Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([C:17](=[O:18])[CH3:19])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: CC(=O)Cl
Reactant: Brc1ccc2ncn(C3CCNCC3)c2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(n2cnc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-(piperidin-4-yl)-1H-benzo[d]imidazole (50 mg, 0.178 mmol) in DCM (5 mL) in pyridine (5 mL) cooled by an ice-bath was added AcCl (14 mg, 0.178 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvents were removed by concentration and the residue used for next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C)C(=O)C.O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:26]([NH:25][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:27][C:28]([OH:30])=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccc(Cl)c2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-(3-chloro-phenyl)-propionic acid (156 mg, 0.78 mmol) (commercially available from Alfa Aesar L19797) in N,N-dimethylacetamide (DMA) (2 mL) was added sodium methoxide (34 mg, 0.62 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 4 h. After cooled, reaction mixture was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4, and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with EtOAc/hexanes (10%-100%), to provide the title compound 20 mg (0.04 mmol) in 26% yield. LC-MS ESI−: 486 (M−1)−.
Reaction SMILES: [ClH:1].C(OCC([NH:10][C@@H:11]([C:19]([N:21]1[CH2:45][CH2:44][CH2:43][C@H:22]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH:35]C(OC(C)(C)C)=O)=[O:24])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C>C(OC(=O)C)C>[ClH:33].[ClH:1].[NH2:10][C@@H:11]([C:19]([N:21]1[CH2:45][CH2:44][CH2:43][C@H:22]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH3+:35])=[O:24])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OCC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1C[NH3+]
Reaction time: 1 h

Procedure:
HCl gas was bubbled through a 0° C. solution of N-(tert-Butoxyacetyl)-D-phenylalanyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide (0.073 mmol, 45 mg) in 0.500 mL ethylacetate for 2 min. Let stir 1 h and concentrated in vaccuo to give D-Phenylalanyl-N-[2-(ammoniomethyl)-5-chlorobenzyl]-L-prolinamide bis(hydrochloride). Mass Spec ES (M+1)=415.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:13]([F:12])[CH:14]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1ccc(N)cc1F
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1F
Reaction time: 0.5 h
Yield: 56 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (890 mg, 4.21 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (587 μl, 4.21 mmol) was added. To this solution, 3-fluoro-4-methoxyaniline (594 mg, 4.21 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified using SP1® Purification System (0%-40%, hexane-ethyl acetate) to give 720 mg (56% yield) to the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:9](=[O:27])[NH:10][C:11]1[CH:12]=[C:13]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:15]3=[C:16]([CH2:20][CH3:21])[NH:17][C:18]([CH:19]=1)=[C:14]23)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:9]([NH:10][C:11]1[CH:12]=[C:13]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:15]3=[C:16]([CH2:20][CH3:21])[NH:17][C:18]([CH:19]=1)=[C:14]23)=[O:27]
Reactant: CCc1[nH]c2cc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)cc3c2c1C=NNC3=O
Agent: Cl
Solvent: C1COCCO1
Product: CCc1[nH]c2cc(NC(=O)[C@H](N)C3CCCCC3)cc3c2c1C=NNC3=O

Procedure:
Preparation of the title compound from Intermediate 189(a) (136 mg, 0.291 mmol) and 4.0 M HCl in dioxane (1.5 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, afforded the title compound (75 mg, 0.186 mmol) as a yellow powder in 64% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:10])=[CH:4][CH:3]=1.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([C:11]2[CH:12]=[N:36][NH:35][N:34]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC(c1ccc(Cl)cc1)(c1cn[nH]n1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21

Procedure:
A solution of tert-butyl 1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-ylcarbamate (200 mg, 0.5 mmol) in trimethylsilyl azide (3 mL) was heated at 100° C. under microwave for 3 h. The resulting mixture was diluted with brine (10 mL) and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to afford the crude product. The product was purified via column chromatography (75% EtOAc/hexanes) to provide the title product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20](O)[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20]([N:29]4[C:25](=[O:35])[C:26]5[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:28]4=[O:30])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)O)s3)s2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of Example 3B (314 mg, 0.87 mmol), phthalimide (140 mg, 0.95 mmol) and triphenylphophine (341 mg, 1.3 mmol) in tetrahydrofuran (25 mL), at room temperature was slowly added diethyl azodicarboxylate (205 uL, 1.3 mmol). The reaction mixture was stirred at room temperature, overnight. The solvent was removed under vacuum and the product was purified on a silica-gel column using a gradient of 10-15% ethyl acetate in hexane and yielded the product as white powder (210 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.63-7.97 (m, 5H) 7.12-7.24 (m, 2H) 7.00 (d, J=3.68 Hz, 1H) 6.81-6.96 (m, 3H) 5.73 (q, J=7.35 Hz, 1H) 4.44-4.59 (heptet, J=6.25 Hz, 1H) 196 (d, J=7.35 Hz, 3H) 1.34 (d, J=6.25 Hz, 6H), MS (DCI): m/z 491 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4(5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5H), 3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz), 1.92-0.95 (m, 9H), 1.28 (s, 3H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+): 284.0776, found: 284.0787.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][C@@H:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C@@H:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (0.11 g, 0.25 mmol, 1 eq), DIPEA (0.17 mL) and TBTU (88 mg, 0.28 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of (R)-(+)-3-aminoquinuclidine dihydrochloride (60 mg, 0.30 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before diluting with DCM and washing sequentially with water (×2), 50% saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum quantity of EtOAc before addition of n-heptane to precipitate (R)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (white solid, 0.13 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH2:12]([Mg]Br)[CH3:13].O.Cl>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1)[CH3:13]
Reactant: Cc1cn2nc(Cl)ccc2n1
Reactant: CC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCc1ccc2nc(C)cn2n1
Temperature: 25 °C

Procedure:
6-Chloro-2-methylimidazo[1,2-b]pyridazine (5.00 g, 29.8 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.08 g, 0.15 mmol) were suspended in dry ether (40 ml)-dry THF (20 ml), and a solution of ethylmagnesium bromide in ether (3 M, 15 ml, 45 mmol) was added dropwise thereto with stirring under ice-cooling over 5 minutes (internal temperature 10° C. or less). The temperature of the reaction solution was increased to room temperature, and the mixture was stirred at the same temperature for 2 hours and under reflux with heating for 3 hours. The reaction solution was left to cool to room temperature under stirring, and water (30 ml) was added little by little. Further, the pH of reaction mixture was adjusted to about 5 to 6 with concentrated hydrochloric acid under stirring at room temperature. The organic layer and the aqueous layer were separated from each other, and the aqueous layer was extracted with ethyl acetate (70 ml×2). The organic layers were combined and washed with water (250 ml×3). The organic layer was dried over magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (chloroform:ethyl acetate=2:1→1:1), and the resulting crude oil was further purified by silica gel column chromatography (ethyl acetate), and the title compound was obtained as pale red oil. The yield was 1.32 g (27.4%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[C:20]([F:29])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[F:29][C:20]1[CH:19]=[C:18]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:16])([F:15])[F:1])=[N:4][N:5]=3)[CH:8]=2)[CH:23]=[CH:22][C:21]=1[O:24][C:25]([F:26])([F:27])[F:28]
Reactant: OB(O)c1ccc2nnc(C(F)(F)F)n2c1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(-c2ccc3nnc(C(F)(F)F)n3c2)ccc1OC(F)(F)F
Temperature: 110 °C

Procedure:
3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-ylboronic acid (56.2 mg, 0.217 mmol), 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (50.0 mg, 0.217 mmol, 1.0 equiv.) and Pd(PPh3)4 (12.6 mg, 0.0109 mmol, 0.05 equiv.) was placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added 2M-Na2CO3 (1.0 mL, 2.0 mmol) and DMF (4 mL) subsequently at ambient temperature. The mixture was heated at 110° C. for 1 hours. The mixture was filtered through Celite (3 g) and the Celite was washed with EtOAc (70 mL). The organic layer was washed with brine (30 mL) and dried with Na2SO4. The solvent was removed under a reduced pressure. Obtained crude mixture was purified by a column chromatography (SiO2=25 g, EtOAc/hexane=1:3 to 1:1, Rf=0.3 with EtOAc/hexane=1:1) to give 6-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine as colorless crystals
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 77 %

Procedure:
Methyl (3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 130 mg (77%) of product as a colorless hard foam.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[O:23][CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32]([O:34]C(C)(C)C)=[O:33])=[O:26])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:32]([C@H:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:25](=[O:26])[CH2:24][O:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:39])([OH:34])=[O:33]
Reactant: Cc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 325 mg (0.60 mmol) (R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 235 mg (91%) of the title compound as a white powder.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8](OC(=O)C)(=[O:10])[CH3:9].CCN(CC)CC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])(=[O:10])[CH3:9]
Reactant: CC(=O)C(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(C)=O
Temperature: 10 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A mechanically stirred 3 l round-bottomed flask under an atmosphere of nitrogen was charged with 3-hydroxy-3-methyl-2-butanone (100.0 g, 979 mmol) and CH2Cl2 (900 ml). A solution of acetic anhydride (92.4 ml, 979 mmol) and CH2Cl2 (50 ml) was added over 10 min and the resulting solution was cooled to 10° C. DMAP (5.98 g, 49 mmol) was added in one portion followed by Et3N (205 ml, 1.47 mol) over 50 min while maintaining an internal temperature below 16° C. After the addition, the mixture was aged for 16 h at room temperature. The resulting solution was poured onto MeOH (200 ml) and after 15 min 2N HCl (400 ml) was added. The phases were separated and the organic phase was washed with water (500 ml) then saturated NaHCO3 (500 ml) then dried over Na2SO4. The solvent was removed under diminished pressure to provide 3-acetoxy-3-methyl-2-butanone as a golden oil (132.5 g): 1H NMR (CDCl3, 400 MHz) δ 2.12 (3H, s), 2.09 (3H, s), 1.47 (6H, s); 13C NMR (CDCl3, 100.61 MHz) δ 206.6, 170.2, 83.5, 23.4, 23.2, 21.0.
Reaction SMILES: C[O:2][C:3]1[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:20])[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][C:12]1([CH:13]=[CH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:20])[CH2:4][C:3]1=[O:2]
Reactant: C=CC1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 60 °C
Reaction time: 96 h
Yield: 58.5 %

Procedure:
To a solution of Example 181C (42 mg, 0.16 mmol) in methanol (1 mL) was added a solution of 1 N NaOH (0.5 mL, 0.5 mmol). The reaction solution was stirred at 60° C. for 96 h. The solution was cooled to room temperature, acidified with 0.1 N HCl, and extracted with ethyl acetate (3× 1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (20%-40% ethyl acetate/hexane) afforded product as an off-white solid (24 mg, 60%).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[C:22]([F:24])[C:21]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=3[CH3:40])[CH2:29][CH2:28]2)=[O:26])=[C:20]([F:41])[CH:19]=1>>[F:41][C:20]1[CH:19]=[C:18]([N:11]2[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]2(=[O:15])=[O:16])[CH:23]=[C:22]([F:24])[C:21]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])[CH2:29][CH2:28]1)=[O:26]
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 52 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (482 mg) described in Preparation Example 1 and (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 109 and by the reaction and treatment in the same manner as in Example 32, the title compound (498 mg) was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9]1)C1C=CC=CC=1>CO>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
The product from Step B (3.75 g, 11.3 mmol) was dissolved in methanol (75 mL) in a Parr bottle, and the vessel purged with argon. To this was added 10% palladium on carbon (0.80 g) and the reaction hydrogenated under 60 psi hydrogen for 24 h. The catalyst as removed by filtration through Celite, and the filtrate evaporated in acuo to give the title compound as an oil. 1HNMR (300 MHz, CDCl3) δ 4.08 (1H, br s), 3.90 (1H, d, J=12 Hz), 2.5-3.8 (6H, m), 1.80 (1H, m), 1.60 (1H, m), 1.46 (9H, s), 1.30 (4H, m),0.90 (3H, t, J=7 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].S([O-])(O)(=O)=O.[K+].CCOCC>O>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH:10]=[O:24])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.29 h

Procedure:
Lithium aluminum hydride (2.5 equiv.) is added to a stirred solution of compound (7). Reduction is complete within 15-20 minutes. The mixture is hydrolyzed with a solution of potassium hydrogen sulfate in water. Ether is added and the aqueous phase is separated and extracted. The organic phases are combined, washed with 1N HCl saturated sodium hydrogen carbonate and saturated sodium chloride, and dried with magnesium sulfate. The solvent is evaporated to leave the desired product