Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][C:26]#[C:27][CH3:28])[C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30]3)=[N:19][C:18]=2[N:17]([CH3:43])[C:15]1=[O:16].C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]([CH2:44][O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][C:26]#[C:27][CH3:28])[C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:30]3)=[N:19][C:18]=2[N:17]([CH3:43])[C:15]1=[O:16]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(O)COc1ccccc1)c(=O)n2C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)COc1ccccc1)c(=O)n2C
Temperature: -60 °C

Procedure:
A solution of 107 μl dimethylsulphoxide in 0.5 ml methylene chloride is added dropwise to 64 μl oxalyl chloride in 2 ml methylene chloride with stirring at −60° C. After five minutes a solution of 345 mg of 1-(2-hydroxy-3-phenoxy-propyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 1.5 ml methylene chloride is added dropwise and after another 15 minutes 0.42 ml of triethylamine are added. Then the cooling bath is removed and the reaction mixture is allowed to warm up to ambient temperature. For working up it is diluted with methylene chloride and washed with water. The organic phase is dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (4:1 to 1:1) as eluant.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.C1CCCCC1.[CH2:18]([SH:21])[CH2:19][CH3:20].[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:18]([S:21][CH:29]([S:7][CH2:4][CH2:3][CH3:2])[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCS
Reactant: O=CCc1ccccc1
Solvent: O
Solvent: C1CCCCC1
Product: CCCSC(Cc1ccccc1)SCCC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser and magnetic stirring bar and hot plate equipped with magnetic stirring apparatus is placed 0.2 grams of para-toluenesulfonic acid, 5 ml cyclohexane and 7.6 grams (0.1 mole) of n-propyl mercaptan. With stirring over a period of 25 minutes, 6 grams (0.05 moles) of phenyl acetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 8.5 hours. During the refluxing period, water of reaction is removed. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate and filtered. The filtrate is distilled on a Microvigreux column yielding the following five fractions:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Yield: 37.5 %

Procedure:
A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg, 3.0 mmol; 38% yield). MS (DCl/NH3): 266 (M+1)+, 283 (M+18)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]2=[O:17])[CH:7]=[C:6]([NH2:18])[CH:5]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[CH:24](OCC)(OCC)OCC>CC(O)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[C:6]([N:18]2[CH:24]=[N:22][N:21]=[N:20]2)[CH:7]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]2=[O:17])[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(-n2ccc(C)cc2=O)c1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(-n2cnnn2)cc(-n2ccc(C)cc2=O)c1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a solution of 3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acid methyl ester (500 mg, 1.93 mmol) and NaN3 (233 g, 3.58 mmol) in AcOH was added HC(OEt)3 (1378.6 mg, 9.3 mmol) at room temperature. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by silica-gel chromatography to give 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid methyl ester as a light yellow solid (602 mg, 100%). MS (M+H)=312.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1.[CH:15]1([CH2:18]/[C:19](=[N:21]/[S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])/[CH3:20])[CH2:17][CH2:16]1.C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH:15]1([CH2:18][C:19]([NH:21][S:22]([C:24]([CH3:25])([CH3:27])[CH3:26])=[O:23])([CH3:20])[C:13]2[S:14][C:10]([CH3:9])=[CH:11][N:12]=2)[CH2:16][CH2:17]1
Reactant: Cc1cncs1
Reactant: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A 2.0M solution of lithium diisopropylamide in THF (745 μl, 1.49 mmol) was added dropwise to a solution of 5-methylthiazole (148 mg, 1.49 mmol) in dry THF (0.5 ml) cooled to −78° C. and once the addition was complete the reaction was stirred for 30 minutes at −78° C. followed by addition of dry toluene (1.5 ml). To a solution of (NE)-N-(2-cyclopropyl-1-methyl-ethylidene)-2-methyl-propane-2-sulfinamide (CAN 1426426-70-1, 150 mg, 745 μmol) in dry toluene (1.5 mL) was added a 2.0M solution of trimethylaluminum in heptane (410 μl, 820 μmol). The previous solution was then added to the reaction mixture cooled at −78° C. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and was then diluted with ethyl acetate. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (123 mg, 55%). MS (ESI, m/z): 301.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:52]([O:54][CH3:55])=[O:53]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:26]([O:25][C:23]([C:17]1[CH:16]=[N:15][N:14]([C:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]4[CH2:41][CH2:40][N:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:38][CH2:37]4)=[CH:34][CH:35]=3)[CH:9]=[CH:10][CH:11]=2)[C:18]=1[C:19]([F:21])([F:22])[F:20])=[O:24])[CH3:27]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)OC)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (194 mg, 0.34 mmol) in DCM (2 mL) were added diisopropyl ethyl amine (0.60 mL, 3.41 mmol) and methyl chloroformate (0.08 mL, 1.02 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 626.9 [M+H]+.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[C:9]2[CH2:32][N:33]([S:37]([C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)(=[O:39])=[O:38])[C:34]([CH3:36])([CH3:35])[C:8]2=[N:7]1)=O)C.O.NN>CO.ClCCl>[NH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:10]1[C:9]2[CH2:32][N:33]([S:37]([C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)(=[O:39])=[O:38])[C:34]([CH3:36])([CH3:35])[C:8]=2[NH:7][N:6]=1)=[O:31]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC1(C)c2[nH]nc(NC(=O)c3ccccc3CN)c2CN1S(=O)(=O)c1cc(F)cc(F)c1

Procedure:
To a suspension of 5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.23 g, 0.34 mmol) in methanol (15 mL) and dichloromethane (1.5 mL) was added hydrazine hydrate (50 microL, 1.02 mmol). After stirring at reflux for 1 hour the volatiles were removed under reduced pressure and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/7N NH3 in methanol 95:4:1 affording the title compound as colorless oil (93 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[CH:11]=1)([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:15])([CH3:16])[CH2:14][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:11]1
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC1(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(C)C=C(c2ccccc2N)CC1(C)C
Temperature: 90 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene (441 mg, 1.8 mmol) produced in Example (54b), ethanol (10 mL) and water (3.3 mL) were added ammonium chloride (48.1 mg, 0.899 mmol) and iron powder (352 mg, 6.3 mmol), followed by stirring for 5 hours at an external temperature of 90° C. After further adding ammonium chloride (9.63 mg, 0.18 mmol) and iron powder (100 mg, 1.8 mmol) to the reaction mixture, stirring was continued for 12 hours at an external temperature of 75° C. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 331 mg of the title compound as a colorless oil.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC>O>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: Cc1ccnc(OCc2ccc(Br)cc2)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)4-methyl-pyridine (5.70 g, 20.5 mmol) described in Manufacturing Example 43-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 9.21 mL, 24.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 20 minutes at −78° C. N,N-dimethylfornamide (3.16 mL, 41.0 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.58 g, 55.4%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.Cl>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:13][C:11](=[O:12])[CH2:10][C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (2.0M solution in heptanes/tetrahydrofuran/ethylbenzene, 500 ml) in tetrahydrofuran (2 L) at 0° C. was added ethyl acetoacetate (62 ml). After 40 min 3-chlorobenzyl bromide (100 g) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was acidified with 2N HCl and the organic phase was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5-10% ethyl acetate in isohexane.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][CH2:21]Cl>C1COCC1>[CH2:6]([N:13]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:19][O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)CNCc1ccccc1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(Cc1ccccc1)C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 34.85 mL, 55.76 mmol) was added to N-benzyltrimethylsilylmethylamine (10 g, 55.76 mmol) in dry THF (140 mL) and stirred at −78° C. under nitrogen atmosphere. After 45 minutes, methoxymethyl chloride (4.3 mL, 55.76 mmol) in THF (6 mL) was added and then stirred for another 3 hours. The THF was evaporated, and the residue was dissolved in hexane, washed with water, and dried over sodium sulfate. The solvent was evaporated to give under reduced pressure to give N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]([CH3:25])[O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]([CH3:25])[O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:35]([C:32]3[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=3)=[O:36])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1OCC(c2cc(N)ccc2F)(C(F)F)N=C1NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1OCC(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (140 mg, 0.375 mmol), 5-cyano-2-pyridinecarboxylic acid (83 mg, 0.562 mmol) and HOAT (92 mg, 0.675 mmol) in 2 mL DMF was cooled to 0-5° C. EDC (108 mg, 0.562 mmol) followed by DIPEA (97 mg, 0.750 mmol) was added. The reaction mixture was allowed to warm up to room temperature. After 135 minutes, the mixture was partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1->2/1 to give the title compound as a diasteromeric mixture (white foam).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1[O:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (202 mg, 1.22 mmol), the crude 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (200 mg, 0.81 mmol) and cesium carbonate (527 mg, 1.62 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 20 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(3′-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, yield 50.8%) as a colorless slime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:44][O:45][C:46](Cl)=[O:47]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:46]([O:45][CH3:44])=[O:47])[N:15]=1)([CH3:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole in THF was added triethylamine, followed by methylchlorocarbonate. The mixture was stirred at room temperature for 20 min. After a routing aqueous work up, the crude product was purified by prep HPLC to give methyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.2 (s, 3H), 3.4 (m, 1H), 3.7 (m, 4H), 4.6 (m, 1H), 5.1 (m, 1H), 6.9 (m, 1H), 7.2 (m, 6H), 7.7 (m, 3H), 7.95 (m, 2H), 8.2 (m, 1H); LC/MS M+H 578 (observed).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10]CC(OCC)=O.[NH3:17].[CH2:18]([OH:20])[CH3:19]>>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10][C:18](=[O:20])[CH2:19][NH2:17]
Reactant: CCOC(=O)CNc1c(Br)cc(Br)cc1Br
Reactant: N
Reactant: CCO
Product: NCC(=O)Nc1c(Br)cc(Br)cc1Br
Temperature: 0 °C
Reaction time: 72 h

Procedure:
IV (7.5 g, 0.018 mole) and absolute ethanol (300 ml) were placed in a flask and warmed slightly to dissolve all of the crystals. Then the solution was saturated with anhydrous ammonia while the flask was cooled in ice water. White needles separated after the clear solution stood at room temperature for 3 days. The mixture was cooled in ice water, and the crystals were filtered and washed with a small amount of cold ethanol. A second crop of crystals, 1.1 g, was obtained by evaporating the filtrate to a volume of 35 ml and cooling in ice water. The total yield was 6.1 g (89%), mp 185°-185.5° C. Anal. calcd. for C8H7Br3N2O: C, 24.84; H, 1.82; Br, 61.96; N, 7.24. Found: C, 24.83; H, 1.87; Br, 61.82; N, 7.26.
Reaction SMILES: O=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[NH:3]1.O=P(Cl)(Cl)[Cl:21].CCN(C(C)C)C(C)C.O>C1(C)C=CC=CC=1>[Cl:21][C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ccsc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 641.4 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 1.50 g, 5.79 mmol) was suspended in dry toluene (15 ml). POCl3 (1.2 eq, 0.64 mmol, 6.99 mmol) and DIEA (0.8 eq, 0.81 mmol, 4.65 mmol) were added and the mixture vigorously stirred at 120° C. for 3 hours under nitrogen atmosphere. The mixture was hydrolyzed by addition of ice and water. The compound was extracted with CH2Cl2 (4×). The combined extracts were dried over Na2SO4 and the black solution filtered through a pad of celite. After evaporation of the volatiles in vacuo, the resulting solid was triturated in a mixture of AcOEt and hexanes. Filtration and drying provided methyl 4-chlorothieno[3,2-c]quinoline-7-carboxylate as a yellow fluffy solid (1.14 g, 71% yield). LCMS (ES): 95% pure, m/z 278 [M+1]+, 1H NMR (CDCl3, 400 MHz) δ 4.01 (s, 3H), 7.72 (d, J=4.8, 1H), 7.74 (d, J=5.2, 1H), 8.14 (d, J=8.4, 1H), 8.25 (d, J=8.4, 1H), 8.85 (d, J=1.6, 1H) ppm.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:11][C:10](=[O:12])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[F:2])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21]2
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1F
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.4 %

Procedure:
To a solution of (2-fluoro-phenyl)-phenylamino-acetic acid hydrochloride (I261) (217 mg, 0.77 mmol), (R)-quinuclidin-3-ol (338 mg, 2.66 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.332 mmol) in dry THF (15 mL), is added PS-DCC (1.0 g, 1.33 mmol). The mixture is shaken at RT for 15 hours. Then (R)-quinuclidin-3-ol (49.0 mg, 0.38 mmol) and PS-DCC (290 mg, 0.38 mmol) are added again and the reaction is shaken for additional 3 hours at RT. The resin is removed by filtration and washed several time with EtOAc. The solvent is evaporated, the residue is taken up with EtOAc and washed with NaHCO3, water and brine. The organic phase is dried (Na2SO4), filtered and evaporated to afford the title compound as a brown oil (225 mg, 82% yield).