Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][C:23](O)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(N(CC)CC)C.[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:22][C:23]([N:45]4[CH2:46][CH2:47][C:42]5([O:41][CH2:40][CH2:39][O:38]5)[CH2:43][CH2:44]4)=[O:24])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a mixture of 20.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid and 250 ml of dimethylformamide were added 16 ml of triethylamine, 10.4 g of 1,4-dioxa-8-azaspiro[4.5]decane and 16 ml of diethyl phosphorocyanide, and the mixture was stirred for 20 minutes. After addition of water, the resulting crystalline precipitate was collected by filtration, washed with water and dried to give 26.4 g of crude crystals. Recrystallization from methylene chloride-ethyl acetate gave 27.1 g of colorless crystals melting at 238°-239° C.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH3:29])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([C:7]2[O:8][C:9]3[C:17]([O:18][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=4[CH3:29])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: O=c1cc(N2CCOCC2)oc2c(O)cccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1Oc1cccc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
To a mixture of 2-(4-morpholinyl)-8-hydroxy-4H-1-benzopyran-4-one (77 mg, 0.31 mmol), 4-fluoro-2-methylphenylboronic acid (48 mg, 0.31 mmol) and copper acetate (57 mg, 0.31 mmol) suspended in dichloromethane (3.1 ml) was added triethylamine (216 uL, 1.56 mmol) and the mixture was stirred at room temperature for 24 h. The solvent was removed and the product chromatographed through a silica column with 0-10% methanol in dichloromethane to yield an off white solid (37 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH:16]3[CH2:21][CH2:20][C:19]4([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=O.O1CCCC1.[AlH4-].[Li+]>>[CH2:20]1[C:19]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17][CH:16]([O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13]3)[CH2:21]1
Reactant: COC(=O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(Spiro[5.5]undec-3-yloxy)-naphthalene-2-carboxylic acid methyl ester (0.374 g, 0.00106 mol) in tetrahydrofuran (10 mL, 0.1 mol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (3.18 mL, 0.00318 mol) at 0° C. The reaction was then allowed to warm to room temperature while stirring for 2 h, Rochele's salt was then added and stirred the resulting mixture was stirred at room temperature for 1 h. After extraction with ethyl acetate, and solvent removal under vacuum, (6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methanol was obtained as a while solid (0.28 g, 83%). ESI-MS: 307.5 (M+H)+. 100%). 1H NMR (400 MHz, CDCl3) δ 7.74-7.70 (m, 3H), 7.44 (d, J=10.0 Hz, 1H), 7.16 (m, 2H), 4.81 (s, 2H), 4.40 (m, 1H), 1.94-1.26 (m, 18H).
Reaction SMILES: C([N:14]1[C@:22]2([CH2:24][OH:25])[O:23][C@:15]1([C@H:18]([C@@H:20]2[OH:21])[OH:19])[CH2:16][OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>CO.O.[Pd].[C]>[NH:14]1[C@:22]2([CH2:24][OH:25])[O:23][C@:15]1([C@H:18]([C@@H:20]2[OH:21])[OH:19])[CH2:16][OH:17]
Reactant: [H][H]
Reactant: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: OC[C@]12N[C@](CO)(O1)[C@@H](O)[C@@H]2O
Yield: 91 %

Procedure:
A mixture of N-benzhydryl-2,5-anhydro-2,5-imino-D-glucitol (Formula XI, R3 =Ph2CH 8.40 g, 25.5 mmol) and 0.42 g of 20% PD(OH)2 /carbon in 100 mL of MeOH was set shaking on a Parr apparatus under 60 psig of hydrogen overnight. This solution was then filtered and concentrated. Hexane (ca. 300 mi) was added, and the solvent was then removed from a white solid, which was washed with ca. 200 mL of hexane. The product was recrystallized from ETOH/CH3CN to give 3.79 g (91%) of white needles, mp 139°-142.50° C. (corrected). Both 1H and 13C NMR in D2O supported the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[N:7]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=2)[N:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(Br)nc(N)c1=O
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)nc(N)c1=O
Yield: 17.9 %

Procedure:
A solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), Pd(PPh3)4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95° C. for 12 h under N2. The mixture was concentrated and purified by silica gel chromatography (PE:EA=3:2) to give the title compound (20.0 mg, 18%). 1H NMR (DMSO-d6 400 MHz): δ 8.35 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 280.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17](Br)=[C:16]([CH3:24])[CH:15]=1)=[O:12])[CH3:2].[C:26]([O:30][C:31](=[O:54])[NH:32][C:33]([C:35]1[S:36][C:37]([S:52][CH3:53])=[C:38]([S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](B(O)O)[CH:44]=2)(=[O:42])=[O:41])[CH:39]=1)=[NH:34])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH3:24])[C:17]([C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([S:40]([C:38]3[CH:39]=[C:35]([C:33]([NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:54])=[NH:34])[S:36][C:37]=3[S:52][CH3:53])(=[O:41])=[O:42])[CH:48]=2)=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A 25 mL round bottom flask was charged with 6-[3-(4-bromo-3-methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester (110 mg, 0.264 mmol, Example 278: step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (234 mg, 0.529 mmol, Example 140: step a), aqueous Na2CO3 (2M, 1.06 mL, 2.12 mmol), ethanol (1.06 mL, anhydrous) and toluene (2.11 mL, anhydrous). A stir bar was added, the solution was degassed for 10 min, and Pd(PPh3)4 (76 mg, 65.8 μmol) was added. The reaction mixture was stirred under Ar at 80° C. for 5 hrs, then cooled to rt. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC (50–100% EtOAc/hexanes) afforded the title compound as a brown oil (74 mg, 37%). ESI-MS (m/z): Calcd. for C33H41N5O9S3: 748.2 (M+1); found: 747.8.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Br:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:11]([N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH3:14])=[O:12]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:11]([N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH3:14])=[O:12]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reactant: N#CCCCBr
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
CsCO3 (5.17 g, 15.87 mmol) was added to a solution of 4-bromo-butyronitrile (0.63 mL, 6.35 mmol) and 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (1.80 g, 5.29 mmol, Step 3B) in DMF (20 mL). The mixture was stirred at room temperature for approximately 16 hrs and was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and was dried over MgSO4. The organic filtrate was evaporated to yield 3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide as a light yellow solid (2.0 g). MS [M+H]+: 408.9; tR=2.39 min. (method 1)
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]2[CH:21]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[C:20](=O)[C:19]3[C:18]([C:29]([O:31]CC)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13]2)[CH:8]=[CH:9][C:10]=1[F:11])=[O:4].O.[NH2:36][NH2:37]>CO>[F:11][C:10]1[CH:9]=[CH:8][C:7]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:29](=[O:31])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:21]2[C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:34])=[O:4]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)c(C(=O)N(C)C)c1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1cc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (130 mg) in hydrazine monohydrate (85%, 2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain the title compound (30.0 mg, yield 30%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.72 (s, 3H), 2.97 (s, 3H), 3.43 (s, 3H), 4.67-4.70 (d, J=10.8 Hz, 1H), 4.95-4.97 (d, J=10.8 Hz, 1H), 6.72-6.73 (d, J=1.2 Hz, 1H), 6.89-6.89 (d, J=0.8 Hz, 1H), 7.15-7.23 (m, 2H), 7.34-7.41 (m, 3H), 7.48-7.49 (m, 1H), 7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[C:33]([C:30]1([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5](=[O:6])[C:4]([F:20])([F:21])[F:3])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)#[N:34]
Reactant: O=C(NCCc1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: N#CC1(c2ccc(CBr)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
20 mg (0.51 mmol) of a sodium hydride suspension in mineral oil (60%) were suspended in 4.2 ml DMF. At 0° C. 134 mg (0.42 mmol) of 2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide dissolved in 1 ml DMF were added dropwise and the reaction mixture was stirred for 30 min at 0° C. Then 100 mg (0.42 mmol) of 1-(4-bromomethyl-phenyl)-cyclopropanecarbonitrile dissolved in 1 ml DMF were added and the reaction mixture was stirred at 0° C. for 3 h. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/diethyl ether=1:1) to yield 135 mg (72%) of N-[4-(1-cyano-cyclopropyl)-benzyl]-2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide as a yellow viscous oil. MS (ISP) 458.4 (M+NH4)+. MS (ISP). 499.1 (M+OAc)−.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:18][CH2:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:8][C:4]=1[C:5]([NH:18][CH2:19][C:20](=[O:21])[NH:22][CH:23]([CH3:25])[CH3:24])=[O:7]
Reactant: CC(C)NC(=O)CN
Reactant: C[C@@H](CO)COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CNC(=O)c1cc(OC[C@@H](C)CO)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid hydrochloride (200 mg, 0.76 mmol), 2-amino-N-isopropylacetamide*HCl (INTERMEDIATE I.1) (105 mg, 0.70 mmol) and triethylamine (0.23 mL, 1.68 mmol) in DMF (5 mL) was stirred at room temperature for 5 min. EDC (176 mg, 0.92 mmol) and HOBt (124 mg, 0.92 mmol) were added and stirring continued at room temperature for 16 h. The mixture was partitioned between ethyl acetate and sat. NaHCO3 (aq.) and the aqueous extracted with additional ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE VIII.1) was used directly in the next reaction.
Reaction SMILES: [OH2:1].Cl.Cl.C1(C[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3OC)[CH2:18][CH2:17]2)C2C(=CC=CC=2)CCO1.[CH:30](OCC)=[O:31]>>[CH:15]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[CH:24][C:25]([O:31][CH3:30])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1)=[O:1]
Reactant: CCOC=O
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: O
Agent: Cl
Product: COc1ccc(N2CCN(C=O)CC2)cc1

Procedure:
A mixture of 1-(4-methoxyphenyl)piperazine (XI, 7.41 g) and ethyl formate (108 ml) is stirred at reflux for 3 hr. The mixture is then cooled, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give 1-formyl-4-(4-methoxyphenyl)piperazine (VI), NMR (CDCl3) δ3.05, 3.54, 3.71, 3.78, 6.88, 8.10.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)#[C-:2].[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(Cl)Cl>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([C:3]3[N:1]=[CH:2][O:31][C:30]=3[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=3)=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: Cc1cccc(C=O)n1
Reactant: [C-]#[N+]C(c1ccc2c(c1)OCO2)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2ocnc2-c2ccc3c(c2)OCO3)n1
Yield: 22.5 %

Procedure:
A solution of 5-[isocyano-(toluene-4-sulfonyl)-methyl]-benzo[1,3]dioxole (40 mg, 0.127 mmol), 6-methyl-pyridine-2-carbaldehyde (15.4 mg, 0.127 mmol, 1 equiv) and potassium carbonate (26 mg, 0.19 mmol, 1.5 equiv) in methanol (1 mL) was shaken at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, and resulting residue was partitions between water (1 mL) and methylene chloride (1 mL). The organics were purified by silica gel chromatography (20% acetone in hexane) to provide 2-(4-Benzo[1,3]dioxol-5-yl-oxazol-5-yl)-6-methyl-pyridine as a colorless oil (8 mg, 22%) [LCMS: Rt-2.34 min; M+H=281.2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[N:33]([C:34]([C:36]4[C:37]([CH3:41])=[N:38][O:39][CH:40]=4)=[O:35])[CH2:32][CH2:31][N:10]2[C:11](=[O:30])[C:12]2[N:13]([C:15]4[N:20]=[C:19]([CH3:21])[N:18](COCC[Si](C)(C)C)[C:16]=4[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.COC1C=CC([C@]23N(C(C4C(C)=NOC=4)=O)CCN2C(=O)C2N(C4N(COCC[Si](C)(C)C)C=NC=4C=2)C3)=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[N:33]([C:34]([C:36]4[C:37]([CH3:41])=[N:38][O:39][CH:40]=4)=[O:35])[CH2:32][CH2:31][N:10]2[C:11](=[O:30])[C:12]2[N:13]([C:15]4[NH:20][C:19]([CH3:21])=[N:18][C:16]=4[CH:17]=2)[CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@]23Cn4c(cc5c4nc(C)n5COCC[Si](C)(C)C)C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: COc1ccc([C@@]23Cn4c(cc5ncn(COCC[Si](C)(C)C)c54)C(=O)N2CCN3C(=O)c2conc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C23Cn4c(cc5nc(C)[nH]c54)C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Either (5aS)-5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(1H)-one or its regioisomer (5aS)-5a-(4-methoxyphenyl)-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(3H)-one (27 mg, 0.048 mmol) similarly prepared according to steps (a), (b) and (c) was dissolved in dichloromethane (0.9 mL) and treated with trifluoro acetic acid (2.1 mL). The mixture was stirred at room temperature. After one hour the LCMS indicated complete deprotection. The mixture was then concentrated in vacuo and the residue obtained purified by flash chromatography using the biotage SP4 (0-5% MeOH gradient in EtOAc) to yield either 5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(1H)-one (2) or its regioisomer 5a-(4-methoxyphenyl)-2-methyl-6-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5a,6,7,8-tetrahydro-5H-imidazo[1,2-a]imidazo[4′,5′:4,5]pyrrolo[1,2-d]pyrazin-10(3H)-one (8.5 mg, 40% yield). ESI-MI m/z [M+H]+ 447.09. 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 1H), 8.46 (br s, 1H), 7.43 (br d, J=8.9 Hz, 2H), 6.82-6.73 (m, 2H), 6.69 (s, 1H), 6.05 (d, J=13.1 Hz, 1H), 4.46 (d, J=12.8 Hz, 1H), 4.35 (ddd, J=10.7, 8.8, 4.6 Hz, 1H), 4.00 (td, J=8.9, 5.6 Hz, 1H), 3.83 (tdd, J=13.2, 9.8, 6.6 Hz, 2H), 3.72 (s, 3H), 2.52 (s, 3H), 2.42 (d, J=0.5 Hz, 3H). The compounds in Table 1 were similarly prepared by reference to the general method(s) and/or synthetic examples.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-amino-5-nitropyridine (4.0 g, 28.8 mmol ) in dichloromethane (15 ml) were added 176 mg (31.6mmol) of 4-N,N'-dimethylaminopyridine (DMAP), 4.41 ml of triethylamine (31.6 mmol) and 2.16 ml (31.6 mmol) of acetyl chloride in turn, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous solution of potassium carbonate was added to the mixed suspension to neutralize it. Extraction with chloroform was repeated three times, and the extract was dried over magnesium sulfate. The solvent was removed, and the residue was subjected to silica gel column chromatography (eluent: chloroform). Recrystallization from chloroform-hexane gave 2.14 g of the intended product as a flesh-colored powder (yield: 49%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:21][N:20]([CH3:22])[C:12]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CN(C)C1(c2cccs2)CCNCC1
Yield: 98 %

Procedure:
HCl gas was passed through a solution of 6 g (1 eq) tert-butyloxycarbonyl-4-(dimethylamino)-4-(thiophen-2-yl)piperidine in 120 ml chloroform at 0° C. for 1 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the solvent was removed under reduced pressure and 5.3 g (98%) of product were obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11]OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:11]
Reactant: NOS(=O)(=O)O
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: O
Product: N#Cc1cc(Cl)ccc1O
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.3 %

Procedure:
5-chloro-2-hydroxybenzaldehyde (300 g, 1.92 mol) and hydroxylamine-O-sulfonic acid (260 g, 2.30 mol) were suspended in water (4.5 L) at room temperature, which was then stirred at 60° C. for 7 hours. Water (3 L) was added to the reaction mixture, which was then cooled with ice, followed by filtering a crystal before further washing with water (1.5 L). The precipitated crystal was suspended in water (1.5 L), filtered, washed with water, and subjected to tray drying at 50° C. for 22 hours to obtain 272 g of the title compound (white crystal, yield: 93%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C([N:24]([CH:27]([CH3:29])C)[CH2:25]C)(C)C.Cl.N1CCC1>ClCCl.C(O)C>[N:24]1([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=3[F:11])[N:6]=2)[CH2:25][CH2:29][CH2:27]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCC3)nc2c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.11 g, 0.38 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and ethanol (7 ml), then diisopropylethylamine (0.21 ml, 1.23 mol) and azetidine hydrochloride (71.5 mg, 0.76 mmol) were added. After stirring at an external temperature of about 60° C. for 3 hours, the reaction liquid was concentrated under reduced pressure and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a colorless solid (85 mg, 74%).