Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:8][C:7]=1[CH2:22]O>C(OCC)(=O)C>[Cl:3][CH2:22][C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CO)c2)c1
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Reaction time: 1 h

Procedure:
Add thionyl chloride (0.59 mL, 8.07 mmol) to a solution of 5-(4-fluoro-3-hydroxymethyl-phenylethynyl)-nicotinonitrile (1.85 g, 7.33 mmol), (prepared as described in EXAMPLE 142). After 3 h add an additional 0.2 mL of thionyl chloride and stir for another 1 h. Dilute the reaction mixture with ethyl acetate and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify the crude material by silica gel chromatography, eluting with a gradient from 85:15 to 75:25 hexanes:ethyl acetate, then elute with 50:50 hexanes:ethyl acetate to give the title compound. Further purify by additional silica gel chromatography, eluting with 90:10 (70:30 hexanes:dichloromethane):ethyl acetate. Combine clean fractions from both chromatographies and concentrate to give the title compound as a crystalline solid (1.5 g, 75%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:16]=O>S(=O)(=O)(O)O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]=1[CH2:16][NH:5][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Product: C=CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Acrylamide (7.10 g; 0.10 mol) is added in small increments to a stirred solution of p-nitrotoluene (1.85 g; 0.05 mol) and paraformaldehyde (1.6 g; 0.05 mol) in concentrated sulfuric acid (60 ml). This reaction mixture is stirred for 24 hours at room temperature and then poured onto ice. A precipitate results which is collected and recrystallized from ethyl acetate to give 4.4 g of product as colorless crystals. This product has the following characteristics: melting point of 155° to 158.5° C.; i.r. 3230, 1620, 1655, 1660 cm-1 (sh).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]=[O:27])[C:10]3[N:14]=[C:13]([O:15]CC)[N:12](C(OC(C)(C)C)=O)[C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[F:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])I.CN(C=O)C.CN(C(N(C)C)=C(N(C)C)N(C)C)C>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([OH:27])[C:31]([F:34])([F:33])[C:30]([F:36])([F:35])[F:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: FC(F)(F)C(F)(F)I
Agent: CN(C)C(=C(N(C)C)N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(C(O)C(F)(F)C(F)(F)F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.26 mmol), pentafluoroiodoethane (350 mg, 1.42 mmol) and DMF was cooled to −15° C. under nitrogen. Tetra(dimethlamino)ethylene was added (0.33 mL, 1.42 mmol) and the reaction mixture was irradiated with a sun lamp. A thick precipitate formed, and after 30 minutes, the reaction mixture was diluted with ethyl acetate filtered. The filtrate was washed with water and the organic layer was concentrated and dissolved in ethanol (3 mL) and 4M HCl in dioxane (1 mL) and heated to 70° C. for 1 h. The reaction mixture was concentrated and purified by reverse-phase HPLC to give the desired product as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[C:39]1[S:40][CH:41]=[C:42]([Sn](C)(C)C)[N:43]=1.N#N>O1CCOCC1.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>[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[C:39]1[S:40][CH:41]=[C:42]([C:2]2[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[N:24]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[N:23]=[N:22][N:21]=5)[CH2:16][CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)[N:43]=1
Reactant: C[Sn](C)(C)c1csc(C2OCCO2)n1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1COCCO1
Product: COc1cnc(-c2csc(C3OCCO3)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 100 °C

Procedure:
To a sealable 75 mL flask containing 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.3 g, 0.643 mmol) was added a solution of 2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (0.210 g, 0.655 mmol) in 1,4-Dioxane (10 ml). The mixture was flushed with N2 and Pd(PPh3)4 (0.149 g, 0.129 mmol) was added. The mixture was again flushed with N2, and the flask was sealed and heated in an oil bath to 100° C. After 20 h of heating, the mixture was cooled to rt. The mixture was transferred to a rb flask using MeOH as the transfer solvent. The solvent was removed under reduced pressure. The residue was re-dissolved in DMF, and was passed through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC. After the prep HPLC, a mostly-pure sample was collected as an off-white solid. A small portion of this material was removed and re-purified by flash chromatography (0-5% MeOH in dichloromethane gradient) [20 mg after the purification]. The remainder of the product was carried forward to the next step with no additional purification (0.305 g). LCMS: m/e 588.1 (M+H)+, ret time 1.30 min (method 3). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.20 (s, 1 H) 8.38 (s, 1 H) 8.22 (s, 1 H) 8.11 (s, 1 H) 7.68-7.72 (m, 2 H) 7.57-7.66 (m, 3 H) 6.29 (s, 1 H) 4.16-4.20 (m, 2 H) 4.07-4.10 (m, 2 H) 3.99 (s, 3 H) 3.67-3.71 (m, 2 H) 3.41-3.45 (m, 2 H) 3.30-3.32 (m, 2 H) 3.15-3.19 (m, 2 H).
Reaction SMILES: [C:1]1([C:7]2([C:28]([OH:30])=[O:29])[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@:15]3([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])[C:41](Cl)=[O:42].Cl>O1CCCC1.O>[CH3:50][O:49][C:45]1[CH:44]=[C:40]([CH:39]=[C:38]([O:37][CH3:36])[C:46]=1[O:47][CH3:48])[C:41]([N:17]1[CH2:18][CH2:19][C@:15]([CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:28]([OH:30])=[O:29])[CH2:8][CH2:9]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:16]1)=[O:42]
Reactant: O=C(O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCNC2)CC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine (S)-3-(2-(4-phenyl-4-carboxypiperidin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (50 g, 112 mmol) and sodium bicarbonate (30 g) in tetrahydrofuran (1300 mL) and water (300 mL). Add portionwise over about 45 minutes, a solution of 3,4,5-trimethoxybenzoyl chloride (26 g, 112 mmol) in tetrahydrofuran (130 mL). After 2 hours, dilute with water (1000 mL). Adjust the pH to about 4 using concentrated aqueous hydrochloric acid to give a solid. Collect the solid by filtration and rinse with water. Triturate the solid with methanol (1300 mL) and water (1300 mL). Filter, rinse with water and dry in vacuo to give the title compound.
Reaction SMILES: CN1C(CCCC(O)=[O:15])=NC2C=C(N(CCCl)CCCl)C=CC1=2.O1CCN(C(O)C)CC1.[CH:33]1([N:39]=[C:40]=[N:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.CN(C1C=CN=CC=1)C>[CH:42]1([NH:41][C:40]([NH:39][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:15])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: CC(O)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.25 h

Procedure:
Bendamustine free base (1.0 g, 2.79 mmol) in dichloromethane (90 ml), morpholinoethanol (0.44 ml, 3.35 mmol) and DMAP (20 mg) were added with stirring. A solution of N,N′-Dicyclohexylcarbodiimide (0.63 g, 3.05 mmol) in dichloromethane (90 ml) was added dropwise over 50 min. After 15 min, a clear reaction solution was obtained and after 70 min a precipitate of dicyclohexyl urea occurred. The reaction mixture was stirred at ambient temperature for a total time of 24 h. After concentration to half of the volume and cooling to 0° C., the precipitate was removed by filtration. Then the solution was extracted with diluted HCl (1 ml 37% HCl to 60 ml Water, 30 ml+2×15 ml portions). The aqueous phase was treated with 25% NH3 (1.6 ml, pH 7-8) and extracted with dichloromethane (20+2×10 ml). Evaporation of the combined organic solvents resulted in a crude oil (1.38 g) that was purified via column chromatography (40 g silica, 10% MeOH/dichloromethane) to afford a slightly yellowish oil (1.26 g) that crystallized after seeding. Further drying in vacuum resulted in 1.08 g (82%) of product as slightly yellowish crystals.
Reaction SMILES: N[OH:2].[C:3]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[CH:11]3[O:13][CH:12]3[C:7]=2[CH:6]=1)#[N:4].[OH-].[NH4+].[N:20]1[CH:25]=CC=CC=1>C(O)=O.O>[C:3]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[C@@H:11]([OH:13])[C@H:12]([NH:20][CH:25]=[O:2])[C:7]=2[CH:6]=1)#[N:4]
Reactant: c1ccncc1
Reactant: NO
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC=O)[C@@H]1O

Procedure:
The aminoalcohol (0.9 g), obtained by stirring 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran with ethanolic ammonium hydroxide), was heated under reflux in formic acid (15 ml) and pyridine (1 ml) during 19 hr. The cooled solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulphate. Filtration and evaporation left an orange coloured oil which was chromatographed (chromatotron, ethyl acetate-pentane gradient elution on silica gel 2 mm, flow rate 9 ml/min.) to give after one recrystallisation from ethyl acetate, the title compound (220 mg), of m.p. 228.5°-230.5° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:30][C:20]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cccc3ccccc23)CCc2cc(OCCn3ccnc3)ccc21
Yield: 87.6 %

Procedure:
According to the method of Example 6, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.475 g, 1.85 mmol) was reacted with 1-naphthaldehyde (0.448 g, 2.87 mmol) in 3.0 mL of 4% KOH in EtOH for 6 hours at room temperature to afford 0.639 g (88%) of the title compound as a bright yellow solid, mp 147-148° C.: CI-MS m/e 494 (M+), 495 M++1);
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P(Br)(Br)([Br:24])=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:24][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2 g) in DMF (35 ml) was added phosphoryltribromide (2.45 g) at room temperature, and the mixture was stirred at 50° C. overnight. The mixture was poured into saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with water and brine successively, dried over MgSO4 and concentrated in vacua. The resulting residual solid was recrystallized from EtOH-hexane to give the title compound (1.70 g) as a brown solid.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28](Cl)=[O:29])[CH2:23][CH2:22][C:21]2=[O:31]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:29])[CH2:23][CH2:22][C:21]2=[O:31]
Reactant: O=C1CCC(C(=O)Cl)c2ccc(Cl)cc21
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCC(=O)c3cc(Cl)ccc32)C(CN2CCCC2)C1
Yield: 111.1 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.87 g of 6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.92 g of the title compound, melting at 268°-274° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C(OO)=O)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC(S[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([CH2:30][C:31]([OH:33])=[O:32])[C:21]=2[CH3:34])=CC=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].Cl>C(#N)C.C(OCC)(=O)C>[NH4+:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:35]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([CH2:30][C:31]([O-:33])=[O:32])[C:21]=2[CH3:34])(=[O:39])=[O:37])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)[O-]
Product: [NH4+]
Reaction time: 3 h

Procedure:
3-Chlorobenzenecarboperoxoic acid (0.4 g) was added to a solution of the product from step c) (0.19 g) in acetonitrile (4 ml). The reaction was stirred for 3 h, 1M aqueous sodium thiosulphate (5 ml) was added and stirred for a further 15 min, 10% aqueous HCl and ethyl acetate were added and the organic phase separated. The aqueous phase was re-extracted with ethyl acetate and the combined organic solution washed with brine, dried and concentrated to a solid which was purified by reverse phase chromatography to give the title compound as a solid (0.12 g)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C@H:12]([CH3:37])[CH2:13][CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>C1COCC1>[Cl:36][C:27]1[C:28]([C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:15]([CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:14][CH2:13][C@@H:12]([CH3:37])[O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(O[C@H](C)CCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCN(Cc1cccc(C(F)(F)F)c1Cl)C[C@@H](C)c1ccccc1)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
A solution of 2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}phenyl)acetic acid methyl ester (20 mg, 0.036 mmol) in THF (1 ml) at 0° C., was treated with LiAlH4 (100 uL of a 1N solution in THF), and the reaction was stirred at 0° for 45 minutes. Ethyl acetate (1 ml) was added, the reaction warmed to RT, and water (2 ml) was added. The mixture was extracted with ethyl acetate. The organic extracts were dried and the solvent removed. The residue was chromatographed over silica gel (hexane/Ethyl acetate:3/7) to give the title compound as a pure oil (15 mg, 91%). MS (ESI) 520.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:33]([O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([O:37][C:38](=[O:47])[C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH:13]=3)=[CH:10][CH:11]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:22])=[CH:43][CH:44]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)Cc1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)c1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To [4-((R)-4-tert-Butyl-cyclohex-1-enyl)-phenyl]-acetic acid ethyl ester (95 mg. 0.32 mmol) in anhydrous THF (5 mL), chilled to −78° C. was added 380 uL (0.38 mmol) of 1M lithium hexamethyldisilazane in THF. The resulting solution was stirred for 1 hr before 4-Bromomethylbenzoic acid tert-butyl ester (94 mg, 0.35 mmol) was added. The reaction mixture was allowed to warm to rt overnight then quenched with saturated NH4Cl solution. After partitioning between ethyl acetate and brine the organic portion was dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude by prep TLC (Analtech, 2 mm silica plates) using an hexane/ethyl acetate (10:1) gave 63 mg of product. 1H NMR (500 MHz, CDCl3): 7.83 (d, J=8.5 Hz, 2 H), 7.31 (d, J=8.5 Hz, 2 H), 7.20 (d, J=8 Hz, 2 H), 7.14 (d, J=8 Hz, 2 H), 6.12 (m, 1H), 4.03 (q, J=7 Hz 2 H), 3.80 (t, J=8.5 Hz, 1H), 3.41 (dd, =14, 8.5 Hz, 1 H), 3.03 (dd, J=14, 7 Hz, 1 H), 2.56-2.4 (m, 2H), 2.35-2.2 (m, 1H). 2.05-1.9 (m, 2H), 1.56 (s, 9 H), 1.36-1.2 (m, 2 H), 1.11 (t, J=7 Hz, 3 H), 0.89 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH3:49])[CH:43]=[CH:42][C:41]([CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:41]1[CH:40]=[CH:39][C:38]([CH3:49])=[CH:43][CH:42]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(C)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccc(C)cc1
Yield: 67.9 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 12.9 g at a yield of 67.9% in the same manner as in Example 1 except that 12 g (47.8 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 60 ml of THF and 8.41 g (52.5 mmol) of CDI was added; 14.5 g (143 mmol) of diisopropylamine and 60 ml of THF were added and 89.5 ml (143 mmol) of 1.63N BA solution was added dropwise; 23.5 ml (143 mmol) of methyl p-tolylacetate instead of methyl phenylacetate was dissolved in 60 ml of THF; and 48 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 100 g of 4N hydrochloric acid was added, and 240 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:20][O-:21].[Na+].[OH2:23]>CN(C)C=O>[CH3:20][O:21][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:23])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: C[O-]
Reactant: O
Reactant: Cc1ccccc1-c1c(Cl)nc2ccccc2c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccccc2C)c(=O)[nH]c2ccccc12

Procedure:
A mixture of 2,4-dichloro-3-o-tolylquinoline (3 g.) and sodium methoxide (1.9 g.) in dimethylformamide (30 ml.) was heated at 60° for 6 hr. The mixture was cooled and poured into water (500 ml.), and the mixture was extracted with ethyl acetate (2×100 ml.). The ethyl acetate extract was washed with water (2×50 ml.) and then dried (MgSO4). The solvent was evaporated and the residue (containing 2,4-dimethoxy-3-o-tolylquinoline) was used without further purification. A mixture of said residue (2.6 g.) and 2M-hydrochloric acid (50 ml.) was heated at 100° for 2 hr. The mixture was cooled and filtered. The solid residue was crystallised from ethyl acetate-petroleum ether (b.p. 60°-80°) to give 4-methoxy-3-o-tolylquinolin-2-one, m.p. 215°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C(B(CC)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]([C:26]([F:27])([F:28])[F:29])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: CCB(CC)c1cccnc1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cccnc3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 3-diethylboranyl-pyridine, (118 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 510 (M+1).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:38]=[CH:37][C:12]2[C:13](=[O:36])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=4[N+:33]([O-])=O)=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:38]=[CH:37][C:12]2[C:13](=[O:36])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][C:24]=4[NH2:33])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)COc1cc(Nc3ccc(C(F)(F)F)cc3N)ccc1C2=O

Procedure:
In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II) chloride dihydrate is dissolved in 15 ml of ethanol, and 0.095 g (0.20 mmol) of (18) is added. Yield: 0.061 g (76.4%); melting point: 93.9° C.; C21H16F3N3O2 (Mr=399.38); LC 19.06 min