Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(O)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)OC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of 3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (115 mg, 0.31 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (154 mg, 0.47 mmol, 1.5 eq). The reaction mixture was stirred for 30 min at room temperature then isopropyl bromoacetate (68.4 mg, 0.38 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 2 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 30:1 to 20:1) to give the title compound as a colorless oil (155 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and TEA (1.0 g, 9.9 mmol) in CH2Cl2 (40 mL) was slowly added MsCl (0.63 g, 5.5 mmol). The reaction mixture was stirred for 30 min at −20° C. and then water (60 mL) was added. The aqueous phase was separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate that was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 45.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, 0.0607 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,3-dichlorobenzenesulfonyl chloride (0.0479 g, 0.195 mmol) to obtain 4-(2,3-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0186 g, yield 37%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: [H][H]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1

Procedure:
(S)—N-((3aS,4R,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide (0.400 g, 1.001 mmol) from Step B of Example 249 and ethanol (40 mL) were added to 20% Pd(OH)2 on carbon, wet (0.080 g, 0.570 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under 30 psi hydrogen at 55° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (S)-4-methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.46 (d, J=6.9, 1H), 4.46-4.38 (m, 1H), 3.74 (s, 4H), 3.45 (dd, J=2.0, 11.3, 1H), 3.31-3.21 (m, 2H), 3.10 (dd, J=7.0, 11.0, 1H), 2.89 (dd, J=2.3, 11.0, 1H), 2.83-2.77 (m, 2H), 2.76-2.67 (m, 4H), 2.09 (td, J=6.0, 11.8, 1H), 1.95-1.87 (m, 1H), 1.84 (dq, J=6.0, 9.7, 2H), 1.71-1.57 (m, 2H), 1.49 (ddt, J=6.3, 9.1, 12.5, 1H), 0.94 (dd, J=6.3, 11.2, 6H); MS (ESI+) m/z 310 (M+H)+
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[NH2:12][CH:13]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C>ClCCl>[N:15]1([CH2:14][CH:13]([NH:12][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Reactant: CCOC(=O)CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCC(=O)NC(COCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 12 h

Procedure:
A solution of ethyl 4-(chloroformyl)butyrate (0.714 g, 0.004 mol) in dichloromethane (5 ml) was added dropwise to a stirred solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 32c; 1.0 g, 0.0038 mol) and triethylamine (0.4 g, 0.004 mol) in dichloromethane (20 ml) at room temperature. The solution was stirred for 12 hours, washed with an aqueous saturated solution of ammonium chloride and dried (Na2SO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, 2% ethanol in chloroform) to give ethyl 5-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethyl]amino]-5-oxopentanoate as a pale-yellow oil.
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=1)[CH2:12][C:13]([OH:22])=[O:14])([OH:51])=[O:8]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 74.8 %

Procedure:
A mixture of 10.2 g (0.0145 mol) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on charcoal in 500 ml of THF was shaken in a hydrogen atmosphere at room temperature for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to a solid which was recrystallized from acetonitrile to give 5.66 g (75% yield, mp 110°-114°) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)[N:11]=2)=[CH:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.C1COCC1>O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:25])[CH3:24])[CH2:20][CH2:21]3)[N:11]=2)=[CH:2]1
Reactant: NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 661.6 %

Procedure:
To a flask was added compound 62 (10.2 mg), acetic anhydride (0.5 mg), pyridine (0.1 mL) and THF (1 mL) at 0° C. The mixture was warmed to rt slowly and stirred for 1 hr, then poured into water and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated to provide 10.9 mg (94%) of the desired product as a white solid. 1H NMR (400 MHz, DMSO) δ 12.30 (s, 1 H), 8.70 (d, 1 H), 8.40 (s, 1 H), 8.25 (m, 1 H), 8.20 (d, 1 H), 7.80 (d, 1 H), 7.25 (m, 1 H), 7.10 (d, 1 H), 4.60 (d, 2 H), 3.90 (m, 1 H), 3.15 (m, 2 H), 1.85 (m, 2 H), 1:80 (s, 3 H), 1.40 (m, 2 H). MS (ESI) m/z: 337 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[C@@H:20]12[CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:24][CH2:23][CH2:22][NH:21]2>CN(C)C=O.C(#N)C>[Cl:12][C:11]1[C:2]([N:27]2[CH2:28][C@@H:20]3[C@@H:25]([CH2:24][CH2:23][CH2:22][NH:21]3)[CH2:26]2)=[N:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19]
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@@H]4CCCN[C@@H]4C3)ncc2c1=O

Procedure:
200 mg (0.67 mmol) of 7,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acid are stirred with 190 mg (1.5 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture of 1.7 ml of dimethylformamide and 1.7 ml of acetonitrile under argon overnight. The precipitate is isolated and washed with acetonitrile. The crude product is purified on silica gel (eluent: dichloromethane/methanol/aqueous ammonia solution 75:20:25).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:14][C:15]1[CH:16]=[C:17]([NH2:29])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C1C[O:33][CH2:32]C1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:29][C:32]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:2]=2[Cl:1])=[O:33])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: C1CCOC1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: NCc1ccc(C(F)(F)F)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)NCc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
0.770 g (4.457 mmol) CDT was added at 0° C. to a solution of 0.870 g (4.151 mmol) 2-chloro-4-trifluoromethyl-benzylamine (Example 168a) in 50 mL abs. THF and the mixture was stirred for 1 h at RT. 1.080 g (4.449 mmol) 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b) was added and the mixture was refluxed for 5 h. The reaction mixture was evaporated down i. vac. and the residue was taken up in dichloromethane. The org. phase was washed with 15% aqueous potassium carbonate, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:41])[CH2:25][O:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:42][I:43]>C(Cl)(Cl)Cl>[I-:43].[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:41])[CH2:25][O:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N+:35]1[CH:39]=[CH:38][N:37]([CH3:42])[CH:36]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CI
Reactant: C=C(COC(=O)CCCCCCCn1ccnc1)COC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: C=C(COC(=O)CCCCCCC[n+]1ccn(C)c1)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [I-]
Temperature: 22 °C
Reaction time: 24 h

Procedure:
1-Octadecylaminocarbonyloxy-3-[8-(1-imidazolyl)octanoyloxy]-2-methylenepropane (from Preparation 33) (0.55 g) was dissolved in chloroform (10 ml). Methyl iodide (6 ml) was added, and the mixture stirred at 22° C. for 24 hours. The mixture was evaporated to dryness in vacuo to give the desired product.
Reaction SMILES: O.[OH-].[Li+].[NH:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][C:6]([N:8]([CH2:10][C:11]([N:13]([CH3:22])[C@H:14]([C:18]([O:20]C)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9])=[O:7].Cl>C1COCC1.CO.O>[NH:4]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:5][C:6]([N:8]([CH2:10][C:11]([N:13]([CH3:22])[C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9])=[O:7]
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
From 600; Lithium hydroxide monohydrate (249 mg, 5.9 mmol) was added to a solution of 600 (740 mg, 1.98 mmol) in 15 mL of THF—CH3OH—H2O (3:1:1) at 25° C. and the resulting reaction mixture was stirred for 3 h. The reaction mixture was poured onto 3M aqueous HCl (8 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to give 7 (638 mg, 712 mg theoretical, 90%) as a white solid which was employed directly in the next reaction without further purification: white foam, mp 57-60° C.; 1H NMR (CDCl3, 400 MHz) 5.67 and 5.58 (two s, 1H), 4.63 (d, 1H, J=10.4 Hz), CH), 4.10-3.82 (m, 4H), 3.05, 3.04, 3.01 and 2.88 (four s, 6H), 2.30-2.20 (m, 1H), 1.43 and 1.41 (two s, 9H), 1.04 and 0.88 (two d, 6H, J=6.7 Hz); IR (KBr)max 3421, 2974, 1706, 1656, 1495, 1419, 1367, 1292, 1250, 1171, 1053, 953, 870, 837, 670 cm−1.
Reaction SMILES: [Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12]O)=[C:8]([Cl:17])[CH:7]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12][Br:20])=[C:8]([Cl:17])[CH:7]=1
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A stirred solution of 2.5 grams (0.0075 mole) of 2-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]ethan-1-ol and 3.1 grams (0.0094 mole) of carbon tetrabromide in 150 mL of methylene chloride was cooled to 0-4° C. and 6.0 grams (0.0152 mole) of triphenylphosphine was added portion-wise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:5 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:16]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28].CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>CO>[F:30][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]4[CH2:26][CH2:25][N:24]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:23][CH2:22]4)[CH:16]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CN1c2nc(-c3cccc(C4CCNCC4)c3)ccc2N(CC2CC2(F)F)S1(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN1c2nc(-c3cccc(C4CCN(S(C)(=O)=O)CC4)c3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial was added 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(3-piperidin-4-ylphenyl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (31-3) (0.030 g, 0.064 mmol), NMP (1 mL), DIPEA (0.060 mL, 0.344 mmol), and finally methanesulfonyl chloride (0.0374 mL, 0.480 mmol). The reaction mixture was then permitted to stir at room temperature for 1 hour. The crude reaction mixture was then diluted with methanol, then filtered. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-{3-[1-(methylsulfonyl)piperidin-4-yl]phenyl}-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (31-4) as a tan solid. HRMS (M+H)+: observed=513.1430, calculated=513.1436.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH2:1]([O:3][N:4]([CH3:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCONC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl ethoxycarbamate (XCIII, 2.48 g, 15.38 mmol) in DMF (10 mL) was added dropwise to the suspension of 60% sodium hydride (0.66 g, 16.92 mmol) in DMF (5 mL) at 0° C. After 30 min. methyl iodide (1.95 mL, 31.32 mmol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature for 24 h. Water (100 mL) was added and the product was extracted with ethyl acetate (3×50 mL), dried over Na2SO4, and concentrated in vacuo to yield tert-butyl ethoxy(methyl)carbamate (XCIV, 2.34 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm) 3.81 (2H, q, J=7.0 Hz), 3.00 (3H, s), 1.41 (9H, s), 1.12 (3H, t, J=7.0 Hz).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17]1[S:18][C:19](C)=[N:20][N:21]=1.[C:23]([O-])([O-])=[O:24].[K+].[K+]>CC(C)=O>[CH3:13][C:7]1[C:8](=[O:12])[O:9][C:10]2[C:5]([C:6]=1[CH3:14])=[C:4]([O:24][CH3:23])[CH:3]=[C:2]([C:19]1[S:18][C:17]([CH3:16])=[N:21][N:20]=1)[CH:11]=2
Reactant: O=C([O-])[O-]
Reactant: Cc1nnc(CCl)s1
Reactant: Cc1c(C)c2ccc(O)cc2oc1=O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2nnc(C)s2)cc2oc(=O)c(C)c(C)c12

Procedure:
A mixture of 5.0 g of 7-hydroxy-3,4-dimethylcoumarin, 3.9 g of 2-chloromethyl-5-methyl-1,3,4-thiadiazole, 3.5 g of K2CO3 and 100 ml of acetone was refluxed for 20 hours and evaporated down, and the residue was partitioned in H2O/methylene chloride. After the undissolved constituents had been separated off, the organic phase was washed once with 1 N NaOH and then with H2O, dried over Na2SO4 and evaporated down, and the residue was recrystallized from methanol and dried.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:9][C:10]([OH:12])=O.[OH:18][C@@H:19]([C@@H:21]1[C@@H:24]([C@@H:25](C)[C:26](=O)N2CCSC2=S)[NH:23][C:22]1=[O:35])[CH3:20].N1C=CN=C1>O1CCCC1>[OH:18][C@@H:19]([C@H:21]1[C:22](=[O:35])[NH:23][C@@H:24]1[C@@H:25]([CH3:26])[C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:20]
Reactant: C=CCOC(=O)CC(=O)O
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1CCSC1=S
Agent: CC[O-]
Agent: [Mg+2]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a stirred suspension of magnesium ethoxide (14.7 g) in tetrahydrofuran (250 ml) was added allyl hydrogen malonate (38.8 g) at 30° C. under nitrogen atmosphere. The resultant mixture was stirred at ambient temperature for 10 hours. To this mixture were added (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (24.7 g) and imidazole (8.8 g), and the mixture was allowed to heat to 60° C. for 1 hour. After evaporation of the solvent in vacuo, the residue was taken up into a mixture of ethyl acetate (300 ml) and brine (200 ml). After adjusting to pH 3.5 with concentrated hydrochloric acid at 5° C., the organic layer was separated and diluted with brine (200 ml). After adjusting to pH 8 with 30% aqueous potassium carbonate at 5° C., the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane and acetone (19:1-1:1 v/v) to give allyl (4R)-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (19.46 g).
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:12])[CH2:10]Br)[CH3:7]>C1COCC1.[Zn].[O-2].[Zn+2]>[CH2:6]([O:8][C:9](=[O:12])[CH:10]=[C:4]([NH2:5])[CH:1]1[CH2:3][CH2:2]1)[CH3:7]
Reactant: N#CC1CC1
Reactant: CCOC(=O)CBr
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Cyclopropanecarbonitrile (2.7 g, 40.5 mmol) was dissolved in dry THF (100 mL) and firstly zinc (13.2 g, 202.3 mmol) and then zinc oxide (1.6 g, 20.2 mmol) were added followed by dropwise addition of ethylbromoacetate (6.7 g, 40.5 mmol). The mixture was sonicated in a 35 kHz ultrasonic bath under N2 for 2 hours. After 30 minutes a green colour was observed. The mixture was filtered through celite to remove the zinc and zinc oxide. The filtrate was added to 20 ml of 50% K2CO3 (aq) solution. A thick precipitate formed which was filtered to remove the solid and the aqueous was extracted with 100 ml EtOAc. The extract was washed with 20 ml brine, dried over MgSO4 and concentrated in vacuo to give the crude product (3.8 g). The crude material was purified by column chromatography on silica gel eluting with 90:10 pentane:EtOAc to give the title compound (1.32 g) as a yellow oil.