Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH:2]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:4]1)=[O:1]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (534 mg) and triethylamine (1.1 ml) were dissolved in DMSO, sulfur trioxide-pyridine complex (610 mg) was added and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was washed successively with 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (377 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.Cl.C[N:41](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25]([NH2:41])=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 64 %

Procedure:
A mixture of (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (180 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (161 mg), 1-hydroxybenzotriazole ammonium salt (128 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15.5 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from ethanol to give the title compound (115 mg, yield 64%) as colorless crystals. melting point 147-148° C. MS 571 (MH+).
Reaction SMILES: [Na+].[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-])=[O:22])[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5].[CH2:36]([O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43])[CH:37]=[CH2:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH:43][C:21]([C:19]1[N:20]=[C:16]2[CH:15]=[C:14]([CH3:24])[C:13]([C@H:25]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C:26]([O:28][CH3:29])=[O:27])=[C:12]([N:9]3[CH2:10][CH2:11][C:6]([CH2:2][CH2:3][CH:4]=[CH2:5])([CH3:35])[CH2:7][CH2:8]3)[N:17]2[CH:18]=1)=[O:22])[CH:37]=[CH2:38]
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Reactant: C=CCOc1ccccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Yield: 60 %

Procedure:
A yellow solution of (S)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt (40 mg, 0.081 mmol, 1 equiv), 2-allyloxybenzylamine (18 mg, 0.113 mmol, 1.4 equiv), DIPEA (0.042 mL, 0.243 mmol, 3 equiv), and HATU (43 mg, 0.113 mmol, 1.4 equiv) in DMF (0.81 mL) was stirred 2 h. The reaction was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to provide the product (30 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3) [note: appears to be at least two rotamers, only major rotamer transcribed] δ 8.21 (s, 1H), 7.81 (t, J=6.1 Hz, 1H), 7.26-7.16 (m, 2H), 6.97-6.85 (m, 2H), 6.19-6.06 (m, 2H), 5.93-5.82 (m, 1H), 5.47 (dq, J=17.3, 1.5 Hz, 1H), 5.31 (dq, J=10.5, 1.4 Hz, 1H), 5.14-4.95 (m, 2H), 4.72 (d, J=6.0 Hz, 2H), 4.63 (dt, J=5.0, 1.5 Hz, 2H), 3.70 (s, 3H), 3.61-3.48 (m, 2H), 3.07 (d, J=13.8 Hz, 1H), 2.85 (d, J=12.0 Hz, 1H), 2.45 (d, J=1.0 Hz, 3H), 2.17-2.07 (m, 2H), 1.71-1.40 (m, 6H), 1.24 (s, 9H), 1.13 (s, 3H); LCMS (ESI, M+1): 617.4.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:7]=1.[OH-].[K+].Br[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33]>O.C1(C)C=CC=CC=1>[Br:33][C:32]([F:35])([F:34])[C:31]([F:37])([F:36])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33])=[CH:16][CH:15]=2)([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33])=[CH:25][CH:26]=2)[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(c1ccc(OC(F)(F)C(F)(F)Br)cc1)(c1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 12.2 %

Procedure:
A 1 liter 5-necked round bottom flask is fitted with a mechanical stirrer, a Dean Stark trap topped with a nitrogen padded reflux condenser, and a thermocouple attached to a temperature controller. A mixture of DMSO (450 ml), toluene (150 ml), and 1,1,1-tris(4'-hydroxyphenyl)ethane (55.1 g, 0.18 mole) is added to the flask under nitrogen purge. After stirring for 15 minutes under a vigorous nitrogen purge, potassium hydroxide (85% pellets, 80.0 g, 1.2 mole) is slowly added to the reaction flask. The mixture is then stirred at reflux for 48 hours with azeotropic removal of water. The resulting suspension is cooled to 35° C. in an ice bath and 1,2-dibromotetrafluoroethane (155 g, 0.60 mole) is added at a rate that maintains a temperature of 30°-35° C. When the addition is complete, the mixture is heated to 50° C. with continuous stirring for 3 hours. After filtration, the solvents are removed by heating under vacuum on a rotary evaporator. The brown residue is purified by column chromatography on neutral alumina using hexane as eluent to provide as product 1,1,1-tris(4'-[2"-bromotetrafluoroethoxy]phenyl)ethane (18.3 g, 0.022 mole, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17]([O:19]CC)=[O:18])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[Li+].[OH-]>C1COCC1.CO.O.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17]([OH:19])=[O:18])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: CCOC(=O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the product of Step 1 (41.1 mg, 0.1 mmol, 1 equiv) in THF-methanol-water (3:2:1, total 1.2 mL) was added LiOH (12.0 mg, 0.5 mmol, 5 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was diluted with 1M HCl (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (10 mL) twice and dried with MgSO4 to afford 38.3 mg white solid as product, yield 99%. 1H NMR (CDCl3, 400 MHz) δ=5.02 (s, 2H) 7.22 (d, J=8.8 Hz, 2H) 7.58 (dd, J=8.7, 1.2 Hz, 2H) 8.16 (d, J=1.6 Hz, 2H). ESI (m/z): 379.6 (M−H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH2:27][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: C1CCNCC1
Product: COc1cc(Nc2ncc(CN3CCCCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 16 mg (0.19 mmol) piperidine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde. The reaction was not complete and the same amount of reagent was added like in example 57. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 36 mg (50%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-piperidin-1-ylmethyl-thiazol-2-yl)-amine as a yellow oil. MS ISP (m/e): 384.3 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.64 (s, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 7.08 (s, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 3.85 (s, 3H), 3.59 (s, 2H), 2.42 (m, 4H), 2.30 (s, 3H), 1.59-1.54 (m, 4H), 1.45-1.43 (m, 2H).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.C(Cl)CCl.[NH2:24][C@@H:25]([CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>C(Cl)Cl>[C:1]([NH:24][C@@H:25]([CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[C@H:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:27])(=[O:12])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: CCCCOCCOCC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCOCCOCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Methylene chloride (20 ml), 3,6-dioxadecanoic acid (705.0 mg, 4.0 mmol), triethylamine (1.40 ml, 10.0 mmol) and EDC (1.15 g, 6.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (944.0 mg, 4.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=30:1) to obtain the title compound (815 mg, yield 52%) as colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OC1CNCc2sccc21
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(OC2CNCc3sccc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 5) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].FC(F)(F)C(O)=O.[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31](=[O:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1.C(O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31]([CH2:1][CH3:2])([OH:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: CC[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13.4 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of ethylmagnesium bromide (0.714 mL, 2.142 mmol, 3 M in Et2O) was added dropwise to the stirred solution and stirred for 20 min. To this was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h and then slowly warmed to rt and stirred for 16 h. The reaction mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (14.2 mg, 10% yield) as a TFA salt. LC-MS (M+H)+ 497.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14 (1 H, br. s.), 7.45-7.97 (2 H, m), 7.05-7.20 (6 H, m), 4.63-4.77 (2 H, m), 4.36-4.49 (1 H, m), 3.88 (3 H, s), 1.88-2.35 (4 H, m), 1.71 (2 H, q, J=7.4 Hz), 1.24-1.51 (1 H, m), 1.03 (3 H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:68]=[CH:67][C:48]([C:49]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][CH3:61])=[CH:57][CH:58]=3)[C:53]([CH2:62][C:63](O)=[O:64])=[C:52]2[CH3:66])=[O:50])=[CH:47][CH:46]=1>C(#N)C>[CH:1]1([N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[C:63](=[O:64])[CH2:62][C:53]2[C:54]3[C:59](=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[N:51]([C:49](=[O:50])[C:48]3[CH:47]=[CH:46][C:45]([Cl:44])=[CH:68][CH:67]=3)[C:52]=2[CH3:66])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1csc(NC2CCCCC2)n1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a suspension of 2 g (0.02 mol) of N-Cyclohexyl-N-thiazol-2-yl amine in 20 mL of acetonitrile at rt was added 6.1 mL (0.044 mol) of triethylamine and 10.24 g (0.022 mol) of PyBroP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (Aldrich or NovaBiochem)]. To the reaction mixture was then added 3.93 g (0.01 mol) of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to 0° C. and the white precipitate was isolated by filtration. The filtrate was concentrated to ˜10 mL, recooled to 0° C., refiltered and the filtrate was concentrated to an oil. The residue was dissolved in 100 mL of dichloromethane and the solution was washed twice with 1N HCl, and once with 1N NaHCO3 solution. The organic phase was dried (Na2SO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 0-50% EtOAc in heptane) to give the title compound. 1H NMR (CDCl3) δ 7.74 (1H, d), 7.66 (2H, d), 7.50 (2H, d), 7.40 (1H, d), 6.95 (1H, bs), 6.82 (1H, d), 6.67 (1H, dd), 4.59 (1H, bt), 3.84 (3H, s), 3.61 (2H, s), 2.22 (3H, s), 0.9-2.0 (10H, m)
Reaction SMILES: [CH2:1]=[CH:2][CH:3](O)/[CH:4]=[CH:5]/[C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].P(Br)(Br)[Br:18]>CCOCC>[Br:18][CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=CC(O)/C=C/C#CCC#CCCCCC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCCCC#CCC#C/C=C/C=C/CBr

Procedure:
A solution of (E)-1,4-pentadecadien-6,9-diyn-3-ol (8.5 g) in ether (200 mL) was cooled to -40° and treated over 5 min with phosphorous tribromide (3.7 mL) dissolved in ether (70 mL). The cooling bath was removed and the reaction mixture was warmed to 0° over 1 hour and then poured onto ice. The ether extract was then washed with water, sodium carbonate solution (10 mL) and dried (MgSO4). Removal of the solvents and purification of the residue by liquid chromatography (two columns, hexane) gave (E,E)-1-bromo-2,4-pentadecadien-6,9-diyne as pure material (7.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Br)=[CH:5][CH:4]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])(=O)C.[K+]>C(O)CCC.O.CCOCC>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:26]2[C:21]([F:20])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(Cn2cnc3c(Br)ncnc32)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCO
Product: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-(4-Methoxybenzyl)-6-bromo-9H-purine (2.7 g, 8.5 mmol), 2-fluoropyridin-3-ylboronic acid (1.8 g, 13 mmol) and potassium acetate (2.5 g, 25 mmol) in 1-butanol (50 mL) and water (10 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2(PtBu2Ph)2 (0.063 g, 0.10 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 45 min. The reaction mixture was allowed to cool to RT and diluted with Et2O (300 mL). The mixture was washed with water (2×100 mL), brine (50 mL), dried over Na2SO4, and filtered. Some product precipitated before the filtration so the Na2SO4 was washed with 3:1 CHCl3:IPA to dissolve all product. The combined filtrate was concentrated in vacuo to ˜50 mL as a suspension. The suspension was diluted with Et2O (200 mL) and hexane (200 mL) and the solid collected by suction filtration. The solid was washed with hexane (50 mL) and dried under a stream of N2 with vacuum suction for 14 h to afford 2.39 g (crop 1) as a pale orange fine crystalline solid. The mother liquors were concentrated in vacuo to ˜100 mL to afford a second crop of product. The second crop was collected by suction filtration, washed with hexane (100 mL) and dried under a stream of N2 as above to provide 200 mg (crop 2) as a pale orange fine crystalline solid. MS (ESI, pos. ion) m/z: 336.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:42]3[CH2:44][CH2:43]3)=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:42]1([C:38]2[N:37]=[CH:36][C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:45])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)=[C:40]([CH3:41])[CH:39]=2)[CH2:43][CH2:44]1
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CC2)ncc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M228) (305 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (206 mg, 82%).
Reaction SMILES: [C:1]([N:4]([CH3:21])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)(O)[C:24]#[N:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:4]([CH3:21])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:24]#[N:25])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Reactant: CC(C)(O)C#N
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
tert-Butyl 2-acetyl-1-[4-(hydroxymethyl)phenyl]-2-methylhydrazinecarboxylate (1.27 g), acetone cyanohydrin (550 mg) and 1,1′-(azodicarbonyl)dipiperidine (1.63 g) were dissolved in THF (60 ml), and tributylphosphine (1.31 g) was added at 0° C. The obtained mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (910 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][CH2:20][C:21]1[CH:29]=[CH:28][C:27]3[O:26][CH2:25][O:24][C:23]=3[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1ccc2c(c1)OCO2
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc2c(c1)OCO2
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with piperonylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).