Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=1>ClCCl.CCN(C(C)C)C(C)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[O:50])[N:59]([C:56]3[CH:57]=[CH:58][C:53]([Cl:52])=[CH:54][CH:55]=3)[CH3:60])=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Reactant: CNc1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
PyBroP (606 mg, 1.3 mmol) was added to a solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (382 mg, 11.0 mmol) in dichloromethane (20 ml) and DIEA (to pH9). The mixture was stirred for 1 h at room temperature then (4-chloro-phenyl)-methyl amine (156 mg, 1.1 mmol) was added. The mixture was stirred for 2 days at room temperature then solvents were concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (210 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfinyl-6-phenyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH:29]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH:29][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 53 using the procedures of Example 54 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.1 (br s, 1H), 8.26 (s, 1H), 8.01 (d, 2H), 7.84-7.81 (m, 2H), 7.74-7.71 (m, 3H), 7.59 (s, 2H), 7.39 (t, 2H), 3.89 (s, 3H), 2.91-2.89 (m, 1H), 1.03 (d, 4H); LC-MS (ESI): Calculated mass: 487.55; Observed mass: 488.1 [M+H]+ (rt: 1.42 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:22][CH2:23][O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc(OCCOC3CCCC3)cc2)cc1

Procedure:
A solution of 24 g (0.12 mol) of 4-benzyloxyphenol in 100 cc of DMF is added dropwise to a 50% suspension of 6.2 g (0.132 mol) of NaH in 50 cc of DMF. When the evolution of gas has ended, a solution of 36 g (0.127 mol) of 2-cyclopentyloxyethyl tosylate in 100 cc of DMF is then added. The mixture is stirred for half an hour. It is then heated for 2 hours at 55°-60° C. with stirring. The reaction mixture is poured into iced water. Extraction is carried out with diethyl ether. The ether phase is washed with dilute sodium hydroxide solution and then with water, dried and evaporated to dryness.
Reaction SMILES: O.O.Cl[Sn]Cl.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1.Cl>CCO>[Cl:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cn1ccnc1Sc1ccc(N)cc1Cl
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a solution of SnCl2.2H2O in EtOH (10 ml) at 60° C. was added 426A (1.80 g, 6.67 mmol). Concentrated HCl (8 ml) was added and the mixture was heated at 60° C. for 15 min. Cooled to rt, the mixture was concentrated under reduced pressure. The residue was basified to pH>12 and extracted with EtOAc (4×50 ml). The combined organic layers were washed with 1N KOH (20 ml), H2O (20 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave 426B (1.31 g, 82%) as a white solid. The solid was used in next step without further purification. It has a retention time of 3.53 min (standard LC1 method, 8 min run). MS Found: (M+H)+=240.1
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH2:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCCN(C)C(=O)CCl
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 80.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and N-butyl-2-chloro-N-methylacetamide (8.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: NC1C=CC(C)=CC=1.N[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1OC)[C:13]([NH:15]C1C=CC(F)=C(F)C=1)=[O:14]>>[C:13]([NH2:15])(=[O:14])[C:12]1[CH:24]=[CH:25][CH:26]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Solvent: Cc1ccc(N)cc1
Product: NC(=O)c1ccccc1
Yield: 103.2 %

Procedure:
The title compound was synthesized as in Example 1 using p-toluidine (0.87 g, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.56 g, 2.0 mmol) to give 0.25 g of benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]amino]-sulfonyl]amino]-. Microanalysis: C22H20F2N4O5S; calculated: C=53.87; H=4.11; N=11.42. found: C=53.56; H=4.14; N=11.27. MS: M++1=491 Da. Mp 194-197° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:35][NH2:36]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:35][NH2:36])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 217.1, 1.10 g, 2.45 mmol, 1.00 equiv) in ethanol (40 mL). Hydrazine hydrate (20 mL) was added to the reaction mixture, and the reaction was stirred 80° C. for 15 h. After cooling to ambient temperature, the mixture was concentrated in vacuo, then diluted with 50 mL of H2O. The resulting mixture was extracted with 3×50 mL of dichloromethane. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 900 mg (82%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH3:33][O:34][CH2:35][C:36](N(OC)C)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:37]
Reactant: COCC(=O)N(C)OC
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Product: COCC(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12

Procedure:
2-Methoxy-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 2,N-dimethoxy-N-methyl-acetamide (Journal of Medicinal Chemistry, 47(10), 2405-2408; 2004) following general procedures as described in these Examples, to afford a pale yellow solid. MP 229-230° C., M+H=358.
Reaction SMILES: [C:1]([CH2:3][C:4]12[CH2:12][CH:8]3[CH2:9][CH:10]([CH2:11]1)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:7]3)[CH2:5]2)#[N:2].[CH2:21]([OH:23])C.Cl.[NH2:25]O.C([O-])([O-])=O.[Na+].[Na+]>O>[O:23]1[CH:21]=[N:25][C:1]([CH2:3][C:4]23[CH2:12][CH:8]4[CH2:9][CH:10]([CH2:11]2)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])([CH2:7]4)[CH2:5]3)=[N:2]1
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CC#N)(C3)C2
Reactant: CCO
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(Cc1ncon1)(C3)C2
Yield: 51 %

Procedure:
To a stirred solution of the compound obtained from step I (0.25 g, 0.9 mmol) in a 1:1-mixture of ethanol and water (9 mL) at room temperature was added hydroxylamine hydrochloride (0.32 g, 4.5 mmol) followed by solid Na2CO3 (0.57 g, 5.4 mmol). The reaction mixture was refluxed for 12 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethylacetate and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was dissolved in trimethyl orthoformate (0.2 mL) and a catalytic amount of camphor sulfonic acid was added. The reaction mixture was refluxed for 4 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography to obtain tert-butyl [1-(1,2,4-oxadiazol-3-ylmethyl)tricyclo[3.3.1.03,7]non-3-yl]carbamate (0.15 g) in 51% yield as viscous liquid. m/z (M+1), 320; 1H NMR (CDCl3) 300 MHz δ 8.62 (s, 1H), 4.71 (bs, 1H), 2.79 (s, 2H), 2.48-2.38 (m, 1H), 2.35-2.28 (m, 1H), 2.10-1.88 (m, 4H), 1.74 (dd, J=2.8, 10.5 Hz, 2H), 1.65-1.38 (m, 4H), 1.43 (s, (H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+]>O.CO.C(OCC)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1N
Yield: 78.4 %

Procedure:
A mixture o f 2.9 g (6.95 mmol) of 4-[(3-bromo-4-fluorophenyl)amino]7-methoxy-6-nitro-quinoline-3-carbonitrile, 6.5 g (121.6 mmol) of ammonium chloride and 4.05 g (73 mmol) of iron in 50 ml of water and 50 ml of methanol for 6 hours. The mixture was diluted with hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 2.11 g of light yellow solid: mass spectrum (electrospray, m/e): M+H 386.7 and 388.8.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.31 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (64 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (94.5 mg, 76%) as a yellow foam: mp 87-90° C. (foam to gel); EI-HRMS m/e calcd for C21H23N3O3S (M+) 397.1460, found 397.1460.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](OC)=[N:5][CH2:4]1)[CH3:2].[Cl-:10].[NH4+:11]>CO>[ClH:10].[CH2:1]([CH:3]1[CH2:4][NH:5][C:6](=[NH:11])[CH2:7]1)[CH3:2]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: CCC1CN=C(OC)C1
Solvent: CO
Product: CCC1CNC(=N)C1
Product: Cl

Procedure:
The product of EXAMPLE 211 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[NH:22]1[CH2:32][CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23]1.[CH2:33]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:33][N:22]4[CH2:32][CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: CCOC(=O)C1CCCNC1
Reactant: C=O
Solvent: CCO
Product: CCOC(=O)C1CCCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.10 g, 0.36 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with ethyl nipecotate (0.068 g, 0.43 mmol), and 37% aqueous formaldehyde (0.036 g, 0.46 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain ethyl (Z)-1-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-3-carboxylate (0.056 g, 35%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
4-t-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was added dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir for 18 h, gradually warming to ambient temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and extracted twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a colorless oil (12.5 g, 100%) 1H NMR (300 MHz, CDCl3): δ 7.28 (d, 2H, J=5.5), 6.80 (d, 2H, J=5.5), 4.70 (q, 1H, J=6.6), 4.22 (q, 2H, J=7.1), 1.59 (d, 3H, J=6.6), 1.28 (s, 9H), 1.25 (t, 3H, J=7.1). MS [EI+] 251 (M+H)+, 268 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:22]#[N:23])=[C:4]([O:34][CH3:35])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:45][CH2:44]C1>CCOCC>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:44](=[O:45])[NH:23][CH2:22]2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CNC(C#N)c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 100 mg of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino]acetonitrile in 4 mL of THF was added 620 μL of a 1 M solution of LiAlH4 in Et2O. The cooling bath was removed and the mixture was stirred for 45 min at r.t. The mixture was recooled to 0° C. and carefully quenched by dropwise addition of 24 μL of water, 24 μL of 15% aqueous NaOH solution, and 60 μL of water. The solids were filtered, washing liberally with Et2O, and the filtrate was concentrated. The residue was dissolved in 2 mL of CH2Cl2 and cooled to 0° C. Triethylamine (55 μL) and then triphosgene (32 mg) were added. The mixture was stirred for 45 min at 0° C. The reaction mixture was partitioned between 10 mL of EtOAc and 10 mL of water. The aqueous was extracted with 10 mL of EtOAc and the combined organics were washed with 10 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 15% EtOAc in hexanes followed by a linear gradient of 15→100% EtOAc in hexanes over 10 CV to provide the title compound. Mass spectrum (ESI) 517.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:17])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][C:27]([CH3:34])([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29]>CC(C)(CCC)C(O)=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:28](=[O:29])[C:27]([CH3:34])([CH3:26])[CH2:31][CH2:32][CH3:33])=[C:20]([O:25][C:28](=[O:29])[C:27]([CH3:34])([CH3:26])[CH2:31][CH2:32][CH3:33])[CH:19]=1)=[O:17])[CH3:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(CC(=O)c1ccc(O)c(O)c1)Cc1ccccc1
Reactant: CCCC(C)(C)C(=O)Cl
Agent: CCCC(C)(C)C(=O)O
Agent: CS(=O)(=O)O
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CN(C)Cc2ccccc2)cc1OC(=O)C(C)(C)CCC

Procedure:
Using a procedure similar to that described above in Example 3A, 3,4-dihydroxyphenyl N-benzyl-N-methylaminomethyl ketone methanesulfonate is reacted with two mole equivalents of 2,2-dimethylpentanoyl chloride in 2,2-dimethylpentanoic acid to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl N-benzyl-N-methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is debenzylated by catalytic hydrogenation in the presence of palladium-on-charcoal hydrogenation catalyst, in the same manner as the debenzylation procedure described above in Example 124, to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is catalytically hydrogenated in anhydrous ethyl alcohol in the presence of 10 percent palladium-on-charcoal hydrogenation catalyst until one mole equivalent of hydrogen is absorbed. There is thus obtained 3,4-bis(2,2-dimethylpentanolyoxy)-alpha-(methylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:24]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])[CH2:36][CH2:35]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][N:37]2[CH2:38][CH2:39][N:34]([CH:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[CH2:35][CH2:36]2)=[O:11])[CH:2]=1
Reactant: NCCCCN1CCN(C2CCCc3ccccc32)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(C=Cc1cccnc1)NCCCCN1CCN(C2CCCc3ccccc32)CC1

Procedure:
Batch size: 2.7 g (18 mmol) 3-(3-pyridyl)-acrylic acid, 3.15 g (19 mmol) CDI and 5.0 g (17.4 mmol) 4-[4-(1,2,3,4-tetrahydro-naphthalin-1-yl)-piperazin-1-yl]-butylamine.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of methyl chloroglyoxylate (2.98 ml, 32.4 mmol) in dichloromethane (10 ml) was added dropwise at a slow speed to a mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (5.476 g, 21.6 mmol), sodium hydrogencarbonate (3.62 g, 43.2 mmol), dichloromethane (40 ml) and water (40 ml), and stirred at 0° for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.71 g, 91.5%) as a white solid.