Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[CH3:46][O:47][C:48]1[CH:49]=[N:50][C:51]([NH2:54])=[N:52][CH:53]=1>ClCCl>[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[C@H:20]([C:21]([NH:54][C:51]3[N:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][N:50]=3)=[O:23])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Reactant: COc1cnc(N)nc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC[C@@H](C(=O)Nc2ncc(OC)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
1-Methylimidazole (158 μl, 1.987 mmol) was added into the solution of 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (319 mg, 0.662 mmol) in dichloromethane (DCM) (4.5 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (53.8 μl, 0.696 mmol) was added dropwise at 0° C. To the reaction mixture was added 5-(methyloxy)-2-pyrimidinamine (87 mg, 0.696 mmol). After stirring for 30 min at ambient temperature, the solvent was removed under reduced pressure to give a residue which was purified by RP-HPLC to yield 2-propen-1-yl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[5-(methyloxy)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate (173 mg, 0.294 mmol, 44% yield). MS (ES+) m/z 589.1 (MH+).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[CH:14]1([C:19]([C:4]2[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)c1ccccc1
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)C2CCCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of cumene (16.4 g, 137 mmol) and aluminum chloride (21.9 g, 164 mmol) in dichloromethane (200 mL) was added cyclopentanecarbonyl chloride (20 g, 151 mmol) at −50° C. (the inside temperature), and the mixture was stirred for two hours until the temperature reached −10° C. (the inside temperature).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[O:16]1[CH:7]2[CH2:6][C:5]3[C:10]([CH2:9][CH:8]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2ccccc2C1
Solvent: ClCCl
Product: c1ccc2c(c1)CC1OC1C2
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
To a solution of 1,4-dihydronaphthalene (8.6 g, 86% purity, 56.8 mmol) in dichloromethane (100 mL) at 0° C., m-chloroperoxybenzoic acid (17.0 g, 77% Purity, 75.8 mmol) in dichloromethane was added. After stirring for 5 h at 0° C., the solution was filtered to separate out the precipitated m-chlorobenzoic acid. The organic layer was washed with saturated Na2CO3, water, and brine (2×50 mL each). The organic layer was dried and concentrated under reduced pressure, the residue was purified by chromatography to give compound 2 (6.1 g, 73%). 1H NMR (CDCl3): δ 3.17 (d, J=17.4 Hz, 2H), 3.31 (d, J=16.8 Hz, 2H), 3.46 (s, 2H), 7.02-7.15 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=C(C=CC=1)C(OO)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:17])=[N:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Ic1cnc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc2ncc(I)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 3-iodo-1,5-naphthyridine (D-14) (2.750 g, 10.7 mmol, 1.0 eq) in CH2Cl2 (30 mL), 3-chloroperoxybenzoic acid (2.780 g, 16.1 mmol, 1.5 eq) was added. After the resulting mixture was stirred at RT for 2 h, saturated sodium carbonate solution (50 mL) was added, and extracted with CH2Cl2 (10×30 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (50% EA-PE) to afford the desired product 7-iodo-1,5-naphthyridine 1-oxide (D-15) (1.574 g, 54% yield) as a solid. 1H NMR (400 MHz, CDCl3-d6) δ: 9.45 (dd, J=2.0 Hz, J=0.8 Hz, 1H), 9.18 (d, J=2.5 Hz, 1H), 8.54 (d, J=6.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.59-7.55 (m, 1H); ESI-MS m/z: 272.95 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C

Procedure:
{(R)-1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (first step a) is dissolved in methanol (2 ml). (4 M) HCl in 1,4-dioxane (15 ml) is added and the reaction mixture is stirred at room temperature over night. The compound is purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% HCl). The compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 596.38 (MH+).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25](O)=[O:26])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.C(OC(=O)[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41](=[O:46])[NH:42][CH:43]2[CH2:45][CH2:44]2)[CH2:37][CH2:36]1)(C)(C)C>>[CH:43]1([NH:42][C:41]([C@H:38]2[CH2:39][CH2:40][C@H:35]([NH:34][C:25]([C:22]3[C:18]4[N:19]=[CH:20][N:21]=[C:16]([C:8]5[C:9]6[O:13][CH2:12][O:11][C:10]=6[CH:14]=[CH:15][C:7]=5[O:6][CH2:5][CH:1]5[CH2:2][CH2:3][CH2:4]5)[C:17]=4[NH:24][CH:23]=3)=[O:26])[CH2:36][CH2:37]2)=[O:46])[CH2:45][CH2:44]1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Product: O=C(N[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:29][CH:30]=3)=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:15])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Under ice-cooling, 628 mg (5.5 mmol) of methanesulfonyl chloride was added dropwise to a solution of 1.83 g (5 mmol) of 1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 1.52 g (15 mmol) of triethylamine in methylene chloride. After the mixture was stirred at room temperature for 1 hour, 5 ml of morpholine was added thereto and the mixture was stirred overnight. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1 g (57%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 35 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.35 mL, 2.50 mmol) and benzoyl chloride (260 μL, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2.5 h. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Mass spectral analysis showed the presence of some bis-amide in addition to the desired product. The tan foam was treated with 1N aqueous HCl solution (50 mL) at 100° C. for 5 h. HPLC analysis showed that all of the bis-amide had been converted to the desired product. The reaction was cooled to room temperature and treated with 10% NaOH until the pH˜11. The mixture was extracted with CHCl3 (3×30 mL). The combined organic extracts were washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. Purification by column chromatography (SiO2, 5-10% MeOH/CHCl3) gave 100 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)benzamide as a white powder. m.p. 184-187° C.; MS 434 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.40 (m, 1 H); 8.06 (d, J=8.3 Hz, 1 H); 7.76-7.74 (m, 2 H); 7.60 (d, J=7.8 Hz, 1 H); 7.54-7.37 (m, 4 H); 7.19 (t, J=7.3 Hz, 1 H); 6.48 (s, 2 H); 4.79-4.72 (m, 2 H); 3.91-3.84 (m, 2 H); 3.78 (t, J=6.9 Hz, 2 H); 3.48 (t, J=5.5 Hz, 2 H); 3.25 (s, 3 H); 3.20 (t, J=6.3 Hz, 2 H); 13C (75 MHz, DMSO-d6) δ166.7, 152.0, 151.9, 145.2, 134.8, 132.7, 131.4, 128.6, 127.4, 126.7, 121.4, 120.5, 115.1, 70.4, 69.4, 69.2, 58.4, 45.5, 27.6.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([O:27]CC)=[O:26])[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([OH:27])=[O:26])[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2]
Reactant: CCOC(=O)c1cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cc(C(=O)O)cc(C(=O)O)c2)c1F
Temperature: 60 °C

Procedure:
To 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid, diethyl ester (0.97 g, 2.0 mmol) in tetrahydrofuran/water (20 mL, 1/1) was added lithium hydroxide (0.42 g, 10 mmol). After heating at 60° C. for 90 minutes, the material was partitioned between ethyl acetate and 2 N HCl. The organic layer was separated, dried (MgSO4), and the solvent removed in vacuo to give 5-[(6-(3-cyanophenoxy)-3,5-difluoro-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid; NMR (DMSO) 8.25 (s,1), 7.85 (s,2), 7.4-7.7 (m,3), 7.3 (m,3), 2.4 (s,3) ppm.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][NH2:14]>C(O)(C)C>[NH:13]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[NH2:14]
Reactant: NN
Reactant: Nc1ncnc2cc(F)ccc12
Solvent: CC(C)O
Product: NNc1ccc2c(N)ncnc2c1
Reaction time: 0.5 h

Procedure:
7-Fluoro-quinazolin-4-ylamine (0.306 mmol, 50 mg) is dissolved in Hydrazine (2 mL) and heated in an open flask until all the liquid is gone. The resulting solid is taken up in isopropanol and stirred for 30 minutes and the solid is collected by filtration. This gives desired product 7-Hydrazino-quinazolin-4-ylamine (32 mg, LC/MS m/z=176 [M+H]+) as a tan powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][S:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:21]([S:20][CH3:19])=[C:22]2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)CSC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CSc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 5-methylthio-4-oxopentanoate as starting materials and t-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[N:1]1([C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 1,2,3,4-tetrahydroquinoline, 10.46 ml of triethylamine, 270 ml of tetrahydrofuran and then 15.13 g of para-nitrophenyl chloroformate are introduced into a 1 l round-bottomed flask. The reaction medium is stirred at ambient temperature for two hours and then filtered. The solvent is evaporated under reduced pressure and the residue is taken up in dichloromethane and washed with a 2N aqueous hydrochloric acid solution and then twice with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 21.5 g of 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH:4]=1.[CH3:19][Mg]Br>C1COCC1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH:10][S@@:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:12])[CH3:19])[CH:4]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(C(F)(F)F)ccn1
Solvent: C1CCOC1
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid 1-(4-trifluoromethyl-pyridin-2-yl)-meth-(E)-ylideneamide (0.34 g, 1.22 mmol) in THF (5 mL) at −78° C. was slowly added methylmagnesium bromide (3.0 M in Et2O) (0.73 mL, 2.2 mmol). The reaction mixture was stirred at −78° C. for 30 min then quenched cold with saturated aqueous NH4Cl. The mixture was warmed to room temperature, diluted with water, and extracted with EtOAc (2×). the combined organics were dried over MgSO4 and concentrated. NMR analysis showed an approx 8:1 mixture of diastereomers. The residue was purified by chromatography with 50% to 100% EtOAc/hexanes to afford 225 mg (63%) of (R)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.75 (d, J=5.3 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=5.3 Hz, 1H), 4.77 (d, J=4.9 Hz, 1H), 4.67 (quin, J=6.3 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.27 (s, 9H). The single diastereomer obtained was assigned as RSR based on literature precedent (Kuduk, et. al. Tetrahedron Lett. 2004, 45, 6641).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[C:8]#[N:9]>>[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:10]([CH3:14])[C:7]=1[C:8]#[N:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(Cl)c1C#N
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of aqueous 90% nitric acid was cooled to -35° C., and 40.0 grams (0.264 mole) of 2-chloro-6-methylbenzonitrile was added in one portion. The reaction mixture was then allowed to warm to ambient temperature, where it was stirred for about 18 hours. After this time, the reaction mixture was poured into 3000 mL of ice-water. After the ice melted, the resultant solid was collected by filtration and dried. The NMR spectrum of the solid indicated that it was about 75% pure product. The solid was recrystallized twice from methanol, yielding 13.9 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 85.5°-87.5° C. The NMR spectrum was consistent with the proposed structure. The filtrates from the recrystallizations were combined and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding an additional 20.4 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 87.5°-89.5° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:18]([F:40])[CH2:19][O:21]2)[N:6]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80) gave tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:2](=[O:3])[O:4][CH3:5])=[CH:19][CH:18]=2)[N:13]=1
Reactant: Nc1ccc(-c2noc(-c3ccccn3)n2)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2noc(-c3ccccn3)n2)cc1

Procedure:
1.4 g. (0.015 mole) of methyl chloroformate is added to a mixture of 2.4 g. (0.01 mole) of 5-(2-pyridyl)-3-(4-aminophenyl)-1,2,4-oxadiazole, from part (b), and 2.1 g. of potassium carbonate in 50 cc. of dioxane. The resulting mixture is refluxed for 0.5 hours. It is then concentrated to dryness and the residue is crystallized from benzeneethyl acetate to yield [4-[5-(2-pyridyl)-1,2,4-oxadiazol-3-yl]-phenyl]carbamic acid, methyl ester.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:18])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][C:15]#[C:16][CH3:17])=[O:11])CC#CC>C1(C)C=CC=CC=1>[O:6]1[CH2:1][CH2:17][C:16]#[C:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:18]
Reactant: CC#CCCOC(=O)CCC(=O)OCCC#CC
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)OCCC#CCCO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a dry 100 mL Schlenk-tube, which has been flooded with argon, [Mo(≡N)(OSiPh3)3)(bipy)] (109.2 mg, 0.10 mmol) and MnCl2 (12.6 mg, 0.10 mmol) were suspended in dry toluene (15 mL) and the mixture was heated to 80° C. Additional dry toluene (35 mL) and succinic acid dipent-3-inyl ester (278.3 mg, 1.00 mmol) were added after 30 min, the reaction mixture was stirred for 24 h at 80° C. and was filtered after cooling over a short silica gel column. The filtrate was concentrated and the residue was purified by column chromatography (hexane/EtOAc 4:1). 1,6-dioxacyclododec-9-ine-2,5-dione was isolated as colorless oil (yield: 81%). 1H NMR (400 MHz, CD2Cl2): δ=4.21-4.14 (m, 4H), 2.61 (s, 4H), 2.44-2.37 (m, 4H); 13C NMR (100 MHz, CD2Cl2): δ=171.9 (2×C), 79.0 (2×C), 61.6 (2×CH2), 30.2 (2×CH2), 19.7 (2×CH2); IR (film): v=2965, 2915, 2840, 1729, 1458, 1421, 1383, 1353, 1336, 1267, 1251, 1158, 1053, 1030, 1000, 952, 837 cm−1; MS (EI) m/z (%): 166 (1), 101 (14), 78 (100), 66 (59), 65 (16), 55 (7), 40 (12), 28 (7); HRMS (ESI): m/z: calculated for C10H12O4+Na: 219.0628; found: 219.0627.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:10]=[CH:11][CH:12]=[CH:13]4)=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 110 °C

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (1.67 g, 12 mmol), 2-(quinolin-6-yl)acetic acid (1.65 g, 8.8 mmol), and HCl (2000 μl, 24 mmol) was heated in an oil bath at 110° C. for 20 min before it was heated in a microwave (Personal Chemistry) at 180° C. & 15 min. The mixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly until the suspension is ˜neutral in pH. The mixture was filtered and washed with H2O (2×5 mL). A brown solid was obtained (2.2 g). The solid was treated with aqueous Na2CO3 (3 g, 20 mL, pH ˜11) and heated at 50° C. for 30 min. The blue mixture was cooled to room temperature, and filtered. The black solid was washed with H2O and lyophilized to give the product.