Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.OC(C(F)(F)F)=O.[NH2:20][C@H:21]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:26][CH2:25]1)=[O:23].CCN(C(C)C)C(C)C.C([O:62][C:63](=O)[NH:64][CH2:65][CH2:66][CH2:67][NH2:68])(C)(C)C>>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@@H:21]([NH:20][C:63]([NH:64][CH2:65][CH2:66][CH2:67][NH2:68])=[O:62])[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH2:28][CH2:29]2)=[O:23])=[CH:47][CH:46]=1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)NCCCN)CC1

Procedure:
Following the procedure of Example 51, N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl][(3-aminopropyl)amino]carboxamide, TFA salt was prepared from triphosgene (Avocado Chemical Company) (45 mg, 0.152 mmol), (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one TFA salt (200 mg, 0.36 mmol), DIEA (0.32 mL, 0.916 mmol), and tert-butyl-N-(3-aminopropyl)carbamate (Aldrich Chemical Company) (96 mg, 0.55 mmol). The Boc protecting group was removed by treating the compound with a soln of 50% TFA and CH2Cl2 (2 mL) for 2 h. The organic solvent was removed in vacuo to give the desired product. Preparative TLC purification with 60% Hexane, 35% CH2Cl2 and 5% 2N NH3 in MeOH afforded 90% pure compound. This was further purified by preparative HPLC (TFA buffer) to afford the title compound (TFA salt) as a white solid (10 mg). MS (ESI, pos. ion) m/z: 537 (M+H); MS (ESI, neg. ion) m/z: 535 (M−H). Calc'd for C24H33ClN6O4S: 536.20.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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(COC)OC>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(Cl)c(CC3CCN([C@H]4CC[C@@H](O[Si](C)(C)C(C)(C)C)CC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.400 g, 0.658 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.411, 1.97 mmol), tetrakis(triphenylphosphine)palladium (0.076 g, 0.0658 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 1.8 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.301 g (85%) of the title compound: mass spectrum (m/z): 538(M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:15]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]3[C:40]4[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=4[C:45]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=4)=[N:44]3)[CH2:13][CH2:12]2)=[C:19]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2NS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cccc(Cl)c1N1CCN(CC(O)Cn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (145 mg, 0.37 mmol) was dissolved in 3 mL of CH2Cl2 and treated with 1.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (90 mg) was dissolved in absolute EtOH (1.0 mL) and treated with 96 mg (0.24 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography (silica, 0-5% MeOH/CH2Cl2) provided 138 mg (20% over 4 steps) of N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.45. MS (electrospray): exact mass calculated for C28H34ClF3N6O5S2, 690.17; m/z found, 691.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.65 and 7.59 (AB pattern, J=8.4 Hz, 4H), 7.36 (d, J=8.1 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.54-4.44 (m, 2H), 4.21-3.94 (m, 3H), 3.77-3.52 (m, 4H), 3.41 (m, 2H), 2.96 (s, 3H), 2.81 (s, 3H), 3.05-2.73 (m, 4H), 2.66-2.20 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([F:18])[C:10]=1F>>[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([F:18])[C:10]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Product: O=[N+]([O-])c1cc(F)c(Sc2ccncc2)c(F)c1

Procedure:
is synthesized analogously to C2 from 4-mercaptopyridine and 1,2,3-trifluoro-5-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH3:35])[CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CNCc1cccnc1
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)Cc3cccnc3)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step G (0.125 g, 0.262 mmol), 3-(methylaminomethyl)pyridine (0.038 g, 0.314 mmol), 1-hydroxy benzotriazole (0.039 g, 0.288 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.055 g, 0.288 mmol) were combined in amine-free N,N-dimethylformamide (1.1 mL), followed by addition of N,N-diisopropylethyl amine (0.068 mL, 0.393 mmol). The reaction was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform, and recrystallized from diethyl ether/pentane to afford 0.140 g of the title compound as a white crystalline solid, m.p. 178-179° C., 98.0% pure by analytical HPLC (Primesphere C-18, 2.0×150 mm, 45% acetonitrile/water, 0.2 mL/min.).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].CN(C)C=O.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: C=CCN(CCO)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CCN(CCCl)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
16.7 parts by weight of N-hydroxyethyl-N-allyl-2,6-dinitro-4-trifluoromethylaniline is dissolved in 50 parts by weight of benzene. After adding 1 part by weight of dimethylformamide and dripping in 30 parts by weight of thionyl chloride at room temperature the whole is boiled for two hours under reflux. The volatile constituents are distilled off from the reaction mixture at 20 mm Hg, the residue is taken up in ethyl acetate, the solution is washed with ice-water, then with 10% sodium bicarbonate solution and finally again with water and the organic phase is dried over sodium sulfate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]([CH2:16][OH:17])=[O:15]>COC(OC)(C)C>[CH3:11][C:1]1([CH3:6])[O:17][CH2:16][C:14](=[O:15])[CH2:13][O:12]1
Reactant: O=C(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(=O)CO1
Temperature: 25 °C

Procedure:
p-Toluenesulfonic acid (0.18 g) was added to a solution of 1,3-dihydroxyacetone (2.75 g, 30.5 mmol) in 2,2-dimethoxypropane (25 ml). The reaction was heated to reflux for 1.5 hs. The reaction was allowed to cool to room temperature and was concentrated to give the 2,2-dimethyl-1,3-dioxan-5-one as a crude oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:37])([F:36])[F:35])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CCN(S(F)(F)[F:45])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH:9]([F:45])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:35])([F:37])[F:36])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 19.3 %

Procedure:
A solution of diethyl[hydroxy(4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)methyl]phosphonate (Example 133, 8.00 mg, 0.014 mmol) and DAST (7 mg, 0.043 mmol) in DCM (3 mL) was stirred at 0° C. for 1 h. The was treated with sat. NaHCO3 (aq) (3 mL). The layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and residue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 1.5 mg of the desired product (yield: 19%). 1H NMR (CD3OD, 400 MHz): δ=1.24 (t, J=7.6 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H), 2.90 (s, 3H), 4.00-4.17 (m, 4H), 5.82 (dd, J=7.2, 44.0 Hz, 1H), 7.20 (dt, J=1.2, 8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.50 (dt, J=2.0, 8.8 Hz, 1H), 7.64 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 8.43 (d, J=7.2 Hz, 1H). MS (ES+): m/z 556.14 [MH+]. HPLC: tR=1.50 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:20]([OH:22])=O)[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([C:20]([Cl:24])=[O:22])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCc1ccc(-c2ccccc2)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.29 g of 4-heptylbiphenylcarboxylic acid was added to 10 ml of benzene, and 2.36 g of PCl5 was added little by little under stirring at room temperature, followed by 4 hours of heat-refluxing. Thereafter, the solvent was distilled off to obtain 4-heptylbiphenylcarboxylic acid chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:25])=[O:9])=[O:4]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (1.37 g, 4.69 mmol, 1.00 equiv) in dichloromethane (17 mL) was added 2 drops of N,N-dimethylformamide followed by the addition of oxalyl dichloride (3.63 g, 28.14 mmol, 6.00 equiv). The resulting solution was stirred for 1 h at 50° C. in an oil bath then concentrated under vacuum to afford 1.41 g (87%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride as a gray-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH:21](Br)[CH3:22]>>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)CCCBr
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester with 1,4-dibromopentane yielded [4-(5-Bromo-pentyloxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 372 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([OH:14])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:15](O)[CH3:16]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)Cc1n[nH]c2cc(F)ccc12
Product: CCOC(=O)Cc1n[nH]c2cc(F)ccc12
Yield: 39.3 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)acetic acid (4.63 g, 23.8 mmol) was dissolved in anhydrous ethanol (60 mL) concentrated sulfuric acid (2.0 mL), and heated under reflux for 16 hours. After concentrated under reduce pressure to remove most of ethanol, water (20 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the product 2.08 g, at a yield of 39.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[CH3:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13](=[O:30])[N:12]([CH3:11])[C:16]=2[CH:17]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccncc1Br
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Temperature: 90 °C
Yield: 55.2 %

Procedure:
A mixture of 1-(3-bromopyridin-4-yl)ethanone (50 mg, 0.250 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (68.8 mg, 0.250 mmol), polymer bound PalladiumTetrakis (56.8 mg, 6.25 μmol) and sodium carbonate (250 μl, 0.500 mmol) in toluene (1 mL) and ethanol (1 mL) was heated to 90° C. in microwave for 45 min. After filtration through a pad of Na2SO4, the solvent was removed in vacuum. The residue was purified by flash column (MeOH—CH2Cl2, v/v, 1%-1.5%) and yielded colorless solid (37 mg). ESI-MS m/z: 269.0 [M+1]+, Retention time 1.03 min; 1H NMR (400.3 MHz, CDCl3): δ 2.13 (s, 3H), 344 (s, 3H), 6.95 (d, J=1.48 Hz, 1H), 7.07 (dd, J=8.2, 1.68 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.37 (d J=5 Hz, 1H), 8.69 (s, 1H), 8.73 (d, J=5 Hz, 1H).
Reaction SMILES: Br.[F:2][CH:3]([F:27])[O:4][C:5]1[C:6]([OH:26])=[C:7](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17]S3)[CH:8]=[CH:9][CH:10]=1.[CH3:28][C:29](O)=O>>[F:2][CH:3]([F:27])[O:4][C:5]1[C:6]([OH:26])=[C:7](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[CH:29]=[CH:28][CH:17]=[CH:18][N:19]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Agent: Br
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2ccccn12

Procedure:
The Step 1 intermediate (4.3 g, 9.674 mmol) was treated with 48% hydrobromic acid (20 mL) in glacial AcOH (20 mL) as described in Intermediate 6 gave 3.1 g of the product as white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.44 (t, J=7.2 Hz, 3H), 4.44 (q, J=7.2 Hz, 2H), 6.92 (d, J=7.8 Hz, 1H), 7.12 (t, J=74.1 Hz, 1H), 7.15-7.22 (m, 2H), 7.48 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.75 (d, J=9.3 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 8.08 (d, J=15.9 Hz, 1H), 9.24 (d, J=6.9 Hz, 1H), 9.83 (br, 1H); APCI-MS (m/z) 375.16 (MH)+.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[SH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: CO/C=C/C(C)=O
Reactant: Sc1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)/C=C/Sc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 16.7 %

Procedure:
To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 15.0 ml, 0.13 mol) and 2-naphthalenethiol (21.16 g, 0.13 mol) in benzene (180 ml) was added p-toluene sulfonic acid-monohydrate (75 mg, 0.4 mmol), followed by heating, while stirring, on an oil bath at 50° C. for 70 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with ethyl acetate four times. The ethyl acetate layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine twice and then dried with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (670 g, n-hexane:methylene chloride:ethyl acetate=1:0:0-1:3:0-2:0:1), followed by recrystallizing from n-hexane-ethyl ether to thereby obtain the titled compound as a light brown crystalline.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: NN
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Yield: 74.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.5 g, 14.60 mmol) in ethanol (25 mL) was added hydrazine hydrate (2.1 g, 43.8 mmol). The reaction mixture was refluxed for 3-4 h. The reaction mixture was concentrated to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.46 (s, 2H), 6.31 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 8.25 (s, 1H); MS (m/z): (184.01 M)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N)CN>[Cu]I.O1CCOCC1>[O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 40 h
Yield: 45.5 %

Procedure:
To a sealed-vial was added (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (162 mg, 0.756 mmol), potassium phosphate (321 mg, 1.51 mmol), iodobenzene (0.101 mL, 0.907 mmol), ethylenediamine (0.020 mL, 0.30 mmol), dioxane (3 mL) and molecular sieves followed by copper(I) iodide (57.6 mg, 0.302 mmol). The vial was purged with nitrogen gas and sealed. Then the reaction was stirred at 110° C. for 40 hr. The reaction was diluted with EtOAc (30 mL) and washed with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give (S)-tert-butyl 2-oxo-1-phenylpiperidin-3-ylcarbamate (100 mg, 0.344 mmol, 45.6% yield) as a white solid. Anal. Calcd. for C16H22N2O3 m/z 290.3. found: 291.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.40 (t, J=7.70 Hz, 2H), 7.33-7.20 (m, 3H), 5.56 (br. s., 1H), 4.37-4.20 (m, 1H), 3.78-3.66 (m, 2H), 2.63 (dd, J=12.37, 5.77 Hz, 1H), 2.16-1.97 (m, 2H), 1.81-1.661 (m, 1H), 1.47 (s, 9H).