Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]=[CH2:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Yield: 98.6 %

Procedure:
25.0 g (0.0899 mol) of tert-butyl-dimethyl-(2-vinyl-5-methoxy-benzyloxy)-silane (15) was dissolved in 100 mL of ethyl acetate and was placed in a 1 L Parr Shaker bottle. 1.93 g (0.0084 mol) of catalyst (PtO2) was added and the solution was placed under 30 PSI of hydrogen for 25 minutes. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to yield crude product. The crude product was chromatographed on a silica gel column with 40% CHCl3 in hexane to afford 24.85 g (99%) of tert-butyl-dimethyl-(2-ethyl-5-methoxy-benzyloxy)-silane (16).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[CH2:15][NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)N1CNc2ccncc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of N-isopropyl-4-aminopyridine-3-sulfonamide (Preparation 7) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 24 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is redissolved in 20 cm3 of methanol. The possible insoluble material is removed by filtration. The filtrate, treated with 40 cm3 of water and stored for 2 hours at +4° C., produces a precipitate of the isopropoxymethylenated derivative of Preparation 7. It is collected on a filter, washed with water, dried and recrystallized from a CHCl3 /petroleum ether (40°-60° C.) (1/2) mixture. The dry product is introduced into an open round-bottomed flask and brought to a temperature of 180°-190° C. After 15 to 30 minutes, the molten mass solidifies. It is then cooled and then dissolved in a small volume of chloroform. The addition of 1 volume of petroleum ether (40°-60° C.) causes precipitation of crystals of the title compound. They are collected on a filter, washed with petroleum ether (40°-60° C.) and dried.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([NH:36][NH:37]C(OC(C)(C)C)=O)=[O:35])=[CH:32][CH:31]=1)=[O:28]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:37][NH:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:47])=[CH:46][CH:45]=1)=[O:35]
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl)hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 496 mg of the title compound (82%) as a yellow solid in 99.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16](O)=[O:17].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:23][CH3:21])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (1.50 grams, 0.0046 mole) and carbonyldiimidazole (0.94 gram, 0.0058 mole) were dissolved in DMF. The reaction mixture was stirred for 10 minutes, then 7 ml. of 40% aqueous methylamine were added. The reaction mixture was stirred for three hours at room temperature, then poured into 150 ml. of water and filtered. The precipitate was dried to 1.51 grams, then recrystallized from 10:1 cyclohexane/toluene, yielding 1.23 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide, mp=143°-144° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:25]1([C:31]2[S:35][C:34](CO)=[N:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Br:5][CH2:1][C:34]1[S:35][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:32][N:33]=1
Reactant: OCc1ncc(-c2ccccc2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ncc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
CBr4 (8.65 g, 26.1 mmol) and Ph3P (5.1 g, 19.6 mmol) were added to a solution of (5-phenylthiazol-2-yl)methanol (2.5 g, 13.07 mmol) in dry CH2Cl2 (30 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was diluted with diethyl ether and filtered. The clear filtrate was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5-10% EtOAc in petroleum ether) to afford 2-(bromomethyl)-5-phenylthiazole (2 g, yield 60%). 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.57-7.55 (m, 2H), 7.45-7.36 (m, 3H), 4.76 (s, 2H). MS (ESI) m/z: Calculated for C10H8BrNS: 254.95. found: 256.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][CH:13]2[CH:5]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=32)[CH2:4][CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:28].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]I.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6](/[CH:26]=[C:27](/[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)\[CH3:28])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(c1)C1CCN(C)CCC1N2
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccncc1
Temperature: 85 °C

Procedure:
3,9-Dimethyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (107.5 mg, 0.5 mmol), potassium phosphate tribasic (212 mg, 1 mmol) in DMF and the mixture purged with nitrogen. The reaction mass was heated at 85° C. for 5 min. In another flask was added 4-(1-bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol) in DMF. This mixture was purged with nitrogen and heated at 90° C. for 5 min. The reaction mixtures were combined and heated at 90° C. overnight. The reaction mass was poured into water to obtain a precipitate. The precipitate was filtered and purified with silica column chromatography (100-200 mesh), by neutralizing the silica gel with 2-3 drops of aq. ammonia and using 0-2% MeOH:DCM as eluant. The compound was further purified by reverse phase HPLC to obtain the product. 1HNMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 8.10 (d, 2H), 7.62 (s, 1H), 7.38 (s, 1H), 7.05 (d, 2H), 3.80 (m, 2H), 3.40 (m, 2H), 3.30 (m, 2H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: CS(O[CH:6]([CH2:28][F:29])[CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[CH:19][C:17]=3[N:18]=2)[O:11][N:10]=1)(=O)=O.[N-]=[N+]=[N-].[Na+].CS(C)=O>O>[CH:25]1([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][C:14]([C:12]4[O:11][N:10]=[C:9]([O:8][CH2:7][CH:6]([NH:10][C:9](=[O:8])[CH3:13])[CH2:28][F:29])[CH:13]=4)=[N:18][C:17]=3[CH:19]=2)[CH2:26][CH2:27]1
Reactant: CS(=O)(=O)OC(CF)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NC(CF)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Temperature: 100 °C
Reaction time: 4 h
Yield: 117.7 %

Procedure:
A mixture of 2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]isoxazol-3-yl}oxy)-1-(fluoromethyl)ethyl methanesulfonate (97.3 mg), sodium azide (29.7 mg) and dimethyl sulfoxide (2 mL) was stirred at 100° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with triphenylphosphine (71.8 mg), THF (3 mL) and water (1 mL), and the obtained mixture was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with acetic anhydride (1 mL), triethylamine (1 mL) and ethyl acetate (3 mL), and the obtained mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained residue was separated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (52.3 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)[Si](OC[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOC[C@@H]4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 90.9 %

Procedure:
The title product (134 mg, yield: 77%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 67.7 mg, 0.13 mmol) and 4-((R)-4-((R)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 109, 94.4 mg, 0.11 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→30% EtOAc/hexanes), providing the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)=[CH:10][C:11](=[O:15])[O:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Reactant: C#CC(O)(CC)CC
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (343 mg, 0.78 mmol) and 3-ethyl-1-pentyn-3-ol (80 mg, 0.71 mmol) in THF (7 mL) N,N-diisopropylethylamine (622 uL, 3.6 mmol) and copper iodide (204 mg, 1.07 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 10:90) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.89 (s, 1H), 7.7-7.6 (m, 1H), 7.53 (d, 1H), 7.45-7.32 (m, 4H), 7.27 (d, 1H), 6.42 (s, 1H), 5.79 (s, 2H), 3.78 (s, 1H), 2.0-1.74 (m, 4H), 0.78 (t, 6H).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[CH2:26]([O:25][C:23]([C:22]([CH3:29])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[CH3:28])=[O:24])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 12-L 3-neck round-bottom flask was equipped with an overhead air-driven stirrer apparatus, condenser, nitrogen inlet, thermometer/thermocouple, and heating mantle. The flask was charged with ethyl acetate (450 mL) and 21% (wt.) sodium ethoxide in ethanol solution (3318 mL, 8.87 moles, 2 eq). The resulting mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux for 30 min. The mixture was then allowed to cool slightly below reflux, and 4-(4-hydroxyphenyl)butyric acid (800 g, 4.43 moles) was added. The flask contents were re-heated to reflux for 30 min, at which point ethyl 2-bromoisobutyrate (EBIB, 1954 mL, 13.32 moles, 3.0 eqs.) was added. After 1 h at reflux, the flask was equipped with a 2-L addition funnel, which was charged sodium ethoxide in ethanol solution (1660 mL, 4.43 moles, 1 eq.). The sodium ethoxide solution was added dropwise to the refluxing reaction over 1 h. After an additional 30 min at reflux, HPLC analysis showed the reaction was complete. The heat source was removed and the flask contents were cooled to 5-10° C. and then transferred to a 22-L bottom-outlet flask. While stirring, the mixture was quenched with dilute phosphoric acid (6000 mL), transferred to a 20-L Buchi flask, and concentrated in vacuo to remove ethanol. The resulting aqueous mixture of crystals and excess EBIB was refrigerated overnight. The crystals were then filtered and washed with water (2000 mL). The solids were removed from the funnel and placed in a 20-L Buchi flask equipped with an overhead stirring apparatus. After the addition of water (2000 mL), the solids were stirred at ambient temperature for 30 min, then filtered and washed with heptane (2×2500 mL)). The solids were then placed in the vacuum oven and dried at 45° C. to afford the title compound as an off-white solid (1247 g, 95.5%). 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3 H), 1.57 (s, 6 H), 1.92 (m, 2 H), 2.35 (t, 2 H), 2.60 (t, 2 H), 4.23 (q, 2 H), 6.76 (d, 2 H), 7.03 (d, 2 H). 13C NMR (CDCl3) δ 14.1, 25.4, 26.3, 33.3, 34.2, 61.4, 119.4, 129.1, 134.9, 153.7, 174.4, 179.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:17][O:16][C@H:15]1[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(N[C@@H]4CN(S(C)(=O)=O)C[C@@H]4OC)c(C(N)=O)cnn3c2)cn1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 37.8 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL), was added (6-methoxypyridin-3-yl)boronic acid (3.54 mg, 0.023 mmol), X-Phos (0.85 mg, 1.16 μmol) and potassium phosphate (2M, 0.040 mL, 0.081 mmol). The mixture was heated at 100° C. for 3 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.0 mg, 37% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.41 (d, J=2.0 Hz, 1H), 8.21-8.10 (m, 1H), 7.96-7.90 (m, 1H), 7.89-7.85 (m, 1H), 7.59 (s, 2H), 7.16-6.99 (m, 1H), 6.88-6.79 (m, 1H), 5.13-4.90 (m, 1H), 4.12 (br. s., 1H), 4.00-3.90 (m, 4H), 3.74-3.67 (m, 1H), 3.58 (dd, J=11.6, 2.2 Hz, 1H), 3.50 (br. s., 3H), 3.42-3.34 (m, 1H), 2.90 (s, 3H), 2.64 (s, 1H); MS (ES+) m/z: 461.2 (M+H); LC retention time: 2.09 min (analytical HPLC Method H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20].CCN(CC)CC.S(Cl)(Cl)(=O)=O>C1COCC1>[C:19]([C:21]1[CH:22]=[C:23]([S:27]([N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:17]=[C:16]([Cl:18])[CH:15]=2)[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (1.40 g, 4.91 mmol) in THF (15 mL) was added 3-cyanobenzene-1-sulfonyl chloride (0.9 g, 4.46 mmol) and Et3N (1.22 mL, 8.93 mmol) at rt for 2 h. Additional sulfonyl chloride (0.35 g) and Et3N (0.5 mL) were added. The reaction mixture was stirred at rt for 15 h. The mixture was concentrated and the residue was diluted with ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with brine, saturated aq NaHCO3 solution, dried over MgSO4, and concentrated to give a glassy material which was purified by flash silica gel column chromatography on silica gel (ISCO. Column: 24 g. Eluent: A: hexane. B: ethyl acetate. Condition: A to 25% of B (50 min gradient) to obtain the desired product as a white solid (1.8 g, 81%). 1H NMR (CDCl3): δ 8.08-8.02 (m, 2H), 7.93-7.90 (m, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.25-7.24 (m, 1H), 7.13-7.09 (m, 2H), 6.98 (t, J=8.0 Hz, 2H), 6.90 (d, J=4.0 Hz, 2H), 4.38 (s, 2H), 4.30 (s, 2H); MS (ESI): [M−H]−=506.9.
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:16]([NH:24][C:25]([NH:8][C@H:3]([CH3:2])[C:4]([F:7])([F:6])[F:5])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=S)NC(=O)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Dissolve (R)-1-methyl-2,2,2-trifluoroethylamine hydrochloride (3.73 g, 25 mmol) in chloroform (50 mL) containing triethylamine (3.5 mL, 25 mmol). Cool to 0° C. in an ice bath and dropwise add benzoyl isothiocyanate (3.35 mL, 25 mmol) over 10 min. Warm the mixture to room temperature and stir overnight. Concentrate in vacuo and purify by chromatography on silica gel (200 g) eluting with hexane/EtOAc (19:1 to 4:1 over 40 min; 50 mL/min) to afford the desired intermediate as a light yellow oil (6.2 g, 90%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:14]3=[O:30])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:24][C:20]1[C:17]2[CH2:18][CH2:19][CH:13]([N:11]3[CH:12]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)[CH:3]=4)[N:9]=[N:10]3)[C:14](=[O:30])[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1C(n2cc(-c3cccc(Cl)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(n2cc(-c3cccc(-c4cccnc4)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
3-[4-(3-Chlorophenyl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (30 mg, 0.068 mmol), pyridin-3-ylboronic acid (12.67 mg, 0.103 mmol), palladium acetate (3.07 mg, 0.014 mmol), potassium phosphate tribasic (29.0 mg, 0.137 mmol), and S-Phos (8.42 mg, 0.021 mmol) were added to a microwave vial. The reactants were suspended in THF (414 μL) and H2O (41 μL) and the vial sealed. The reaction mixture was irradiated at 120° C. in the microwave for 10 minutes, The completed reaction was filtered and concentrated in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 6-fluoro-3-[4-(3-pyridin-3-ylphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.