Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[O:21][CH:20]1[OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)[O:21][C:20]1=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(COCC2(COCc3ccc(OC)cc3)OC(O)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(COCC2(COCc3ccc(OC)cc3)OC(=O)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of oxalyl dichloride (1.9 mL, 23 mmol) in dichloromethane (65 mL) at −78° C. was added a solution of dimethyl sulfoxide (3.3 mL, 47 mmol) in dichloromethane (5 mL) and the resulting solution was stirred at this temperature for 30 minutes. A solution of starting material ((3R,4S,5S)-3,4,5-tris-benzyloxy-6,6-bis-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-2-ol, (I-1d, 5.6 g, 7.7 mmol) in dichloromethane (15.0 mL) was then added dropwise and the resulting mixture was stirred for 30 minutes allowing the temperature to rise to −60° C. Triethylamine (9.7 mL, 69.5 mmol) was added dropwise and the mixture allowed to warm up to 0° C. over 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel eluting with a gradient of 0 to 60% ethyl acetate in heptane to produce the product (I-1e) (4 g, 72% yield).
Reaction SMILES: [F:1]/[C:2](=[CH:23]\[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)=[C:26]([O:36][CH3:37])[CH:25]=1)/[C:3]([NH:5][NH:6][C:7](=O)[CH:8]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1)[CH2:9][CH2:10][CH2:11][Cl:12])=[O:4]>P(Cl)(Cl)(Cl)=O>[Cl:12][CH2:11][CH2:10][CH2:9][CH:8]([C:7]1[O:4][C:3](/[C:2](/[F:1])=[CH:23]/[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)=[N:5][N:6]=1)[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1
Reactant: COc1cc(/C=C(\F)C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C(\F)c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid N′-{(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (84 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for 7.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 81 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][N:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].Cl.[CH3:36][O:37][NH2:38].N#N>CCO>[CH3:36][O:37]/[N:38]=[CH:24]/[C:23]1[CH:26]=[CH:27][C:20]([O:19][C:16]2[CH:17]=[N:18][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Reactant: CON
Agent: Cl
Agent: N#N
Solvent: CCO
Product: CO/N=C/c1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 6-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)oxy)nicotinaldehyde (101) (60 mg, 0.126 mmol) in dry EtOH (1.265 mL) was added O-Methylhydroxylamine hydrochloride (21.13 mg, 0.253 mmol) in a 5 mL vial under N2 atmosphere. The reaction mixture was stirred at RT overnight. The reaction mixture was evaporated and the crude residue was purified on silica (ISCO, 12 gram column, gradient to 75% EtOAc/Hexanes over 25 minutes) to afford the title compound. Yield=18 mg (26.9%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.3 Hz, 1H), 8.11 (dd, J=8.7, 2.4 Hz, 1H), 8.04 (s, 1H), 7.67 (dd, J=8.7, 2.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.36 (td, J=8.8, 6.4 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.83-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.63 (d, J=14.3 Hz, 1H), 5.10 (d, J=14.3 Hz, 1H), 3.99 (s, 3H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.20 (d, J=17.7 Hz), −103.89 (ddd, J=31.3, 21.1, 13.6 Hz), −108.11 (d, J=9.5 Hz), −110.21 (d, J=45.0 Hz), −110.90 (d, J=45.0 Hz). MS (ESI): m/z 504.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][CH:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:9]3[CH2:19][CH2:18][CH2:17][CH:10]3[C:11]=2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:16][O:15][C:13]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:9]3[CH2:19][CH2:18][CH2:17][CH:10]32)=[C:5]([CH2:3][OH:2])[CH:14]=1
Reactant: COC(=O)c1cc(OC)cc2c1CC(c1ccc(OC)cc1)C1CCCC21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2Cc3c(CO)cc(OC)cc3C3CCCC23)cc1
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
Combine 8-Methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-6-carboxylic acid methyl ester (0.16 g, 0.44 mmol), lithium aluminum hydride (0.08 g, 1.31 mmol) in tetrahydrofuran (10 ml) and stir for 2.5 hours. Add water (0.05 g), add 15% NaOH (0.05 g), add water (0.15 g) and stir 30 minutes. Add EtOAC, filter ppt. Rinse organic layer with water, then 1 n HCl, then water. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield the titled compound (0.153 g, 100%). H NMR (CDCl3): 7.22 (d, J=8.8, Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.71(s, 1H), 4.7 (s, 2H), 3.81 (s, 3H), 3.45 (m, 1H), 3.1 (m, 1H), 2.85 (m, 2H), 2.55 (m, 1H), 2.2 (m, 1H), 1.6-1.3 (m, 5H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCCCCCCCBr
Reactant: O=[N+]([O-])c1cc(CCNCc2ccccc2)ccc1OCc1ccccc1
Product: O=[N+]([O-])c1cc(CCN(CCCCCCCCN(CCc2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
Similarly, by employing 1,8-dibromooctane in the above condensation with N-benzyl-4-benzyloxy-3-nitrophenethylamine as described above there is obtained the corresponding N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-ethyl]-octamethylenediamine which is carried through the same sequence of reactions, namely reduction with Raney nickel and hydrogenation with palladium-on-carbon, to yield N,N'-bis[2-(3-amino-4-hydroxyphenyl)-ethyl]-octamethylenediamine.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][C@H:31]([C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][C@@H:31]([OH:32])[C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:38]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Reactant: CNC[C@@H](O)c1ncccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C[C@@H](O)c2ncccn2)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A mixture of N-(4-fluorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (216 mg, 0.570 mmol), (1R)-2-(methylamino)-1-pyrimidin-2-ylethanol dihydrochloride (Preparation 104, 155 mg, 0.686 mmol) and diisopropylethylamine (600 μL, 3.44 mmol) in dry DMF (10.0 mL) was stirred at 60° C. for 20 hours. The solution was then diluted with water (75 mL). The resulting precipitate was collected by filtration and the collected solid was dried at 60° C. in vacuo, providing 209 mg of a tan solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43]C(C)(C)C)=O)[CH2:37][CH2:36]1>C(OCC)(=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][CH:35]5[CH2:36][CH2:37][N:38]([C:41](=[O:43])[CH2:1][N:6]([CH3:12])[CH3:7])[CH2:39][CH2:40]5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h

Procedure:
Using the general procedure for amide bond synthesis, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid was first reacted with tert-butyl 4-aminopiperidine-1-carboxylate. The product was diluted to ethyl acetate, washed by sodium bicarbonate aqueous solution and brine. Organic extract was dried and concentrated to a residue. It was then dissolved in a mixture of TFA and MeOH (1:1) and stirred for 1 h. After which, it was concentrated in vacuo, separated between ethyl acetate and sodium bicarbonate aqueous solution. Organic extract dried and concentrated to a residue, which was subjected to amide bond synthesis with 2-(dimethylamino)acetic acid. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (m, 2H) 1.61 (m, 4H) 1.73 (br. s., 4H) 1.99 (s, 3H) 2.19 (s, 6H) 2.73 (m, 1H) 3.14 (m, 3H) 3.80-3.95 (m, 3H) 3.95-4.20 (m, 4H) 4.26 (m., 1H) 4.81 (d, J=8.1 Hz, 1H) 7.19 (d, J=6.8 Hz, 1H) 7.92-8.10 (m, 2H) 8.18-8.35 (m, 2H). [M+H] calc'd for C30H39F3N8O4, 633. found 633.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])[N:4]=1.C(Cl)(Cl)(Cl)[Cl:23]>>[Cl:23][C:11]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C(c1ccccc1)c1nc(OC)cc(OC)n1
Product: COC(=O)C(Cl)(c1ccccc1)c1nc(OC)cc(OC)n1

Procedure:
Methyl 2-(4,6-dimethoxypyrimidin-2-yl)-2-phenylacetate (2.0 g) and N-chlorosuccimimide (2.0 g) were stirred at reflux in carbon tetrachloride (25 ml) under a bright light for 18 hours. The reaction mixture was filtered and evaporated to dryness, and the residue was purified by column chromatography on silica eluting with ether:hexane (1:1), yielding the desired product (2.16 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[C:18]([N:28]=[N+]=[N-])[C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])[CH3:3].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:28][C:18]1[C:19](=[O:27])[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:17]=1[CH2:16][CH2:15][C@@H:14]1[C@@H:24]2[CH2:25][CH2:26][C@@:9]2([CH3:10])[C@H:11]1[CH2:12][CH2:13][C@@H:8]2[C:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 55 %

Procedure:
To a stirred solution of N-(1,1-dimethylethyl)-4-azido-3-oxoandrost-4-ene-17β-carboxamide (1.3 g, 3.15 mmole) in tetrahydrofuran (20mL)-water (7 mL) was added triphenylphosphine (1.41 g, 5.38 mmole). The reaction was heated at reflux temperature for 16 hours. Most of the tetrahydrofuran was removed under vacuum. Dichloromethane was added to the mixture and the organic solution was placed atop a column of silica gel and flash chromatographed (hexane-30% ethyl acetate). The fractions containing the product were combined and concentrated to a white solid which was crystallized from diethyl ether to give the 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.67 g, 54.9%). IR 3476, 3442, 3382, 1672, 1659, 1620(m), 1580(m) cm-1 ; MS (CI) m/z 387 (100%, M+ +1); (EI) m/z 386 (10%, M+), 343 (100%); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 --Me), 1.16 (s, C19 --Me), 1.34 (s, tBu-Me's), 3.49 (2H, br s, NH2), 5.08 (1H, s, NHCO); 13C NMR (CDCl3) δ 132.97, 138.39, 171.69, 194.22. This compound has the following structure: ##STR5##
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][CH3:23])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:17]([O:16][C:14]([N:12]1[CH2:13][CH:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][CH3:23])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCC1CC(O)CN1C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
A solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methoxymethylpyrrolidine (4.48 g) and tetrabutylammonium fluoride (1 Mol tetrahydrofuran solution, 13 ml) in tetrahydrofuran (45 ml) was stirred at 0° C. for eight hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was separated, washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:2, V/V) to give (2S,4R)-1-(tert-butoxycarbonyl-4-hydroxy-2-methoxymethylpyrrolidine (2.82 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Nc2ccccc2)cc1

Procedure:
Under a flow of argon, in a 300 mL-recovery flask, 20 g of 4-bromobenzonitrile, 30 mL of aniline, 1.50 g of tris(dibenzylideneacetone)dipalladium(0)[Pd2(dba)3], 2.1 g of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl[BINAP], 21.1 g of sodium tert-butoxide and 313 mL of dehydrated toluene were placed, and reacted at 85° C. for 6 hours.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=1[NH:19][C:20](=[O:36])[CH2:21][CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>CN(C)C=O.C(OCC)(=O)C>[N:37]1([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=2[NH:19][C:20](=[O:36])[CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:29][C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: c1c[nH]cn1
Reactant: CSc1cccc(COCCCOS(C)(=O)=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cccc(COCCCn2ccnc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
251 mg of the crude crystals of N-{2-[3-(mesyloxy)propoxy]methyl-6-methylthiophenyl}-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] were suspended in 3 ml of dimethylformamide. 162 mg (2.39 mmol) of imidazole were added to the suspension, and the mixture was stirred for 5.5 hours at 90° C. At the end of this time, the reaction mixture was allowed to return to room temperature, after which it was diluted with ethyl acetate and washed several times with water. The solvent was then removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through 15 g of silica gel. Fractions eluted with mixtures of methylene chloride and methanol ranging from 100:2 to 100:7 by volume were collected. Recrystallization from a mixture of methylene chloride and methanol afforded 162 mg (yield 68%) of the title compound as crystals, melting at 176.5°-177° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:28])=[C:12]([CH:27]=2)[C:13]([N:15]2[CH2:18][CH:17]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:16]2)=[O:14])[NH:4][N:3]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.CCOC(C)=O.CC#N>[N:30]1([C:9]2[C:8]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[CH:27][C:12]([C:13]([N:15]3[CH2:16][CH:17]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:18]3)=[O:14])=[C:11]([CH3:28])[CH:10]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(F)c(-c2[nH]nc(C)c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N2CCC2)c(-c2[nH]nc(C)c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 120 °C
Reaction time: 20 h
Yield: 42.5 %

Procedure:
Into a 5-mL sealed tube, was placed a solution of 4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 377.2, 120 mg, 0.31 mmol) in dioxane (3 mL). Azetidine (833 μL, 12.4 mmol) and Cs2CO3 (1.01 g, 3.09 mmol) were added to the reaction. The reaction mixture was stirred for 20 h at 120° C., then cooled with a water/ice bath. The resulting solution was diluted with 30 mL of EtOAc. The organic layer was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm; mobile phase, Water with 10 mmol NH4HCO3 and MeCN (36.0% MeCN up to 50.0% in 6 min, up to 95.0% in 2 min, down to 36.0% in 1 min); Detector, waters 2489 254 & 220 nm. This resulted in 56 mg (43%) of the title compound as a white solid. m/z (ES+) 426 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[ClH:29]>CO.ClCCl.O1CCOCC1>[ClH:29].[ClH:29].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-piperidinyl}carbamate (8.72 g, 22.36 mmol) in methanol (90 ml) and dichloromethane (150 mL) was treated with 4 M hydrogen chloride in 1,4-dioxane (150 mL) (added in a slow stream, some exotherm and rapid precipitation observed) and stirred at room temperature for 2.5 h. The mixture was evaporated to dryness and the residue was triturated with ether. The solid was filtered off, washed with ether and dried to give the amine salt as a grey-green solid (8.06 g, 99%).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH2:29][CH2:28][OH:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: OCCc1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CCO)[n+]4c3)[C@H](C)[C@H]12
Yield: 26.8 %

Procedure:
The same procedure as in Example 1 was repeated except that 87 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 100 mg of 3-(2-hydroxyethyl)imidazo[5,1-b]thiazole were used, thereby obtaining 25 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[Cl:30][CH2:31][C:32]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:33]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
Triethylamine (0.6 g, 6 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.8 g, 2.5 mmol) in THF (70 ml). After stirring for 5 min, chloroacetyl chloride (0.34 g, 3 mmol) was added and the resulting mixture was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml), washed with water (20 ml), 2N HCl (30 ml), water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the resulting solid was slurried in dichloromethane (10 ml) and ether (10 ml) and filtered to give 0.76 g (84%) of the product: 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.87 (t, J=5.9 Hz, 1H), 7.88–7.68 (m, 3H), 5.19–5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 4.19 (s, 2H), 2.96–2.83 (m, 1H), 2.65–2.51 (m, 2H), 2.11–2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.88, 169.90, 167.53, 167.01, 166.67, 138.46, 134.90, 133.22, 131.63, 127.26, 122.14, 48.94, 42.61, 38.27, 30.99, 22.05.