Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28]>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:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:3]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(-c2cccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
A flask containing a mixture of 1-(3-bromophenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (prepared according to the general procedures described above, 80 mg, 0.20 mmol) and 4-cyanophenylboronic acid (57 mg, 0.39 mmol) was evacuated and refilled with N2 (2×). To this was added Pd(PPh3)4 (34 mg, 0.029 mmol) in one portion with minimum exposure to air. The flask was again evacuated and refilled with N2 (3×). Degassed solutions of DME-EtOH (4:1 v/v, 2 mL) and aq Na2CO3 (2M, 0.6 mL) were added via syringe and the solution was stirred under N2 for 10 min at rt and then at 85° C. for 19 h. The reaction was then cooled to rt, filtered, and purified using the Waters mass-directed HPLC purification system. Further recrystallization from acetonitrile yielded 1-(4′-cyano-1,1′-biphenyl-3-yl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid (18.5 mg, 22% yield). MS (ES+): m/z430 (100) [MH+]. 1H NMR (400 MHz, CD3OD): δ=8.66 (s, 1H), 8.61 (d, J=2.4Hz, 1H), 8.45 (dd, J=4.8 Hz, 1.2 Hz, 1H), 8.34 (dd, J=1.0 Hz, 0.4 Hz, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.88-7.86 (m, 3H), 7.86-7.82 (m, 4H), 7.80 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.43 (dd, J=8.4 Hz, 5.2 Hz, 1H), 7.67 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[S:13]1[CH:14]=[CH:15][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12]1
Reactant: Brc1ccsc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)ccn2-c1ccsc1
Temperature: 180 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
A mixture of indole (5.64 g, 48.3 mmol), 3-bromothiophene (4.84 mL, 51.6 mmol), potassium carbonate (7.16 g, 51.6 mmol), cuprous bromide (298 mg, 2.1 mmol) and N-methylpyrrolidinone (57 mL) is stirred at 180° C. under nitrogen atmosphere for 48 hr. After cooling to room temperature, the reaction mixture is poured into water (300 mL) and then extracted with ethyl acetate. The extract is washed with water, with brine, dried, filtered and concentrated to give a brown oil that is purified by chromatography eluting with heptane-10% dichloromethane. Product containing fraction are combined and concentrated to afford 1-(thien-3-yl)-1H-indole (6.20 g, 64% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1.Br[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1>>[CH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:53]=[CH:54][C:45]=1[CH2:44][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), from tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate by alkylation with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 721 (M+H)+.
Reaction SMILES: Cl.O[CH2:3][C@H:4]1[N:14]2[C:15]3[N:6]([C:7](=[O:17])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]2=[O:16])[CH2:5]1.C(N(CC)CC)C.CS(Cl)(=O)=O.CS([O-])(=O)=O.[F:35][C:36]([F:47])([F:46])[C:37]([NH:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)=[O:38]>C(Cl)Cl>[O:16]=[C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7](=[O:17])[N:6]3[CH2:5][C@@H:4]([CH2:3][N:43]4[CH2:44][CH2:45][C@@H:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]([F:46])([F:47])[F:35])[CH2:42]4)[N:14]1[C:15]=23
Reactant: O=C(NC[C@@H]1CCNC1)C(F)(F)F
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CN1CC[C@@H](CNC(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a 100 mL round-bottomed flask was added (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione HCl (for a preparation see Example 47(c)) (350 mg, 1.589 mmol), triethylamine (0.266 ml, 1.907 mmol) in DCM (20 ml) 0° C. to give a orange solution. Methane sulfonylchloride (0.135 ml, 1.748 mmol) was added and the reaction was allowed to warm to rt and stir for 1 h. LCMS indicated that the methanesulfonate had formed. The reaction was diluted with DCM (100 mL) and washed with 2×25 mL of a saturated aqueous NaHCO3 solution. The organic phase was separated and dried over Na2SO4. The solution was concentrated under vacuum, diluted with acetonitrile (20.00 ml) and pyridine (0.500 ml) was added. 2,2,2-trifluoro-N-[(3R)-3-pyrrolidinylmethyl]acetamide (550 mg, 2.364 mmol) was added and the reaction was heated to 80° C. and stirred for 25 h. LCMS indicated a complete reaction. The reaction was cooled to rt and concentrated under vacuum. The reaction mixture was diluted with DCM (100 mL) and washed with 25 mL of a saturated NaHCO3 solution. The organic phase was separated and dried over Na2SO4. The crude product was purified on silica eluting with 0-15% MeOH/DCM to give product (240 mg, 0.602 mmol, 37.9% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=[O:3])[CH3:2].[CH2:35](O)[CH2:36][OH:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:32][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:21]([NH:20][C@H:16]([CH2:17][CH2:18][OH:19])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1]3([CH3:2])[O:37][CH2:36][CH2:35][O:3]3)[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:33]
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
150 mg (0.31 mmol) of (S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of benzene was treated with 34.6 uL (0.62 mmol) of ethane-1,2-diol and 59 mg (0.31 mmol) of p-toluenesulfonic acid monohydrate. The reaction was stirred at 70° C. for 2 h after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 25.5 mg (16% yield) of 4 was obtained and characterized by LCMS and HNMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: Oc1c(F)cccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1F
Yield: 83.2 %

Procedure:
2,6-Difluorophenol (8.6 g, 66 mmol) was treated with tert -butylchlorodimethylsilane (17.4 g, 0.12 mol) and imidazole (13.1 g, 0.19 mol) by the method in Example 1 to give 13.41 g (83%) of tert-butyldimethylsilyl 2,6-difluorophenyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:39]([C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)=[O:40])[C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred solution of the crude 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-indazole (0.078 g, 0.20 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.086 g, 0.40 mmol) in dichloromethane (1 mL) was added HATU (0.15 g, 0.40 mmol) and Et3N (0.10 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30% ethyl acetate in hexanes) to afford the desired product (0.034 g, 0.058 mmol, 11% for 2 steps).
Reaction SMILES: [PH4+].[Li]CCCC.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[CH2:14]1C[O:17][CH2:16][CH2:15]1>>[O:7]1[CH2:12][CH2:11][C:10](=[CH:14][CH2:15][CH2:16][OH:17])[CH2:9][CH2:8]1
Reactant: O=C1CCOCC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Agent: [PH4+]
Product: OCCC=C1CCOCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a suspension of the phosphonium salt (90.2 g, 1.5 eq) in dry THF (1100 mL) at 0° C. under nitrogen atmosphere was added n-BuLi (2.5 M, 216 mL, 0.54 mol). The solution was stirred for 1 h, followed by addition of dihydro-2H-pyran-4(3H)-one (15 g, 0.15 mol). Stirring was continued at rt overnight. The mixture was quenched with satd aq NH4Cl, and then filtered. The filtrate was dried over Na2SO4, and concentrated under vacuum to give the crude product, which was purified by column chromatography to give the product (13.1 g, 61%). 1H NMR (CD3OD) δ 2.1-2.3 (m, 6H), 2.5 (s, 1H), 3.5-3.7 (m, 6H), 5.1-5.2 (t, 1H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[C:12](O)(=[O:14])[CH3:13]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:11][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1
Reactant: CC(=O)O
Reactant: Oc1ccc2c(c1)CCCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)CCCC2
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To 5,6,7,8-tetrahydro-2-naphthol 14 (10 mmol, 1.48 g) placed in a flask flushed with argon at room temperature, was slowly added TiCl4 (11 mmol, 1.2 mL). The resulting dark cherry-colored mixture was stirred at room temperature, and when gas evolution ceased, 15 mmol (1.07 mL) of acetic acid was added to the solid. The resulting thick solution was stirred at room temperature for 15 min, then brought to 120° C. and left to stir at this temperature for an additional hour. The reaction mixture was then cooled to room temperature, diluted with CH2Cl2 (30 mL) and quenched with H2O (30 mL). A cloudy solution was obtained which was easily extracted with CH2Cl2. The organic layer was washed with H2O (2×30 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a mixture of hexanes/EtOAc (95/5) to give 15 as a yellowish solid (1.14 g, 59% yield). mp 70-72° C.; 1H NMR (CDCl3) δ 1.77 (m, 4H), 2.59 (s, 3H), 2.76 (m, 4H), 6.68 (s, 1H), 7.41 (s, 1H), 11.96 (s, 1H); 13C NMR (CDCl3) δ 22.87, 23.42, 26,72, 28.82, 30.17, 117.82, 118.21, 128.10, 131.04, 147.71, 160.09, 204.16; IR (KBr, v cm−1) 2934, 1621, 1491, 1344; MS (ESI) 191 (M+1). Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.91; H, 7.46.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:21])(C(OCC)=O)[C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([F:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(F)c1ccc(Cl)nn1
Yield: 88.4 %

Procedure:
A solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate 45B (60.2 g, 189 mmol) in 300 mL TFA/DCM (1:1) was stirred at 25° C. for 2 hrs and then concentrated to dryness via rotary evaporation. The resulting residue was dissolved in EtOAc (300 mL), washed with saturated NaHCO3 solution, dried over MgSO4, and then concentrated to dryness to give the title compound, ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate 45C (36.6 g, 167 mmol, 89%). The material was used immediately without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.20 Hz, 3 H) 4.23 (qd, J=7.12, 4.42 Hz, 2 H) 6.43-6.62 (m, 1 H) 8.00-8.12 (m, 2 H). ESI-MS:m/z 219.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11]1>CN(C)C=O.C(OCC)(=O)C>[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:8][CH3:9])=[O:18])=[CH:11]1
Reactant: CCI
Reactant: O=C(O)/C=C/c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccsc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
11.5 g of potassium carbonate and 6.8 ml of iodoethane are added to 11 g of (E)-3-(3-thienyl)-2-propenoic acid, obtained in step 4.1, in solution in 50 ml of dimethylformamide, and the mixture is stirred for 48 hours at 20° C. The medium is taken up in ethyl acetate and it is washed with water. The organic phase is dried over anhydrous sodium sulfate and it is concentrated to give 12.5 g of oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C1C(=CC=CC=1)O.C1(C)C(C)=CC=CC=1.[OH-].[Ca+2:45].[OH-]>O.CO>[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Ca+2:45].[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCC(CCCCC)c1ccc(O)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCC(CCCCC)c1ccc(O)c(C(=O)[O-])c1

Procedure:
The title compound in 4 g of base oil XOMAPE 150 (13.2 g, Basicity Index 1.48) was prepared as outlined in Example 4 by employing 5-(pentadecy-6-yl)salicylic acid (Example 15, 3.3 g), a commercial lower alkyl (i.e. less than C20) salicylic acid (Infineum M7103, obtainable from Infineum UK Limited, 3.70 g), xylene (203 g), calcium hydroxide (4 g), and a promoter (methanol:water (97%:3%), 23.4 ml).
Reaction SMILES: [Cl:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl-].[Br:16][C:17]1[C:18]([OH:45])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl-:1].[Br:16][C:17]1[C:18]([O:45][C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(C(=O)Oc2c(Br)cc(OC)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 66 %

Procedure:
With the exclusion of air, 43.9 g of 4-chlorocarbonyl-1-ethoxycarbonyl-piperidine are dissolved in 250 ml of anhydrous acetonitrile (degassed) and 53.4 g of [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride are added to the solution. In the course of 30 minutes, at 25° to 30°, 20 g of pyridine are added dropwise to the resulting suspension. The mixture is heated for 5 hours under reflux and is then hydrolysed with 100 ml of sodium carbonate solution (15%); the organic phase is separated off, washed in succession with 100 ml of 1N hydrochloric acid and 100 ml of water and concentrated by evaporation in vacuo and the oily residue that remains is dissolved in 50 ml of dichloromethane. In the course of 30 minutes, at 20°, with vigorous stirring, 200 ml of ethyl acetate are added dropwise to that solution and the product crystallises out. The resulting crystal suspension is concentrated to 150 ml under a weak vacuum using a rotary evaporator and then stirred for 2 hours at 0°. Filtering with suction and drying yield [(3-bromo-2-[(1-ethoxycarbonylpiperid-4-yl)carbonyloxy]-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride [m.p.: 196°, IR (KBr): 3415, 3060, 2855, 2780, 1600, 1565, 1385, 1270, 1190, 1165 cm-1 ; 1H-NMR (360 MHz, CDCl3): 1.28 (t, 3H, CO2CH2CH3), 1.45 (m, 2H), 1.75 (m, 2H), 2.58 (m, 1H), 2.87 (m, 2H), 3.47 (s, 3H, OCH3), 4.00 (m, 2H), 4.13 (q, 2H, CO2CH2CH3), 5.37 (br. d, 2H, CH2P+), 6.87 (dd, 1H), 7.07 (dd, 1H), 7.54 to 7.87 (m, 15H) ppm]; yield 66% of the theoretical yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:3][CH:2]=1.C(=O)C=C.N1C=CC(CCC=O)=CC=1.C(=O)CC>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:3][CH2:2]1
Reactant: O=CC=Cc1ccncc1
Agent: C=CC=O
Agent: O=CCCc1ccncc1
Solvent: CCC=O
Product: O=CCCC1CCNCC1

Procedure:
Alternatively, hydrogenation of the 3-pyridin-4-yl-2-propen-1-one is carried out by (i) hydrogenating the 2-propen-1-one until conversion to the corresponding 3-pyridin-4-ylpropan-1-one is complete, (ii) optionally alkylating the propan-1-one with a compound of the formula L-R20 or X-R21 (wherein R20 and R21 are as defined above), and then (iii) continuing hydrogenation to give the corresponding 3-piperidin-4-ylpropan-1-one. Hydrogenation of the propenone to the 3-pyridin-4-ylpropan-1-one is carried out with an appropriate catalyst (5% palladium on carbon, 20% palladium hydroxide, etc.) in a suitable solvent (e.g., THF, acetic acid, DMF, ethanol, etc.) at 5 to 60 psi and requires 1 to 48 hours. The preparation of a compound of Formula I(b) in which R7 is 3-(4-methoxyphenyl)prop-1-yl is described in Example 13.
Reaction SMILES: [CH2:1]([C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>C(O)C.C(O)=O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[N:15][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([CH2:1][C:2]2[CH:3]=[C:4]([CH3:10])[C:5]([N:6]=[CH:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[C:7]([CH3:9])[CH:8]=2)=[CH:17][C:16]=1[CH3:18]
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Reactant: O=Cc1ccccn1
Solvent: O=CO
Solvent: CCO
Product: Cc1cc(Cc2cc(C)c(N=Cc3ccccn3)c(C)c2)cc(C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a suspension of 2a (0.50 g, 1.97 mmol) in absolute ethanol (2 ml) was added 2-pyridinecarboxaldehyde (0.56 ml, 5.91 mmol, 3 eq.) and one drop of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 17 as a yellow solid (0.28 g, 18%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:24][C:25](=[O:33])[C:26]([O:29]C(=O)C)([CH3:28])[CH3:27].Cl.C(OCC)(=O)C>O.CO>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH:8]=[CH:7][C:6]=1[NH:24][C:25](=[O:33])[C:26]([OH:29])([CH3:27])[CH3:28]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)C(C)(C)OC(C)=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)C(C)(C)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of lithium hydroxide monohydrate (0.106 g) in water (1 ml) was added to a stirred solution of N-[2-chloro-4-(4-acetamidophenylsulphonyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 16) (0.230 g) in methanol (2 ml) and the mixture was stirred at ambient temperature for 2 hours. Water (5 ml) was added and the solution was acidified to pH 2-3 with 1M hydrochloric acid. Ethyl acetate (20 ml) was added and the organic layer was washed with water (20 ml) and brine, then dried. Volatile material was removed by evaporation and the off-white solid was washed with ether to give the title compound (0.150 g) as a solid. NMR (CDCl3): 1.3 (s, 6H), 2.2 (s, 3H), 7.4 (s, 1 H), 7.7 (d, 2H), 7.8 (m, 3H), 7.9 (s, 1H), 8.7 (d, 1H), 9.6 (s, 1H); MS (ESP−): 409.