Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1.O>CCCC[N+](CCCC)(CCCC)CCCC.[I-].C1COCC1>[N:31]1[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][N:5]2[CH2:6][CH2:7][CH2:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[C:4]2=[O:3])[N:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Reactant: BrCc1ccccc1-n1nccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(Cc3ccccc3-n3nccn3)C2=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
NaH (308 mg, 7.69 mmol, 60% in mineral oil) was added to an ice-cold solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (1.127 g, 4.08 mmol), 2-(2-(bromomethyl)phenyl)-2H-1,2,3-triazole (described separately as building block) (1.0 g, 4.16 mmol) and TBAI (78 mg, 0.208 mmol) in THF (30 mL). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and stirred for 4 h. To the mixture water was added and the solution was extracted twice with ethyl acetate. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by flash-column chromatography over silicagel (eluent: gradient 5%-65% ethyl acetate/heptane) to yield the title compound (1.77 g, 99%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.11 (s, 2H), 7.61-7.59 (m, 1H), 7.52-7.46 (m, 2H), 7.23 (d, 1H), 4.53 (s, 2H), 3.69-3.65 (m, 2H), 3.11-3.07 (m, 2H), 3.03 (br s, 2H), 1.86-1.72 (m, 6H), 1.45-1.40 (m, 2H), 1.38 (s, 9H); LCMS RtA=1.17, [M+H]+=426.4].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]([C:17]3[S:21][N:20]=[C:19]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[N:18]=3)[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:27](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]([CH3:27])[CH2:13][CH2:14][N:15]([C:17]3[S:21][N:20]=[C:19]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[N:18]=3)[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)O
Reactant: CN(CCNCCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(CCc1ccc2c(c1)OCO2)CCN(C)c1nc(-n2ccnc2)ns1
Temperature: 25 °C

Procedure:
N′-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-ethane-1,2-diamine (438 mg, 1.20 mmol) was dissolved in methanol (8 mL) and acetic acid (1.0 mL) and stirred at room temperature for 15 minutes. After this period, the sodium triacetoxyborohydride (750 mg, 3.60 mmol) was added and the reaction was allowed to stir at room temperature After this period, the reaction mixture was concentrated down under vacuum. The crude material was purified by Prep LCMS and the fractions were concentrated down. This material was then neutralized with 1M NaOH and extracted with DCM to afford 303 mg of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-N′-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N,N′-dimethyl-ethane-1,2-diamine. [M+H]+ 387.31; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.62 (s, 1H), 7.05 (s, 1H), 6.66-6.53 (m, 3H), 5.85 (s, 1H), 3.12 (m, 3H), 2.68-2.60 (m, 6H), 2.31 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][C:22]=1[Cl:23].C1COCC1.O>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2([OH:1])[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (418 mg) prepared by the method described in WO2004/074291 in THF (12 mL) was added 0.5 M 3,4-dichlorophenylmagnesium bromide-THF (4.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([CH3:42])([CH3:41])[C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[C:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)([CH3:42])[CH3:41])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Product: CN(C(=O)C(C)(C)c1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isobutyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 2-(4-fluoro-phenyl)-2-methyl-propionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 602.3 [M]+.
Reaction SMILES: [Si]([O:8][C@H:9]([C:43]1[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:21]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.CO.N>O1CCCC1>[NH3:11].[CH:34]([N:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][C@@H:27]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[OH:26])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:43]1[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=1)[OH:8])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Agent: F
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C

Procedure:
N-(5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(7-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenoxy}heptyl)amino]ethyl}-2-hydroxyphenyl)methanesulfonamide (Preparation 20, 68 mg, 0.087 mmol) was dissolved in tetrahydrofuran (3 ml) and N,N-diethylethanamine trihydrofluoride (71 μl, 0.43 mmol) was added dropwise. After 18 hours a mixture of methanol (4 ml) and 880 ammonia (8 ml) were added and after 15 minutes the solvent was removed in vacuo. The residue was dissolved in dichloromethane and the solvent removed in vacuo again and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97/310.3 to 88/12/1.2 by volume) to furnish the title compound as a white solid, 30 mg.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:25]=O)=[CH:18][N:19]2[CH3:24].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:25][NH:6][CH3:5])=[CH:18][N:19]2[CH3:24]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2c(F)cccc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(F)c12
Yield: 77 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 4-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 77%)was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[C:39]1[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:39]5[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Reactant: Cn1nccc1O
Product: Cn1nccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-hydroxy-1-methyl-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methylpyridin-4-ylboronic acid (0.28 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 44 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-methylpyridin-4-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1CCNCC1.[CH:15](=[O:24])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]2[O:7][CH:15]([OH:24])[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
p-Cresol (150 g, 1.387 mol) was stirred with piperazine (72 g, 0.832 mol, 0.6 eq) in toluene (1.5 L, 10 ml/g) and then heated at reflux under Dean & Stark conditions for at least 30 minutes to remove water giving a clear pale yellow solution. Trans-Cinnamaldehyde (262 ml, 275 g, 2.081 mol, 1.5 eq) was then added over 2 hours whilst maintaining the reaction mixture at reflux under Dean & Stark conditions. Once the addition was complete, heating of the reaction mixture was continued at reflux under Dean & Stark conditions for a further 4 hours. The black solution was allowed to cool to 80° C. and then slowly quenched over 45 minutes with a solution of 0.67M HCl(aq) (750 ml, 0.601 mol, 1.3 eq). The two-phase solution was then stirred vigorously for at least 12 hours at a temperature of 75-80° C. The stirring was then stopped and the mixture allowed to cool to room temperature and the phases separated. The toluene solution was then washed with 1M HCl(aq) (750 ml, 5 ml/g), then water (3×750 ml, 5 ml/g). The 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol was not isolated but instead the toluene solution was used directly in the reductive amination step (Example 2).
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Br[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>>[Cl:27][C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:28][C:29]1[CH:30]=[C:31]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccncc1
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (350 mg, 0.59 mmol) is coupled to 4-bromopyridine hydrochloride (115 mg, 0.59 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([C:32](=[O:34])[CH3:33])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)CNc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CC(C)C)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-boc-4-(2-isobutylamino-phenyl)-piperazine (333 mg, 1.0 mmol, 1.0 eq), Et3N (0.42 mL, 3.0 mmol, 3.0 eq) and DMAP (6 mg, 0.05 mmol, 0.05 eq) in DCM (10 mL) was added acetic anhydride (0.14 mL, 1.5 mmol, 1.5 eq). The mixture was stirred at r.t. overnight. The reaction was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was separated and aqueous layer was extracted with DCM (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford the title compound (375 mg, 1.0 mmol, 100%). LRMS (ESI+): 376.18 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:4][N:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloronicotinic acid (2.0 g, 13 mmol) and HBTU (4.8 g, 13 mmol) in DMF (20 mL, 200 mmol) at 0° C. were added N,N-diisopropylethylamine (6.6 mL, 38 mmol) and 4-(trifluoromethyl)benzylamine (2.2 mL, 15 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform). The product was not thoroughly dried proceeding to the next reaction. Assumed 100% conversion.
Reaction SMILES: Cl[C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1>[OH-].[K+].[Pd]>[O:15]=[C:7]1[C:6]2[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=[CH:2][C:11]=2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]1
Reactant: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(Cl)c2[nH]1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c(C(=O)O)cccc2[nH]1

Procedure:
To a solution of 25 (7.90 g, 29.5 mmol) in 10% aqueous KOH solution (100 mL) was added 10% Pd/C (0.500 g). The reaction mixture was hydrogenated (50 psi) on a Parr hydrogenation apparatus at room temperature for 4 h. The catalyst was filtered off on a pad of celite and the filtrate was acidified with 2N HCl to pH=6.5, where a solid precipitated and was collected through a filtration. The solid was washed with with H2O (100 mL) and Et2O (100 mL), and dried in vacuum at 60° C. to give an off-white solid (26, 6.79 g, 98.6%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.12 (d, J=8.2 Hz, 1H), 7.76 (t, J=8.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 6.74 (s, 1H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:32]([O:49][CH2:50][CH2:51][NH:52][CH3:53])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Si:32]([O:49][CH2:50][CH2:51][N:52]([CH3:53])[C:11](=[O:13])[CH2:10][C@@H:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=1[S:25]([C:28]([F:29])([F:30])[F:31])(=[O:26])=[O:27])[CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:45]([CH3:47])([CH3:48])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Yield: 92.9 %

Procedure:
The title product (590 mg, yield: 93%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 24 utilizing (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 400 mg, 0.8 mmol) and 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (INTERMEDIATE 26, 251 mg, 0.8 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→100% EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13](Cl)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1
Reactant: Nc1ccccn1
Reactant: Clc1cc(Cl)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ccccn2)c2nccn2n1
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A solution of 2-aminopyridine (0.388 g, 4.12 mmol) in 8 mL of N,N-dimethylformamide was treated with 60% sodium hydride/mineral oil (0.167 g, 4.18 mmol) and the lightly bubbling, pale yellow solution was stirred for 30 min., in which time it became a dark yellow cloudy solution. The solution was added via Pasteur pipette to a flask containing 6,8-dichloro-imidazo[1,2-b]pyridazine (0.310 g, 1.65 mmol), and the cloudy orange solution was stirred for 16 h then partitioned between 80 mL of a saturated aq. NH4Cl solution and 80 mL of ether. The organic layer was sequentially washed with two 40 mL portions of water and 40 mL of a saturated aq. NaCl solution; dried over MgSO4, filtered and concentrated to a pale yellow solid. Column chromatography (0->33% EtOAc/hexanes) afforded 0.141 g (35%) of (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-pyridin-2-yl-amine as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].O>CC(N(C)C)=O>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Reaction time: 8 h

Procedure:
Phenyl chloroformate (1.08 mol) was added dropwise at a temperature <20° C. to a stirring solution of 4-nitrobenzenamine (1.02 mol) in DMA (500 ml) on ice and the mixture was stirred overnight. The mixture was poured into water (1000 ml), stirred till a homogenously suspension and filtered off, yielding phenyl (4-nitrophenyl)carbamate (intermediate 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:31])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.33 h

Procedure:
OsO4 (6 mg, 0.023 mmol) was added to a stirred mixture of 1-[(4-methylphenyl)sulfonyl]-4-vinyl-1H-indole (68 mg, 0.23 mmol; Intermediate 4) and 2,6-lutidine (54 μL, 0.46 mmol) in dioxane (6 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.197 g, 0.92 mmol) in water (1.5 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 20 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and combined with Intermediate 5 batch 2.