Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([O:26][C:27]([N:29]=[C:30]=[S:31])=[O:28])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:30]([NH:29][C:27]([O:26][CH2:24][CH3:25])=[O:28])=[S:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NC(=S)NC(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Methyl ester 1-1 (394 mg, 1.58 mmol) was dissolved in methylene chloride (4.0 mL) and diisopropylethylamine (0.82 mL, 4.73 mmol). The solution was cooled to 0° C. and ethoxycarbonyl isothiocyanate (0.21 mL, 1.73 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred 30 min. Methylene chloride (20 mL) was added, and the organic layer was washed with water (20 mL), 10% aqueous HCl (20 mL), and saturated brine (20 mL). The organic layer was dried with MgSO4, filtered and the solvent was removed in vacuo to yield the product as a yellow oil in 92% yield (502 mg, 1.45 mmol). 1H NMR (300 MHz, CDCl3): δ=10.10 (d, 1H, J=6.6 Hz), 8.11 (s, 1H), 7.27 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 5.25 (t, 1H, J=6.3 Hz), 4.23 (q, 2H, J=7.2 Hz), 3.73 (s, 3H), 3.32 (dd, 1H; J=14.1, 6.0 Hz), 3.20 (dd, 1H, J=13.8, 6.0 Hz), 1.30 (t, 3H, J=7.2 Hz); 13C NMR (75 mHz, CDCl3): δ=179.4, 170.8, 152.6, 134.2, 133.4, 130.8, 129.0, 63.2, 59.2, 53.6, 52.8, 36.8, 14.4; ESI-MS calcd for C14H17ClN2O4S [M+Na]+: 267.0495. found 267.0495.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[CH:12]=NO.B(F)(F)F.CC[O:22]CC>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:11](=[O:15])[C:12]2=[O:22]
Reactant: CCOCC
Reactant: COc1cccc(NC(=O)C=NO)c1Cl
Agent: FB(F)F
Product: COc1ccc2c(c1Cl)NC(=O)C2=O
Temperature: 90 °C
Yield: 63 %

Procedure:
Compound 245d (10.46 g, 45.74 mmol) was added portionwise to BF3.Et2O at 40° C. The mixture was then heated at 90° C. for 3 hrs. After cooling down to room temperature, the reaction mixture was poured into crushed ice and extracted with EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc). The compound obtained was recrystallized from EtOH to yield compound 246d as a brown solid in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.96 (s, 3H), 6.79 (d, J=9.10 Hz, 1H), 7.52 (d, J=9.10 Hz, 1H), 11.40 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2([C:33]([F:36])([F:35])[F:34])[CH2:17][CH2:16][N:15]([C:18]3[CH:28]=[CH:27][C:21]([C:22](OCC)=[O:23])=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClCCl.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.CCCCCC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:33]([F:34])([F:35])[F:36])[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[C:20]([C:29]([F:30])([F:31])[F:32])[C:21]([CH2:22][OH:23])=[CH:27][CH:28]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:8]=1
Reactant: CCOC(=O)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: OCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Ethyl 6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoro-methyl)nicotinate (1.7 g) was added to dichloromethane (50 ml). Then, 1.0 mol/l hexane solution (10 ml) of diisobutyl aluminum hydride was added dropwise thereto at −70° C. After continuing the stirring at −70° C. for 30 minutes, ethyl acetate (50 ml) and sodium sulfate decahydrate (3.0 g) were added. After further stirring at room temperature for 1 hour, the reaction liquid was filtered by suction on Celite. The filtrate was distilled off under reduced pressure and the purified by silica gel column chromatography to obtain [6-{3-[3,5-bis-(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]-methanol (1.55 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH:9]([CH3:13])[O:10][CH2:11][CH:12]=1)(=O)=O.CC1(C)C(C)(C)OB([C:24]2[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:13][CH:9]1[CH2:8][C:7]([C:24]2[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:12][CH2:11][O:10]1
Reactant: CC1CC(OS(=O)(=O)C(F)(F)F)=CCO1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC1CC(c2cnc(N)cn2)=CCO1
Temperature: 120 °C
Yield: 45.4 %

Procedure:
To a solution of 2-methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.637 g, 2.88 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (0.914 g, 3.74 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.235 g, 0.288 mmol) in DME (9.82 mL) was added 2M Na2CO3 (3.27 mL). The reaction mixture was heated at microwave synthesizer (120° C., 10 min). Ethyl acetated was added, and washed with sat NaHCO3, and water. Then the desired compound was extracted to 1N HCl aqueous layer, and washed with EtOAc. Basified with 2N NaOH, and the product was extracted to EtOAc layer. EtOAc organic layer was washed with water and dried over Na2SO4. Filtered and concentrated to provide 250 mg of desired compound. LCMS (m/z): 192.2 (MH+), 0.40 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromobenzoyl chloride (12.43 g, 56.6 mmol) and N,O-dimethyl hydroxyamine hydrochloride (8.29 g, 85.0 mmol) in CH2Cl2 (200 ml) was added triethylamine (23.7 ml, 170 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours. Water (200 ml) was added and the aqueous layer was extracted with CH2Cl2 (150 ml×2). The combined organic layer was washed with 2N HCl (200 ml), saturated aqueous NaHCO3 (200 ml), and brine (200 ml), dried over Na2SO4, and concentarated in vacuo to give 14.9 g (quant.) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]>>[CH3:31][C:32]([NH:40][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 75 %

Procedure:
A procedure similar to that described in Example 3(b) was repeated, except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-methyl-1-phenylethylamine were used as starting materials, in relative proportions similar to those used in that Example, to give the title compound in a yield of 75%.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16].CO>O.C(O)(=O)C>[NH2:17][CH2:14][CH2:15][CH2:16][N:13]([CH2:3][CH2:2][CH2:1][NH2:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: C=CC#N
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCN(CCCN)CCCN
Yield: 373.1 %

Procedure:
670 g of laurylamine (C12 -fraction: 73 mole %, and C14 -fraction: 23 mole %) were reacted in the manner already described in Example 1 with 373 g of acrylonitrile in 68 g of water, 34 g of methanol and 14 g of concentrated acetic acid, and the product was then hydrogenated. 2,020 g of bis-(3-aminopropyl)-laurylamine were obtained after the hydrogenation. 954 g of this triamine were condensed with 640 g of ethylene oxide. 1,590 g of bis-(3-aminopropyl)-laurylamine ethoxylate (99%) were obtained. 257 g of this ethoxylate and 538 g of water were reacted with 146 g of 70% by weight strength H2O2. The triamine-trioxide was obtained in 935 g of a 30% by weight strength aqueous solution.
Reaction SMILES: N1CCOCC1.[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[F:14].C1(N)CCCCC1.O>CO>[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]([OH:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C(O)/C=C/C(O)c1ccc(-c2ccc(F)c(F)c2)cc1
Solvent: NC1CCCCC1
Solvent: CO
Solvent: C1COCCN1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)c(F)c2)cc1
Yield: 44 %

Procedure:
Prepared analogous to Example 46 from the morpholine salt of 4-(3',4'-difluoro-4-biphenylyl)-4-hydroxy-crotonic acid in methanol. Melting point of the cyclohexylamine salt: 170°-171° C. (from water). Yield: 44% of theory.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][NH2:37])=[N:34][CH:35]=1)(=[O:29])=[O:28].[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56](O)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1.CC(N(C)C)=O>CN1C(=O)CCC1>[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:52])[F:53])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56]([NH:37][CH2:36][C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:35][N:34]=2)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC(=O)N(C)C
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 20.4 %

Procedure:
HBTU (30 mg, 0.079 mmol) was added to {[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride (20 mg, 0.090 mmol), 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (Example 92 (a), 27 mg, 0.072 mmol) and DMA (23 μl, 0.31 mmol) in NMP (0.25 ml) and the mixture was stirred in a sealed vial overnight. The product was purified by preparative HPLC and freeze-dried to give the title compound as a white solid (8 mg, 20%).
Reaction SMILES: [C:1]12([NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O>[C:1]12([NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]=[C:14]([NH:29][CH2:26][CH:27]=[CH2:28])[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(NC34CC5CC(CC(C5)C3)C4)c2c1
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NC23CC4CC(CC(C4)C2)C3)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To 82 mg (0.25 mmol) of 4-(1-adamantylamino)-2-chloro-6-nitroquinazoline was added 1.00 ml (13.33 mmol) of allylamine, and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 77 mg (88.7%) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([Br:21])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.C1COCC1.[CH3:27][C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C(NC(C)C)(C)C>O.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.[Cu](I)I.C(OCC)(=O)C>[OH:32][C:28]([CH3:29])([CH3:27])[C:30]#[C:31][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([Br:21])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: NC1=NC2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(O)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A resealable tube was charged with 7-iodo-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (0.500 g, 1.092 mmol), tetrakis(triphenylphosphine)palladium (0.126 g, 0.109 mmol) and copper iodide (0.021 g, 0.109 mmol). THF (2.183 mL, 1.092 mmol) was added followed by 2-methylbut-3-yn-2-ol (0.138 g, 1.637 mmol) and diisopropylamine (1.556 mL, 10.92 mmol). The tube was sealed and stirred at RT overnight. The reaction was diluted with water (25 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (374 mg, 0.903 mmol, 83% yield) (104420-10-1) as a light yellow foam. MS m/z=414.0 [M+H]+. Calc'd for C19H17BrN3O3: 414.0.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[C:13]1([C:19]2[N:23]3[C:24]4[C:29]([CH:30]=[CH:31][C:22]3=[N:21][N:20]=2)=[CH:28][C:27]([S:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[CH:26][CH:25]=4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)([C:35]2[S:34][C:33]([S:32][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[N:23]3[C:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:20][N:21]=[C:22]3[CH:31]=[CH:30]4)=[N:37][CH:36]=2)[OH:42])[CH2:40][CH2:39]1
Reactant: O=C(C1CC1)C1CC1
Reactant: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
iPr2NH (0.12 g, 0.84 mmol) was dissolved in THF (2 mL) and cooled to −78° C. n-Butyllithium (2.5M, 0.37 mL, 0.84 mmol) was added dropwise, followed by 10f (150 mg, 0.42 mmol) in THF (5 mL). Dicyclopropylmethanone (53 mg, 0.46 mmol) in THF (0.25 mL) was added, and the reaction was stirred overnight at room temperature. The reaction was quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product, 10g.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].C(Cl)Cl.[CH3:15][NH:16][S:17]([Cl:20])(=[O:19])=[O:18]>O>[CH3:11][O:10][C:8]([N:16]([CH3:15])[S:17]([Cl:20])(=[O:19])=[O:18])=[O:9]
Reactant: COC(=O)Cl
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N(C)S(=O)(=O)Cl
Yield: 91 %

Procedure:
158.2 parts of pyridine are added at -10° C., while stirring, to a solution of 188.8 parts of methyl chloroformate in 1,200 parts of methylene chloride. Then 259.2 parts of methylsulfamic acid chloride are added at the same temperature while stirring, and the mixture is stirred for half an hour at 0° C. and for one hour at 25° C. The reaction mixture is then stirred for 6 minutes with 600 parts of water at 5° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 341 parts (91% of theory) of N-methoxycarbonyl-N-methylsulfamic acid chloride, of boiling point 49°-51° C./0.13 mbar and nD25 =1.4600, are obtained.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[C:17]1([C:14]2[O:13][C:12]([C:10]([N:8]3[CH2:9][CH:6]([O:5][C:24]4[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=4)[CH2:7]3)=[O:11])=[N:16][N:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 66.1 %

Procedure:
Intermediate 53B (5.0 g, 15.5 mmol) was dissolved in DMA (40 mL) and 4-hydroxybenzaldehyde (2.17 g, 17.8 mmol) was added followed by Cs2CO3 (5.8 g, 17.8 mmol). The mixture was stirred at 110° C. for 5 h. Water was added and the mixture was extracted trice with DCM. The solution was filtered through a phase separator and the solvent was removed by evaporation. Ether was added to the residue and the formed solid was filtered and washed with ether. The product was dried in vacuo to give 3.58 g (66%) of 71A as a beige solid. 1H NMR (500 MHz, CDCl3): δ 4.37 (m, 1H), 4.70 (m, 1H), 4.79 (m, 1H), 5.18 (m, 2H), 6.91 (d, 2H), 7.53 (t, 2H), 7.60 (t, 1H), 7.87 (d, 2H), 8.16 (d, 2H), 9.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.CCN(CC)CC.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:22][CH:19]2[CH2:21][CH2:20]2)=[O:11])[CH:3]=1
Reactant: NC1CC1
Reactant: O=C(O)c1c[nH]c(=O)c(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1c[nH]c(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylic acid (200 mg, 0.917 mmol), Et3N (0.1 mL), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (348 mg, 0.917 mmol) in DMF (5 mL) was added cyclopropanamine (52.4 mg, 0.917 mmol). The mixture was stirred at room temperature for 2 hours and purified via preparative HPLC, eluting with a gradient of 1-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product was dried under vacuum to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:34][N:32]([CH3:33])[C:31]([CH:19]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)=[O:35]
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(-c3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
The sulfonamide compound 54 (1.1 g, 2.06 mmol) was dissolved in THF (30 mL) and diluted with water (30 mL). Lithium hydroxide (0.2 g, 8.26 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×25 mL). The organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried and concentrated to yield the desired acid compound 55 (1.05 g, 98%). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 8.09 (d, J=9.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 4.33 (m, 1H), 2.81-2.87 (m, 3H), 2.75 (s, 3H), 2.61-2.67 (m, 1H), 2.56 (t, J=8.0 Hz, 2H), 2.53 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: II.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[SH:11].COC1C=CC(S([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=2[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[S:11][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=1[CH3:37]
Reactant: COc1ccc(S(=O)(=O)c2c(C)n(CC(=O)O)c3ccc(C)cc23)cc1
Reactant: Sc1c(Cl)cccc1Cl
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(Sc1c(Cl)cccc1Cl)c(C)n2CC(=O)O

Procedure:
Iodine (0.51 g) was added to a solution of 2,6-dichlorobenzenethiol (0.36 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by reverse phase HPLC. The solvent was evaporated in vacuo and the oily residue treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (0.22 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][NH2:17])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([C:12]([CH3:23])([CH3:22])[O:11][SiH2:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl chloroformate (1.98 mL, 25.2 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) and DIPEA (7.33 mL, 42.0 mmol) in CH2Cl2 (100 mL) at rt. The mixture was stirred for 1 h at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl, aq. 1M NaOH, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5) yielded the title compound (5.39 g, 75%). LC-MS: tR=1.02 min; ES+: 344.38.