Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[N:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[N:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@H](C)O)CC5)cn4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](O)CN1CCN(c2cnc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 23 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-1-yl) propan-2-ol (230 mg, 0.34 mmol) was hydrolyzed with lithium hydroxide (44 mg, 1.03 mmol) in THF/methanol/water (4/4/2 mL) to yield 40 mg (18.5% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.83-8.75 (m, 3H), 8.44-8.43 (d, 1H), 8.22 (s, 1H), 7.972-7.970 (d, 1H), 7.68 (s, 1H), 7.44-7.32 (m, 1H), 7.16-6.96 (m, 3H), 5.44 (s, 2H), 4.70-4.45 (m, 3H), 4.30-4.10 (m, 2H), 3.80-3.60 (m, 2H), 3.60-3.30 (m, 4H), 1.27-1.25 (d, 3H). MS: m/z=513.3 (M+1), HPLC: 97.55% in method B.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnc2ccc(NC3CCOCC3)nn12
Temperature: 40 °C
Yield: 81.6 %

Procedure:
A mixture of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.4 g, 6.6 mmol), tetrahydro-2H-pyran-4-amine (1.0 g, 9.9 mmol), cesium carbonate (4.3 g, 13 mmol), and DMF (10 mL) was maintained at 40° C. for 16 h, then cooled to RT and partitioned between ethyl acetate (100 mL) and H2O (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×40 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by flash chromatography (SiO2) to afford 3-bromo-N-(tetrahydro-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine (1.6 g, 80%) as a light yellow solid: 1H NMR (400 MHz, MeOD-d4) δ 7.58 (d, J=9.9 Hz, 1H), 7.42 (s, 2H), 6.71 (d, J=9.9 Hz, 1H), 3.95-4.08 (m, 3H), 3.60 (td, J=11.5, 2.3 Hz, 2H), 2.16 (d, J=11.5 Hz, 2H), 1.53-1.69 (m, 2H); LCMS (ESI) m/e 297.1 [(M+H)+, calcd for C11H13BrN4O 297.0].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([CH:21]=O)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.C(Cl)Cl>[C:27]([N:31]1[CH2:36][CH2:35][N:34]([CH2:21][C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:20]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]=4[NH:12][C:13]=3[CH:14]=2)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(C=O)ccc12
Reactant: CC(C)(C)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(CN3CCN(C(C)(C)C)CC3)ccc12
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
A suspension of methyl 2-(3-chlorophenyl)-7-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (80 mg, 0.22 mmol) in DMF (1 mL) was stirred for 5 min and then diluted with DCM (10 mL). 1-tert-butylpiperazine (38 mg, 0.26 mmol) was added and the suspension was cooled in an ice bath. Sodium triacetoxyborohydride (125 mg, 0.592 mmol) was added and the suspension was left stirring for 0.5 hr. Acetic acid (0.025 mL, 0.44 mmol) was then added and the bath removed. The reaction was left stirring at RT overnight, diluted with DCM, and washed with sat. aq. NaHCO3 solution followed by water (2×). After drying with sodium sulfate, the solvent was removed and radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) afforded methyl 7-((4-tert-butylpiperazin-1-yl)methyl)-2-(3-chlorophenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (45 mg, 0.092 mmol, 42% yield) as a yellow solid. MS (ESI) m/z 491.19 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.49 (1H, s), 8.36 (1H, d, J=7.94 Hz), 8.24 (1H, s), 8.20 (1H, s), 8.04 (1H, d, J=7.63 Hz), 7.53 (1H, t, J=7.78 Hz), 7.35-7.39 (1H, m), 7.33 (1H, d, J=7.93 Hz), 4.09 (3H, s), 3.70 (2H, s), 2.63 (8H, br. s.), 1.07 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[OH-].[NH4+:14]>>[NH2:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)cc(N)n1
Reaction time: 8 h

Procedure:
2-chloro-6-methyl-4-(trifluoromethyl)pyridine (5.0 g) and conc ammonium hydroxide (150 mL) were heated at 180° C. in a steel reaction vessel with mechanical stirring overnight. The contents were allowed to cool and partitioned between CH2Cl2 and water. The CH2 Cl2 layer was dried (MgSO4) and concentrated in vacuo leaving 2-amino-6-methyl-4-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCOC(C)=O.[CH3:19][N:20](C)C=O>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:19]#[N:20])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
A mixture of 4-bromo-3-nitrobenzaldehyde (1 g, 4.35 mmol) in dimethylformamide (10 mL) was added cuprous cyanide (584.8 mg, 6.53 mmol). The resultant solution was stirred at 160° C. for 5 hours. After cooling, a standard aqueous/EtOAc workup was followed. Purified by silica gel column chromatography to give product (430 mg, yield 56.1%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([NH:38][CH2:37][CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]2)=[CH:13][CH:12]=3)[N:19]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Product: CN1CCN(CCCNc2ccc3oc(-c4cc5ccccc5cn4)cc(=NO)c3c2)CC1

Procedure:
2-isoquinolin-3-yl-6-[3-(4-methyl-piperazin-1-yl)-propylamino]-chromen-4-one oxime was prepared in 85% overall yield using the method described in examples 35 and 35A, starting from 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 4B) and 3-(4-methyl-piperazin-1-yl)-propylamine. The title compound was isolated as a yellow solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1.[CH3:15][O:16]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2ccc(OC)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ccc(OC)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 2,7-dimethoxynaphthalene 2 (65 mmol; 12.26 g) is dissolved in 150 cm3 of anhydrous dichloromethane under an inert atmosphere. TiCl4 (91 mmol; 10cm3) is added by syringe, at 0° C., followed by dropwise addition, by means of a dropping funnel, of α,α-dichloromethyl methyl ether (99 mmol; 9 cm3) in solution in 40 cm3 of the same solvent. Stirring is continued at 0° C. for 1 h and then at room temperature for 4 h 30. The reaction medium is poured onto an ice/3N HCl mixture (250 cm3), stirred vigorously and then extracted with CH2Cl2. The organic phase is washed with water and then with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and evaporated. The residue is taken up in ether, the solution is filtered and the filtrate is evaporated to dryness. 2,7-Dimethoxynaphthaldehyde 3 is isolated pure in the form of a beige-colored powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([N:17]([S:18]([CH3:21])(=[O:19])=[O:20])[CH3:25])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1

Procedure:
Mix 5-methanesulfonylamino-N-methyl-N-propyl-isophthalamic acid methyl ester (2.09 g, 6.36 mmol), iodomethane (1.35 g, 9.55 mmol), potassium carbonate (1.38 g, 10 mmol), and tetrabutylammonium bromide (206 mg, 0.64 mmol) in DMF (10 mL) at room temperature for 30 min. Dilute with ethyl acetate and wash with 10% aqueous potassium carbonate, 1 N lithium chloride and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:dichloromethane) to give the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Yield: 75 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester ((147 mg, 0.5 mmol) and 2,6-dichloro-benzothiazole (102 mg, 0.5 mmol) to yield the title product (172 mg, 75% yield); 1H NMR (400 MHz, DMSO-d6); δ 1.41 (s, 9H), 1.75-2.04 (m, 4H), 3.24-3.35 (m, 2H), 3.89-4.12 (m, 3H), 7.08 (d, J=9.2 Hz, 2H), 7.38 (d, J=9.2 Hz, 2H), 7.45 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:28][C:29]1[N:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([CH3:36])=[CH:32][C:33]=1[CH:34]=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][C:29]1[N:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([CH3:36])=[CH:32][C:33]=1[CH:34]=[CH2:3]
Reactant: Cc1cc(C=O)c(C)n1-c1ccccc1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1cc(C)n(-c2ccccc2)c1C
Yield: 80 %

Procedure:
To a solution of bromomethyl(triphenyl)phosphonium bromide (2.2 g, 5 mmol) in dry THF (50 mL), n-BuLi (2.5 M, 2 mL, 5 mmol) was added dropwise at −78° C. under nitrogen. The reaction mixture was stirred 30 min at this temperature and compound 5 (1.0 g, 5 mmol) was added, then the cooling bath was removed. Stirring was continued for another hour. The solvent was completely removed under reduced pressure. The residue and Pd(OAc)2 (56 mg, 0.25 mmol), Na2CO3 (1.86 g, 17.5 mmol), n-Bu4NCl (8.34 g, 30 mmol) were dissolved in dried DMF (20 mL). The reaction mixture was stirred at 100° C. for 3 hrs. The reaction was quenched by adding 20 mL of water, and the aqueous phase was extracted with EtOAc (30 mL×3). The combined extracts were dried over Na2SO4, the mixture was filtered and the filtrate was concentrated in vacuo to give the desired product as a colorless oil (Purity: 90%, yield: 80%). MS[M++1]=198, LC-MS: tR=2.76 min.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(O)cc1
Yield: 44 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-hydroxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (44% yield); 1H-NMR (d6-DMSO) 1.37 (9H, s), 3.65 (2H, t), 4.05 (2H, t), 6.20 (1H, s), 6.68 (2H, d), 7.00 (2H, d), 9.25 (1H, s); 13C-NMR (CDCl3) 27.7, 41.7, 66.8, 114.7, 126.4, 131.4); MS ES(+) 222.1 (M+-tBu); Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.59; H, 7.05; N, 4.85. IR λmax=3402, 1672 cm−1.
Reaction SMILES: CCOCC.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 153 °C

Procedure:
1,4-diphenoxybenzene is prepared by the Ullmann ether synthesis as follows. 4-Phenoxyphenol (186.2 g, 1.0 mol) is dissolved in 1600 g of DMF with 300 mL toluene under nitrogen. A 50% KOH solution (112.0 g, 1.0 mol) is added followed by azeotropic removal of the water and stripping of the toluene. Bromobenzene (157.0 g, 1.0 mol) and cupric oxide (3.2 g, 0.04 mol) are then added and the reaction solution held at reflux (153° C.) for 24 hr. The DMF is then removed by stripping and the residue worked up to give 1,4-diphenoxybenzene.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2[F:32])=[N:11][CH:12]=[C:13]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Si:17]([O:16][CH2:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2[F:32])=[N:11][CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Under a hydrogen atmosphere, a mixture of 3-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)pyridine (2.81 g), 10% palladium-activated carbon (280 mg) and ethyl acetate (30 mL) was stirred at room temperature for 30 min. The catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure to give the title compound (2.33 g) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:63]([N:67]1[CH:72]=[CH:71][C:70](OS(C(F)(F)F)(=O)=O)=[C:69]([Cl:81])[C:68]1=[O:82])[CH2:64][CH2:65][CH3:66]>FC(C1C=CC=CC=1)(F)F.C(Cl)Cl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:63]([N:67]1[CH:72]=[CH:71][C:70]([N:6]2[CH2:5][CH2:4][C:3]([CH2:2][OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][CH2:7]2)=[C:69]([Cl:81])[C:68]1=[O:82])[CH2:64][CH2:65][CH3:66]
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Reactant: OCC1(c2ccccc2)CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: CCCCn1ccc(N2CCC(CO)(c3ccccc3)CC2)c(Cl)c1=O
Temperature: 100 °C

Procedure:
4-Hydroxymethyl-4-phenylpiperidine (0.172 g, 0.9 mmol), palladium(II) acetate (0.007 g, 0.03 mmol), cesium carbonate (0.391 g, 1.2 mmol) and Xantphos (0.035 g, 0.06 mmol) were added to a solution of intermediate D9 (0.2 g, 0.6 mmol) in trifluoromethylbenzene (2 ml). The reaction mixture was heated at 100° C. for 24 hours in a sealed tube, after which it was cooled to room temperature. Subsequently, it was diluted with DCM, H2O (5 ml) and extracted with EtOAc (3×5 ml). The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The crude product was purified first by column chromatography (silica gel; eluent: DCM/EtOAc from 90/10 to 0/100) and then by reversed phase HPLC. The desired fractions were collected, evaporated in vacuo and finally freeze dried to yield compound E22 (0.041 g, 18%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To the compound (346 mg, 0.917 mmol) obtained in Example 178b were added ethanol (4 mL) and 2N aqueous sodium hydroxide solution (0.915 mL, 1.83 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (237 mg, 71%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(F)C=CC=2F)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 4-chloro-N-[5-fluoro-2-fluorophenyl]benzenesulfonamide (500 mg, 1.65 mmol), triphenylphosphine (909 mg, 3.47 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (719 mg, 3.30 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.682 mL, 3.47 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22° C. with stirring. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H2O. The mixture was extracted with ether (3×15 mL). The combined organic extracts were washed with NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 466 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzene-sulfonamide as a yellow oil in 56% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.O.N.N#N>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: [Ni]
Agent: N
Agent: N#N
Solvent: CCO
Solvent: O
Product: COc1ccc2cccc(CCN)c2c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
56 g 7-methoxy-1-naphthaleneacetonitrile, 120 ml ammonia water, 332 ml 95% ethanol, 20 g Raney-Ni were added into autoclave. H2 was introduced after vacuuming it. The operation was repeated for 3 times. The reaction was stirred for 12 hours while H2 was introduced and the condition of 300 atm and 60° C. was maintained. After completion of the reaction, the reaction was kept overnight at room temperature. On the next day, it was vacuumed and N2 gas was introduced. The autoclave was opened up, and the reaction solution was filtered to remove the catalyst. The filtrate was vacuum evaporated until dry to obtain 56 g light green oil. The content is measured as 96.95% by HPLC, and the yield is 95%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][CH2:19][CH2:20][CH2:21]Cl)[CH:13]=[CH:14][CH:15]=1.O.C(OCC)(=O)C>C(#N)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][CH2:19][CH2:20][CH2:21][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cccc(CO)c1)OCCCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(CCCOC(=O)Nc2cccc(CO)c2)CC1
Temperature: 65 °C

Procedure:
10 g (100 mmol) of N-methylpiperazine are added to a solution of 2.4 g (10 mmol) of 3-chloropropyl (3-hydroxymethylphenyl)carbamate in 10 ml of acetonitrile. The solution is refluxed for 4 h. The mixture is then hydrolysed by addition of water and cooled to about 65° C., and ethyl acetate is added. The mixture is then cooled to room temperature, during which the product is obtained as a solid between the organic and aqueous phases. The product is filtered off and rinsed with water, acetonitrile and ethyl acetate. The product is subsequently dried at 50° C. for several hours; ESI: 308 (M+H).