Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[C:42]([C:47]([O:49][CH3:50])=[O:48])[C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=1>O1CCCC1>[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([CH:42]([C:47]([O:49][CH3:50])=[O:48])[C:43]([O:45][CH3:46])=[O:44])[CH2:19][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[CH:39][CH:40]=1
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)C(=O)OC
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a vigorously stirring mixture of molecular sieves (5.25 g) and tetra-n-butylammonium fluoride (0.882 g) was added dry tetrahydrofuran (10 ml) at 0° C. 2-Methyl-1-nitro-3-(trifluoromethyl)benzene (0.425 ml; 2.8 mmol) was added to the suspension followed by the addition of a solution of 2-[(4-methoxyphenyl)methylene]propanedioic acid, dimethyl ester (0.44 g; 1.75 mmol) in 5 ml of tetrahydrofuran. After 30 minutes of 0° C. the reaction was brought to room temperature and stirred for another 20 minutes. The reaction was quenched with 30% acetic acid until a light yellow color was observed and thereafter was diluted with 45 ml of ethyl ether, filtered and washed twice with 30 ml of ethyl ether. The combined organic solution was washed with sodium hydrogen carbonate and dried over magnesium sulfate. Concentration and chromatography provided 0.72 g of the title compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCNCC2=O)CC1
Reactant: C=O
Product: CN1CCN([C@H]2CC[C@H](C(=O)Nc3c(C(=O)Nc4ccc(Cl)cn4)oc4cccnc34)CC2)C(=O)C1

Procedure:
N-(5-Chloropyridin-2-yl)-3-({[trans-4-(2-oxopiperazin-1-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxamide (60 mg) obtained in Example 125 and 35% aqueous formaldehyde solution (19 μl) are treated in a similar manner to Example 120 to give the title compound (46 mg).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34](=[O:41])[N:35]2[CH2:40][CH2:39]S[CH2:37][CH2:36]2)[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34]([N:35]2[CH2:40][CH2:39][S:3](=[O:5])(=[O:2])[CH2:37][CH2:36]2)=[O:41])[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCSCC1)CC1CCCCC1
Reactant: O=S([O-])OO
Agent: [K+]
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCS(=O)(=O)CC1)CC1CCCCC1

Procedure:
The compound was synthesized in a similar fashion to Example 6. An OXONE oxidation was employed title compound of Example 51 to furnish the sulfone. A procedure was used as described in McCarthy, J. R. et al. Org. Synth., CV9, 446. 1H NMR (CD3OD, 400 MHz) δ 0.73-0.79(m, 2H), 1.00-1.19(m, 7H), 1.10(d, J=6.8 Hz), 1.34-1.75(m, 6H), 2.34-2.37(m, 1H), 2.64-2.71(m, 2H), 2.94-3.08(m, 7H), 3.79-4.01(m, 5H), 6.53-6.56(m, 2H), 6.87-6.89(m, 2H). HPLC-MS calcd. for C25H36F3N3O5S (M+H+) 548.2. found 548.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH3:18][NH2:19].C1COCC1>>[CH3:18][NH:19][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: CN
Reactant: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: C1CCOC1
Product: CNc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cn1
Yield: 93 %

Procedure:
1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine (265.9 mg, 1.036 mmol) and methylamine 2M in THF (2.590 mL of 2 M, 5.180 mmol) were heated overnight in a sealed tube at 60° C. The mixture was purified by chromatography on silica (Companion 12 g) eluting with 0.5-15% MeOH:DCM, yielding N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (243 mg, 93%). MS (ES+) 252.1.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1ccnc1C1(O)CCC(=O)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1C1(O)CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:22]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:23]5[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=5)=[CH:32][CH:31]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1

Procedure:
[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (66 mg, 49%). m.p.=216-218° C.; LCMS (m/e) 442 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.56 (d, 1H, J=4.3 Hz), 8.42 (d, 1H, J=7.9 Hz), 7.95 (d, 1H, J=7.8 Hz), 7.90 (d, 1H, J=8.0 Hz), 7.78-7.68 (m, 3H), 7.64 (d, 2H, J=8.6 Hz), 7.36 (dd, 1H, J=4.9 and 7.7 Hz), 7.09 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.90 (d, 1H, J=4.8 Hz), 3.08 (s, 3H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]4[OH:30])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A stirred mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (165 mg, 0.53 mmol) from Step 5 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (122 mg, 1.06 mmol), and DIEA (137 mg, 1.06 mmol) in anhydrous DMA (3 mL) was sealed and heated at 100° C. for 15 h. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (44 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.39 (dd, J=1.1, 4.7 Hz, 1H), 8.08 (dd, J=1.2, 8.0 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.10-7.19 (m, 2H), 5.50 (s, 2H), 4.70 (br s, 1H), 3.25-3.45 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.14-1.32 (m, 4H). LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=2)[C:15]#[N:16])O1.O.[NH2:21][NH2:22]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=2)[C:15]#[N:16])=[N:22][NH:21]1
Reactant: NN
Reactant: N#Cc1ccnc(C=C2OC(=O)c3ccccc32)c1
Solvent: O
Product: N#Cc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 90 °C

Procedure:
To crude 2-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)-isonicotinonitrile (iii-int)(approx 4.0 mmol) suspended in water (30 mL) and hydrazine monohydrate (2 mL). The reaction mixture was then heated to 90° C. for 90 minutes and then cooled to room temperature. The resulting suspension was filtered and washed with methanol (5 mL), water (10 ml) and then ethyl ether (2×30 mL). A buff solid was isolated with single peak in LC-MS analysis. (0.61 g, 26.7% over 3 steps); m/z (LC-MS, ESP), RT=3.48 mins, (M+H)=263.0.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 4-ethoxycarbonylphenylboronic acid were reacted to provide 4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-carboxylic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:29]([O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O.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]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=2[O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cccc(Br)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2OCc2ccccc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-1-carboxylic acid ter-butylester (0.75 g, 2.426 mmol) [CAS 375853-82-0] (synthesis described in WO 2004072025 A2 20040826) in 1,4-dioxane (7 ml) and an aqueous saturated solution of K2CO3 (3.5 ml), was added 2-benzyloxy-1-bromo-3-fluoro-benzene (1.023 mg, 3.638 mmol) [1036724-55-6]. The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.14 g, 0.121 mmol). The reaction was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. After cooling to room temperature, the reaction mixture was diluted with water and washed with EtOAc. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (silica gel; starting from Heptane/DCM up to 100% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D51 (0.727 g, 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cn1nccc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1-methyl-1H-pyrazole-5-carboxylic acid, as starting materials, MS (LC/MS): 409.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17]Br)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(COC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1
Reaction time: 6 h
Yield: 56 %

Procedure:
A solution of 121 mg of trans-6-(4-chlorobenzyloxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 73 mg of imidazole and 81 mg of sodium iodide in 3 ml of dimethylformamide was heated, with stirring, at 130°-140° C. for 6 hours, after which the mixture was treated and the product purified essentially as described in Example 34(b)(i), to give 66 mg of the title compound, in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5](Cl)=[O:6].[F:14][C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([NH:18][NH2:19])=[O:17].N1C=CC=CC=1.Cl>C(OCC)C>[F:1][C:2]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:19][NH:18][C:16](=[O:17])[C:15]([F:14])([F:24])[C:20]([F:22])([F:23])[F:21])=[O:6]
Reactant: NNC(=O)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)CCC(F)([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC(F)([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of 0.95 g (0.0045 mole) of 4-fluoro-4,4-dinitrobutyryl chloride in 20 mL of anhydrous diethyl ether stirred at 20° C. was added 0.8 g (0.0045 mole) of N-(perfluoropropionyl)hydrazine followed by the dropwise addition of 0.4 mL of pyridine. After 5 minutes, dilute hydrochloric acid (10 mL) was added, the ether layer was separated, dried (Na2SO4) and the volatiles were removed to give the product N-(4-fluoro-4,4-dinitrobutyryl)-N'-(perfluoropropionyl)hydrazine, 1.05 g, mp 128°-132° C. Crystallization from 1,2-dichloroethane gave 0.93 g (58%), mp 135°-136° C. 1H NMR (acetone d6 +D2O): 2.80 (t, 2H), 3.36, 3.58 (d of t, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.O1CCCC1>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C:32]1[CH:41]=[CH:42][C:29]([CH2:28][C:27]2[CH:2]=[C:1]([C:3]3[C:4]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:25][N:24]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 70 %

Procedure:
To a solution of di-tert-butyl (3-ethynylpyridin-2-yl)imidodicarbonate (12 g) described in Manufacturing Example 2-4-1, 2-(4-(2-nitro-ethyl)-benzyloxy)pyridine (19.4 g) described in Manufacturing Example 2-1-4, 4-dimethylaminopyridine (230 mg) and tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (28.8 g) in 4 portions over the course of 8 hours at room temperature with stirring. After addition was complete, this was stirred at room temperature for a further 22 hours. Silica gel was added to the reaction solution, and the solvent was concentrated under a reduced pressure. The resulting silica gel was purified by silica gel chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain an oily product (11.8 g, containing about 70% of title compound) containing the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([CH3:13])[C:4]=1[N+:14]([O-])=O.N#N>[Pd].CO>[CH3:1][O:2][C:3]1[C:4]([NH2:14])=[C:5]([CH3:13])[C:6]([C:9]([F:10])([F:12])[F:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(F)(F)F)c(C)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1ccc(C(F)(F)F)c(C)c1N
Reaction time: 0.03 h

Procedure:
1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene (258 mg, 1.10 mmol), methanol (11.0 mL), and palladium on carbon (77.4 mg) were combined in a N2-purged round bottom flask. A balloon containing H2 was affixed to the flask, and the solution was saturated with H2 for 2 minutes. The reaction mixture was allowed to stir under H2 atmosphere for 12 hrs. Upon completion, as judged by LCMS, the reaction mixture was filtered through a plug of Celite and the solvent was removed in vacuo to afford 6-methoxy-2-methyl-3-(trifluoromethyl)benzenamine. MS m/z=206 [M+H]+. Calc'd for C9H10F3NO: 205.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:47][C@H:46]([C:45]([OH:44])=[O:51])[CH:48]([CH3:50])[CH3:49])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 233 and L-valine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.18-12.73 (br.s, 1 H), 8.94 (s, 1 H), 7.98 (d, 1 H), 7.23 (m, 7 H), 6.97 (m, 7 H), 6.82 (d, 2 H), 4.14 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.34 (m, 2 H), 2.03 (m, 1 H), 1.92 (m, 2 H), 0.87 (dd, 6 H); MS (ESI+) m/z 674 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([F:12])=[CH:5][C:6]=1[NH:9][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of compound 3 (0.062 g, 0.21 mmol, 1.0 equiv) in methanol (0.560 mL) was added zinc powder (0.068 g, 1.04 mmol, 5.00 equiv) followed by ammonium chloride solution (55.3 mg, 1.04 mmol, 5.00 equiv) drop wise. After being stirred for 4 h at RT, DIPEA (48.0 μL, 0.260 mmol, 1.25 equiv) and ethyl chloroformate (20.0 μL, 0.210 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by neutral alumina column chromatography (EtOAc/Hexane 18:82) to afford to compound 4A (0.017 g, 21%) as an off-white solid. TLC: 50% EtOAc/Hexane (Rf: 0.50); 1H NMR (500 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 7.00 (t, J=8.5 Hz, 2H), 6.88 (d, J=11.5 Hz, 1H), 6.26 (br s, 1H, Exc), 4.40 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.75 (br s, 1H, Exc), 3.50 (s, 2H, Exc), 1.30 (t, J=7.0 Hz, 3H); LC-MS: m/z=340 (M++1) at RT 3.46 (94.3% purity); UPLC purity: 95.2%
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19].[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>ClCCl>[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19]
Reactant: NCCCO
Reactant: O=CCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ccc1Cl

Procedure:
Sodium triacetoxyborohydride (1.86 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.57 g, Example 29b) and 3-amino-1-propanol (0.8 ml) in dichloromethane (150 ml). After 24 h the crude reaction mixture was purified by chromatography (eluting with 5-20% methanol in dichloromethane+1% ammonia) to give the subtitled compound as a white solid (1.05 g).
Reaction SMILES: C(O[C:5]1([CH2:11][CH3:12])[O:9][CH:8](C)[CH2:7][O:6]1)(=O)C.[C:13](=O)([O-])[O-:14].[K+].[K+].O1CCCC1>O>[CH2:11]([C:5]1([CH2:13][OH:14])[O:6][CH2:7][CH2:8][O:9]1)[CH3:12]
Reactant: CCC1(OC(C)=O)OCC(C)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CO)OCCO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
A mixture of methyl(2-ethyl-1,3-dioxolan-2-yl) acetate (1.39 g, 7.94 mmol), potassium carbonate (2.19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, which was subjected to NH silica gel pad filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 71.5%) as colorless oil.