Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[O:33]=[C:34]1[NH:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][O:35]1>>[C:41]([O:40][CH2:39][C@@H:37]1[CH2:36][O:35][C:34](=[O:33])[N:38]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1)(=[O:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2N2CCCS2(=O)=O)CC1
Yield: 87.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (3.12 g) described in Preparation Example 179 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.33 g), the title compound (3.47 g) was obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:26])([F:25])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (3.5 g, 0.008 mol) was added portionwise to a cold (10°), well stirred mixture of 1-(4-fluorobenzoyl)piperazine hydrochloride (2.0 g, 0.008 mol) in chloroform (50 ml) and sodium carbonate (10.0 g) in water (50 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After half an hour, the mixture was filtered and the filtrate separated. The chloroform layer was dried (MgSO4). The solvent was removed by evaporation to give a yellow gum. The gum was crystallised from ethanol-water, then purified by column chromatography (basic Al2O3-chloroform) followed by recrystallisation from ethanol, to give the pure title compound (0.9 g), m.p. 172°-174.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH:14](O)[CH2:13][C@@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:36])CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([C@:8]12[CH2:15][CH:14]([F:36])[CH2:13][C@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC(O)C[C@@H]2C1=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)OC(C)(C)C)CC(F)C[C@H]2C1=O
Reaction time: 1 h
Yield: 71 %

Procedure:
(1S,5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (1.0 g, 2.89 mmol) was dissolved in methylene chloride (15 mL). Bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (0.59 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for one hour. The reaction solution was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1→4:1→1:1) to give 711 mg (71%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: COc1cccc(CBr)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cccc(OC)c2)c(=O)[nH]c1=O
Yield: 64.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (252 mg, yield: 64.2%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:28])=[C:21]([F:27])[CH:22]=2)[N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:28])[N:17]=[C:16]([NH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[C:25]([CH3:26])=[N:24]2
Reactant: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-[(6,7-Difluoro-3-methylquinoxaline-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.524 g) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white solid (0.289 g), MH+ 293.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)/C(=N\OC(=O)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 24.7 %

Procedure:
2-(2-Triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid (10 g) was suspended in 140 ml of anhydrous dichloromethane, and 6.7 ml of triethylamine was added to this suspension under ice cooling with stirring. To the resulting solution was added a solution of benzoyl chloride (3.2 g) in dichloromethane (20 ml). The mixture was stirred at room temperature for one hour, the insoluble matters were filtered off, and the filtrate was washed twice with 20ml 1N hydrochloric acid and 30 ml of saturated sodium chloride solution each and dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure, and the brown viscous residue (12 g) was purified by silica gel column chromatography using chloroform containing 10 to 15% methanol as eluent, giving 3 g of the objective compound as light brown crystals.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH2:16][CH2:17][C@H:11]2[N:10]([C:18](=[O:31])[CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(OCC)C>[C:39]([NH:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH2:16][CH2:17][C@H:11]2[N:10]([C:18](=[O:31])[CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1
Agent: Br
Solvent: CCOCC
Product: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1)c1ccccc1
Yield: 56 %

Procedure:
Using (3aR*,10aS*)-9-(3-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one hydrobromide and benzoyl chloride, the title compound was synthesized in otherwise the same manner as Example 20. Yield 56%, m.p. 244°-246° C. (diethyl ether).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[CH3:12][CH2:13][C:14]([CH2:16][C:17](OC)=[O:18])=O>C(O)(=O)C>[CH2:13]([C:14]1[CH:16]=[C:17]([OH:18])[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:12]
Reactant: Nc1ncc[nH]1
Reactant: CCC(=O)CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(O)n2ccnc2n1
Temperature: 25 °C

Procedure:
20.0 g (151.4 mmol) commercially available (Aldrich) 2-aminoimidazole sulfate and 19.7 g (151.4 mmol) methyl 3-oxo-n-valerate were heated with reflux in 27 ml acetic acid for 7 h. After cooling to room temperature remaining solids were removed by filtration, and the filtrate was diluted with water, neutralized with sodium hydroxide, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, evaporated in vacuo, while the title compound crystallized in colorless crystals, which were filtered with suction, washed with hexane, and dried in vacuo, m.p. 93°-94° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[OH:3].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[C:7]([O:6][C:4]([N:2]([CH3:1])[O:3][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1CCC(=O)O1
Reactant: CN(O)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Product: CN(OC(=O)CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of N-methyl-N-boc hydroxylamine 3 (536 mg, 3.65 mmol) in ichloromethane (8 mL) were added DMAP (134 mg, 1.10 mmol) and succinic anhydride (548 mg, 5.48 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was poured into a saturated solution of ammonium chloride (10 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layer was washed with water (20 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by silica flash column chromatography using 45% EtOAc/hexane as eluent to give the corresponding acid as a white solid (693 mg, 2.81 mmol, 77%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.42 (s, 9H), 2.65-2.70 (m, 4H), 3.17 (s, 3H).
Reaction SMILES: N.[Na].[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C(OCC)C>[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1
Reactant: CI
Reactant: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To 400 parts of liquid ammonia are added a trace of ferric chloride and 3 parts of sodium. The mixture is stirred for 30 minutes, after which 14.8 parts of 2-[p-(2-thenoyl)phenyl]acetic acid are added slowly during 30 minutes, and the mixture is further stirred for 45 minutes. 13.6 parts of methyl iodide are added dropwise and the reaction mixture is stirred for 2h. 30 400 parts of diethyl ether are then added and the mixture is stirred overnight. The ammonia is evaporated and the resulting solution is acidified with diluted hydrochloric acid. The ethereal layer is separated and extracted with 10% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ethereal solution is dried on sodium sulfate and the ether is evaporated in vacuo. The residue is triturated in petroleumether, filtered off and crystallized twice from acetonitrile, first at -20° C and then at 0° C, yielding p-(2-thenoyl)hydratropic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[C:21]([Cl:31])[CH:20]=2)[C:12]=1[F:32])=[O:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([Cl:31])[CH:20]=2)[C:12]=1[F:32])=[O:8]
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(trimethylsilyl)ethynyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (120 mg, 0.187 mmol) in THF (5 ml) was added TBAF (1.0 M solution in THF) (0.281 ml, 0.281 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (103 mg, 0.181 mmol, 97% yield). LC-MS (ES−) m/z 566 [M−H].
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>[Pd].C(O)C>[NH2:8][CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C1CC2(CCC1NCc1ccccc1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC2(CCC1N)OCCO2
Reaction time: 6 h
Yield: 93.2 %

Procedure:
Ethyl 8-[(phenylmethyl)amino]-1,4-dioxaspiro[4.5]-decane-7-carboxylate (397.2 g, 1.3 mole) was combined with 2563 ml of ethanol and 80 g of 5% palladium on activated carbon and hydrogenated at 50 p.s.i. for 6 hours at 45°-50° C. The catalyst was separated by filtration, and the filtrate was evaporated. When taken up in methylene chloride a semi-solid precipitated and was filtered out. The filtrate was evaporated to yield 277.7 g (97.4%) of the title product.
Reaction SMILES: CS(O[C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][C@H:7]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:6]([N:28]=[N+:29]=[N-:30])[C@@H:11]([CH3:12])[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (+/−)-(1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.20 M) was added NaN3 (7.0 equiv.). The solution was submerged in a 70° C. oil bath and left stirring under Ar for 4 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methyl cyclohexyl)carbamate in 87% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.68 min.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:46])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Yield: 75.4 %

Procedure:
To a mixture of 6-benzenesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (100 mg, 0.26 mmol; see U.S. Patent Application Publication No. 2004/0254215) and benzene (4.5 mL) was added benzoyl peroxide (6.3 mg, 0.026 mmol). Resulting mixture was refluxed for 15 min. prior to the addition of N-bromosuccinimide (51 mg, 0.29 mmol). Reaction mixture was refluxed overnight. It was concentrated and the crude product was purified by silica gel chromatography (eluting with 20%-80%) ethyl acetate/hexanes to provide the title compound (91 mg). MS-(+)-ion: M+1=466.18, 464.14.
Reaction SMILES: [CH2:1](OC(=O)C(OC1C=C(C(F)(F)F)C=C(N)C=1)(C)C)C.[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[C:31]([N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH3:1])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1cc(N)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1cc(N(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-amino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into 2-(3-tert-butoxycarbonylamino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at nitrogen to yield 2-[3-(tert-butoxycarbonyl-methyl-amino)-5-trifluoromethyl-phenoxy]-2-methyl-propionic acid ethyl ester and deprotected again to yield the title compound as light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C2(CO)CCN(C(OC(C)(C)C)=O)CC2)[CH:5]=[CH:6][CH:7]=1.[OH:23][CH2:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]1>>[CH2:31]([N:28]1[CH2:29][CH2:30][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:45])[F:47])[CH:39]=2)([CH:24]=[O:23])[CH2:26][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(Cl)c2)CC1
Product: O=CC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1

Procedure:
Using standard Swern oxidation reaction conditions (see step (v)/Example 80 or step (iii)/Example 81), tert-butyl 4-(hydroxymethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.2 mmol, 0.43 g) was oxidized to give 1-benzyl-4-(3-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:36]([O:38][CH:39]([O:46][CH2:47][CH3:48])[C:40]#[C:41][C:42]([O:44][CH3:45])=[O:43])[CH3:37]>C1COCC1.O>[CH2:47]([O:46][CH:39]([O:38][CH2:36][CH3:37])/[C:40](/[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])[CH3:48]
Reactant: CCOC(C#CC(=O)OC)OCC
Reactant: CCCCCCCCc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1ccc(O/C(=C\C(=O)OC)C(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of 2.06 g (10 mmol) of 4-octylphenol in 50 mL of THF was added 0.85 g (15 mmol) of powdered KOH and 3.98 g (15 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 2.8 g (15 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 2.1 g (54%) of an oil, used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][CH:41]([NH2:43])[CH3:42])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:43][CH:41]([CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[CH3:42])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)N)n1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)Nc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (907 mg, 3.01 mmol) in acetonitrile (150 mL) was added diisopropylethylamine (1.05 g, 6.03 mmol) followed by 5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-amine (920 mg, 3.01 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h while monitoring by LC-MS. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica) using 2-3% of methanol in chloroform to give 2-chloro-7-(2,4-difluorophenyl)-N-(5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine as a yellow solid (650 mg, 1.140 mmol, 37.8% yield). LC-MS (M+H)+=570.0. 1H NMR: (400 MHz, CDCl3) δ ppm 8.85 (1H, s), 8.07 (1H, d, J=8.4 Hz), 8.00-7.96 (2H, m), 7.00-6.97 (1H, m), 6.81-6.78 (2H, m), 4.47-4.31 (5H, m), 2.72-2.64 (3H, m), 2.50 (3H, s), 2.04-1.98 (3H, m), 1.78-1.74 (2H, m), 1.32-1.25 (3H, m).