Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([C:17]2[O:18][C:19]3[N:20]=[C:21]([S:30][CH3:31])[N:22]=[C:23]([O:26][CH2:27][CH2:28][CH3:29])[C:24]=3[N:25]=2)[CH:14]=[C:13]([CH3:32])[C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].ClC1C=CC=C(C(OO)=[O:41])C=1.[OH-:44].[Na+]>ClCCl>[CH3:31][S:30]([C:21]1[N:22]=[C:23]([O:26][CH2:27][CH2:28][CH3:29])[C:24]2[N:25]=[C:17]([C:15]3[CH:16]=[C:2]([CH3:1])[C:3]([O:4][CH2:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[C:13]([CH3:32])[CH:14]=3)[O:18][C:19]=2[N:20]=1)(=[O:41])=[O:44]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
250 mg of tert-butyl [2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)phenoxy]acetate were dissolved in 5 ml of dichloromethane. At 0° C., 268 mg of 3-chlorperbenzoic acid were then added, after which the mixture was stirred at room temperature for 12 h. The mixture was treated with 1 M aqueous sodium hydroxide solution, the layers were then separated and the organic layer was subsequently extracted twice with dichloromethane. The combined organic phases were washed with 10% strength aqueous sodium bisulfite solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. This gave 268 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)=[O:12]>C(OCC)(=O)C.O1CCCC1.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=1)=[O:12]
Reactant: O=C(C#CCOC1CCCCO1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCCOC1CCCCO1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
4-(Tetrahydro-2H-pyran-2-yloxy)-1-(1-trityl-1H-imidazol-4-yl)-2-butyn-1-one (29.63 g) was dissolved in a mixture of ethyl acetate (200 ml) and tetrahydrofuran (800 ml). 10% Palladium carbon (2.6 g) was added and the mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. 10% Palladium carbon was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to give the title compound (28.53 g) as a brown solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[C:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:11][CH:12]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Yield: 85 %

Procedure:
Analogously to Example 25, 4-(1-cyano-1-methylethyl)-aniline is reacted with 4-methoxybenzoic acid chloride to give a yield of 85% of theory of the title compound in the form of beige crystals; m.p. 169°-171° C. A sample thereof is recrystallised from ethanol and then has a melting point of 172°-174° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[Cl:22][C:23]1[CH:28]=[C:27]([N:29]=C=O)[CH:26]=[C:25]([Cl:32])[CH:24]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:29][C:27]2[CH:28]=[C:23]([Cl:22])[CH:24]=[C:25]([Cl:32])[CH:26]=2)=[O:7])[C@H:9]([C:19]([NH:36][CH:33]2[CH2:35][CH2:34]2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC1CC1
Product: CC(C)(C)ON=C1C[C@@H](C(=O)NC2CC2)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and cyclopropylamine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=427.6.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=[O:12].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH:10]([CH3:9])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of lithium diisopropylamide (Aldrich, 100 mL, 2M solution in THF) in THF (950 mL) at −78° C. was added a suspension of 4-benzyloxypropiophenone (Lancaster, 50 g) in THF (75 mL) over one minute. After 45 minutes, ethyl bromoacetate (Aldrich, 23 mL) was added during one minute. After one hour, the mixture was allowed to warm to 0° C. over 3 hours. The reaction was quenched with saturated NH4Cl (500 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by chromatography over silica gel using 10% ethyl acetate in hexane as eluant to provide the above compound as a colorless liquid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:44][N:43]1[C:39]([C:37]([NH:36][C:34]2[CH:35]=[C:30]([O:29][C:26]3[CH:27]=[CH:28][C:23]4[N:24]([CH:47]=[C:21]([NH:20][C:5]([CH:3]5[CH2:4][CH:2]5[CH3:1])=[O:7])[N:22]=4)[N:25]=3)[CH:31]=[CH:32][C:33]=2[CH3:46])=[O:38])=[CH:40][C:41]([CH3:45])=[N:42]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CC1CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2C)n(C)n1
Yield: 70.3 %

Procedure:
In the same manner as in Example 279 and using 2-methylcyclopropanecarboxylic acid (97 mg, 0.97 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (155 mg, 70%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([NH:24]C(OC(C)(C)C)=O)=[CH:20][CH:19]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)NC(CC(=O)OC(C)(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(CC(=O)OC(C)(C)C)c2ccc(N)cc2)no1
Reaction time: 4 h
Yield: 64.5 %

Procedure:
A solution of (R) 3-(4-tert-butoxycarbonylamino-phenyl)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propionic acid tert-butyl ester (2 g, Reference Example 11) in dichloromethane (50 mL) was treated with trifluoroacetic acid (5 mL). After four hours [the reaction was monitored by TLC: no more starting material was visible after about 4 hours] at room temperature the reaction mixture was poured carefully onto a mixture of sodium hydrogen carbonate solution (100 mL, 5% w/v) and dichloromethane (50 mL). The organic layer was separated then dried and then evaporated to give the title compound (1.0 g) as a yellow oil which slowly crystallised on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:3]=[C:4]([NH2:17])[N:5]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[O:15][CH3:16])[N:7]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1-c1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COc1ccc(Cl)cc1-c1nc(N)cc(Nc2ccc(Br)cc2)n1
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a stirred suspension of the hydrochloride salt of 6-chloro-2-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.020 g, 0.065 mmol) in ethanol (5.0 ml) was added 4-bromoaniline (0.022 g, 0.13 mmol). After heating under reflux for 20 hours, the solvent was evaporated under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided a solid which was treated with methanol (10 ml) and stirred while a solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, the solvents were evaporated under reduced pressure. The residue was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.011 g, 42% yield) as a beige powder. 1H NMR (DMSO-d6) δ 3.83 (s, 3H, CH3), 5.74 (s, 1H, Ar), 6.50 (s, 2H, NH2), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.40-7.45 (m, 3H, Ar), 7.55 (d, 1H, J=2.7 Hz), 7.65-7.67 (m, 2H, Ar), 9.16 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]#[N:4])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: N#CCBr
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(-c2ccc(OCC#N)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Bromoacetonitrile (84 mg, 0.7 mmol), K2CO3 (166 mg, 1.2 mmol) and KI (53 mg, 0.32 mmol) were added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (250 mg, 0.64 mmol) in DMF (2 ml). The mixture was stirred at RT for 3 h. Cold water was added and the solution was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain (E)-3-(3′-adamantan-1-yl-4′-cyanomethoxybiphenyl-4-yl)-acrylic acid methyl ester (240 mg, 88%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([CH:41]([CH:43]2[CH2:45][CH2:44]2)[OH:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([CH:43]2[CH2:44][CH2:45]2)=[O:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Dess Martin periodinane (60 mg, 0.14 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (74 mg, 0.12 mmol) in dichloromethane (5 ml) and the mixture stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (30 ml), washed with NaHCO3 solution (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to give 2,4-dichloro-N-{4-cyclopropanecarbonyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide as a yellow solid (38 mg, 51%). 1H NMR (CDCl3): 8.32 (1H, s, py); 8.08 (1H, d, Ar); 7.57 (2H, d, Ar); 7.46 (1H, s, py); 7.36 (1H, d, Ar); 7.27 (2H, d, Ar); 2.89 (4H, m, 2×CH2 pip); 2.17 (1H, m, COCH); 1.54 (4H, m, 2×CH2 pip); 1.33 (2H, m, CH2 pip); 0.82 (4H, m, 2×CH2 cprop). HPLC (Luna 2, Gradient 5): rt=6.47 minutes. LCMS rt=7.24 minutes, 627 (M+H)+. By a similar method using the appropriate starting materials the following can be prepared:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[CH:4][CH:3]=1.O=[C:22]([CH3:36])[CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:25][CH2:24][CH2:23][CH:22]([N:18]1[CH2:17][CH2:16][CH:15]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:20][CH2:19]1)[CH3:36]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc(N(Cc2ccsc2)C2CCNCC2)cn1
Product: CC(CCN)N1CCC(N(Cc2ccsc2)c2ccc(Cl)nc2)CC1

Procedure:
Using general procedure B with the amine from above (65 mg, 0.21 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (115 mg, 0.529 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amine as a yellow oil (60 mg, 75% over 2 steps).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)CC)[CH3:2].[CH3:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:15]=2[O:19][CH2:20][CH2:21][CH3:22])[N:10]1[C:29](=[O:31])[CH3:30].ClC(Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.C(N)C>ClCCl>[C:29]([N:10]1[C:11]2[C:16](=[C:15]([O:19][CH2:20][CH2:21][CH3:22])[C:14]([CH:23]3[CH2:28][CH2:27][N:26]([C:6]([NH:3][CH2:1][CH3:2])=[O:35])[CH2:25][CH2:24]3)=[CH:13][CH:12]=2)[CH2:17][CH2:18][C@@H:9]1[CH3:8])(=[O:31])[CH3:30]
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Agent: CCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOc1c(C2CCN(C(=O)NCC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 186.8 %

Procedure:
Triethylamine (0.05 mL, 0.35 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20.0 mg, 0.06 mmol) in dichloromethane (5 mL). The reaction was cooled to 0° C. and triphosgene (6.3 mg, 0.02 mmol) dissolved in dichloromethane (3 mL) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. Pyridine (3 μL, 0.03 mmol) and ethylamine (2.7 mg, 0.06 mmol) were then added in sequence and the solution was stirred overnight. The reaction was quenched via the addition of water (5 mL) and 1 M citric acid (1 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-5% methanol in ethyl acetate) to afford (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-N-ethylpiperidine-1-carboxamide (15 mg, 61%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97-1.05 (m, 6H), 1.15 (t, J=7.04 Hz, 3H), 1.18-1.27 (m, 1H), 1.37-1.53 (m, 2H), 1.63 (br d, J=11.73 Hz, 2H), 1.69-1.78 (m, 2H), 2.02 (s, 3H), 2.15-2.30 (m, 2H), 2.63-2.79 (m, 3H), 2.90-3.07 (m, 3H), 3.60-3.75 (m, 2H), 4.07 (br d, J=16.12 Hz, 2H), 4.50-4.62 (m, 1H), 6.45 (br t, J=5.42 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 402 [M+H]+.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[OH2:17]>CO>[CH3:7][S:8]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:1])=[O:17]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C#N)cc1
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C#N)cc1
Reaction time: 3 h

Procedure:
A solution of oxone (18.42 g, 0.03 mol) in water (70 ml) was added dropwise to the vigorous stirred solution of 4-methylthiobenzonitrile (1.49 g, 0.01 mol) in methanol (50 ml) at 20° C. and stirring was continued for three hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to finish the title compound (1.3 g, 72.2%), mp 145-149° C. The compound was used with out any purification for the next step. 1H-NMR (CDCl3):δ 3.1 (s, 3H), 7.8-7.9 (d, 2H), 8.08-8.1 (d, 2H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I)([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]1([C:19]2[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCC
Reactant: O=[N+]([O-])c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4,4,5,5-Tetramethyl-2-(4-indanone-1-yl)[1,3,2]-dioxoborolane (2.17 g, 8.4 mmol) and o-nitroiodobenzene (2.70 g, 10.9 mmol) were dissolved in a mixture of dioxane (30 mL) and water (5 mL). K2CO3 (2.30 g, 16.7 mmol) and Pd(PPh3)4 (0.48 g, 0.4 mmol) were added. The reaction mixture was heated in a flow of argon to 80° C., kept at this temperature over a period of 24 h (TLC monitoring: hexane/ethyl acetate, 4:1), cooled, and filtered through Celite. The filtrate was evaporated. The residue was dissolved in CH2Cl2. An undissolved precipitate was filtered off. The filtrate was partially evaporated, and the product was purified in a short silica gel column (hexane/ethyl acetate) to give 2.5 g of a product containing PPh3O. The product was cyclized without additional purification.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:28])([F:27])[C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O.N1C=CC=CC=1>[Cl:29][C:23]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:17]([F:27])([F:16])[F:28])[N:26]=[CH:25][CH:24]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a −78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at −78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at −78° C. for 20 minutes, followed by warming to −50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to −15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94%) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].
Reaction SMILES: N(C1C=C(C=CC=1C)C(NOC)=[O:7])N.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24](NOC)=[O:25])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36](I)[CH:35]=1.C(N(CC)CC)C>C(O)C>[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24]([OH:25])=[O:7])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Reactant: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 (242 mg, 1.19 mmol, 1.0 eq) in 25 mL of ethanol was added 2-benzoyl-3-phenylamino-acrylonitrile 4 (296 mg, 1.19 mmol, 1.0 eq, preparation: Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (161 μL, 1.19 mmol, 1.0 eq) and the mixture was heated to 65° C. All solids dissolved when temperature reached 65° C. After three hours, LC-MS indicates consumption of the hydrazine. The solids were filtered to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (95 mg, 25%) as a beige solid: HPLC (4 minute gradient) tR 2.10 min; MS m/z 322 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 7.99 (d, 1=7.6, 1H), 7.81 (s, 2H), 7.78 (s, 1H), 7.57 (m, 4H), 7.02 (s, 2H, NH2), 2.18 (s, 3H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 187.6, 166.3, 152.0, 141.3, 141.2, 139.6, 135.9, 131.6, 131.2, 130.1, 129.8, 128.6, 127.8, 102.6, 17.4 ppm.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Reactant: C#CC(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(O)C#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12

Procedure:
15.98 g (46.6 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 5 5.48 ml (69.9 mmol) of (±)-3-butyn-2-ol were heated for 6 h at 90-5° C. in 47 ml of toluene with 47 ml of triethylamine, 163.5 mg (233 μmol) of bis-triphenylphosphine-palladium(II)-dichloride and 8.9 mg (46.6 23 μmol) of copper(I) iodide. The reaction was filtered and the solid washed with toluene. The filtrate was evaporated in vacuo to dryness, the residue taken up in 150 ml of dichloromethane, extracted twice with 50 ml of 1 N HCl, dried with sodium sulfate, and filtered through 120 g of silica gel in a column. The title compound (11.11 g) was recovered as an off-white solid. A recrystallized sample from di-isopropyl ether had mp 129-31° C.