Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br.C(O)(=O)C>[CH2:1]([C@H:8]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)Cc1cscn1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@H](Cc1ccccc1)Cc1cscn1
Yield: 69.9 %

Procedure:
The resultant compound from Example 35 (364 mg) was stirred for 2 h in 30% HBr in acetic acid (5 ml). The solvent was evaporated and the residue was dissolved in 1M HCl and washed with ether. The aqueous phase was adjusted to pH 4 with solid NaHCO3 and extracted with chloroform which was dried over Na2SO4 and evaporated to afford 186.5 mg (70%) of an oil. 1H NMR (CDCl3) δ8.78 (d,1H), 7.15-7.35 (m,5H), 6.99 (d,1H), 3.00-3.30 (m,4H), 2.81 (dd,1H).
Reaction SMILES: [F:1][CH:2]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1.[OH:25]OS([O-])=O.[K+]>CO>[F:1][CH:2]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([S:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:25])[CH2:5]1
Reactant: O=S([O-])OO
Reactant: Oc1ccc(S[C@@H]2CCN(CC(F)CCc3ccccc3)C2)cc1
Agent: [K+]
Solvent: CO
Product: O=S(c1ccc(O)cc1)C1CCN(CC(F)CCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
(2RS,3R)-4-[1-(2-Fluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (0.56 g, 1.62 mmol) was dissolved in MeOH (50 ml), cooled to 0° C. and treated with oxone (0.5 g, 0.81 mmol). After 4 hours stirring at 0° C., reaction mixture was quenched with saturated NaHCO3 (65 ml). Aqueous phase was extracted with CH2Cl2 (6 times). Combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed by MPLC over silica gel (CH2Cl2—MeOH, 99:1 then 98:2) then by preparative HPLC (EtOH-heptane, 08:92, detection at 254 nm) to provide (2R,3R, S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol (30 mg, first fraction, 5%), MS: m/e=362.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cccc(C(F)(F)F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:11][CH:10]([OH:12])[CH:9]2[N:13]([C:16](=[O:23])[CH:17]([NH2:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15][CH:8]12)=[O:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:33]([N:43]([CH3:49])[C@H:44]([C:46](O)=[O:47])[CH3:45])([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C)[C@H](C(O)=O)C)(OCC1C=CC=CC=1)=O>CN1C(=O)CCC1.O>[CH2:36]([O:35][C:33](=[O:34])[N:43]([CH:44]([C:46](=[O:47])[NH:22][CH:17]([C:16]([N:13]1[CH2:14][CH2:15][CH:8]2[N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH:10]([OH:12])[CH:9]12)=[O:23])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:45])[CH3:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(N)C(C)(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution containing 56 (5.10 g, 15.6 mmol) and DIPEA (3.6 mL, 20.3 mmol) in NMP (20 mL) was cooled to 0° C. In a separate flask at 0° C., Cbz-N(Me)Ala-OH (4.1 g, 17.2 mmol), HATU (6.6 g, 17.2 mmol), and DIPEA (3.6 mL, 20.3 mmol) were dissolved in NMP (80 mL). A portion of the HATU/Cbz-N(Me)Ala-OH solution (72 mL, ˜1.0 equiv) was then added to the cooled solution of 56. After 45 min, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed successively with 10% H3PO4, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.0 g (82%, 2 steps) of 57 as a white foam. Mass spectrum, m/z [546.0] (M+H)+.
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][OH:9]>O>[CH:8]([OH:9])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CO
Reactant: CCCCCCC
Solvent: O
Product: OC(c1ccccc1)c1ccccc1
Yield: 16.7 %

Procedure:
A procedure analogous to that described in Example 5 was used for obtaining a liquid mixture of 1,3-diketones, using CE-810 (Procter & Gamble) as the starting methyl ester. This ester had the following chain length distribution: C6: 4.1 weight %; C8: 52.8%; C10: 42.7%; and C12: 0.3%. For the preparation of potassium benzhydroxide, 103.36 g (0.561 mol) of benzhydrol was reacted with 0.55 mol of potassium hydroxide as described in Example 4. After addition of the ester (71.5 g; 0.425 mol), acetophenone (44.06 g; 0.367 mol) was added over a period of 12 minutes and the mixture was allowed to react for a total of 70 minutes. The mixture was allowed to cool to room temperature, and was acidified with 10% sulfuric acid. The cumene layer was washed with water until the washes were neutral, and then concentrated under vacuum in a rotary evaporator. The residue was treated with heptane, allowed to stand for a few minutes, and then filtered, affording pure benzhydrol (63.2 g; 61.1% yield). The heptane was removed under vacuum. More benzhydrol was obtained by adding 500 mL of heptane, 500 mL of methanol, and 250 mL of water, stirring, removing the lower layer, and repeating this extraction several times. Upon evaporation of the lower layer under vacuum in a rotary evaporator, and washing the resulting crystals with heptane, 17.3 g of benzhydrol (16.7% yield) was obtained. Evaporation of the solvents in the upper layer afforded 80.0 g (85% yield) of CBM with a purity of over 95% (GC).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:31][C@H:30]([O:32][CH2:33]C(OCC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:32][C:30]([CH3:31])([CH3:29])[CH2:33][O:32][C@H:30]1[CH2:31][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Reaction time: 6 h

Procedure:
Ethyl [(trans-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (0.08 g) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.46 mL) was added at room temperature. The reaction mixture was stirred for 6 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.056 g, 72%).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13])=[O:5].[C:25](Cl)(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>N1C=CC=CC=1>[C:25]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][N:7]1[C:8](=[O:13])[CH2:9][CH2:10][C:11]1=[O:12])=[O:5])(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCC(O)CC(=O)ON1C(=O)CCC1=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)ON1C(=O)CCC1=O

Procedure:
To a solution of 5.6 g of N-[3(R,S)-hydroxytetradecanoyloxy]succinimide in 150 ml pyridine cooled to 0° are added 4.9 g of tetradecanoylchloride and the reaction mixture maintained at 4° for 12 hours. Excess reagent is destroyed with water, the mixture concentrated by evaporation and the residue chromatographed over silica gel (toluene/ethylacetate=95/5) to obtained the title compound as a syrup.
Reaction SMILES: [CH:1]1([C:4]2[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]4)=[CH:12][C:11]=3[O:27][CH3:28])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[ClH:31].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:31].[CH:1]1([C:4]2[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][NH:18][CH2:17]4)=[CH:12][C:11]=3[O:27][CH3:28])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CN(C(=O)OC(C)(C)C)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(C2CNC2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of tert-butyl 3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-carboxylate prepared in (4) in ethyl acetate (30 mL) was added 4 N HCl/ethyl acetate (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at RT for 30 min. The reaction mixture was stirred in an ice-bath. The precipitated solid was collected on a filter and dried to give the title compound (2.61 g, 54%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[N:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:66]([F:69])([F:68])[F:67])=[C:56]([C:58]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:59])[CH:57]=1>CN(C=O)C.O>[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:66]([F:68])([F:67])[F:69])=[C:56]([CH:57]=1)[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:26](=[O:28])[CH2:25][NH:24][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:21][N:20]=2)=[O:23])[CH2:64][CH2:65]1)=[O:59]
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 38.9 %

Procedure:
DIPEA (151 mg, 0.2 mL, 1.17 mmol) was added to a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (100 mg, 0.39 mmol) in DMF (2 mL). HOBT (63 mg, 0.46 mmol) and EDCI (89 mg, 0.46 mmol) were then added at room temperature. After 2 minutes, (5-fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl-methanone hydrochloride salt (146 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 78 mg (39% yield) of 5-phenyl-pyridine-2-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.81%. 1H NMR (DMSO-d6): δ 9 (s, 1H), 8.8 (bt, 1H), 8.3 (d, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 5H), 4.4-4.2 (dd, 2H), 3.8-3.4 (m, 6H), 3.3-3.1 (m, 2H).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]([C:37]3[S:41][C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=4)=[N:39][CH:38]=3)[CH:34]=[CH:35][CH:36]=2)=[CH:27]1.Cl.Cl[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH3:56]>C(Cl)Cl.CO>[CH2:53]([N:54]([CH2:57][CH3:58])[CH2:55][CH2:56][O:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]2[S:41][C:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)[CH:32]=3)=[CH:38][N:39]=2)=[CH:44][CH:45]=1)[CH3:52]
Reactant: Oc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-[5-(3-thiophen-3-yl-phenyl)-thiazol-2-ylamino]-phenol and using (2-chloroethyl)-diethylamine hydrochloride. The title compound: ES-MS: 450.0 [M+H]+; single peak at tR=3.98 min (System 2); Rf=0.14 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[CH:8][CH2:7][CH2:6][C:5]1=[O:12])([CH3:3])[CH3:2].C[O-].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH:1]([C:4]1[C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: COC1=CCCC(=O)C1C(C)C
Agent: C[O-]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(C(C)C)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 2-isopropyl-3-methoxy-cyclohex-3-enone (6 g) in dry THF (120 mL), sodium methoxide (1.5 g) was added in portions at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled in an ice bath and neutralized with 10% sodium hydrogen phosphate solution. The organic layer was separated, then the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as a yellow liquid (5.4 g, 90%). 1H NMR (CDCl3): δ 1.09 (d, 6H, 2×CH3), 1.95 (m, 2H, CH2), 2.31 (t, 2H, CH2), 2.54 (t, 2H, CH2), 3.2 (m, 1H, CH), 3.78 (s, 3H, OCH3).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][CH:19]=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:29]=[O:30])C>>[N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:29]=[O:30])=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCN1CCCCC1)N1CCCCc2[nH]ccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1

Procedure:
3-Piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one (225 mg, 0.8 mmol) was formylated with POCl3 (91 μL, 1.2 eq.) and DMF(1 mL) using standard Vilsmierer condition to give 96 mg of 4-(3-piperidin-1-yl-propioyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:59]1([C:64]2[CH:71]=[CH:70][C:67]([CH2:68][NH2:69])=[CH:66][CH:65]=2)[CH:63]=[CH:62][N:61]=[CH:60]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:69][CH2:68][C:67]3[CH:66]=[CH:65][C:64]([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=[CH:71][CH:70]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCc1ccc(-n2ccnc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3ccc(-n4ccnc4)cc3)cs2)c1-c1ccc(F)cc1
Yield: 46.4 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (50 mg, 0.14 mmol), HATU (106 mg, 0.28 mmol), DIEA (0.049 mL, 0.28 mmol) and 4-(1H-imidazol-1-yl)benzylamine (96 mg, 0.56 mmol) in DMF (2.0 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 50→70% ethyl acetate/hexane) to give the title compound (33.4 mg, 0.065 mmol, 46.7%) as a white powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Sn]([N:23]=[N+:24]=[N-:25])(C)(C)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]3[NH:25][N:24]=[N:23][N:13]=3)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-c2nnn[nH]2)ccc1NC1CCCCC1
Yield: 88.1 %

Procedure:
A solution of 1.10 g (4.49 mmol) of 4-cyclohexylamino-3-nitrobenzonitrile, Compound 127, and 1.11 g (5.39 mmol) of Me3SnN3 in 50 mL toluene was refluxed overnight. The crystals were collected by filtration, washed with toluene, dried, and treated with 50 mL 4M HCl in dioxane for 4 h. The solids were collected by filtration, washed with dioxane, and dried yielding 1.14 g (88%) red solids. MS: 289.15 (M+H+).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].[NH4+].[Cl-]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[OH:24]
Reactant: O=Cc1ccccc1Cl
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccccc1Cl)c1ccncc1Br
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Add n-BuLi (48.2 mL, 77.1 mmol, 1.6N in hexane) to a −70° C. solution of diisopropylamine (10.8 mL, 77.1 mmol) in THF (130 mL) in a flame-dried flask. After 30 minutes add 3-bromo-pyridine (2.48 mL, 25.7 mmol) dropwise and stir the mixture at −70° C. After 4 hours, add 2-chloro-benzaldehyde (2.95 mL, 26.2 mmol) dropwise, stir at −70° C. After 1 hour, warm reaction to RT, quench reaction with dropwise addition of 60 mL saturated NH4Cl solution. Extract with Et2O (3×), wash with brine, dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexane to afford the title compound: MS(IS) 299 (M+1); TLC (50% EtOAc/hexanes) Rf=0.23.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[C:24]1([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: C#CC1=CCCCC1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (115 mg, 96%); 1H NMR δ (CDCl3): 8.39 (d, J=8.53 Hz, 1H), 7.9 (br s, 1H), 7.37 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.22 Hz, 1H), 6.25 (m, 1H), 2.32-2.12 (m, 7H), 1.76-1.6 (m, 4H); LCMS m/z: 239.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[F:11][CH2:12][CH:13](O)[CH2:14][F:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:13]([CH2:14][F:15])[CH2:12][F:11])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: OC(CF)CF
Product: COc1ccc(Br)cc1OC(CF)CF
Yield: 56.9 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (765 uL, 9.87 mmol) and 1,3-difluoro-2-propanol (765 uL, 9.87 mmol) to afford titled compound as a colorless solid (1.58 g, 55%). 1H NMR (DMSO-d6) 7.28 (d, J=2.4, 1H), 7.14 (dd, J=8.8, 2.4, 1H), 6.97 (d, J=8.8, 1H), 4.55-4.35 (m, 5H), 3.75 (s, 3H). LC/MS (Method B) 3.50 min, [M+1]+ 281/283.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4].Br[CH2:28][CH2:29][CH3:30].Cl>CN(C)C=O>[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reaction time: 1 h
Yield: 84.9 %

Procedure:
Sodium hydride (2.96 g of a 60% w/w dispersion in mineral oil) was added to dry dimethylformamide (DMF, 100 ml), under a nitrogen atmosphere. The mixture was stirred and cooled in an ice-bath, and a solution of methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (20 g) in DMF (75 ml) added slowly. After 1 h, 1-bromopropane (9.13 g) was added slowly. After 2 h, the mixture was carefully acidified with 2M hydrochloric acid (100 ml), extracted with ethyl acetate (twice), and the extract washed with 1M hydrochloric acid, water, and brine. The dried (MgSO4) solution was evaporated, and the residue dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was evaporated and the product crystallised from ether to give methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (19.2 g, 85%) as white needles; mp 98°-99°; partial NMR (250 MHz, DMSO-d6): 0.82 (t, 3H, CH3), 1.75 (m, 2H, CH2), 3.83 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.1 (m, 4H, ArCH2Ar' and NCH2), 9.95 (s, 1H, CHO).