Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][NH:7][C@@H:6]([CH2:9][OH:10])[CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)(Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([CH:4]1[CH2:8][N:7]2[S:18](=[O:20])(=[O:19])[O:10][CH2:9][C@H:6]2[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CN[C@@H](CO)C1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of ((2R)-4-isopropylpyrrolidin-2-yl)methanol (1.639 g, 11.44 mmol) and triethylamine (3.18 mL, 22.89 mmol) in DCM (100 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride, 1.0 M solution in DCM (13.73 mL, 13.73 mmol) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated onto a plug of silica gel and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH (with 2 M NH3) in DCM to give (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211.9 mg, 1.032 mmol, 9% yield) as light yellow oil. m/z (ESI, +ve) 206 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-].O.Cl>C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0° C. was added a solution of LiBH4 (2.063 g, 94.76 mmol) in one shot. The suspension was stirred at 0° C. for 1 h then at room temperature overnight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layers were dried over Na2SO4 filtered and concentrated to afford title compound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13 (found) 256.3 (M+K).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Cl:35]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>CC#N.C(Cl)Cl>[Cl:35][C:17]1[C:18]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:19][N:20]([C:21]2[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:16]=1[C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2cccnc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(O)c1nn(-c2cccnc2C(F)(F)F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1-(2-(trifluoromethyl)-pyridin-3-yl)-1H-pyrazol-3-yl)propan-2-ol (10.6 g, 21 mmol) in MeCN (200 mL) was added N-chlorosuccinimide. The resulting solution was heated to 75° C. in a heating mantle. After stirring for 3 hours at 75° C. heating was discontinued and the solution was concentrated under reduced pressure to afford a yellow foam. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane. Fractions that Were pure by TLC analysis were combined and concentrated under reduced pressure to afford a white sticky foam that was contaminated with succinimide as evidenced by NMR analysis. This material was taken up in CH2Cl2 and washed with saturated aqueous Na2CO3 (2×). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-chloro-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-3-yl)propan-2-ol (6.7 g, 60% yield) as an off-white foam. 1H NMR (400 MHz CDCl3): δ 8.85 (1H, m), 8.06 (1H, t), 7.86 (1H, m), 7.82-7.73 (2H, m), 7.67-7.62 (1H, m), 7.58 (1H, t), 7.28 (1H, d), 7.01 (1H, d), 3.08 (3H, s), 2.93 (1H, s), 1.73 (6H, s). MS(ES): 542 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of [4-(4,6-diphenylpyrimidin-2-yl)-phenyl]methanol, 0.38 g (1.11 mmol), triethylamine, 0.34 mL (2.45 mmol), and 6 mL of methylene chloride was cooled to 0° C. via ice-water bath. Methanesulfonyl chloride, 0.10 mL (1.23 mmol) was added dropwise over 5 minutes. The solution stirred for 2 h at 0° C. The solution was quenched with 20 mL of water and diluted with 20 mL of ethyl acetate. The organic layer was washed with water, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was recrystallized with EtOAc-Heptane (1:2) to afford the desired product in 0.44 g (95%) as a yellow solid. 1H NMR (DMSO-d6) 8.77 (d, 2H, J=9.0), 8.44-8.41 (m, 4H), 8.30 (s, 1H), 7.68-7.61 (m, 8H), 5.37 (s, 2H), 3.11 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1(S(O)(=O)=O)C=CC=CC=1.[CH3:19][C:20](=[CH2:22])[CH3:21].[OH-].[Na+]>C(Cl)Cl>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:4]
Reactant: C=C(C)C
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
To a 12L round-bottomed flask fitted with a mechanical stirrer, high efficiency reflux condenser (≤-10° C.), adJustable diptube inlet, and overhead nitrogen bubbler was charged a slurry of L-proline (600 g, 5.22 mole) in methylene chloride (6.0L, K.F.≤0.01%). The slurry was cooled to 5° C. and maintained at <20° C. as benzenesulfonic acid (1.24 kg, 7.83 mole) was slowly added. The reaction mixture, now homogeneous, was further cooled under nitrogen to 0°-5° C. and liquefied isobutylene (5.86L, 67.8 mole) was added subsurface via the diptube over 2 hours. The batch was then aged for 3 days at 5° C. under nitrogen. Upon completion, the batch was slowly quenched under nitrogen into well-stirred cold (0°-5° C.) aqueous sodium hydroxide (15.6L, 1.0 molar, 15.6 moles). The biphasic mixture was stirred for 10 minutes after which, the layers were allowed to separate. The pH of the aqueous layer measured 12-13. The lower methylene chloride layer was removed and set aside. The upper aqueous layer was then reextracted with methylene chloride (2×2.0L). The methylene chloride extracts were combined and concentrated under vacuum at ≤25° C. to a volume of 6.0L. The batch was then washed with aqueous sodium hydroxide (2×4.0L, 0.3 molar, 2.4 moles). The aqueous wash layers were combined and subsequently extracted with methylene chloride (2L). The methylene chloride extracts were then combined, dried over sodium sulfate (500 g), filtered, and concentrated under vacuum at ≤25° C. to about 1.5L (cf.50% soln K.F.≤0.06%). The batch was stored cold (0°-5° C.) under nitrogen. The concentrated product must be kept at 0°-5° C. to avoid exothermic decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:28][CH2:29][CH2:30][OH:31])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC2(CCCO)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (13.4 g, 60 mmol) in THF (450 mL) was added to a solution of LDA (76 mmol) in THF (30 mL) at −78° C. under an atmosphere of nitrogen. After stirring at −78° C. for 30 min, a solution of (3-bromopropoxy)-tert-butyldimethylsilane (16.8 mL, 72 mmol) in THF (30 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was poured into ice/H2O (400 mL), and extracted with Et2O (3×500 mL). The organic extracts were washed with H2O (500 mL) and brine (500 mL), dried and evaporated. The residue was dissolved in methanol (400 mL) and was added 1M HCl (200 mL). The resulting solution was stirred at room temperature for 1 h and evaporated. Silica gel chromatography (heptane, EtOAc 5:1) of the residue gave the title product as an oil (14.4 g, 81%). 1H NMR (DMSO-d6) δ1.25 (2H, m); 2.18 (2H, t, J=8.8 Hz); 3.31 (2H, q, J=6.2 Hz); 4.34 (1H, t, J=6.2 Hz); 5.12 (1H, d, J=13.2 Hz); 5.17 (1H, d, J=13.2 Hz); 7.15 (2H, t, J=8.8 Hz); 7.58 (2H, dd, J=6.0 and 8.8 Hz); 7.72 (1H, s); 7.78 (2H, br d, J=6.0 Hz.). 13C NMR (DMSO-d—6) δ27.4; 37.3; 59.8; 71.0; 90.7; 110.5; 114.8; 115.2; 118.8; 123.2; 125.6; 126.9; 127.1; 132.0; 139.9; 140.6; 149.5; 160.9; 162.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([OH:36])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([O:36][CH3:39])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1coc(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C[C@@H](C)C(=O)OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester (54 mg, 0.106 mmol) in DMF (1 mL) is added K2CO3 (29.2 mg, 0.211 mmol) and MeI (16.5 mg, 0.116 mmol), and the resulting mixture is stirred at room temperature overnight. Then ice/water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to give (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester which is used without further purification. HPLC Retention time 1.55 minutes (condition C): MS 526.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C([Mg]Cl)(C)C.[C:28](=[O:30])=[O:29]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:28]([OH:30])=[O:29])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(I)cc(Br)cc3c2C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(C(=O)O)cc(Br)cc3c2C1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of the product of step C (300 mg, 0.62 mmol) in tetrahydrofuran (1.5 mL) was added isopropylmagnesium chloride (1 M in tetrahydrofuran) (0.75 mL, 0.75 mmol) dropwise under an argon atmosphere at −20° C. over 5 min. The reaction mixture was stirred at −15° C. to −10° C. for 1 h before dry CO2 gas was bubbled through the reaction mixture over 15 min. The reaction mixture was slowly allowed to reach to ambient temperature and stirred overnight. The mixture was quenched with aqueous saturated ammonium chloride solution (10 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to give 8-bromo-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-6-carboxylic acid (125 mg, 50%) as a white solid. The crude product was directly used for the next step.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[Cl:15]CCCl.CC(O)C>O=P(Cl)(Cl)Cl>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: ClCCCl
Reactant: O=[N+]([O-])c1cnc(O)c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Temperature: 102.5 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
Stir a slurry of 1-hydroxy-4-nitroisoquinoline (62.2 g, 327 mmol) in POCl3 (180 mL) mechanically under nitrogen and heat to 100-105° C. for 1 hour resulting in a homogeneous dark brown solution. Exchange the condenser for a short-path distillation head, and remove excess POCl3 under reduced pressure (ca. 10-30 torr) resulting in a pot temperature of 55° C. To this mixture add 1,2-dichloroethane (150 mL), and warn the mixture to 70° C. to obtain a homogeneous solution. Cool the solution to 15° C., then add i-PrOH (450 mL) over 5 minutes resulting in an exotherm to 33° C. Stir the slurry for 3.5 hours at 15° C. then filter and wash with i-PrOH (3×100 mL). Air-dry the resulting solid overnight to afford 1-chloro-4-nitroisoquinoline (52.08, 76% yield) as a tan solid. (ES+): m/z 209/211 (M++H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.6 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (13.7 g) in DMSO (140 ml) was added potassium tert-butoxide (4.31 g) under ice-cooling and the mixture was stirred for 1.5 hours at ambient temperature. After cooling, 1,4-dioxaspiro[4,5]decan-8-one (5.0 g) was dropwise added to the solution under ice-cooling and then stirred for 1 hour at room temperature. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (150 ml). The extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was washed with a mixture of hexane and ethyl acetate (5:1 v/v) (300 ml). The resulting precipitates were collected and were chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 8-methylene 1,4-dioxaspiro[4,5]decane (5.56 g).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (533 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (701 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH:16]=[CH2:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:22]([O:21][C:19]([NH:18][C@H:13]1[CH:14]([CH2:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A 10% palladium carbon catalyst (15 mg) was added to a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:4)] (230 mg, 0.66 mmol) in ethanol (8 mL), followed by stirring in a hydrogen atmosphere under an ordinary pressure at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (148 mg, 100%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35]N)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: CS(=O)(=O)c1cccc(NN)c1
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (3-methane sulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=459.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[CH:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](OC2C=CC=CC=2)=[N:44][C:45]#[N:46])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH:20]/[C:43](=[N:44]/[C:45]#[N:46])/[O:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN/C(=N/C#N)Oc1ccccc1)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (190 mg, 0.35 mmol) and diphenyl cyanocarbonimidate (83 mg, 0.35 mmol) in DCM (10.0 mL) was added DIEA (0.12 mL, 0.70 mmol). The reaction mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to give (S,Z)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-((cyanoimino)(phenoxy)methylamino)pentyl 6-fluoroisoquinolin-3-ylcarbamate, which was used without further purification. LRMS (M+H+) m/z 650.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]3[CH3:32])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:32][C:22]1[N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{4-[(1-t-butoxycarbonyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone (1.1 g, 2.53 mmol) was dissolved in chloroform (10 mL), trifluoroacetic acid (10 mL) was added and the mixture stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate and 2N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated and dried to obtain the target substance (0.83 g, 98%) as a lavender-colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([N:9]=[C:10]=S)[CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)[CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: S=C=Nc1cc(Cl)c(Cl)cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To 4,5-dichloro-2-isothiocyanatopyridine (0.25 g, 1.22 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.43 mL, 3.05 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.29 g, 1.24 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.57 mL, 3.66 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(4,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.09 g, 0.27 mmol, 22% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.81 (s, 1 H), 8.32 (d, J=6.10 Hz, 1 H), 7.03 (s, 1 H), 3.83 (d, J=9.46 Hz, 1 H), 3.57 (d, J=9.77 Hz, 1 H), 2.98 (s, 2 H), 2.71-2.79 (m, 2 H), 2.65 (t, J=7.78 Hz, 2 H), 1.99 (s, 1 H), 1.86 (s, 1 H), 1.53-1.61 (m, 2 H), 1.41-1.49 (m, 1 H). MS (LC/MS) R.T.=0.78; [M+H]+=327.0.