Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7](Br)[N:6]=1)=[O:4].[OH-:23].[Na+].[CH3:25]O>>[CH3:17][C:12]1[N:11]([C:10]2[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([O:23][CH3:25])=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:9]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: [Na+]
Product: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2 g, 5.30 mmol) was dissolved in MeOH (40 ml) and treated with 2M NaOH (20 ml) to give a suspension which was stirred at RT for 1 h to afford a clear solution. The solvent was removed in vacuo and the resulting residue was acidified to pH1 with 5M HCl. The mixture was extracted with EtOAc (200 ml) and the organic extract was dried (MgSO4) and concentrated in vacuo to afford the title compound as a dark brown solid which was used in the next step without further purification; LC-MS Rt=1.50 min [M+H]+ 315.2.1/316.2 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ14.42-12.61 (COOH, b), 8.25 (1H, s), 5.84 (2H, s), 4.13 (3H, s), 1.97 (6H, s); 19F NMR (400 MHz, DMSO-d6) δ −62.43 (CF3, s).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml), and a solution of m-chloroperbenzoic acid (130 mg) in methylene chloride (6.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 270) (180 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9](C)[N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:21]=1.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(OCCO)C>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:10]1[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:21][C:6]=2[CH:7]=[N:8][N:9]=1
Reactant: COC(CN)OC
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Solvent: CCOCCO
Product: COC(CNC1=NN=Cc2ccccc2N1)OC

Procedure:
A mixture of 2.66 grams (8.42 m moles) o=7-chloro-3-methyl-2-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine, 1.0 grams (9.32 m moles) of aminoacetaldehyde dimethyl acetal (98%) and 10 ml of 2-ethoxyethanol was stirred and refluxed under nitrogen for about 18 hours. The solvent was removed in vacuo on a rotary evaporator, and the residue was dissolved in diethyl ether. The resulting solution was washed in water, dried with magnesium sulfate and concentrated in vacuo. The dark residue was found to be a mixture and was chromatographed on a column containing 170 grams of alumina. The column was washed with benzene. The desired dimethoxyethylamino-1,3,4-benzotriazepine intermediate was obtained on elution with successive portions of methylene chloride and chloroform. The fractions were combined and evaporated to yield a red viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)cc1Cl
Yield: 93 %

Procedure:
Reaction of 2-chloro-4-fluoro-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (93% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 6.99 (1H, m, aromatic), 7.12 (1H, m, aromatic), 7.87 (1H, m, aromatic), 8.41 (1H, s, CH).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([CH2:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)COC1(CCNCC1)C2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)Cc1ccccc1CO2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-12.34 (c=0.57, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:19][C:18]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]3)=[N:17][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([C:15]#[N:16])[CH:9]=1.[C:32](=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][C:39]1([OH:43])[CH2:42][NH:41][CH2:40]1.[Li+].[OH-]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:19][C:18]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]3)=[N:17][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:43][C:39]2([CH2:38][CH3:32])[CH2:42][NH:41][CH2:40]2)=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(O)CNC1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2nc3nc(-c4ccc(F)c(C#N)c4)c(Cl)cc3[nH]2)CC1
Agent: [Cs+]
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC1(Oc2ccc(-c3nc4nc(O[C@H]5CC[C@H](C(=O)O)CC5)[nH]c4cc3Cl)cc2C#N)CNC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl trans-4-{[6-chloro-5-(3-cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}cyclohexanecarboxylate (30 mg, 0.075 mmol) in DMSO (400 μL) was added cesium carbonate (48.9 mg, 0.150 mmol) and 3-methylazetidin-3-ol (2.55 mg, 0.150 mmol). The reaction was heated to 90° C. over 4 h. The reaction was cooled, then quenched with citric acid, and extracted with EtOAc. LiOH (100 μL, 0.200 mmol) was added and the reaction was stirred overnight. The reaction was then quenched with citric acid (2 mL, 10% w/v) and extracted with EtOAc (2×5 mL). The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified via reverse phase HPLC to afford the title compound as white powder. LC-MS: calculated for C24H24ClN5O4 481.2, observed m/e: 482.1 (M+H)+ (Rt 0.8/2 min).
Reaction SMILES: Cl[Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([NH:21][Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1=C(C)C([Si](C)(C)[Si](C)(C)Cl)C(C)=C1C
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)[Si](C)(C)NC(C)(C)C)C(C)=C1C
Temperature: 25 °C

Procedure:
To a solution of 3.000 g (11.0 mmol) 1-chloro-2-(tetramethylcyclopentadienyl)-1,1,2,2-tetramethyldisilane in 50 mL ether was added 2.422 g (33.1 mmol) tertbutylamine. Precipitate formed rapidly. The slurry was stirred for several days at room temperature, then was gently heated to drive the reaction to completion. The solvent was removed, the residue was extracted with pentane, the amine hydrochloride was filtered and the pentane was removed under reduced pressure to give the product as a yellow oil. The yield was 3.150 (92.5%). Mass spec: m/e 309. 1H NMR (C6D6) δ 2.75 (s, 1H), 1.95 (s, 6H), 1.82 (s, 6H),1.08 (s, 9H), 0.51 (s, 1H), 0.24 (s, 6H), 0.16 (s, 6H); 13C NMR (C6D6) δ 135.2, 134.4, 55.2, 50.3, 34.1, 14.9 11.6, 3.3, −1.4.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:42])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([O:27]C2CCCCO2)[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]#[C:23][CH3:24])[C@H:15]([O:34]C2CCCCO2)[CH2:14][C:13]1=[O:41])(=[O:3])[CH3:2]>C(O)(=O)C.O.C1COCC1>[C:1]([NH:4][C:5](=[O:42])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:27])[C:20]([CH3:25])([CH3:26])[CH2:21][C:22]#[C:23][CH3:24])[C@H:15]([OH:34])[CH2:14][C:13]1=[O:41])(=[O:3])[CH3:2]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)NC(C)=O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)NC(C)=O

Procedure:
400 mg. of (5Z,13E)-(11R,15R)-16,16-dimethyl-9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid acetylamide is agitated for 16 hours at 25° with 12 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/2-5% methanol, 190 mg. of the title compound is obtained as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:8][CH2:9]2)=[N:3]1.[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:17][CH:18]=3)=[O:20])[CH2:8][CH2:9]2)=[N:3]1
Reactant: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cn(C)nc3-c3sccc32)cc1

Procedure:
As described for Example 5, 2,4,5,6-tetrahydro-2-methyl -6-(4-aminobenzoyl)pyrazolo[3,4-d]thieno[3,2-b]azepine is reacted with 2-methylbenzoyl chloride to give the product as crystals (from ethyl acetate), m.p. 257°-260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[F:11][C:4]1[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=[C:2]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Br)cc2[nH]cnc12
Agent: [Mo]
Agent: [C-]#[O+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)c2nc[nH]c2c1
Temperature: 155 °C
Reaction time: 0.01 h
Yield: 63 %

Procedure:
To a 2.5-5 mL microwave tube, was added 6-bromo-4-fluoro-1H-benzo[d]imidazole (160 mg, 0.744 mmol) suspended in de-gassed 1,4 dioxane (1.5 mL). To this was added trans-di(u-acetato)bis[o-(di-o-tolylphino)benzyl]di-palladium (II) (26 mg, 0.043 mmol) and molybdenum hexacarbonyl (100 mg, 0.38 mmol), along with sodium carbonate (237 mg, 2.23 mmol) dissolved in de-gassed water (2 mL). The mixture was stirred for 20 seconds and then heated at 155° C. in the microwave for 10 minutes, keeping the pressure under 16 bar. The vessel was vented before handling and left to stand overnight at room temperature. Water (2 mL) and ethyl acetate (3 mL) were added to the reaction, and then the mixture was filtered through Celite®. The filtrate was partitioned with ethyl acetate and separated. The aqueous fraction was washed with ethyl acetate once more and the combined organic layers were set aside. Another portion of water (5 mL) was added to the aqueous layer and acidified with 0.5 M HCl to pH 3; a brown precipitate was formed. The mixture was allowed to stand in the refrigerator at 4° C. for 1 hour. The mixture was filtered and washed with water to give 4-fluoro-1H-benzo[d]imidazole-6-carboxylic acid as a grey solid, (63% yield). 1H NMR (500 MHz, DMSO-d6) □ ppm 1299 (br. s., 1H) 8.47 (s, 1H) 8.02 (s, 1H) 7.52 (d, J=11.71 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>C([O-])(O)=O.[Na+].O.C1COCC1>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:13])[CH2:11][OH:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CO)(CO)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)-2-methylpropane-1,3-diol (1 g, 5.52 mmol, 1.0 eq) in sat. aq. NaHCO3 (4 mL), water (2 mL) and THF (4 mL) was added phenyl chloroformate (0.76 mL, 6.08 mmol, 1.1 eq) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (10 mL) and the solvent evaporated. The crude product was purified by CC using chloroform/MeOH (95:5) as eluent to get phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (1.1 g, 60%) as a white solid (TLC system: chloroform—MeOH; 9:1; Rf: 0.4).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([OH:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1.[H-].[Na+].O>CN(C=O)C>[CH:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:8]1[N:7]3[O:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]3=[N:18][C:9]=1[CH:10]=[N:11]2
Reactant: On1c(CCCCCl)nc2cnc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)ncc1nc3n(c12)OCCCC3
Yield: 106.2 %

Procedure:
A stirred solution of 2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-1-ol (0.167 g, 0.606 mmol) in 6 mL of anhydrous DMF was treated with 60% NaH in mineral oil (0.032 g, 0.787 mmol). After 45 minutes the mixture was poured into 20 mL of water and washed with ethyl acetate. The organic portions were combined, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.154 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:24])[CH:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30].Cl>C1COCC1.O>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:24])[CH:11]=[CH2:12]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C=CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(CC(=O)c1ccc(Br)cc1)(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Diallyl-2-(3-trifluoromethylbenzyl)malonate (1.03 g, 3.01 mmol) in anhyd THF (20 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 84 mg, 3.31 mmol) in anhyd THF (20 mL) at room temperature. The clear solution was stirred at room temperature for 30 min and then a solution of 2,4′-dibromoacetophenone (1.0 g, 3.61 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to 50° C. for 3 h (TLC control), cooled to room temperature and then water (10 mL) was added cautiously. The reaction mixture was acidified to pH 3 with 2 N hydrochloric acid and then extracted with ethyl acetate (3×30 mL). The combined extract was washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10% ethyl acetate in heptane) afforded the title compound as a colorless oil (1.23 g)
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:19])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)OCOC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Triethylamine (32.4 ml) was added to N-tert.-butyloxycarbonyl β-alanine (40 g) in N,N'-dimethylformamide at room temperature under a nitrogen atmosphere in a 1 l round bottom flask. The solution was stirred 15 minutes and chloromethyl pivalate (36.6 g) [M. Rasmussen & N. J. Leonard, J. Amer. Chem. Soc., 89, 5439 (1967)] was added dropwise at 0° C. The solution was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate, filtered, washed with water, then brine, and evaporated to give 70 g crude material which was chromatographed (silica gel) eluting with 15% ethyl acetate-hexane to give 62.5 g of product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.[C:8](Cl)(=[O:12])C(Cl)=O.[CH2:14]([N:16](CC)CC)C>C1C=CC=CC=1.CN(C)C=O>[CH3:8][O:12][N:16]([CH3:14])[C:5]([CH:3]1[CH2:4][CH:2]1[CH3:1])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC1CC1C(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL benzene and 2 mL N,N-dimethylforrnamide) at 0° C. was added 10.5 mL of oxalyl chloride and the mixture stirred at 0° C. for 30 minutes then warmed to room temperature for 30 minutes. At this time, 14.6 g of N,o-dimethylhydroxylamine hydrochloride was added followed by 41 mL of triethylamine. The mixture was stirred at room temperature for one hour then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([O:17]N3C(=O)CCC3=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4].[CH3:25][O:26][CH2:27][C:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([NH2:40])[CH2:35][CH2:34]2)([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:40][CH:36]3[C:37]4[C:33](=[CH:32][C:31]([C:28]([CH3:30])([CH3:29])[CH2:27][O:26][CH3:25])=[CH:39][CH:38]=4)[CH2:34][CH2:35]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4]
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: COCC(C)(C)c1ccc2c(c1)CCC2N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2c1cnn2C(=O)OC
Yield: 55 %

Procedure:
4-(2,5-dioxo-pyrrolidin-1-yloxycarbonylamino)-indazole-1-carboxylic acid methyl ester (0.66 g, 2.00 mmol) was added to a solution of 5-(2-methoxy-1,1-dimethyl-ethyl)-indan-1-ylamine (0.46 g, 2.1 mmol) and diisopropylethylamine (0.26 g, 2.00 mmol) in DMF (6 mL) under nitrogen atmosphere at ambient temperature. After 30 minutes the mixture was diluted with water (6 mL). The resulting precipitate was filtered off, washed with aqueous MeCN twice and dried to obtain desired product (0.48 g, 55%). NMR (DMSO-d6): 8.82 (s, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.88 (d, J 7.5 Hz, 1H), 7.69 (d, J 8 Hz, 1H), 7.52 (t, J 8 Hz, 1H), 7.24 (m, 2H), 6.70 (d, J 7.5 Hz, 1H), 5.18 (m, 1H), 4.02 (m, 3H), 3.38 (s, 2H), 3.20 (s, 3H), 3.10-2.72 (m, 2H), 2.42 (m, 1H), 1.83 (m, 1H), 1.14 (s, 6H). MS (DCI): 437 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53 mg, 0.192 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (55 mg, 0.288 mmol), triethylamine (0.061 mL, 0.441 mmol), HOBT (44.1 mg, 0.288 mmol), and EDC (55.2 mg, 0.288 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature for six hours. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:12])[CH3:11]>>[OH:3][C:1]([CH3:2])([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12]
Reactant: CC(=O)c1ccncc1
Reactant: CCCCCOC(C)=O
Product: CCCCCOC(=O)CC(C)(O)c1ccncc1
Yield: 74 %

Procedure:
The reaction of 4-acetylpyridine (24.2 grams, 0.2 mole) with the enolate of amyl acetate (26.0 grams, 0.2 mole) is carried out as described in Example I. Distillation yields 37.2 grams (74%) of the pure product b.p. 102°-105° C. (air bath temperature) at 0.05 mm Hg.