Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:33])(=O)C>C(OCC)(=O)C.CO>[ClH:33].[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C@@H:6]3[NH:5][C@H:4]([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(N)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: NC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-[(phenylmethyl)oxy]phenyl)-1-pyrrolidinecarboxylate (D12, 45 mg, 0.113 mmol) in a mixture of ethyl acetate and methanol (9/1, 1 ml) was added acetyl chloride (20 μl, 0.282 mmol) at 0° C. The mixture was shaken for 1.5 h and slowly allowed to warm to room temperature. After 4 h under these conditions, additional acetyl chloride (20 μl, 0.654 mmol) was added. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (25 mg, 66%); Rt (HPLC): 3.55 min; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.50 (bs, 1H); 8.15 (bs, 1H); 8.05 (s, 1H); 7.73 (s, 1H); 7.42-7.49 (m, 4H); 7.40 (t, 2H); 7.30-7.36 (m, 1H); 7.08 (d, 2H); 5.15 (s, 2H); 4.60 (dd, 1H); 4.30 (dd, 1H); 2.23-2.40 (m, 2H); 2.10-2.20 (m, 1H); 1.95-2.08 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][CH3:14].[Br:15]N1C(=O)CCC1=O>C(#N)C.[Cl-].[Na+].O>[Br:15][C:6]1[CH:5]=[C:4]([CH2:12][CH2:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][CH3:11]
Reactant: CCCc1ccc(CCC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCc1cc(OC)c(CCC)cc1Br
Temperature: 60 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
To a solution of 2-methoxy-1,4-dipropylbenzene (2.0 g, 10.4 mmol) in acetonitrile (30 mL) at room temperature was added N-bromosuccinimide (1.85 g, 10.4 mmol) in three portions. The solution was stirred at 60° C. for 20 hr and then most of the solvent was removed in vacuo. Extracton in hexanes (2×100 mL) with 50% saturated brine (75 mL) and flash chromatography with silica gel (100% hexanes) provided the title compound as a colorless liquid (2.50 g, 89% yield): 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H, J=7.5 Hz), 0.99 (t, 3H, J=7.6 Hz), 1.60 (m, 4H), 2.50 (t, 2H, J=7.7 Hz), 2.65 (t, 2H, J=7.8 Hz), 3.79 (s, 3H), 6.67 (s, 1H), 7.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: Nc1cc(Cl)ccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 51 %

Procedure:
Starting from 2-amino-4-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (110 mg; 51% yield).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[NH2:21])[NH:17][C:16](=[O:22])[C:15]2([CH3:24])[CH3:23].C(N(CC)CC)C.Cl>C(O)C.C(Cl)Cl>[OH2:9].[OH2:22].[OH2:9].[OH2:9].[CH3:23][C:15]1([CH3:24])[C:14]2[C:18](=[CH:19][C:20]3[NH:21][C:2]([C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[N:11][C:12]=3[CH:13]=2)[NH:17][C:16]1=[O:22]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Product: O
Reaction time: 8 h

Procedure:
3 g. (0.017 mol) Isonicotinic acid chloride hydrochloride are added portionwise to a solution of 2.9 g. (0.015 mol) 5,6-diamino-3,3-dimethylindolin-2-one in 30 ml. methylene chloride containing 4.4 ml. (0.032 mol) triethylamine and the reaction mixture is left to stir overnight. It is then evaporated to dryness in a vacuum, the residue is stirred up several times with water, filtered off with suction and the crystals obtained are heated under reflux for about 12 hours in a solution of 100 ml. ethanol containing 10 ml. concentrated hydrochloric acid. The mixture obtained is evaporated to dryness in a vacuum, the residue is stirred up with 20 ml. water and then rendered neutral with an aqueous solution of ammonia. The product is subsequently filtered off with suction, washed with water, dried and recrystallised from water containing 30% ethanol. The yield is 1.9 g. (36% of theory); m.p. 215° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:51])[C@H:3]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:4](=[O:45])[N:5]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][NH:41]7)=[N:37][CH:36]=6)[CH:31]=5)[CH:26]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1.[CH3:52][O:53][C:54]([NH:56][C@H:57]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:58](O)=[O:59])=[O:55].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C)C=O>[CH3:49][O:48][C:47](=[O:50])[NH:46][C@@H:3]([CH:2]([CH3:51])[CH3:1])[C:4]([N:5]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:58](=[O:59])[C@H:57]([NH:56][C:54]([O:53][CH3:52])=[O:55])[C:61]7[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=7)=[N:37][CH:36]=6)[CH:31]=5)[CH:26]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6]1)=[O:45]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate as 3HCl salt (200 mg, 0.24 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (60 mg, 0.288 mmol), and COMU (154 mg, 0.36 mmol) were all weighed out in a scintillation vial and anhydrous N,N-dimethylformamide (2.4 mL) was added and without stirring to this mixture was then added DIPEA (124 mg, 0.96 mmol) and the mixture was sonicated to dissolve all the reactants as quickly as possible. The mixture was then stirred for 2 h at room temperature. The crude mixture was diluted with EtOAc and washed with brine, 10% Na2CO3, brine and the organic layer was dried over MgSO4. The filtrate was concentrated down and the residue was purified by normal phase column chromatography (5% MeOH/DCM). MS (ESI) m/z 881.84 [M+H]+. (95 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccccc1Br)OC
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-bromophenol (34.8 ml), bromoacetaldehyde dimethyl acetal (35.5 ml), potassium carbonate (124.4 g) and dimethylformamide (500 ml) was stirred at 95° C. under nitrogen for 18 hours, then cooled and poured onto cold water (500 ml). The product was extracted into ether (2×300 ml) and the combined extracts were washed with saturated aqueous sodium bicarbonate solution (300 ml) and brine (300 ml) and dried (MgSO4). The solvent was removed in vacuo to give 2-(2-bromophenoxy) acetaldehyde dimethyl acetal as an oil (69.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20].[CH3:21][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:15]([OH:16])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20]
Reactant: C[Mg]Br
Reactant: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Solvent: C1CCOC1
Product: CC[C@@H](Nc1cccc(C(C)O)c1)c1ccc(Cl)c(C)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of INT 7 (600 mg, 2.09 mmol) in THF (7 mL) at −20° C. was added methylmagnesium bromide (3 M in Et2O, 0.83 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at −20° C. for 1 hour. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (3×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to give INT 10.
Reaction SMILES: [CH:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](F)=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[ClH:22]>CN(C)C(=O)C.O1CCOCC1>[ClH:22].[CH:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)C1CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CCC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To 2.8 mmol 4-cyclobutanesulfonyl-1,2-difluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.3 mmol piperazine, and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/methanol gradient). The product-containing fractions were combined and concentrated in vacuo. The residue was resuspended in 100 ml dioxane, and 6.0 mmol HCl (as a 4 M solution in dioxane) was added. After stirring for 10 min, the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound.
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:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.[CH:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])[CH3:37]>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:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:42]3[CH2:43][CH2:44][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, 1-isopropylpiperazine (24 mg, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 45% acetonitrile/water to yield the final product as a yellowish foamy powder (40 mg, 90% yield). MS (apci) m/z=470.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH2:29][CH2:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H-].[Na+].[H][H].Cl[C:35]([O:37][CH3:38])=[O:36]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH2:29][CH2:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)[C:35]([O:37][CH3:38])=[O:36])(=[O:10])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Reactant: [H][H]
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2-dihydro-furo[2,3-c]quinoline-6-carboxylate (Intermediate 22, 0.29 g) in THF (5 mL) was added slowly to a suspension of sodium hydride (40% oil dispersion, 0.048 g) in THF (15 mL). Once the evolution of hydrogen had ceased, methyl chloroformate (0.147 g) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with a mixture of ether and cyclohexane (1:1) and the solid was collected by filtration to give methyl 7-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxy-carbonyl)amino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylate (0.3 g) as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[NH:5][N:6]=1.CN(C(ON1N=N[C:20]2C=CC=N[C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C@H:44]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)[CH2:45][C@@H:46]([CH2:50][OH:51])[C:47]([OH:49])=[O:48]>CN(C=O)C>[CH2:19]([O:48][C:47](=[O:49])[C@H:46]([CH2:50][OH:51])[CH2:45][C@H:44]([NH:43][C:7]([C:4]1[NH:5][N:6]=[C:2]([Cl:1])[N:3]=1)=[O:9])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)[CH3:20]
Reactant: O=C(O)c1nc(Cl)n[nH]1
Reactant: N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[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: CCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nc(Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
5-Chloro-2H-1,2,4-triazole-3-carboxylic acid (60.8 mg, 412 μmol, 1.5 eq.) and HATU (157 mg, 412 μmol, 1.5 eq.) were dissolved in DMF (4.0 mL), and the resulting mixture was stirred for 5 minutes at room temperature to yield the activated acid. DIPEA (95.7 μL) and (2S,4S)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-pentanoic acid (HCl salt, 100 mg, 275 μmol, 1.0 eq.) were added to the activated acid and the resulting mixture was stirred for 10 minutes. The reaction was quenched with water and the product dried under vacuum. The dried solid was dissolved in AcOH and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (88 mg, 95% purity). MS m/z [M+H]+ calc'd for C23H25ClN4O4, 457.16. found 457.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>ClCCl.COC(C)(C)C>[CH3:1][S:2]([O-:4])(=[O:20])=[O:3].[CH2:6]([N+:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CS(=O)(=O)[O-]
Product: c1ccc(C[N+]23CCC(CC2)C3)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (0.22 mL, 2.85 mmole) in dichloromethane (2 mL) was added dropwise to a ice-cooled solution of N-benzyl-4-hydroxymethyl-piperidine (531 mg, 2.59 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.88 mmol) in dichloromethane (3 mL). The mixture was stirred for 5 min, diluted with tert-butyl methyl ether, washed with water and brine. The solvents were removed to give the sub-title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=4)=[O:40])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=3)=[O:40])[CH2:34][CH2:33]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.83 h

Procedure:
25 ml of trifluoroacetic acid and 0.83 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]-pyrrolidine [prepared as described in step (iii) above] in 5.2 ml of anisole, and the resulting mixture was stirred at the same temperature for 50 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was decanted, in turn, with hexane and with diethyl ether, to give 2.7 g of the title compound as an amorphous solid.
Reaction SMILES: [H-].[Na+].[S:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[CH2:4]1.[CH3:14]I>CN(C)C=O>[CH3:14][S:13][C:5]1[CH2:4][S:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CI
Reactant: S=C1CSc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=Nc2ccccc2SC1
Reaction time: 0.08 h

Procedure:
In a one liter flask is placed 10.8 parts of prewashed sodium hydride in 150 parts of N,N-dimethyl-formamide (DMF) at room temperature. After stirring for five minutes under nitrogen atmosphere, 30 parts of 2H-1,4-benzothiazine-3(4H)-thione[J. Med. Chem., 12, 290(1969)] is added in portions over a period of 30 minutes and continuously stirred at room temperature for 20 minutes. To the reaction mixture is then added 15 parts of methyl iodide and the mixture stirred at room temperature for 20 minutes under nitrogen. Removal of solvent by vacuum distillation under nitrogen affords 3-methylthio-2H-1,4-benzothiazine as the residue. Since the product is subject to spontaneous hydrolytic decomposition, it is not usually isolated for the purposes of this invention but instead employed as the solution in DMF preparable via the foregoing procedure.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([CH2:15][O:16][CH2:17]C(OC)=O)[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Li+].[OH-:23].[CH3:24][OH:25]>O>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([CH:15]([O:16][CH3:17])[C:24]([OH:25])=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)COCc1cccc(C2(OC)CCOCC2)c1
Agent: [Li+]
Solvent: O
Product: COC(C(=O)O)c1cccc(C2(OC)CCOCC2)c1
Yield: 97 %

Procedure:
A solution of methyl 3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxy-acetate (Step 1) (0.5 g, 1.7 mmol) and LiOH (0.18 g, 4.25 mmol) in 10% water and methanol (5 mL) was stirred for 6 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (100 mL) and 1 N HCl (30 mL). The organic layer was separated and washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 0.46 g (97%) of 3-[(4-methoxy)-tetrahydropyran-4-yl]phenyl-methoxyacetic acid as a yellow solid: HRMS calcd for C15H20O5 280.1311. Found 280.1304.
Reaction SMILES: [Cl-].[Li+].[CH:3]([Mg]Cl)=[CH2:4].[C:7]1(=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1>C1COCC1.[Cu]Cl>[CH:3]([C:7]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1)=[CH2:4]
Reactant: CCOC(=O)C=C1CC1
Reactant: C=C[Mg]Cl
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC1(CC(=O)OCC)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under argon, 0.55 g (5.53 mmol) of copper(I) chloride and 0.59 g (13.82 mmol) of lithium chloride are suspended in 150 ml of anhydrous THF. The reaction mixture is cooled to −78° C., 48.8 ml (82.95 mmol) of vinylmagnesium chloride solution (1.7 M in THF) are added and the mixture is stirred for 10 minutes. Over a period of 30 min, a solution of 8.72 g (69.12 mmol) of ethyl cyclopropylideneacetate (Example 1A) in 50 ml of anhydrous THF is then added dropwise. After the addition is ended, the cooling bath is replaced by an ice/acetone bath. After a further 15 min, the reaction is terminated by dropwise addition of 100 ml of 1 N hydrochloric acid. The reaction mixture is saturated with sodium chloride, and 100 ml of a saturated sodium chloride solution which contains 5 ml of a 25% strength aqueous ammonia solution are then added. The mixture is filtered through Celite. The filtrate is washed with ammoniacal sodium chloride solution until the aqueous phase remains colorless. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent and kugelrohr distillation of the residue at 150° C. and 15 mbar gives 7.10 g (67% of theory) of the title compound as a colorless liquid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:31]=[C:30]([CH:32]=[CH2:33])[N:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:33]=[CH:32]/[C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:35])=[CH:24][CH:23]=4)[N:31]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(Nc2ncnc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
To a stirred solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.05 g, 0.152 mmol) in ACN (5 mL) were added N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine (0.041 g, 0.152 mmol), tri-o-tolylphosphine (0.019 g, 0.061 mmol) and triethylamine (0.064 mL, 0.457 mmol). Nitrogen was purged for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.015 mmol) was added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, and the organic layer was concentrated. The crude product was purified by flash chromatography on silica gel using 25% ethyl acetate in hexane to give (E)-4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a pale yellow solid (0.04 g, 42% yield). LCMS: R.T.=1.21 min; [M+H]+=467.33.