Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([NH:34][CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:37]1)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O>[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([N:34]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:37]1)[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
The solution of (S)-(−)-2-tetrahydrofuroic acid (50 mg, 0.43 mmol) in thionyl chloride (0.5 mL) was refluxed for 30 min, and the volatile materials were completely concentrated in vacuo. The crude product was then dissolved in dichloromethane (0.3 mL), which was then added to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (40 mg, 0.066 mmol) and N,N-diisopropylethylamine (34 μL, 0.197 mmol). After the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 64.6%). LC/MS (uplc): MH+ 706.0, 1.40 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1I.BrC1C=CC2[O:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])C=2C=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:3]=2[CH:4]=1
Reactant: Fc1ccc(Br)c(I)c1
Reactant: Cc1oc2ccc(Br)cc2c1C(=O)O
Product: Cc1oc2ccc(F)cc2c1C(=O)O

Procedure:
This intermediate was prepared from 1-bromo-4-fluoro-2-iodo-benzene in two steps according to the preparation of 5-bromo-methyl-benzofuran-3-carboxylic acid (from 1,4-dibromo-2-iodo-benzene).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].[OH-].[Na+]>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)(C)N1CC(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 160 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.butyl)-3-azetidinol and 6.7 parts of 2,3-xylenol 0.2 part of sodium hydroxide was added, and the mixture was heated at 160° C. for 24 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed twice with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 50 parts of 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and was made alkaline by addition of 2 N-sodium hydroxide aqueous solution. The solution was cooled and agitated to form crystals. The resulting crystals were dried and recrystallized twice from ether to yield 9.2 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2>>[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:9]
Reactant: O=C(Cl)CCCBr
Reactant: O=C([O-])[O-]
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [K+]
Product: O=C([O-])CCCBr
Reaction time: 120 h

Procedure:
Five portions of 4-bromobutanoylchloride (0.35 ml×5) and potassium carbonate (0.4 g×5) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCI3 dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:20][C:19]([Cl:29])=[CH:18][N:17]=1.O>CS(C)=O>[Cl:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=3)=[CH:26][CH:27]=2)[C:16]([NH2:15])=[N:17][CH:18]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A mixture of potassium carbonate (376 mg), 5-chloro-2-fluoropyridine (215 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 5 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (450 mg) as a pale yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Temperature: 110 °C

Procedure:
At 50° C., 74.8 g (0.63 mol) of thionyl chloride in 50 ml of dry toluene were added dropwise to a solution of 139.0 g of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 1 l of dry toluene. The mixture was heated to 110° C. for 6 hours, after which the solvent was distilled off. 2-Chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride was obtained in quantitative yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[C:17]([C:20]([NH2:22])=[O:21])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[C:5]([O:23][C@@H:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:26]1[CH2:27][CH2:28][C@@H:24]([O:23][C:5]2[CH:4]=[C:3]([F:2])[CH:8]=[CH:7][C:6]=2[NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[C:17]([C:20]([NH2:22])=[O:21])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:25]1)(=[O:31])[CH3:30]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCNC3)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 99.4 from 4-[4-fluoro-2-((R)-pyrrolidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide hydrochloride and acetic anhydride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>C1COCC1>[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([S:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Glycine (5 mmol) is reacted with 4-biphenylsulfonyl chloride (about 5 mmol) in the presence of 1N NaOH solution (10 ml), ether (21 ml) and THF (2 ml) using the procedure described in Example 5 to give the title product.
Reaction SMILES: [H-].[Na+].COCCOC.Br[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1.C(N(CC)CC)C>O>[CH2:22]([NH:21][C:17]1[CH:16]=[C:15]([C:14]2[O:36][CH2:10][CH2:11][CH2:12][N:13]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(=O)NCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1cccc(C2=NCCCO2)c1

Procedure:
To 0.4 g. of sodium hydride in 100 ml. of 1,2-dimethoxyethane is added 2.14 g. of N-(3-bromopropyl)-3-(4-tetradecenylamino)benzamide and 12 ml. of triethylamine. The turbid solution is heated to reflux for 20 hours. The solution is diluted with 100 ml. of water and cooled overnight. The solid is collected, washed with water, crystallized from cyclohexane, and recrystallized from acetonitrile to yield the product.
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:9][CH2:8]1)=[O:6])C.C(O)C.[OH-].[Na+].Cl>O>[ClH:1].[CH:26]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:16](=[CH:15][CH2:14][CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C

Procedure:
A mixture of the above ester (0.105 g, 0.27 mmol), ethanol (15 ml) and 1 N sodium hydroxide (10 ml) was heated at reflux temperature for 3 h and then cooled to room temperature. Water (75 ml) was added, and the mixture was acidified with 5 N hydrochloric acid and extracted with dichloromethane (3×75 ml), dried (MgSO4) and evaporated in vacuo. The resulting foam was crystallised from acetone affording 0.080 g of the title compound as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:20][OH:21])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methanol (112 mg) obtained from Referential Example 75 was dissolved in methylene chloride (4 mL). To the solution, triethylamine (61 μL) and methanesulfonyl chloride (34 μL) were added at room temperature, followed by stirring for 15 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as an oily product (13.8 mg, 96%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:4]=1[NH:5][CH:6]=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:1][CH2:2][C:3]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:4]=1[N:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]2[OH:15])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ccc(C)cc1CO)C(=O)OCC
Product: CCOC(=O)c1cnc2c(COC(C)=O)cc(C)cc2c1O
Temperature: 130 °C

Procedure:
A mixture of diethyl 2-((2-(hydroxymethyl)-4-methylanilino)methylene)malonate (Preparation 24, 5.0 g) and acetic anhydride (5.0 mL) is heated at 130° C. for 1 h. The acetic anhydride is evaporated, and the residual solid is heated at reflux in diphenyl ether (20 ml) for 1 h. The solution is cooled and diluted with acetonitrile (5 mL) and ether (15 mL). The resulting precipitate is filtered to afford 1.8 g of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[S:21][C:22]2[N:23]=[C:24]([N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[C:36]3[CH2:44][CH3:45])[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:27]=2[N:28]=1)(=O)OC.[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=O)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C1COCC1>[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=[CH:19][C:20]2[S:21][C:22]3[N:23]=[C:24]([N:35]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]4[CH2:44][CH3:45])[N:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:27]=3[N:28]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CP(=O)(OC)OC)sc2n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)sc2n1
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (200 μL, 1.42 mmol) in THF (0.5 mL) at −78° C. was added n-BuLi (556 μL, 1.42 mmol, 2.5 M in hexanes) and the resulting mixture stirred for 20 min. The resulting solution was added to a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (620 mg, 1.27 mmol) in THF (11 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.46 mmol) in THF (1.5 mL) was added. The resulting mixture was stirred at r.t. for 5 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was filtered through a pad of silica affording the title compound (493 mg, 73%). LCMS (method H): RT 3.72 min, [M+H]+ 534.3
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:19]([N:26]([CH3:35])[CH2:27][CH2:28][CH:29]([OH:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O[C:37]1[C:42]2[CH:43]=[CH:44][S:45][C:41]=2[CH:40]=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[S:45]1[CH:44]=[CH:43][C:42]2[C:37]([O:34][CH:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:28][CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:35])=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: CC(C)CC(O)CCN(C)Cc1ccccc1
Reactant: Oc1cccc2sccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Yield: 59.2 %

Procedure:
Add 1,1′-(azodicarbonyl)dipiperidine (1.6901 g, 6.698 mmol) to a stirred solution of 1-(benzyl-methyl-amino)-5-methyl-hexan-3-ol (1.0463 g, 4.445 mmol), 4-hydroxybenzo-thiophene (1.0027 g, 6.676 mmol), tributylphosphine (1.70 mL, 6.82 mmol), and anhydrous toluene (15 mL). Heat the reaction to 70° C. under nitrogen for 18 hours. Cool the reaction to room temperature and dilute with dichloromethane. Filter off the solid material and concentrate the solvent off on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 10% ethyl acetate /dichloromethane to yield 0.9674 g (59%) of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine: mass spectrum (ion spray) m/z=368.3(M+1); 1H NMR (CDCl3) δ 7.46-7.41 (m, 2H), 7.29-7.21 (m, 7H), 6.83 (d, 1H), 4.66-4.60 (m, 1H), 3.47 (s, 2H), 2.54-2.51 (m, 2H), 2.19 (s, 3H), 2.02-1.71 (m, 4H), 1.49-1.42 (m, 1H), 0.95 (d, 3H), 0.89 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51]>>[CH3:53][S:50]([CH2:49][CH2:48][NH:47][C:40]([CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:43][CH2:44][CH3:45])=[O:33])[CH2:35][CH2:36]1)=[O:42])(=[O:52])=[O:51]
Reactant: CS(=O)(=O)CCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)NCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid, was coupled with 2-aminoethyl methylsulfone hydrochloride (Array) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O5S [(M+H)+] 756.2748, observed 756.2749.
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:27]([F:28])=[CH:26][C:13]([C:14]([C:16](=[CH:22]N(C)C)[C:17]([O:19]CC)=[O:18])=[O:15])=[C:12]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[N:11]=2)[CH2:6]1)(=O)C.[ClH:38]>C(O)C>[ClH:38].[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]3[C:13]([C:14](=[O:15])[C:16]([C:17]([OH:19])=[O:18])=[CH:22][N:29]3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[CH:26][C:27]=2[F:28])[CH2:6]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 85.4 %

Procedure:
In 4 ml of ethanol was suspended 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylate, and 4 ml of 6N hydrochloric acid was added thereto, after which the resulting mixture was subjected to reaction under reflux for 3.5 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of ethanol, after which crystals were collected by filtration to obtain 145 mg (yield 85.4%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][N:8]([C@@H:9]2[O:22][C@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH:11]=[CH:10]2)[C:7](=[O:25])[N:6]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:4][C:5]1[CH:24]=[CH:23][N:8]([C@@H:9]2[O:22][C@H:12]([CH2:13][OH:14])[CH:11]=[CH:10]2)[C:7](=[O:25])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccn([C@H]2C=C[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 32 (1.5 g, 4.1 mmol) in THF (30 ml) and 5 ml (5.0 mmol) of a 1M solution of tetra-n-butylammonium fluoride solution in THF were stirred in an ice-bath for 10 minutes and then at room temperature for 1 hour. The solvent was removed in vacuo. The resulting residue was purified by chromatography using 5% methanol in CHCl3 to obtain 0.88 g (85%) of 33 as colorless solid: mp 180°-182° C. dec (benzene-methanol); 1H NMR (DMSO-d6) 6 2.09 (3H, s, COCH3), 3.63 (2H, m, 5'-H), 4.85 (1H, m, 4'-H), 4.99 (1H, t, J=5.27 Hz, OH), 5.95 (1H, br d, J=5.8 Hz, 2'-H), 6.40 (1H, br d, J=5.8 Hz, 3'-H), 6.87 (1H, m, 1'-H), 7.15 (1H, d, J=7.3 Hz, 5-H), 8.20 (1H, d, J=7.3 Hz, 6-H), 10.86 (1H, s, NH).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][C@@H:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([NH:16][CH3:17])=[O:15].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:12][C@@H:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([NH:16][CH3:17])=[O:15])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNC(=O)[C@@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
TsCl (4.75 g, 25 mmol, 1.0 eq) was added portion-wise at rt to a solution of 37 (4.13 g, 25 mmol, 1.0 eq) and DIPEA (3.22 g, 4.4 mL, 25 mmol, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 5 h, then was concentrated under reduced pressure to give an oil. The crude oil was dissolved in ethyl acetate (150 mL), and the solution was washed sequentially with water (100 mL), saturated sodium bicarbonate solution (2×75 mL) and brine (75 mL). The organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to near dryness. The solid was triturated with methyl t-butyl ether (100 mL), filtered and dried to give 4.89 g (61%) of 38 as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:33]C=C)[CH:8]=[C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)=[O:5])[CH3:2].[O-:36][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[OH:36][CH2:2][CH:1]1[O:3][C:4](=[O:5])[C:6]2=[CH:10][C:9]([C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:21]=[CH:20]4)([OH:16])[C:12]([F:15])([F:13])[F:14])=[CH:8][N:7]2[CH2:33]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1OC(CO)Cn2cc(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a chilled (0° C.) solution of 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg, 0.2 mmol, 1 equiv.) in 3 mL of acetone and 1 mL of water was added a solution of KMnO4 (39 mg, 0.25 mmol, 1.2 equiv.) in 3 mL of acetone and 1 mL of water. The ice bath was removed and the reaction was warmed to room temperature. After 2 hours, the reaction was filtered through CELITE® filter aid and the filter cake washed with acetone. The filtrate was concentrated in vacuo diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-95% CH3CN/water 0.1% TFA). The fractions were combined and concentrated to remove CH3CN. The aqueous residue was made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc to provide 25 mg of the title compound as a white solid. MS m/z 476.16 (MH+).