Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.[CH:27]([O:30][C:31](Cl)=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:27]([O:30][C:31]([N:24]1[CH2:25][CH2:26][CH:22]([NH:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:23]1)=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCNC4)ncnc32)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of [1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl-amine (20 mg, 0.048 mmol), isopropylchloroformate (7.2 μL, 0.52 mmol), and triethylamine (20 μL, 0.144 mmol) in DMF (500 μL) was stirred for 2 hours at room temperature. The reaction was purified by HPLC to afford compound A142 as a white solid (9 mg, 41%). Exact mass calculated for C20H23FN6O4S 462.15 found 463.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:13]([CH2:21][CH3:22])[C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:21]([N:13]([CH2:11][CH3:12])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[S:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:22]
Reactant: CCN(CC)c1cccc(S)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: CCN(CC)c1cccc(Sc2ncccc2[N+](=O)[O-])c1

Procedure:
Thus, for example, a compound of the formula ##STR16## is obtained by reaction of 2-chloro-3-nitro-pyridine with 3-diethylaminothiophenol to give 2(3'-diethylaminothiophenoxy)-3-nitro-pyridine, reduction to the 3-amino compound, diazotisation and intramolecular coupling. The oxadiazepine derivative ##STR17## is obtained, for example, by reaction of 3-chloro-4-nitroanisole with 1-diethylamino-3-hydroxynaphthalene to give 1-diethylamino-3-(5'-methoxy-2'-nitro-phenoxy)-naphthalene, reduction to the 2'-amino compound, diazotisation and internal coupling.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][OH:14]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[N:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)CCCCC
Reactant: NO
Product: CCCCCC(CCCCC)=NO
Yield: 80 %

Procedure:
Using the general procedure described in Sedgwick, Organic Chemistry of Nitrogen, pages 169-175 (1937 Edition), 1.2 moles of 6-undecanone is reacted with an alcohol solution of 1 mole of hydroxylamine at room temperature to produce 0.8 moles of 6-undecanone oxime, ##EQU1## contaminated with 3.5% 6-undecanone.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH:7]=[N:8]2.C([S-])C.[Na+]>CN(C=O)C>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(O)cc(O)cc2ncn1-c1ccc(O)cc1
Yield: 59 %

Procedure:
A mixture of 100 mg (0.32 mmol) of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone as prepared in Example 18 or 19, and 524 mg (6.24 mmol) of sodium ethanethiolate in 2 ml of DMF was refluxed for 3.5 hr. DMF was evaporated and the residue dissolved in water. Concentrated HCl was added to adjust the pH to 5. The precipitate was filtered, dried and purified by chromatography on silica gel (loaded with CH2Cl2 and a slight amount of MeOH, eluted with 70% EtOAc in hexane) to yield 51 mg of 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (59%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(OP([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)(=O)OCC)C.[H-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(=Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
1-Methyl-piperidin-4-one (500 mg, 4.42 mmol) was dissolved in THF (10 ml) and added dropwise to a stirred mixture of (4-cyano-benzyl)-phosphonic acid diethyl ester (1.12 g, 4.42 mmol) and NaH (60% oil dispersion, 212 mg, 5.30 mmol) in THF (10 ml) under N2. The solution was stirred at room temperature for 2 h, then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (DCM/MeOH/NH4OH 95:5:0.2). The collected fractions gave 392 mg of 4-(1-methyl-piperidin-4-ylidenemethyl)-benzonitrile as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CCCc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 2.9 g of 4-phenylbutyric acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added and the mixture was stirred for 24 hours at room temperature and removed of insolubles. Ethyl ether was added to the filtrate and the precipitate was collected by filtration. The precipitate was recrystallized from a DMF-ethyl ether mixture to obtain 2.3 g of a white powder of 6-amidino-2-naphthyl 4-phenylbutyrate methanesulfonate.
Reaction SMILES: [CH:1]1([C@H:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=4[F:36])[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([C@@H:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=4[F:36])[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](CC(=O)O)C4CC4)cc3)ccc2C(C)(C)C)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a solution of 22.1 (0.040 g, 0.082 mmol) in THF/MeOH (2/1) (1.5 mL) was added a 1 M solution of LiOH (0.50 mL, 0.500 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford a 22 (0.019 g, 50% yield). MS ESI (neg.) m/e: 475.3 (M−H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1
Yield: 87 %

Procedure:
Using a similar protocol as described in Example 29C employing 4-((dimethylamino)methyl)phenol (8.4 g, 55.5 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (16.8 g, 66.7 mmol) as starting materials afforded 14.8 g (75%) of 33A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.40 (s, 9H), 2.55 (s, 6H), 3.90 (s, 2H), 4.00 (m, 2H), 4.30 (m, 2H), 4.85 (m, 1H), 6.75 (d, 2H), 7.35 (d, 2H), MS (APCI+) m/z 307 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([NH:27][C:28]([C:30]4[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][N:31]=4)=[O:29])=[CH:16][C:17]=3[C@:18]32[CH2:25][CH2:24][S:23][C:22]([NH2:26])=[N:21]3)=[C:9]([F:38])[CH:8]=1)(=O)=O.[O:41]1[CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[NH2:26][C:22]1[S:23][CH2:24][CH2:25][C@:18]2([N:21]=1)[C:17]1[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][N:31]=3)=[O:29])[CH:14]=[CH:13][C:12]=1[O:11][C:10]1[C:19]2=[CH:20][C:7]([C:44]2[CH2:45][CH2:46][O:41][CH2:42][CH:43]=2)=[CH:8][C:9]=1[F:38]
Reactant: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCSC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)cc(F)c2O3)cn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCSC(N)=N2)c2cc(C4=CCOCC4)cc(F)c2O3)cn1

Procedure:
To a microwave vial were charged with (S)-2-amino-5′-fluoro-2′-(5-methoxypyrazine-2-carboxamido)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-7′-yl trifluoromethanesulfonate (0.050 g, 0.083 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.039 g, 0.183 mmol), and PdCl2(dppf)2 (10.22 mg, 0.013 mmol). After purged with N2 for 5 min, potassium carbonate (1.5M in water) (0.167 ml, 0.250 mmol) and Dioxane (0.75 ml) were added. The reaction mixture was microwaved at 110° C. for 10 mins. LCMS indicated complete conversion to the desired product. The reaction mixture was partitioned between EtOAc and water. The organic layer was concentrated and then purified by Shimadzu HPLC to afford 50 mg of (S)—N-(2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-7′-yl)-5-methoxypyrazine-2-carboxamide as off-white solid (TFA salt). MS m/z=534.2 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1.[Pt]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 99.1 %

Procedure:
10.1 g 1-Benzyl-4-(4-fluoro-2-nitro-phenylamino)-piperidine were dissolved in 75 ml THF and 75 ml methanol and hydrogenated with 1.5 g Pt/C (10%). The catalyst was filtered, and the filtrate was evaporated to yield 9.1 g of the target compound as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH2:13](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: ClCCCl
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a mixture of 1H-indazole-6-carboxylic acid (1.0 g) in methylene chloride (15 mL) was added EDC (1.8 g), HOBT (1.27 g), and triethylamine (1.29 mL). The mixture was heated to 40° C. for 30 minutes at which time methanol (10.0 mL) was added. The mixture was stirred at 40° C. for 18 h. The mixture was removed from heat, cooled to room temperature and poured into methylene chloride. The mixture was washed twice with water then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.955 g of the title compound: 1H NMR (CDCl3) δ 3.98, 7.81, 7.86, 8.16, 8.29, 10.6.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:20]([C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol (608, 0.35 g, 0.78 mmol) in dichloromethane (15.0 mL) were added triethylsilane (2.00 mL, 12.52 mmol) and trifluoroacetic acid (1.00 mL, 13.0 mmol). The reaction was stirred at 35° C. overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (609, 0.25 g, 74%). MS (ESI) [M+H+]+=430.9.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[I:12].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[I:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[CH:2]=1
Reactant: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(I)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of 4-amino-3-iodo-5-nitrotoluene (14.0 g) in ethanol (70 ml) was added concentrated sulphuric acid (8 ml) dropwise, then the solution was heated to reflux and solid sodium nitrite (8.9 g) added in small amounts over 30 minutes. The mixture was refluxed a further one hour, and then was poured into ice water. The precipitate was washed with water and dried to yield 3-iodo-5-nitrotoluene (10.2 g). δ (360 MHz, DMSO-d6) 2.40 (3H, s, CH3), 8.07 (2H, bs, 2-H and 6-H) and 8.30 (1H, s, 4-H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C([O:9][C:10](=[O:41])[CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH2:27][N:28](C(OCC2C=CC=CC=2)=O)[CH2:29][CH3:30])[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)C.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]([N:28]([CH2:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:14]2[C:15]([O:18][CH3:19])=[CH:16][CH:17]=[C:12]([CH2:11][C:10]([OH:41])=[O:9])[CH:13]=2)[CH2:29][CH3:30])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-186) was prepared by reacting(2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride according to the procedure described in Example 1, Step 6 and then hydrolyzing the ester with aqueous LiOH in THF at room temperature
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:26][C:25]1([CH3:28])[CH3:27])=[O:23])=[O:19])C1C=CC=CC=1>CO.[Pd]>[CH3:27][C:25]1([CH3:28])[CH2:26][C@@H:24]1[C:22]([NH:21][NH:20][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])=[O:23]
Reactant: CC1(C)C[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 101.2 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-((R)-2,2-dimethylcyclopropanecarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 244 (0.35 g, 0.90 mmol) and Pd/C (0.50 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 245 (0.27 g, quant.) as an off-white solid.
Reaction SMILES: [Sm].II.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>CC#N>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]([CH3:12])[CH:7]=1
Reactant: CCC(=O)Cl
Reactant: COc1cccc(C)c1
Agent: II
Agent: [Sm]
Solvent: CC#N
Product: CCC(=O)c1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of samarium (598 mg, 3.97 mmol) in CH3CN is added iodine (3.0 g, 11.9 mmol, 3 eq.) and the mixture is stirred at RT for 2 hrs. 1-Methoxy-3-methylbenzene (500 μL, 3.97 mmol, 1 eq) is added followed by the dropwise addition of propionyl chloride (3472 μL, 39.7 mmol). After stirring at RT for 1 hr, the reaction is quenched with water (5 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with Na2CO3 (2M, 50 ml), sat Na2S2O4 (4×50 ml), water and brine, dried over MgSO4 and concentrated under reduced pressure. The resulting crude residue is purified by column chromatography on silica gel eluting with 10% EtOAc/iso-hexane to yield 1-(4-methoxy-2-methyl-phenyl)-propan-1-one as a clear oil; m/z 179.16 [M+H]+. Alternatively, intermediate C can be made by an analogous process to that for intermediate DA below.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2].[OH:22]O.Cl>[OH-].[Na+]>[C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]2[O:22][CH:11]2[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(C2OC2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a suspension of 5.6 g of 4-(2-carboxyethyl)benzalacetophenone and 20 ml of 1N sodium hydroxide solution was added 4 ml of 30% hydrogen peroxide at room temperature. The mixture was cooled in an ice-bath and 15 ml of 0.5N sodium hydroxide solution was added dropwise over a few min. with stirring. The reaction mixture was stirred at room temperature for 3 hrs. and then the pH was adjusted from 9.4 to 4.5 by the addition of 1N hydrochloric acid. After about 1/2 hr., the precipitate was collected. The precipitate was dissolved in 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The residue was dissolved in 100 ml of boiling ethyl acetate. About 50 ml of the solvent was evaporated and 50 ml of ether was added. The solution was concentrated to about 25 ml and after standing at room temperature for 17 hrs., the solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried under vacuum at 60°-65° C. to give 3.3 g (55%) of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-2,3-epoxy-1-propanone as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=O)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:15][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)(C)c1cccc2c1CC(=O)C2
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=Cc2c(cccc2C(C)(C)C)C1
Reaction time: 4 h
Yield: 33 %

Procedure:
3.6 g (19 mmol) of indanone c3 were reacted with 3.0 equivalents of methylmagnesium bromide and the mixture was worked up, analogously to instructions I.3. The reaction time was 17 hours at room temperature and a further 4 hours under reflux. The mixture was then refluxed with p-toluenesulfonic acid hydrate for 25 minutes. Chromatography gave 1.2 g (33%) of indene c4 as a yellow oil. Unused starting material could be recovered with hexane/ethyl acetate (9:1).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([CH2:31][CH2:32][CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:41][C:5]1[N:6]=[C:7]([CH2:31][CH2:32][CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Product: CCCc1nc(Oc2cccc(Cl)c2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 104 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3-chlorophenol gave 115 mg (100%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCC(N)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 0° C. mixture of 2,6-dichloro-3-nitropyridine (12 g, 62 mmol) and potassium carbonate (17.1 g, 1.24 mmol) in acetonitrile (200 mL) was added 3-amino pentane by syringe over 30 minutes. After stirring overnight at room temperature, the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and water and the organic layer was washed twice with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-35% EtOAc/Hexanes) provided the title compound as a yellow solid (7.3 g, 48%). m/z=244.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)([C:14]([F:15])([F:17])[F:16])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2(C(F)(F)F)CC(c3cc(Cl)cc(Cl)c3)=NO2)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(C(F)(F)F)CC(c3cc(Cl)cc(Cl)c3)=NO2)cc1[N+](=O)[O-]
Yield: 388.3 %

Procedure:
A solution of methyl 4-[3-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-yl]-2-nitrobenzoate (1 g, 0.43 mmol) and lithium hydroxide (73 mg) in tetrahydrofuran (20 ml) and water (10 ml) was stirred for 1 hour at room temperature. Tetrahydrofuran was then removed and the residue was extracted with ethyl acetate (2×25 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 4-[3-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-yl]-2-nitrobenzoic acid (0.75 g), 1H-NMR (400 MHz, DMSO): 7.85-7.87 (2H, m), 7.82 (1H, m), 7.66-7.69 (1H, m), 7.61-7.62 (2H, m), 4.22-4.46 (2H, m) ppm.