]([S:9]([OH:11])(=[O:10])=[O:20])=[CH:4][C:5]([Cl:8])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)c1cc(Cl)ccc1Cl
Reactant: O
Reactant: CC(=O)N(C)C
Agent: [Cu]
Agent: [Na]
Solvent: CCO
Product: O=S(=O)(O)c1cc(Cl)ccc1-c1ccc(Cl)cc1S(=O)(=O)O
Temperature: 150 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Inside a glove box, a 300 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with anhydrous 2,5-dichlorobenzenesulfonic acid, sodium salt (24.9 g, 0.1 moles), activated copper bronze (12.7 g, 0.2 moles), and DMAc (100 mL). The mixture was heated to 150° C. overnight under nitrogen. The mixture was poured into water (1 L) and the solid removed by vacuum filtration. The filtrate was treated with sufficient sodium carbonate to precipitate residual copper salts, which were removed by vacuum filtration. The solution was evaporated and the residue dried at 150° C. under vacuum. The solids (29.75 g) were dissolved in a mixture of ethanol and water, acidified with acetic acid, filtered, and concentrated to give an oil. The oil was dissolved in ethanol (100 mL) and allowed to set overnight to give a copious white solid, which was collected by vacuum filtration and washed twice with ethanol. The solids were recrystallized twice from ethanol to give 10.05 g (47% yield) of 4,4′-dichlorobiphenyl-2,2′-disulfonic acid, sodium salt. 1H NMR (DMSO-d6): 7.30 (d, 8.2 Hz, 2H), 7.34 (dd, 8.2, 2.3 Hz, 2H), 7.82 (d, 2.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-].[Na+:28]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Temperature: 2 °C
Reaction time: 2 h

Procedure:
A 100 ml round bottomed flask equipped with a magnetic stir bar was charged with acetone (50 ml). Pantoprazole (10 g, 25.7 mmol) was then added to the flask. After the pantoprazole had completely dissolved, the solution was cooled to about 2° C. Forty seven percent sodium hydroxide (aq.) equivalent to 2.4 grams of solid sodium hydroxide (60.0 mmol) was slowly added to the cooled solution. A precipitate began to form immediately. The mixture was stirred for another two hours while the flask was allowed to warm to room temperature. The precipitate was filtered and washed with acetone (20 ml) and dried at 40° C. under vacuum to yield pantoprazole sodium Form II (6.9 g, 65%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>ClCCl>[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:9]([F:27])=[CH:10][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[O:17][C:16]4=[O:26])=[CH:12][C:13]=3[F:14])=[CH:4][CH2:3]2)=[O:41])[CH2:37][O:36]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in dry dichloromethane (20 ml) at 0–4°, was treated with pyridine (648 mg, 8.2 mM) followed by dropwise addition of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (430 mg, 2.64 mM). The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water and brine, dried (sodium sulfate) and evaporated to a gum which crystallised readily on trituration with diethyl ether to give the title compound (788 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][CH:6]=1.Br[CH2:21][CH2:22][O:23]C1CCCCO1>>[Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[N:5]([CH2:21][CH2:22][OH:23])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1

Procedure:
tert-butyl 4-formylpiperidine-1-carboxylate 4a was reacted with aqueous glyoxal in the presence of aqueous ammonium hydroxide in methanol to give tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate 4b, which was bromined to afford tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate 4c. 4c was alkylated with 2-(2-bromoethoxy)tetrahydro-2H-pyran, followed by removal of THP group under acidic condition to yield tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate 4d. Suzuki coupling was performed with bromide intermediate 4d to afford 4e. 4e was reacted with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, followed by quenching with amine afforded 4f, which was treated with hydrogen chloride in methanol or trifloruoacetic acid in DCM to provide the amine intermediates 4g.
Reaction SMILES: O[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(Cl)([Cl:21])=O>>[ClH:21].[Cl:21][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCC(O)Cn2ccnc2)cc1
Product: COc1ccc(CCC(Cl)Cn2ccnc2)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1-[2-Hydroxy-4-(4-methoxyphenyl)-n-butyl]imidazole (2.0 g) was treated with thionyl chloride (10 ml) and the solution stirred for one hour at 60° C. The solvent was then evaporated under reduced pressure and the residue crystallized from ethyl acetate/ether, filtered, washed with ethyl acetate and dried in air to give 1-[2-chloro-4-(4-methoxyphenyl)-n-butyl]imidazole hydrochloride.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([N-:17][CH2:18][CH3:19])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:39]([O:38][C:36]([NH:35][C@H:34]([C:33]([NH:2][C@H:3]([C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([N-:17][CH2:18][CH3:19])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:32])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 18.6 g. of L-arginyl-L-prolyl-N-ethylamide hydrochloride and 7.2 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenylester in 30 ml. of dimethylformamide is allowed to stand for four days, warmed to 50° C. for a half hour and evaporated at reduced pressure and 40° C. to yield an oil. A solid product is obtained by chromatography over silica gel, eluting with chloroform with increasing percent of methanol. Fraction selection is made on the basis of analytical thin layer chromatography and the product, Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-N-ethylamide hydrochloride, obtained solid by precipitating from methanol with ethyl acetate and then by dropping a methanol solution into ethyl ether. The solid is dried at 40° C. and reduced pressure; [α]D25 -68.4° (c 1, methanol).