Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:62]1([S:65]([NH2:68])(=[O:67])=[O:66])[CH2:64][CH2:63]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:68][S:65]([CH:62]4[CH2:64][CH2:63]4)(=[O:67])=[O:66])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Reactant: NS(=O)(=O)C1CC1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (15 mg, 0.022 mmol) and CDI (7.05 mg, 0.043 mmol) in tetrahydrofuran (1 mL) was heated to gentle reflux for 3 h. Cooled down to rt, cyclopropanesulfonamide (5.27 mg, 0.043 mmol) and DBU (9.83 μL, 0.065 mmol) were added and the reaction continued at r.t. overnight. Removed the solvent in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (11 mg, 0.014 mmol, 63.8% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.84 (t, J=7.32 Hz, 3 H) 1.00-1.06 (m, 1 H) 1.09-1.17 (m, 2 H) 1.27-1.38 (m,5 H) 1.38-1.47 (m, 5 H) 1.46-1.63 (m, 14 H) 1.70 (dd, J=8.09, 5.34 Hz, 1 H) 1.86-2.00 (m, 2 H)2.24-2.33 (m, 1 H) 2.39-2.48 (m, 2 H) 2.50-2.58 (m, 1 H) 2.63 (s, 1 H) 2.88-2.97 (m, 2 H) 3.98-4.07 (m,2 H) 4.46 (d, J=9.46 Hz, 1 H) 5.08 (t, J=9.31 Hz, 1 H) 5.28 (d, J=10.38 Hz, 1 H) 5.65-5.75 (m, 1 H) 7.36 (t, J=7.48 Hz, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.59 (d, J=8.55 Hz, 4 H) 7.79 (t, J=9.00 Hz, 2 H). LC-MS (retention time: 3.48 min, method C), MS m/z 793(M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[C@@H:20]([OH:24])[CH2:21][C@@H:22]([OH:23])[C@@H:9]2[CH:8]=[CH:7]1.[O:25]=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:19])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:25])=[O:18])[C:20](=[O:24])[CH2:21][C@H:22]1[OH:23]
Reactant: O=[Cr](=O)=O
Reactant: CCCCC[C@H]1C=C[C@@H]2[C@@H](CC=CCCCC(=O)O1)[C@@H](O)C[C@H]2O
Agent: CCCCC[C@H]1/C=C/[C@@H]2[C@@H](C/C=C\CCCC(=O)O1)[C@@H](O)C[C@H]2O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
The mono-trimethylsilyl derivative of PGF2α 1,15-lactone (above) was dissolved in 6 ml of methylene chloride and added in one portion to the rapidly stirred Collins reagent. The ice bath was removed and the reaction mixture was allowed to stir for 20 min. longer. The mixture was then poured onto a column containing 150 g of neutral silica. With the aid of a house-vacuum, the column was eluted into a 2-liter round bottom flask with 1000 ml of ethyl acetate. Removal of the solvent gave PGE2, 1,15-lactone, 11-trimethylsilyl ether.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[F:15].[CH3:22][C:23]([CH3:37])=[CH:24][CH2:25][CH2:26]/[C:27](/[CH3:36])=[CH:28]/[CH2:29][CH2:30]/[C:31](/[CH3:35])=[CH:32]/[CH:33]=[O:34].Cl>O1CCCC1>[F:13][C:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])([F:15])[CH:33]([OH:34])[CH:32]=[C:31]([CH3:35])[CH2:30][CH2:29][CH:28]=[C:27]([CH3:36])[CH2:26][CH2:25][CH:24]=[C:23]([CH3:22])[CH3:37]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: COP(=O)(OC)C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COP(=O)(OC)C(F)(F)C(O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Combine diisopropylamine (22.24 mL, 0.159 mol) with tetrahydrofuran (250 mL) and cool to -20° C. Add n-butyllithium (63.3 mL, 2.5N in hexane, 0.159 mol) dropwise to the solution. Stir for 30 minutes and cool to -78° C. Add dropwise a solution of dimethyl difluoromethylphosphonate (25.8 g, 0.159 mol) in tetrahydrofuran (20 mL) while maintaining the temperature below -75° C. After addition is complete, stir for 2 minutes and then slowly add a solution of trans, trans-farnesal [prepared according to Biller, S. A; Forster, C. Tetrahedron 1990, 46(19), 6645](14 g, 0.0636 mol) prepared in step a above, in tetrahydrofuran (10 mL) maintaining the temperature below -72° C. After addition is complete, stir for an additional 2 hours at -78° C. and then pour the reaction into 0.1N hydrochloric acid (500 mL). Extract the reaction with diethyl ether (2×1L). Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography [40% ethyl acetate/hexane, Rf (50% ethyl acetate/hexane)=0.44] to provide the title compound (9.3 g, 39%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2ccnc(Cl)c2cc1F
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ccnc(F)c2cc1F
Temperature: 145 °C
Yield: 68.7 %

Procedure:
To a solution of 1-chloro-7-fluoro-6-methoxyisoquinoline (1.5 g, 7.09 mmol) in DMSO was added cesium fluoride (2.15 g, 14.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (950 mg, 68%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.0-7.98 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H), 7.42-7.40 (m, 1H), 7.21-7.19 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −129.05 (1F), −71.98 (1F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH:23][C:35](=[O:36])[C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:38]([CH3:40])[CH3:39])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added acetic anhydride (2.1 mg, 0.021 mmol), followed by pyridine (2 mg, 0.025 mmol). The reaction was warmed to ambient temperature and stirred for 1 hour before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide as an off-white solid (6 mg, 81% yield). MS (apci) m/z=358.2 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][CH:2]=1.[S:15]([Cl:19])(=[O:18])(=[O:17])[NH2:16].Cl>C(#N)C.C(O)(C)C>[ClH:19].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][O:14][S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=[CH:3][CH:2]=1
Reactant: OCCOc1cccc2cccnc12
Reactant: NS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc2cccnc12

Procedure:
Using the procedure of Example 4, 5.4 g (0.029 mole) of 2-(8-quinolinyloxy)ethanol was reacted with sulfamoyl chloride. During work-up of the reaction, a light-yellow material deposited out from the organic-aqueous system. 1H NMR of this material suggested that it might be a quaternary salt. The oily product obtained at the end of the work-up procedure weighed 2.7 g. This oil was dissolved in acetonitrile-isopropyl alcohol and acidified with 37% hydrochloric acid. The mixture was evaporated to almost dryness and then redissolved in methanol. To the solution was added ethyl acetate and most of the methanol was evaporated carefully. The light-yellow solid was collected and dried at 40° C. in vacuum overnight to give 2.4 g solid, mp 138°-140° C.
Reaction SMILES: C(OC1C=C2C(=CC=1OCC=C)N=C(N1CCN(S(C3C=CC(C4C=CC=CC=4)=CC=3)(=O)=O)CC1)N=C2N)C=C.[NH2:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([O:54]C)=[C:49]([O:52]C)[CH:50]=2)[N:45]=[C:44]([Cl:56])[N:43]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([OH:54])=[C:49]([OH:52])[CH:50]=2)[N:45]=[C:44]([Cl:56])[N:43]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: BrB(Br)Br
Agent: C=CCOc1cc2nc(N3CCN(S(=O)(=O)c4ccc(-c5ccccc5)cc4)CC3)nc(N)c2cc1OCC=C
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(Cl)nc2cc(O)c(O)cc12
Temperature: 25 °C

Procedure:
General Procedure for the Synthesis of Sulfonamides (Scheme 4). 6,7-Bis-allyloxy-2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-quinazolin-4-ylamine (43): A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (2.51 g, 10.0 mmol) in CH2Cl2 (30 mL) was cooled to −70° C. under argon, and added boron tribromide (6.01 g, 12.0 mmol). The mixture was allowed to warm up to room temperature over a period of 4 h, cooled to −70° C., added methanol (30 mL), and concentrated. The solid residue was washed with ethyl acetate to obtain 4-amino-2-chloro-6,7-dihydroxyquinazoline [1HNMR (DMSO-d6) δ 7.04 (s, 1 H), 7.51 (s, 1 H)]. A mixture of the first intermediate (0.21 g, 1.0 mmol), allyl bromide (0.432 g, 3.6 mmol) and K2CO3 (0.331 g, 2.4 mmol) in methanol (10 mL) was stirred under reflux for 12 h, concentrated, and purified by silica gel chromatography to afford 4-amino-2-chloro-6,7-diallyloxyquinazoline [1HNMR (DMSO-d6) δ 4.63 (d, J=5.4 Hz, 2 H), 4.70 (d, J=1.5 Hz, 2 H), 5.28 (d, J=1.3 Hz, 2 H), 5.42 (d, J=1.3 Hz, 1 H), 5.49 (d, J=1.3 Hz, 1 H), 6.07-6.11 (m, 2 H), 7.06 (s, 1 H), 7.62 (s, 1 H)]. A solution of the second intermediate (0.291 g, 1.0 mmol) and 1-(biphenyl-4-sulfonyl)piperazine (0.302 g, 1.0 mmol) in 1-butanol (5 mL) was stirred under reflux for 8 h, and concentrated. The solid residue was stirred with methanol under reflux for 30 min, filtered, washed with methanol to yield compound 44. 1HNMR (DMSO-d6) δ 3.36 (br s, 4 H), 4.01 (br s, 4 H), 4.60-4.64 (m, 4 H), 5.26-5.35 (m, 4 H), 6.02-6.13 (m, 2 H), 7.30-7.52 (m, 4 H), 7.72-7.75 (m, 3 H), 7.83-7.86 (m, 4 H), 8.63 (s, 1 H), 8.83 (s, 1H). HRMS (M+H)+ calcd for C30H32N5O4S 558.2169, found 558.2169. Anal. (C30H31N5O4S.HCl) C, H, N.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@H:28]1[C@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:27][C@H:28]3[C@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](N)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4S)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: [H-].[Na+].O1CCCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21]>>[CH2:19]([S:22]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)(=[O:24])=[O:23])[CH2:20][CH3:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)n1ccc2ccc(C=O)cc21
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To sodium hydride (0.174 g, 4.35 mmol) in tetrahydrofuran (6.8 mL, 0.084 mol), 1H-Indole-6-carbaldehyde (59, 0.486 g, 3.35 mol) was added. After 30 minutes, propane-1-sulfonyl chloride (0.565 mL, 5.02 mol) was added. After two hours, it was quenched with 1M HCl (aqueous) and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The desired compound was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in hexane to give 516 mg of desired compound. MS (ESI) [M−H+]−=250.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1Cl)[C:7]#[N:8])([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:7]([C:6]1[CH:9]=[CH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[N:8]
Reactant: NCCCCO
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(NCCCCO)c([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A mixture of 3-nitro-4-chloro-benzonitrile (20.4 g, 112.2 mmol), and 4-aminobutanol (10 g, 112 mmol) and K2CO3 (30.9 g, 224 mmol) in CH3CN (100 ml) was stirred at 23° C. for 12 h. Starting material remains by TLC analysis. Additional 4-aminobutanol (2 g, 22 mmol) was added and stirring continued for 24 h. The mixture is filtered and concentrated. The residue is dissolved in EtOAc and washed with water. The extracts are dried over MgSO4 and concentrated to give 26 g (99%) of 4-(4-cyano-2-nitro-phenylamino)-butan-1-ol as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[F:24][CH:25]([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:24][CH:25]([F:34])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:32][CH:33]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)F)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added 4-(difluoromethoxy)aniline (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100° C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1.O>[F:15][C:10]1[CH:9]=[C:8]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(Br)cc1F
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2ccc(C)c(F)c2)c1
Yield: 75.6 %

Procedure:
A mixture of toluene (22.7 mL) and water (22.7 mL+7.5 mL) was degassed with nitrogen for 30 min. A mixture of cesium carbonate (3.3 g, 1.04 mmol), 4-bromo-2-fluoro-1-methyl-benzene (1.0 g, 5.2 mmol), 3-methoxyphenylboronic acid (0.8 g, 5.2 mmol) and tetrakis triphenyl phosphene palladium (0.294 g, 0.26 mmol) was added to the above degassed aq. toluene and the resulting mixture was refluxed for 5 h. After the reaction was completed, it was cooled and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulphate and concentrated. The residue was purified by column chromatography using 10% ethyl acetate in hexane to obtain the title compound (0.85 g, 74%).
Reaction SMILES: C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1.Br[C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:40]=[C:39]([CH:41]3[CH2:43][CH2:42]3)[NH:38][N:37]=2)[C:32]([C:44]#[C:45][Si](C)(C)C)=[CH:31][N:30]=1.[CH3:50][C:51]1[CH:59]=[CH:58][C:57](B2OC(C)(C)C(C)(C)O2)=[CH:56][C:52]=1[C:53]([NH2:55])=[O:54]>>[CH:41]1([C:39]2[NH:38][N:37]=[C:36]([NH:35][C:33]3[C:32]([C:44]#[CH:45])=[CH:31][N:30]=[C:29]([C:57]4[CH:58]=[CH:59][C:51]([CH3:50])=[C:52]([CH:56]=4)[C:53]([NH2:55])=[O:54])[N:34]=3)[CH:40]=2)[CH2:43][CH2:42]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(N)=O
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2ccc(C)c(C(N)=O)c2)nc1Nc1cc(C2CC2)[nH]n1

Procedure:
Using the same coupling procedure as described in Compound 110, 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)-2-methyl benzamide (Compound 110) (7.4 mg, 2.6%) was prepared from 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. LC-MS (m/z)=359.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.78 (m, 2H), 0.95-1.00 (m, 2H), 1.91-1.95 (m, 1H), 2.43 (s, 3H), 4.88 (s, 1H), 6.47 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.91 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.33 (d, J=1.2 Hz, 1H), 8.57 (s, 1H), 8.73 (s, 1H), 12.37 (bs, 1H).
Reaction SMILES: F[C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH3:8])=[O:6].CN(C)C=O.[CH3:25][S-:26].[Na+]>C(OCC)(=O)C>[CH3:19][C:3]1[C:2]([S:26][CH3:25])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
2.1 g (7.34 mmol) of methyl 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoate were introduced into 20 ml of N,N-dimethylformamide and then admixed with 758 mg (95% by weight; 10.3 mmol) of sodium thiomethoxide. The mixture was stirred at RT for 2 hours and then freed from the solvent. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate, and, finally, the combined organic phases were dried and freed from the solvent. The residue was purified by chromatography, giving 1.28 g of clean product.