Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH:28]4[CH:26]([CH:27]4[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:51][CH2:52]Cl>C(#N)C>[N:1]1([C@:2]23[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:35])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH2:29][CH:28]5[CH:26]([CH:27]5[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:52][CH2:51]1
Reactant: ClCCCl
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 130 °C

Procedure:
To a flame dried 75 mL thick-walled resealable vessel was placed ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (0.453 g, 0.809 mmol) and flame dried potassium phosphate (0.859 g, 4.05 mmol), followed by 1,2-dichloroethane (24 mL) and acetonitrile (12 mL). The reaction mixture was flushed with nitrogen, sealed, and warmed to 130° C. for 36 hours. The crude reaction mixture was cooled to room temperature and filtered through a short bed of silica gel, washed with ethyl acetate to obtain a very pale orange solution, it was evaporated to dryness. White solid was obtained (0.3 g, 0.512 mmole, 63.3%), and used as it is. MS: m/e 586.55 (M+H)+, 2.791 min.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1.N1CCCN2CCCN=C12>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:2]1
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1C=CCC1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
Tetrahedron Letters 2005, 46, 6875-6878. To a solution of cyclopent-2-enone (99.82 g, 1216 mmol) and dimethyl malonate (560 mL, 4887 mmol) in dry toluene (1000 mL) was added 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (5.10 g, 36.6 mmol). The reaction was stirred at room temperature under nitrogen for 16 hrs, then concentrated under reduced pressure to ˜½ volume. The crude product was filtered through a short path of silica gel (3.5×4 cm), eluting with ethyl acetate. The filtrate was concentrated under vacuum pump rotary evaporation (70-75° C. water bath) for 2 hrs, affording the target compound (247.7 g, 1098 mmol, 90% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.76 (3 H, s), 3.74 (3 H, s), 3.37 (1 H, d, J=9.46 Hz), 2.80-2.91 (1 H, m), 2.49 (1 H, dd, J=18.31, 7.63 Hz), 2.29-2.37 (1 H, m), 2.15-2.28 (2 H, m), 2.00 (1 H, ddd, J=18.46, 10.99, 1.37 Hz), 1.58-1.71 (1 H, m).
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9]([Cl:27])=[CH:10][C:11]([F:26])=[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[C:7]=2[O:6][C:5]=1[CH3:28])(=O)[CH3:2].C([O-])(=O)C.[K+].Cl.[CH3:35][O:36][NH2:37]>CO>[Cl:27][C:9]1[C:8]2[C:4]([C:1](=[N:37][O:36][CH3:35])[CH3:2])=[C:5]([CH3:28])[O:6][C:7]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CC(=O)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
50 ml of methanol was added to 0.4 g (1 mmol) of 3-(3-acetyl-4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, 0.5 g (5 mmol) of potassium acetate and 0.5 g (6 mmol) of methoxyamine hydrochloride, followed by stirring at room temperature for 12 hours and further for 8 hours under heating and refluxing. After completion of the reaction, methanol was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed sequentially with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.4 g (yield: 100%) of the desired product as pale yellow crystals. Melting point: 65-67° C., 1H-NMR (solvent: CDCl3): 1.54 (1H,s), 2.21(3H,s), 2.35(3H,s), 3.59(3H,s), 3.91(3H,s), 6.41(1H,s), 7.16(1H,d)ppm
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(CC)CC>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 94.5 %

Procedure:
Methanesulfonyl chloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl 4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et3N (10.8 mL, 77.4 mmol) in THF (230 mL). The resulting suspension was stirred at room temperature for 43 h. The reaction mixture was filtered and the filtrate was concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc) afforded the title compound (7.08 g). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85-1.92 (m, 2H), 1.24 (t, 3H); MS 210 (M++1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ncc[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1nccn1Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a solution of 1H-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) and potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 mL) at 0° C. was added dropwise (bromomethyl)benzene (493 mg, 2.88 mmol). The mixture was stirred at 40° C. for 4 hr. Then the mixture was filtrated, evaporated to remove the acetonitrile from the filtrate, added EtOAc to extract the residues, and washed the extract with brine and water. The organic layer was dried with anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (EtOAc:hexane=1:9) to obtain the title compound (430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=O)=[CH:21][CH:20]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(OCC(F)(F)C(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:26]2[N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:34])([F:15])[CH:31]([F:32])[F:33])=[CH:24][CH:23]=3)[CH:29]=[CH:28][N:27]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(OCC(F)(F)C(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 11.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.72 g of 1-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-2(1H, 3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (0.21 g) and 0.14 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1>>[CH3:19][O:20][C:21]1[C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)n1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2,6-dimethoxypyridine-3-amine as the starting materials.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[CH:19]1([C:13]2[N:8]3[CH:9]4[CH2:10][CH:11]([C:5]5[CH:4]=[C:3]([F:23])[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:27]6[CH:26]=[C:25]([CH3:24])[O:29][N:28]=6)[CH3:31])=[CH:22][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:12]4)[CH2:20][CH2:21]1
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)C2CC(C2)n2c-3nc(C(N)=O)c2C2CC2)no1

Procedure:
Similar to as described in General Procedure E, 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound. MS+447.2. 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=7.5 Hz, 1H), 7.45 (br s, 1H), 7.26 (d, J=10.1 Hz, 1H), 6.92 (br s, 1H), 6.57 (s, 1H), 6.35 (s, 1H), 5.26 (m, 1H), 3.68 (m, 1H), 314 (m, 1H), 2.41 (s, 3H), 1.82 (s, 3H), 1.77-1.61 (overlapping m, 3H), 0.99 (m, 1H), 0.68 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:19][C:10]1([OH:18])[CH2:11][P:12]([O:16][CH3:17])([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1>[CH2:1]([O:8][C@H:9]([C@H:22]([C@@H:21]([C@@H:20]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:19])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:10]([OH:18])[CH2:11][P:12]([O:14][CH3:15])([O:16][CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(C[C@H](O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (13.8 g) in tetrahydrofuran (140 ml) was added sodium borohydride (1.4 g). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate (500 ml) and water (300 ml). The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography (550 ml) with tolueneacetone (2:1). The elute was concentrated under reduced pressure and dried under reduced pressure to give a mixture (12.4 g) of 3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-glycero-D-gulo-heptitol and 1,3,4,5-tetra-O-benzyl-7-deoxy-7-(dimethoxyphosphoryl)-D-glycero-L-gulo-heptitol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=CC=2C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][I:23]>CC(C)=O>[I-:23].[CH2:1]([N+:8]1([CH3:22])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][CH2:20][CH2:19][CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CCC1=O
Reactant: CI
Solvent: CC(C)=O
Product: CCCCC1C[N+](C)(Cc2ccccc2)CCC1=O
Product: [I-]
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of 1-benzyl-3-o-tolyl-piperidine-4-one (5165 mg) in acetone (25 ml) was slowly added methyl iodide (3048 mg) at room temperature. The solution was stirred at room temperature over night. A white solid precipitated and was filtered off. The solid was washed four times with 50 ml of acetone and dried under reduced vacuum. The filtrate was evaporated and the residue was stirred with ethyl acetate. The white solid was filtered, washed with ethyl acetate and dried under vacuum. The two solids were combined to yield 1-benzyl-3-butyl-1-methyl-4-oxo-piperidinium iodide as a yellowish solid (4400 mg). MS (ESI): 294.3 (M−I−).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][O:20]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCCc1ccccc1COC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCCc1ccccc1CO)c1ccc([N+](=O)[O-])cc1
Yield: 92.3 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-[2-(4-nitrobenzoyloxymethyl)phenyl]ethane (24 g) was added to a solution of 300 ml of methanol, 2.6 g of sodium hydroxide and 100 ml of water. The mixture was refluxed for 1 hour. After the reaction, the solvent was distilled off, and water was added. The crystals that precipitated were collected by filtration, washed with water, and recrystallized from ethanol-n-hexane to afford 14.8 g of 1-(4-nitrobenzoyl)amino-2-(2-hydroxymethylphenyl)ethane having a melting point of 137.3° to 137.6° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxyl)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [CH:1](O)=O.[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH2:15])[CH:8]=[CH:7][CH:6]=1.N>O>[NH:4]1[C:5]2=[C:14]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH:10]=[CH:11][CH:12]=[C:13]3[N:15]=[CH:1]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=CO
Agent: N
Solvent: O
Product: C1=Nc2cccc3cccc(c23)N1
Temperature: 100 °C

Procedure:
95.0 g of formic acid are added to 15.8 g of 1,8-diaminonaphthalene and the mixture is stirred at reflux temperature (100° C.) for 1 hour. Then 200 ml of water are added, and the mixture is cooled to 15-20° C. and adjusted to a pH of 8.5 by addition of 25% strength by weight ammonia. It is cooled to 10° C. and subsequently stirred at 10° C. for 1 hour. The product which is precipitated is isolated by filtration, washed with water and dried in vacuo at 800 C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCNC2)cn1
Reactant: O=CCN1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A vial was charged with (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 234, 800 mg, 1.3 mmol) and morpholin-4-yl-acetaldehyde monohydrate hydrochloride (270 mg, 1.47 mmol) in methanol (10 mL). MP-cyanoborohydride (850 mg, 2.0 mmol) beads were added and the resulting mixture was allowed to stir at room temperature overnight. The mixture was filtered and the beads were washed with more methanol. The filtrate was concentrated and purified by Analogix SF15-24 g in DCM/methanol system to give a light yellow solid (380 mg, 45.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][OH:15])[CH:3]=1>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1cc(Br)ccc1-c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=Cc1cc(Br)ccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
IBX (7.45 g, 26.6 mmol) was added to (4-bromobiphenyl-2-yl)methanol (3.5 g, 13.30 mmol) in dmso (40 mL) and stirred at 60° C. for 2 hours. The reaction was cooled in an ice bath and diluted with water and diethyl ether. The ether layer was washed with brine, dried over MgSO4, filtered and evaporated to give 4-bromobiphenyl-2-carbaldehyde (3.32 g, 12.71 mmol, 96% yield) as an orange oil. LCMS: rt=1.66 min.; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-7.39 (m, 3H) 7.43-7.58 (m, 3H) 7.76 (dd, j=8.16, 2.13 Hz, 1H) 8.15 (d, J=2.01 Hz, 1H) 9.91 (s, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:21][CH2:20][N:19]4[C@H:14]([CH2:15][O:16][CH2:17][C:18]4=[O:22])[CH2:13]3)[CH2:9]2)C=CC=CC=1.C(O)=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:21][CH2:20][N:19]3[C@H:14]([CH2:15][O:16][CH2:17][C:18]3=[O:22])[CH2:13]2)[CH2:9]1
Reactant: O=C1COC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CCO
Product: O=C1COC[C@@H]2CN(C3CNC3)CCN12
Temperature: 120 °C

Procedure:
(9aS)-8-[1-(Diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one (85 mg, 0.22 mmol) was dissolved in ethanol (18 mL). The solution was transferred to a 25 mL vial, which contained ethanol (2 mL), 10% palladium on carbon (0.1 g), formic acid (0.1 g, 2.2 mmol) and ammonium formate (0.2 g, 3.17 mmol). The mixture was heated for 5 min at 120° C. using microwave single node heating. The catalyst was filtered off and the solution of crude (9aS)-8-azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one was used in the next step without purification and quantification.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chlorophenyl isocyanate (0.31 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a tan solid (0.39 g, 56% yield), mp=88–90° C.; MS (−) ESI m/z=334 (M+H)+; [α]D25=+22.8° (c=1, EtOH).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:7]=2[C:6]1=O)C.[NH:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[NH:21]>>[F:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:22][C:20]([NH:19][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]=3[C:7]=2[CH:16]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Product: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2cc(F)ccc2N1

Procedure:
In a manner similar to that described for Method H, 4-dimethylaminomethylene-7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-f) and 4-guanidinobenzoic acid were converted to I-5 (98%): HRMS Calcd. for C19H13FN4O3: 365.1049, Found 365.1069.