Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:4].[NH2:32][C:33]([NH2:35])=[S:34]>CC(C)=O>[NH2:35][C:33]1[S:34][CH2:2][C:3]([NH:5][C:6]2[C:7]([CH3:31])=[C:8]3[C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:16]=4)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]3[CH:30]=2)([OH:4])[N:32]=1
Reactant: Cc1c(NC(=O)CBr)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Cc1c(NC2(O)CSC(N)=N2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A mixture of 425A (20 mg, 0.04 mmol) and thiourea (5.4 mg, 0.068 mmol) in acetone (2 ml) was heated at 70° C. for 2.5 h, then stirred at rt overnight. Filtered, the solid was washed with cold acetone and hexanes, dried to give the hydrobromide salt of 425 (14 mg, 63%) as a white solid. It has a retention time of 5.47 min (standard LC1 method, 8 min run). MS Found: (M+H)+=472.0
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]([OH:37])[CH3:36])[N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(Cl)Cl.CCOC(C)=O>[C:35]([C:33]1[N:34]=[C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:38])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:4]=3)[O:17][C:16]2=[O:18])[S:31][CH:32]=1)(=[O:37])[CH3:36]
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 134) (31.0 mg, 0.052 mmol) in CH2Cl2 (6 mL) was added DMP (55 mg, 0.130 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. Next, the reaction was diluted with EtOAc (40 mL) and washed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (40% EtOAc/hexanes) afforded (4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.26 (40% EtOAc/hexanes). LCMS=597.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 8.27 (s, 1H), 7.89 (s, 1H), 7.77-7.82 (m, 4H), 7.71 (d, J=7.9 Hz, 1H), 5.68 (d, J=7.9 Hz, 1H), 5.22 (d, J=16.3 Hz, 1H), 4.85 (d, J=16.4 Hz, 1H), 4.08 (m, 1H), 2.70 (s, 3H), 0.71 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[CH3:14][Si:15]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]1[CH2:23][O:22]1>C(O)C>[CH3:14][Si:15]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:2]([CH3:1])[CH2:3][CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:12][OH:13]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CN(CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C)CC(O)C(O)C(O)C(O)CO
Temperature: 70 °C

Procedure:
N-methyl-D-glucamine (1.42 g; 7.28 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.CN.C(O[BH3-])(=O)C.[Na+].[CH2:35]([N:37](CC)CC)C>O1CCCC1.ClCCl.C(O)(=O)C.O>[CH3:35][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: O=C1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Agent: CN
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(5R)-3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (250 mg, 0.70 mM) was dissolved in a mixture of anhydrous tetrahydrofuran (5 ml) and dichloromethane (5 ml) under nitrogen. Acetic acid (1 drop), methylamine (33% solution in methanol, 31 μL, 0.77 mM) and sodium acetoxyborohydride (222 mg, 1.05 mM) were added, and the mixture stirred at ambient temperature for 3 hours. The mixture was diluted with water (15 ml) and dichloromethane (15 ml), and the pH adjusted to 9 by addition of triethylamine. The organic phase was separated, washed with water (2×15 ml), brine (15 ml), and dried (magnesium sulfate). Evaporation gave the desired product (145 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24](O)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:28]([NH:31][C:24]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:17]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH3:23])=[N:16]2)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCN1c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (200 mg, 0.57 mmol) in dichloromethane (30 mL) was added 2-methylpropan-2-amine (46 mg, 0.63 mmol), triethylamine (115 mg, 1.14 mmol) and T3P (217 mg, 0.68 mmol) dropwise with stifling. The resulting solution was stirred for 3 h at room temperature and then concentrated in vacuo to afford (S)—N-tert-butyl-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxamide as a yellow oil (160 mg, crude).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[C:15]([CH:32]([CH3:34])[CH3:33])=[N:16][C:17]([CH:29]([CH3:31])[CH3:30])=[C:18]([CH2:27][OH:28])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:32]([C:15]1[C:14]([CH:13]=[O:12])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]([CH:27]=[O:28])=[C:17]([CH:29]([CH3:31])[CH3:30])[N:16]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.3 g (48 mmol) of pyridinium chlorochromate and 4.9 g (48 mmol) of neutral alumina are added to a solution of 3.8 g (12 mmol) of the compound from Example 4 in 100 ml of methylene chloride p.a. and the mixture is stirred for 1 h at room temperature. The mixture is filtered over kieselgur with suction and washed with 300 ml of methylene chloride. The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (150 g of silica gel 70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleum ether 2:8).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1CCN2C(=NCCC2)CC1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[C:10]2[C:15]=1[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[N:4][C:3]=1[NH:9]2
Reactant: Cc1cnc(Nc2cc(Cl)ccc2OCC2CCN(C)CC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc2[nH]c3c(OCC4CCN(C)CC4)ccc(Cl)c3c2c1
Temperature: 155 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a stirred solution of Compound 174 (450 mg, 1.06 mmol) in anhydrous and degassed DMF (3 mL), were added Pd(OAc)2 (59 mg, 0.26 mmol) and DBU (0.48 mL, 3.18 mmol), under nitrogen. After being stirred for 6 h. at 155° C. the reaction was quenched by addition of water (5 mL). The solid precipitates out was filtered and washed thoroughly with water. The residue was dried under vacuum and purified by flash chromatography to furnish Compound 175 (237 mg, 65%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]2=[N:15][C:14]=1[CH2:22][N:23]1[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[N:25]([CH:32]2[CH2:34][CH2:33]2)[C:24]1=[O:35])(C(C)(C)C)(C)C.[F-].[NH4+]>CO.[Pd]>[CH:32]1([N:25]2[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:23]([CH2:22][C:14]3[N:15]=[C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]4[C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:24]2=[O:35])[CH2:33][CH2:34]1
Reactant: CC(C)(C)[Si](C)(C)OCC/C=C/c1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cnccn12
Agent: [Pd]
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: O=c1n(Cc2nc3cnccn3c2CCCCO)c2cnccc2n1C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of (E)-3-((3-(4-(tert-butyldimethylsilyloxy)but-1-enyl)imidazo[1,2-a]pyrazin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 11-a (480 mg, 0.978 mmole) and Pd/C 10% (52 mg, 0.05 eq) in MeOH (20 mL) was hydrogenated for 2 h. The reaction mixture was then filtered over dicalite and concentrated to dryness. The resulting white solid (480 mg, 84%) was used directly in the next step. It was redissolved in MeOH and ammonium fluoride (39 mg, 1.1 eq) was added. The reaction mixture was then heated at 60° C. overnight. After concentration, the crude was purified by Prep HPLC on (RP Vydac Denali C18-10 μm, 250 g, 5 cm), with the following mobile phase (0.25% NH4HCO3 solution in water, CH3CN), to give the targeted product P17 in 87% yield (320 mg). m/z=491 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.94 (m, 2H), 0.99-1.10 (m, 2H), 1.36-1.46 (m, 2H), 1.46-1.59 (m, 2H), 2.96 (tdd, J=6.96, 6.96, 3.64, 3.51 Hz, 1H), 3.08 (t, J=7.53 Hz, 2 H), 3.34-3.43 (m, 2H), 4.38 (t, J=5.14 Hz, 1H), 5.22 (s, 2H), 7.23 (dd, J=5.27, 0.75 Hz, 1H), 7.88 (d, J=4.52 Hz, 1H), 8.22 (d, J=5.27 Hz, 1H), 8.40 (s, 1H), 8.44 (dd, J=4.64, 1.38 Hz, 1H), 8.97 (d, J=1.51 Hz, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:22]2[CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18](=[O:25])[C:17]=2[CH:16]=[N:15]1.[CH:26](OCC)=[O:27]>CCCCCC.O1CCCC1.O>[CH3:13][N:14]1[C:22]2[CH2:21][C:20]([CH3:23])([CH3:24])[CH:19]([CH:26]=[O:27])[C:18](=[O:25])[C:17]=2[CH:16]=[N:15]1
Reactant: Cn1ncc2c1CC(C)(C)CC2=O
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cn1ncc2c1CC(C)(C)C(C=O)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (23.8 ml of a 2.60 M solution in hexane) was added slowly to an ice-cold solution of 8.7 ml of N,N-diisopropylamine in 30 ml of anhydrous tetrahydrofuran. The solution was stirred at 0° C. for 15 minutes and treated with 10.8 ml of hexamethylphosporamide; it was then stirred at 0° C. for 15 minutes and cooled to -78° C. A solution of 5 g of 1,5,6,7-tetrahydro-1,6,6-trimethyl-4H-indazol-4-one in 150 ml of anhydrous tetrahydrofuran was added dropwise, followed by the dropwise addition of 8.9 ml of ethyl formate. The reaction was allowed to warm to room temperature and was stirred for 20 hours and 150 ml of water was added and the mixture was extracted with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid and extracted exhaustively with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide a dark oil which crystallized upon standing. Flash chromatography of this material (10% acetone in dichloromethane) on silica gel provided product as light yellow crystals. Recrystallization from hexane/toluene gave 4,5,6,7-tetrahydro-1,6,6-trimethyl-4-oxo-1 H-indazole-5-carboxaldehyde melting at about 131°-132° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:1]([NH:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCNCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of a solution of 5.5 gms of the N-heptylacetamide in 150 ml of diethyl ether and 3.99 gms of lithium aluminum hydride are stirred at room temperature for 18 hours. The reaction mixture is then worked up with H2O/NaOH by the Fieser method, following which the organic layer is dried over MgSO4, filtered, and concentrated under vacuum to give N-heptyl-N-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][NH:38][CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]([CH3:39])[CH3:37])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 99) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (143 mg, 61%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24]([N:26]1[CH2:30][C@@H:29]([CH2:31][O:32][CH3:33])[C@H:28]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:30][C@@H:29]([CH2:31][O:32][CH3:33])[C@H:28]([CH2:34][OH:35])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBAF (1.0 M in THF, 2.45 mL, 2.45 mmol) was added to a solution of trans-tert-butyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (290 mg, 0.81 mmol) in THF (5 mL). The mixture was stirred at rt for 1 hr. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was used without purification in subsequent steps.
Reaction SMILES: [SH:1][C:2]([CH3:17])([CH3:16])[C:3]([CH:5]([CH2:9][C:10](=[O:15])[C:11]([SH:14])([CH3:13])[CH3:12])[C:6](O)=[O:7])=[O:4]>O1CCCC1>[SH:1][C:2]([CH3:17])([CH3:16])[C:3]([CH:5]([CH2:9][C:10](=[O:15])[C:11]([SH:14])([CH3:13])[CH3:12])[CH2:6][OH:7])=[O:4]
Reactant: CC(C)(S)C(=O)CC(C(=O)O)C(=O)C(C)(C)S
Solvent: C1CCOC1
Product: CC(C)(S)C(=O)CC(CO)C(=O)C(C)(C)S
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of 2,3-bis(mercaptoisobutryl) propionic acid 9 (Scheme 1) (1 mmol) in 10 mL of anhydrous tetrahydrofuran, 1.5 mL of 1M BH3. THF is added over a period of 5 minutes (min.). The solution is stirred for another 10 min. and evaporated to dryness. Ten ml of water is added to the residue and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated in vacuo to give the product 21, which is purified by flash column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11](C2C=CC=CC=2)(C2C=CC=CC=2)[PH2]=O)[CH:7]=1)=[O:5])[CH3:2].[Li]CCCC.[CH2:31]([C:35]1[C:39]([CH:40]=O)=[C:38]([CH3:42])[O:37][N:36]=1)[CH2:32][CH2:33][CH3:34]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:40]/[C:39]2[C:35]([CH2:31][CH2:32][CH2:33][CH3:34])=[N:36][O:37][C:38]=2[CH3:42])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C([PH2]=O)(c2ccccc2)c2ccccc2)no1
Reactant: CCCCc1noc(C)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1/C=C/c1cc(C(=O)OCC)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
To a solution of 3-(diphenyl-phosphinoylmethyl)-isoxazole-5-carboxylic acid ethyl ester (410 mg, 1.2 mmol) in THF (10 mL) at −78° C. was added BuLi (1.6 M in hexanes, 0.79 mL, 1.3 mmol) and the mixture warmed up to 0° C. over 1 h and a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (193 mg, 1.2 mmol) in THF (5 mL) added and stirred for 2 h. The mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 7:3) afforded the title compound (75 mg, 21%) as a colourless oil. MS: m/e=305.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:8]([CH3:52])=[N:9][C:10]([CH3:51])=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][CH2:6][C:7]1[C:8]([CH3:52])=[N:9][C:10]([CH3:51])=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30]([C:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=2)=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CN)c(C)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(Example 49A): A solution of acetyl chloride (79 mg) in dichloromethane (1 ml) was added to a solution of 3-aminomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (628 mg) and triethylamine (101 mg) in dichloromethane (15 ml). The solution was left to stand for 1 hour and then water (15 ml) was added. The organic phase was separated, washed with saturated sodium chloride solution (15 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v) to give 3-acetamidomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (594 mg), as a foam; NMR (CDCl3): 1.8(s,3H), 2.5(s,3H), 2.6(s,3H), 4.45(d,2H), 5.0(s,2H), 5.6(br t, 1H), 6.6(s,1H), 6.9-7.0(m, 6H), 7.25-7.6 (complex m,16H), 7.95(dd,1H).
Reaction SMILES: FC1C=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH:5]=CC=1C.CN([CH:27]=[O:28])C>Cl>[CH3:27][O:28][CH2:5][CH2:4][NH:9][C:10]1[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC2=C(c3ccc(I)cc3)C(=O)NC2=O)cc1F
Agent: Cl
Product: COCCNC1=C(c2ccc(I)cc2)C(=O)NC1=O

Procedure:
A solution of 3-(3-fluoro-4-methylphenylamino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione (Example A705, 126 mg, 0.3 mmol) and 2-methoxyethylazine (0.2 mL, 2,3 mmol) in DMF (2 mL) was stirred at room temperature for 113 hours then diluted with hydrochloric acid (0.5M, 50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate solution was washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel using dichloromethane-diethyl ether (99:1 v/v) as eluent to afford the title compound, a solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:23][C@H:11]1[CH2:12][C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](OS(C)(=O)=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl-(dimethyl)silyl]oxy}methyl)cyclopentanol (2.02 g, 0.00560 mol) in CH2Cl2 (55.0 mL, 0.858 mol) at 0° C. was added triethylamine (1.8 mL, 0.013 mol) and methanesulfonyl chloride (0.650 mL, 0.00840 mol) under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 minutes, and then warmed to 23° C. for 1 hour. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered and concentrated to give 2.66 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH2:13][S:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:23])[CH2:13][S:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CSCC(=O)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSCC(N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 456 h

Procedure:
Crude 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylthioethan-1-one (8.3 g prepared as described above), ammonium acetate (25 g) and sodium cyanoborohydride (2.6 g) were dissolved in methanol (120 ml). The solution was kept at room temperature for 19 days and then poured into water (300 ml) and basified to pH 8. The mixture was extracted with ether and the ethereal solution extracted with 2N hydrochloric acid. The acid solution was basified and extracted with ether. The extracts were dried and evaporated to give an oil which was purified by flash chromatography using ethyl acetate as eluant to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylthioethylamine the boiling point of which was not determined.