Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>[NH4+].[Cl-].[Cu]I.CN(C=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)=[CH:11][CH:10]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C
Yield: 107.3 %

Procedure:
To a mixture of 1H-imidazole-4-carbaldehyde (3.71 g, 38.6 mmol), 1-chloro-4-iodobenzene (13.81 g, 57.9 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (1.10 g, 7.72 mmol), copper(I) iodide (0.368 g, 1.93 mmol) and cesium carbonate (25.2 g, 77 mmol) was added DMF (50 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with a saturated solution of NH4Cl. A brown solid develops. Solid was collected, washed with water and air dried. Solid material was then dissolved in 10% MeOH:90% DCM solution and dried (Na2SO4), filtered and concentrated to afford a dark brown solid 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (8.55 g, 41.4 mmol, 107% yield). Material as used without further purification. LCMS m/z 207.1 (M+H)+, Rt 0.58 min.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH:16][C:17]([NH2:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].CNCCNC>[Cu]I.O1CCOCC1>[CH2:9]([NH:16][C:17]([NH:19][C:21]1[CH:27]=[CH:26][CH:25]=[C:23]([NH2:24])[CH:22]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)NCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), K3PO4 (425 mg, 2.0 mmol, 2.0 equiv), benzylurea (225 mg, 1.5 mmol, 1.5 equiv), 3-bromoaniline (109 μL, 1.0 mmol, 1.0 equiv), N,N′-dimethylethylendiamine (22 μL, 0.20 mmol, 0.20 equiv) and dry dioxane (1.0 mL), filled with nitrogen. The test tube was sealed and the reaction mixture was stirred at 80° C. for 24 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with ethyl acetate. The filtrate was concentrated in vacuo. The solid residue was dissolved in ˜2 mL DMF. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane:ethyl acetate 1:2) provided 185 mg (77% yield) of the title compound as a light yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([N:13]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:14](=[O:17])[CH2:15]Cl)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1([N:13]2[CH2:18][C:19]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[O:32][CH2:15][C:14]2=[O:17])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(C(=O)CCl)C2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1(CO[Si](C)(C)C(C)(C)C)CC1)C(=O)CO2
Yield: 65.5 %

Procedure:
To a solution of tert-butyl 4-((N-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-2-chloroacetamido)methyl)-4-hydroxypiperidine-1-carboxylate (1.511 mmol) in anhydrous tetrahydrofuran (20 mL) was added 60% sodium hydride in mineral oil (3.02 mmol) in one portion. The suspension was heated at reflux for 1 h then cooled, quenched with water (1 mL), and evaporated to dryness in vacuo. Purification of the residue by flash chromatography (20-80% ethyl acetate in hexanes) afforded the title product (450 mg, 64% yield) as a colorless oil. MS(ES)+ m/e 455.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.03 (s, 6 H) 0.76-0.98 (m, 13 H) 1.47 (s, 11 H) 1.70-1.89 (m, 2 H) 2.90-3.18 (m, 2 H) 3.35 (s, 2 H) 3.70 (br. s., 2 H) 3.85 (br. s., 2 H) 4.11 (s, 2 H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:42]([NH:44][S:45](=[O:50])(=[O:49])[N:46]([CH3:48])[CH3:47])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:27][C:26]56[CH2:32][N:33]([CH3:35])[CH2:34][C:25]5([CH2:30][N:29]([CH3:31])[CH2:28]6)[CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:42]([NH:44][S:45](=[O:49])(=[O:50])[N:46]([CH3:48])[CH3:47])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([N:23]4[CH2:27][C:26]56[CH2:28][N:29]([CH3:31])[CH2:30][C:25]5([CH2:34][N:33]([CH3:35])[CH2:32]6)[CH2:24]4)=[O:22])[CH2:18][C:17]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CN(C)CC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CC(C(=O)N1CC34CN(C)CC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
10% Pd/C (4 mg, 4 μmol) was added to a suspension of 13-cyclohexyl-N-(dimethylsulfamoyl)-6-((7,10-dimethyl-3,7,10-triazatricyclo[3.3.3.01,5]undec-3-yl)carbonyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 15) (6.0 mg, 8.6 μmol) in MeOH (2 mL). The reaction mixture was vacuum flushed with N2, and then with H2 and stirred under a H2 balloon at rt for 16 h. The reaction mixture was filtered through celite, and concentrated to yield 13-cyclohexyl-N-(dimethylsulfamoyl)-6-((7,10-dimethyl-3,7,10-triazatricyclo[3.3.3.01,5]undec-3-yl)carbonyl)-3-methoxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide (3.1 mg, 4.2 μmol, 49% yield) as an off white solid. LCMS: m/e 703 (M+H)+. LCMS retention time: 2.35 min. (Column: Phenomenex-Luna 3.0×50 mm S10. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][OH:41])=[CH:34][CH:33]=1.[CH2:49]([O:51][C@@H:52]([CH2:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1)[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH3:50]>C1COCC1>[C:32]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:33]=[CH:34][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][O:41][C:62]2[CH:61]=[CH:60][C:59]([CH2:58][C@H:52]([O:51][CH2:49][CH3:50])[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:64][CH:63]=2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.346 ml, 2.2 mmol) was added at 0° C. to a stirred solution of triphenyl-phosphine (0.656 g, 2.2 mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (0.270 g, 1.2 mmol) in dry THF (20 ml) and the mixture stirred for 5 min. A solution of (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) in dry THF (10 ml) was added, the mixture allowed to warm to room temperature, and stirring continued for 48 h. The resulting mixture was evaporated in vacuo and the residue purified by column chromatography on silica gel (20% ethyl acetate in n-heptane) to give (E)-(S)-ethyl 3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate as an oil; 0.288 g (65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH:18]([CH:21]=O)[CH:19]=O>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:21]=[C:18]([Cl:17])[CH:19]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: O=CC(Cl)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2nn3cc(Cl)cnc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2 g; 8.92 mmol; 1 eq.) and 2-chloromalonaldehyde (1.04 g; 9.81 mmol; 1.1 eq.) in AcOH was stirred at room temperature for 18 hours then diluted with water (30 mL). The precipitate was filtered off and purified by column chromatography (DCM/EA, from 95/5 to 80/20) to afford the title compound (1.24 g, 47%) as a white solid. 1H NMR (DMSO-d6) δ 9.57 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H), 4.63-4.57 (m, 4H), 1.47 (s, 9H). HPLC (max plot) 99.1%; Rt 3.75 min.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>C1(C)C=CC=CC=1.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>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)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
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccs2)c1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a mixture of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (0.42 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.034 mmol), sodium carbonate (2.0 M, 2 mL) in toluene (10 mL) was added 2-thienylboronic acid (0.38 g, 3.0 mmol). The reaction mixture was stirred and heated at 80° C. for 16 h. Solvent was evaporated. The residue was chromatographed (silica gel; hexane/EtOAC, 10:1 to 2:1) to afford an oil (0.24 g, 57%): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.26-2.90 (m, 2H), 3.86-3.94 (m, 2H), 4.20 (m, 1H), 4.39 (m, 1H), 4.55 (m, 1H), 7.12 (m, 1H), 7.36 (s, 1H), 7.44 (s, 1H), 8.26 (s, 1H), 8.50 (s, 1H); MS (CI/NH3) m/z 347 (M+H)+.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[NH2:6].[C:12](Cl)(Cl)=[O:13].C1C=CC=CC=1>C1C=CC=CC=1>[Br:2][CH2:3][C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[N:6]=[C:12]=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1CBr
Agent: Br
Solvent: c1ccccc1
Product: O=C=Nc1cc(Cl)ccc1CBr

Procedure:
6.32 g of 2-bromomethyl-5-chloroaniline hydrobromide is added to 30 ml of benzene containing 12.5% phosgene (w/v) and the mixture refluxed in a vessel equipped with a Dean-Stark trap and additional phosgene/benzene added for a total of 250 ml (over a period of 6 hrs; 1/2 ml of water collected in the trap). The reaction mixture is cooled to 20°, insolubles removed by filtration and the filtrate concentrated (solvent removed), then distilled under vacuum to obtain 2-bromomethyl-5-chlorophenylisocyanate (distills at 0.05 mm Hg/50°). Further distillation yields 2-bromomethyl 4-bromo-5-chlorophenyl isocyanate (which may be refined by crystallization from petroleum ether, m.p. 48°-50°) which is useful as an intermediate in Examples 4 and 5 in preparing 6-bromo-7-chloro-4H-1,3-benzoxazine analogs of the title product of this example.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(O)c3ccccc3Oc3ccccc32)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: Cc1ccc(C2(OC[C@H](N)C(=O)O)c3ccccc3Oc3ccccc32)cc1

Procedure:
from 9-(4-methylphenyl)-9H-xanthen-9-ol (Example 1q) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[NH2:28]>>[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[NH2:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(C(N)=O)nc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(C(N)=O)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 66.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-carbamoyl-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (239 mg) was prepared in the same manner as in step a) of Example 1, except that 210 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 342 mg of 5-carbamoyl-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C:16]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[NH:18][N:17]=1)=[O:15].C(N(CC)CC)C>ClCCl.CCOCC>[CH3:12][O:13][C:14]([C:16]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[N:18]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[N:17]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])n(C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
Benzyl chloroformate (5.20 mL, 35.08 mmol) was added to a cooled (0° C.) solution of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (5.400 g, 31.54 mmol) and triethylamine (7.40 mL, 53.08 mmol) in dichloromethane (60 mL), the reaction mixture was stirred at room temperature for 2 hours, then diluted with ether and washed with water and brine, dried over anhydrous MgSO4 and filtered. The organic solvent was removed in vacuo. The residue was purified column chromatography to give 5-nitropyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (3.28 g, 34%). 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 7.32-7.24 (m, 5H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([N:9]([CH2:16][C:17]([F:19])=[CH2:18])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])(=O)C1C=CC=CC=1.C(C1C=CC=CC=1)(=O)C.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[F:19][C:17]12[CH2:15][C:10]([C:11]([O:13][CH3:14])=[O:12])([CH2:18]1)[N:9]([CH3:1])[CH2:16]2
Reactant: C=C(F)CN(C(=C)C(=O)OC)C(=O)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: COC(=O)C12CC(F)(CN1C)C2
Yield: 63.4 %

Procedure:
Methyl 2-[benzoyl(2-fluoroallyl)amino]prop-2-enoate (AR3) (380 mg, 1.44 mmol), acetophenone (30 mg), benzophenone (40 mg) were dissolved in 25 mL of benzene. The solution formed was irradiated in a quartz reactor by 500 W medium pressure mercury lamp at room temperature for 10 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (hexane/EtOAc=3/1) to give methyl 1-fluoro-3-methyl-3-azabicyclo[2.1.1]hexane-4-carboxylate (AR4) (240 mg, 0.913 mmol, 63%). LC/MS: calc'd 264 (MH+), exp 264 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1cc(Cl)ccc1NCc1nnn(C)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2C)[C@H]1O
Yield: 28 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (450 mg, 1.6 mmol) obtained in step 1 of example 2 and N-[(2-methyl-4-chlorophenyl)]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (235 mg, yield: 28%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[S:9][CH:10]=1)C.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1csc(-c2ccc(Cl)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 123.5 %

Procedure:
Dissolve [2-(4-chloro-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (107.4 g, 381.2 mmol) in THF (800 mL) and cool to 0-5° C. Slowly add DIBAL (1.0 M in THF, 800 mL, 800 mmol) over approximately 3.5 h keeping the temperature<5° C. After the addition is complete warm the resulting solution to room temperature and stir mechanically overnight. Cool the solution to 0-5° C. and slowly add additional DIBAL (150 mL) keeping the temperature<5° C. Stir at room temperature for 2.5 h, then cool to 0-5° C. and slowly quench over 5 h with aqueous saturated Rochelle's salt (2900 mL) keeping the temperature<10° C. Extract the mixture with EtOAc (2×3300 mL). Combine the organic solutions and concentrate in vacuo to give an oil (112.9 g). Dissolve the oil in toluene (600 mL) and concentrate in vacuo, then repeat. Dry the residue in vacuo for 6 h to give a residue weighing 107.4 g (110%). ES/MS m/z (35Cl) 240.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[CH2:28][CH2:29][NH:30][CH3:31]>O1CCCC1>[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[CH2:28][CH2:29][N:30]([CH3:31])[C:17](=[O:19])[C:16]1[CH:20]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)[C:13]([Cl:22])=[CH:14][C:15]=1[Cl:21]
Reactant: CNCCC1OCCO1
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: C1CCOC1
Product: CN(CCC1OCCO1)C(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
After a solution of 1 g (2.7 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoic acid and 0.66 g (4.1 mmol) of 1,1-carbonyldiimidazole had been stirred for 1 hour in 20 ml of tetrahydrofuran, 0.55 g (4.1 mmol) of N-[2-(1,3-dioxolan-2-yl)-ethyl]-N-methylamine were added. The mixture was subsequently stirred for a further 16 hours at approximately 20° C. The reaction mixture was then concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=1:1). Yield: 0.4 g.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][C:14](F)=[CH:15][C:8]=3[C:7](=[O:17])[C:6]=2[CH:18]=1.IC1C=CC2C=CC3C=CC(C)=CC=3C(=O)C=2C=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: O=c1c2cc(F)ccc2ccc2ccc(I)cc12
Agent: Cc1ccc2ccc3ccc(I)cc3c(=O)c2c1
Product: O=c1c2ccccc2ccc2ccc(I)cc12

Procedure:
Following the procedure of Step B but substituting for the 3-amino-5H-dibenzo[ a,d]cyclohepten-5-one used therein an equimolecular amount of 3-amino-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one and 3-amino-7-methyl-5H-dibenzo[a,d]cyclohepten-5-one, there are produced respectively, 3-iodo-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one and 3-iodo-7-methyl-5H-dibenzo[a,d]cyclohepten-5-one.
Reaction SMILES: [CH3:1]I.C(OC([N:10]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:22]=3[CH:32]=2)[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@H:42]([O:44][CH2:45][CH3:46])[CH3:43])=[CH:35][CH:34]=2)[C@H:12]([CH2:47][OH:48])[CH2:11]1)=O)(C)(C)C.[H-].[Na+]>>[CH3:1][O:48][CH2:47][C@@H:12]1[CH2:11][NH:10][CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:22]=3[CH:32]=2)[C@H:13]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@H:42]([O:44][CH2:45][CH3:46])[CH3:43])=[CH:35][CH:34]=1
Reactant: CI
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: [H-]
Agent: [Na+]
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COC)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.568 mmol of methyl iodide are added to a suspension of 0.642 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) and 0.963 mmol of NaH (60% dispersion in oil) under argon at 0° C. After stirring for 1 h at 0° C. and 1 h at RT, the reaction mixture is partitioned between TBME and saturated aqueous NaHCO3 solution. The aqueous layer is extracted with TBME (2×)—the combined organic layers are washed successively with H2O and brine, dried with Na2SO4 and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: C(=NO)C1C(=CC=CC=1)O.[Cl:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:24]1[S:28][C:27]([CH:29]=[O:30])=[C:26]([CH3:31])[CH:25]=1>[Cu-]=O.CC#N>[Cl:11][C:12]1[CH:16]=[CH:15][N:14]([C:24]2[S:28][C:27]([CH:29]=[O:30])=[C:26]([CH3:31])[CH:25]=2)[N:13]=1
Reactant: Clc1cc[nH]n1
Reactant: Cc1cc(Br)sc1C=O
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: Cc1cc(-n2ccc(Cl)n2)sc1C=O
Temperature: 82 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A sealed tube was charged with Copper(I) oxide (5.82 μL, 0.244 mmol), salicylaldoxime (134 mg, 0.975 mmol), 3-chloro-1H-pyrazole (500 mg, 4.88 mmol), Cs2CO3 (3178 mg, 9.75 mmol) and Part A compound of Example 1(150 mg, 7.32 mmol) and MeCN (4.877 mL). The tube was purged with N2 and the reaction stirred at 82° C. for 5 h. After cooling to RT, the mixture was diluted with CH2Cl2 (10 mL) and filtered through a pad of CELITE®. The filtrate was concentrated and purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 50:50) to afford 420 mg (38% yield) of the title compound as a brown solid: 1H NMR (500 MHz, CD3OD) δ 9.88 (1H, s), 8.34 (1H, s), 7.62 (1H, s), 7.07 (1H, s), 2.48 (3H, s). HPLC retention time 2.923 min., LCMS (ES): m/z 227 [M+H]+.