Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[N:7]1([CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:20])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=[CH:8]1>C(Cl)(Cl)Cl>[C:4]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:27][CH:26]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: O=C(OCCCO)c1ccc(OCCn2ccnc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)OCCCOC(=O)c1ccc(OCCn2ccnc2)cc1
Yield: 78 %

Procedure:
After adding at room temperature 4.1 ml of diketene dropwise to 10 g of 3-hydroxypropyl 4-[2-(1-imidazolyl)ethoxy]benzoate dissolved in 300 ml of chloroform, the resultant mixture was stirred for further 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 10.1 g of 3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl acetoacetate as colorless crystals (m.p. 49.5°-51.5° C.; yield: 78%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl[C:24]([O:27]C(Cl)=O)(Cl)Cl>ClCCl>[CH3:9][O:8][C:4]1[C:3]2[N:10]([C:11]([O:12][CH2:13][CH3:14])=[O:15])[C:24](=[O:27])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Nc1c(N)cccc1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c(=O)[nH]c2cccc(OC)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
13.0 g (0.062 mol) ethyl (2-amino-6-methoxy-phenyl)-carbamate and 10.3 mL (0.074 mol) triethylamine in 100 mL dichloromethane are added to a solution of 8.20 mL (0.068 mol) trichloromethylchloroformate in 50 mL dichloromethane while cooling with ice. After 4 hours stirring at ambient temperature the reaction mixture is poured onto ice and extracted with dichloromethane. The combined organic phases are washed with water, dried and freed from the solvent. The residue is stirred in diethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:20]1[CH:29]=[N:28][C:27]2[C:22](=[CH:23][C:24]([Cl:31])=[C:25]([Cl:30])[CH:26]=2)[N:21]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[Cl:31])[N:21]=[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=1)[CH:29]=[N:28]2
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: [H][H]
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1
Temperature: 0 °C

Procedure:
In a nitrogen atmosphere, a solution of 3.9 g (0.02 mole) methyl 2-(4-hydroxyphenoxy)propanoate in 20 cc of dimethylformamide was added dropwise at about 15° C. to a suspension of 0.8 g sodium hydride in 10 cc dimethylformamide. When the evolution of hydrogen ceased, 4.7 g of (0.02 mole) 2,6,7-trichloroquinoxaline was added and the reaction mixture was heated for 5 hours at ~130° C. Filtering the reaction mixture yielded a small amount of insoluble material. The filtrate was poured into approximately 200 cc of ice-water. Sodium chloride was added to the solution which was then extracted with 1200 cc of ether (4×300). The ethereal extracts were combined and dried over magnesium sulfate. The ether was removed under vacuum and the crude product was crystallized from CH3OH. Yield 2.8 g, m.p. 100°-105°.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6](=O)[CH2:7][C:8]3([O:14]2)[CH2:13][CH2:12][CH2:11][O:10][CH2:9]3)=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:21]([C:20]1[CH:19]=[C:18]([C:3]2[CH:4]=[C:5]3[C:15](=[CH:16][C:2]=2[CH3:1])[O:14][C:8]2([CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH2:7][C:6]3=[N:32][C:31]#[N:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: Cc1cc2c(cc1-c1cccc(C#N)c1)C(=O)CC1(CCCOC1)O2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1cccc(C#N)c1)C(=NC#N)CC1(CCCOC1)O2
Reaction time: 1 h
Yield: 132.3 %

Procedure:
To a solution of 3-(7-methyl-4-oxo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-6-yl)benzonitrile (72 mg, 0.22 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.44 mL, 0.44 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.114 mL, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (10 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 3 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 104 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:24][CH2:25]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCNCC3)nc(N)n2)cc1)Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccn4)CC3)nc(N)n2)cc1)Oc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester (1 mmol) in dry dichloromethane (20 ml) under N2 was added pyridine-2-carbaldehyde (1.1 mmol). The reaction was stirred at room temperature for half an hour, then Sodium triacetoxyborohydride (1.3 mmol) was then added and stirred over night. Water (10 mL), the biphasic mixture was diluted with dichloromethane and partitioned, and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified in silica to provide yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Sodium azide (515 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-(p-toluenesulfonyloxy)-D-proline methyl ester (B, 1.65 g) in N,N-dimethylformamide (10 mL)-water (2 mL). After stirring at 80-90° C. for 1 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (1.04 g) as a colorless oil.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH:32]=[O:33])=[CH:26][CH:25]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:32](=[O:33])[CH:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: COc1ccc(/C=C/C=O)cc1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: COc1ccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)cc1
Yield: 76 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-methoxyphenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 9 as an off-white solid (102 mg, 76%). Analytical data for 9: 1H NMR (500 MHz, CDCl3) δ 9.38 (d, J=8.1 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.39-7.29 (m, 3H), 7.10-6.93 (m, 6H), 6.88-6.83 (m, 2H), 4.09 (d, J=6.8 Hz, 1H), 3.81 (s, 3H), 3.55 (ddd, J=10.1, 6.8, 4.6 Hz, 1H), 3.29 (dd, J=14.9, 4.6 Hz, 1H), 2.38 (dd, J=14.9, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.6 Hz), 158.4, 155.4 (d, JCF=241.1 Hz), 148.9, 137.1, 136.3, 130.0, 129.7, 129.2, 128.3, 128.0, 118.4 (dd, JCF=12.3, 9.5 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.5 (dd, JCF=24.7, 9.5 Hz), 114.0, 114.5 (dd, JCF=26.8, 3.7 Hz), 111.0 (d, JCF=3.8 Hz), 55.3, 47.5, 38.3, 31.8; IR (film) cm−1 1772, 1617, 1528, 1513, 1481, 1464 1249, 1176, 1118, 1100, 1033, 766, 735, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O3: 447.1. found 447.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=48.1, Rt2 (minor)=56.9 min; er=99:1.
Reaction SMILES: C([N:3](CC)CC)C.CS(Cl)(=O)=O.[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]([C@@H:25](O)[CH3:26])[CH2:21][O:22][CH2:23][CH3:24])([CH3:16])([CH3:15])[CH3:14].P(=O)(O)(O)O>C1COCC1>[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]([C@H:25]([NH2:3])[CH3:26])[CH2:21][O:22][CH2:23][CH3:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)[C@H](C)O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)[C@@H](C)N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.25 mL) and methanesulfonyl chloride (0.457 mL) were added to a solution of tert-butyl((2S,3S)-1-ethoxy-3-hydroxybutan-2-yl)carbamate obtained in the above-described Step 2 (1.06 g) in THF (20 mL), and the reaction solution was stirred at room temperature for 20 minutes. 10% Aqueous phosphoric acid solution was added to the reaction solution. Thereafter, the reaction solution was extracted with ethyl acetate and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. DMF (10 mL) and tetrabutylammonium azide (2 g) were added to the resultant residue, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was returned to room temperature, then diluted with diethyl ether, and washed with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate), and the solvent was evaporated under vacuum. THF (5 mL) and ethanol (5 mL) were added to the resultant residue, and 10% palladium on carbon (600 mg) was added under nitrogen atmosphere. The reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and the solvent was evaporated under vacuum to obtain tert-butyl((2R,3R)-3-amino-1-ethoxybutan-2-yl)carbamate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a beige solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=486.1 [M+H]+, m/z=484.4 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.85 (d, J=11.29 Hz, 1H) 3.16-3.27 (m, 2H) 3.35-3.43 (m, 1H) 4.18-4.25 (m, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.70 (d, J=8.78 Hz, 2H) 7.88-7.96 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07 Hz, 1H) 8.80 (d, J=2.38 Hz, 1H) 8.91 (d, J=2.13 Hz, 1H) 9.03 (d, J=1.88 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH3:10][C:11]1([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:10])([CH3:23])[CH:12]1[C:20]([NH2:22])=[O:21])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CC1(C)c2ccccc2NC1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)SCCC(=O)N1c2ccccc2C(C)(C)C1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 0.052 g of 3-acetylthiopropanoyl chloride in 1 ml of methylene chloride is added slowly to the mixture of 60 mg of 3,3-dimethylindoline-2-carboxamide, 87 mg of potassium carbonate and 9 ml of methylene chloride. The mixture is stirred at room temperature overnight, diluted with methylene chloride and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, water, 0.5N hydrochloric acid and water, dried, evaporated and the residue crystallized from diethyl ether, to yield the 1-(3-acetylthiopropanoyl)-3,3-dimethylindoline-2-carboxamide melting at 156°-158°.
Reaction SMILES: C(O)=O.[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].Br[CH2:19][C:20](=[O:36])[CH2:21][C@H:22]1[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]>>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:19][C:20](=[O:36])[CH2:21][C@H:22]3[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1F
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(F)c(SC)cc2c1=O

Procedure:
In the manner of Example 4, 0.462 g (0.0018 mol) of 7-fluoro-6-methylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.50 g (60%). 1H-NMR(CDCl3) 1.4-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (doublet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH--N), 8.0 (doublet, 1H, aromatic H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([NH:8][C:9](=O)[C:4]=12)=O.B.CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[CH2:9][NH:8][CH2:6]2
Reactant: COc1cccc2c1C(=O)NC2=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1CNC2
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A stirred solution of 3-methoxyphthalimide (8.95 g, 50.56 mmol) in anhydrous tetrahydrofuran (200 ml) at 0° C. was treated dropwise with a solution of borane in tetrahydrofuran (1M, 150 ml, 0.15 mol) and the resulting mixture was stirred and held at reflux for 16 hours. The mixture was cooled to 0° C., methanol (60 ml) was added dropwise followed by 5M hydrochloric acid (60 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the mixture diluted with water (250 ml) and extracted with dichloromethane (3×250 ml). The aqueous layer was basified to pH 12 or above by the addition of 5M sodium hydroxide, extracted with dichloromethane (3×250 ml) and the combined extracts were evaporated to dryness in vacuo to afford 4-methoxyisoindoline (4.44 g, 59%) as a green oil which was used without further purification. 1H NMR (DMSO-d6) 7.18 (1H, t), 6.83 (1H, d), 6.78 (1H, d), 4.07 (2H, s), 4.02 (2H, s), 3.78 (3H, s). MS: [M+H]+ 150.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[N:27]=[CH:28][N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:30]=4)[N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1COCC1.O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[N:27]=[CH:28][NH:29][CH:30]=4)[N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2c[nH]cn2)no1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
Into a flask containing (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide (0.148 g, 0.223 mmol) a solution of THF (9 ml), formic acid (1 ml, 0.223 mmol) and water (0.1 ml) was added. The resulting mixture was stirred at RT. During the next 2 days 7 ml of formic acid was added. The solvents were evaporated, acetonitrile was added and evaporated, repeating this procedure twice. The product was purified with LC/MS-trigger. Yield 42.4%. 1H-NMR (400 MHz; MeOD): δ 1.33 (d, 3H), 4.36 (dd, 1H), 4.45 (dd, 1H), 4.55-4.66 (m, 1H), 6.77 (s, 1H), 7.68-7.75 (m, 2H), 7.78-7.92 (m, 3H), 8.00 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:8]1[N:12]2[CH:13]=[C:14](F)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:7].[NH2:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([OH:29])[CH2:21][CH2:20]1.[H-].[Na+].N>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:8]1[N:12]2[CH:13]=[C:14]([O:29][C@H:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:18])[CH2:20][CH2:21]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:7]
Reactant: CN1CCC[C@@]1(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC[C@@]1(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
To a solution of Intermediate 47b (150 mg, 0.64 mmol) and Intermediate A (126 mg, 0.64 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 90 mg, 2.24 mmol) portionwise. The mixture was stirred at 60° C. for 1.5 h then allowed to cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL), then applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a brown solid (180 mg, 75%). LCMS (Method 4): Rt 0.49, m/z 378 [MH+].
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:42]1(=[O:52])[N:46]([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=3)[CH:4]=2)[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12
Reactant: CCCN(CCC)CCCc1ccc2cc(CO)ccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN(CCC)CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The compound (453 mg) obtained in Example 121-9 was added with triphenylphosphine (516 mg) and phthalimide (245 mg), and then dissolved in anhydrous THF (10 ml). The solution was added with a 40% diethylazodicarboxylate/toluene solution (0.892 ml) in an ice bath and stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (439 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Br[C:19]1[S:20][C:21]([CH3:24])=[N:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[S:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (Compound 1B, 600 mg, 1.916 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (480 mg, 2.68 mmol) in DMF (15 mL) was added potassium carbonate (794 mg, 5.75 mmol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 100% EtOAc) to afford 6-bromo-2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazole (455 mg, 1.106 mmol, 58% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (1H, d, J=1.9 Hz), 7.50-7.56 (1H, m), 7.45-7.50 (1H, m), 5.40-5.52 (1H, m), 3.77-3.88 (2H, m), 3.54-3.66 (2H, m), 2.61 (3H, s), 2.19-2.29 (2H, m), 2.07-2.17 (2H, m). LCMS (m/z)=412 (M+H)+.
Reaction SMILES: N([Si](C)(C)C)=[N+]=[N-].[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]1.[I:17]I>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[I:17][C:11]1[C:12](=[O:15])[CH2:13][CH2:14][C:9]([CH3:16])([CH3:8])[CH:10]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: II
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)C=C(I)C(=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Freshly distilled azidotrimethylsilane (4.61 mL, 34.7 mmol) was added to a stirred solution of 4,4-dimethyl-2-cyclohexen-1-one (available from Aldrich Chemical Co., 3.04 mL, 23.2 mmol) and dichloromethane (35 mL) at 0° C. under argon. The solution was stirred for 2 hours at 0° C. before adding a solution of iodine (11.8 g, 46.3 mmol) in 35 mL of pyridine and 35 mL of dichloromethane. The resulting solution was stirred for 20 hours at room temperature, diluted with ethyl acetate, and was washed with 20% aqueous Na2S2O3, and 10% aqueous HCl, and water, and brine. The solvents were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1, hexanes:ethyl acetate) to give the title compound as a yellow oil.