Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[C:18]([O:25][CH2:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:28])(=O)C>C(Cl)Cl.CCO>[CH2:26]([O:25][C:18](=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:6][C:7]1=[O:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.5 equivalents of 1N sodium hydroxide solution are added dropwise to a stirred mixture of 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone in methylene chloride (11 ml/g) and EtOH (8.5 ml/g) whilst cooling with ice so that the internal temperature does not exceed 14 to 17° C. Then stirring is continued for 0.5 hours at ambient temperature and the methylene chloride is eliminated by evaporation in vacuo at a bath temperature of 30° C. Water is added (11 ml/g) and the mixture is thoroughly stirred. The precipitate is filtered, washed with water, isopropanol and lastly with ether and dried at 100° C.
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3]1([C:10]([Cl:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:10]([F:11])([F:12])[C:3]1([C:2]([Cl:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:17](=[O:16])[NH2:18])[CH2:5][O:4]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A sample of 15 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.055 mols) is dissolved in 75 ml methylene chloride and 7.16 grams of sodium cyanate (0.11 mols) is added. Trifluoroacetic acid, 12.6 grams, (0.11 mols) is added dropwise with stirring at 23°-33° C. The temperature is then raised to 40° C. and stirring continued for 18 hours. The product is filtered and the filtrate washed with water until neutral. Vacuum stripping gives a quantitative yield of crude products which solidified partly. Filtration and recrystallization from a mixture of benzene-hexane and once from cyclohexane yields 2,2-bis(chlorodifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 56°-57° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)c1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)c1

Procedure:
4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (12) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 56 mg (41%). 1H-NMR: 8.64-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 3H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (ddd, 7.5, 5.0, 1.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.71-6.67 (m, 2H), 3.70 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4]2([CH2:21][O:22][CH2:23][CH2:24]1)[C:17]1[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([F:19])[C:12]=1[O:11][C:10]1[C:5]2=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH2:36](I)[C:37]([CH3:40])([CH3:39])[CH3:38]>O>[Br:20][C:7]1[CH:6]=[C:5]2[C:10]([O:11][C:12]3[C:13]([F:19])=[CH:14][C:15]([O:18][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=3[C:4]32[CH2:21][O:22][CH2:23][CH2:24][C:2]([NH2:1])=[N:3]3)=[CH:9][CH:8]=1
Reactant: CC(C)(C)CI
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol (222.7 mg, 0.566 mmol), cesium carbonate (738 mg, 2.265 mmol), and DMF (2832 μL) to give a yellow suspension. The resulting mixture was stirred for 10 min, then neopentyl iodide (225 μL, 1.699 mmol) was added. The vial was capped and heated to 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]#[N:10])[CH:5]=1
Reactant: BrBr
Reactant: Cc1sccc1CCC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)cc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 3-(2-methylthiophen-3-yl)-propionitrile 60 (320 mg, 2.1 mmol) in acetic acid (5 mL) was treated with bromine (0.12 mL, 2.3 mmol) and the mixture stirred at rt for 1 hour. Water was added and the mixture was extracted with EtOAc (2×20 mL). The combined organics were washed with water and dried over MgSO4. Removal of the solvent followed with silica gel column chromatography (eluent: DCM/hexane, 1/1) gave 61 as a colorless liquid (330 mg).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC(CSCCO)=CC=2)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:16][CH:17]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccccc1-c1ccc(CSCCO)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 68 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (1.65 g, 5.21 mmol, 1 eq.) was treated with phenol (0.69 g, 7.29 mmol, 1.4 eq.), triphenylphosphine (1.91 g, 7.29 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.47 g, 1.44 mL, 7.29 mmol, 1.4 eq.). When complete, the reaction was worked up and the product purified by silica gel flash chromatography using 7.5% EtOAc in hexane as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (1.40 g, 68% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C[Si](Cl)(C)C.CC1(C)[O:21][C:20](=O)[CH2:19][C:18](=[O:23])[O:17]1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:20](=[O:21])[CH2:19][C:18]([OH:23])=[O:17]
Reactant: COc1ccccc1N
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1NC(=O)CC(=O)O
Yield: 30 %

Procedure:
To a solution of 2-methoxybenzeneamine (1.1 g, 8.93 mmol) in DCM (90 mL) was added TMSCl (1.1 mL, 8.93 mmol) at room temperature [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 mins before the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.29 g, 8.93 mmol) and then stirring was continued mixture for additional 2 hours. Water (1 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The aqueous phase was collected, acidified with conc. HCl to pH˜4, extracted with EtOAc, the extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 9:1:0.1) to afford the compound 27 (0.56 g, 30% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.62 (bs, 1H), 9.52 (s, 1H), 8.02 (dd, 1H), 7.03 (m, 2H), 6.88 (m, 1H), 3.82 (s, 3H), 3.46 (s, 2H). MS (m/z): 210.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: NC(=O)c1cccc2oc(-c3ccc(N)cc3)nc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of 2-(4-aminophenyl)benzo[d]oxazole-4-carboxamide (150 mg, 0.59 mmol) in dichloromethane (5 mL) was added pyridine (51 mg, 0.65 mmol) and acetyl chloride (49 mg, 0.62 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr, then the solvent was evaporated under reduced pressure and the residue was re-crystallized in methanol to obtain 2-(4-acetamidophenyl)benzo[d]oxazole-4-carboxamide as a white solid (155 mg, yield 89%). 1H-NMR (400 MHz, DMSO-d6) δ 2.10 (s, 3H), 7.49-7.53 (t, J=8 Hz, 1H), 7.83-7.85 (d, J=8 Hz, 2H), 7.95-7.99 (m, 3H), 8.23-8.26 (d, J=8 Hz, 2H), 8.48 (s, 1H), 10.36 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.55 mL, 11.7 mmol) in DCM (5 mL) was added dropwise to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid C4c (2.5 g, 10.7 mmol) in DCM (15 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 30 minutes. N-Ethyl-N-isopropylpropan-2-amine (2.74 mL, 16.0 mmol) was added in one portion followed by 5-methylpyridin-2-amine (CAS 1603-41-4) (1.27 g, 11.73 mmol) in DCM (5 mL) dropwise. The resulting solution was stirred at ambient temperature for 1 hour. 1M Citric acid (10 mL) was added and the mixture extracted with EtOAc (20 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and evaporated to provide the crude product. Purification by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane furnished (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (1.4 g). 1H NMR (400 MHz, CDCl3) δ 0.2 (6H, s), 1.01 (9H, s), 2.32 (3H, s), 3.41 (3H, s), 3.66-3.75 (2H, m), 4.40-4.42 (1H, m), 7.52 (1H, d), 7.14-7.16 (2H, m), 9.04 (1H, s), m/z (ESI+) (M+H)+=326; HPLC tR=2.75 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][N:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C=C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(=Cc2cccc(Br)c2CC)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.2 %

Procedure:
To a solution of 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (0.53 g, 1.891 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added potassium carbonate (3.92 g, 28.4 mmol), followed by ethyl bromoacetate (0.190 mL, 1.702 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated to afford ethyl {4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinyl}acetate (D142) (0.693 g). MS (ES): C18H24BrNO2 requires 365.1. found 366.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][NH2:19])=[CH:16][N:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: NCc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CN)cn2)ccn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of (2-methylpyridin-4-yl)boronic acid 15-1 (476 mg, 3.48 mmol), (6-chloropyridin-3-yl)methanamine 18-1 (496 mg, 3.48 mmol), Pd(PPh3)4 (202 mg, 0.175 mmol) and K3PO4 (1113 mg, 5.25 mmol) in dioxane (5 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 7% ammonia-saturated methanol in dichloromethane as eluent to give (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 as an oil.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]([NH2:28])[C:15]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]2[C:15]=1[NH:29][C:2](=[O:4])[NH:28]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nc(SCc2ccccc2)nc(Cl)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
A solution of triphosgene (0.92 g) in DCM (25 ml) was added dropwise to a solution of the product from example 2, step (e) (0.69 g) and triethylamine (0.55 ml) in DCM (25 ml) at −10° C. The cooling bath was then removed and the suspension stirred for 2.5 h. Upon cooling to 0° C. NaHCO3 (20 ml) was added with vigorous stirring before recovering the organics by extracting with DCM (3×50 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield a crude yellow solid. This material was triturated with EtOAc and filtered to afford a pink solid (360 mg, 48%). The filtrate was concentrated and again triturated with EtOAc to provide a second crop (170 mg, 70% overall)
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[C:4]([Cl:12])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:3]([Cl:13])=[C:4]([Cl:12])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)c1Cl
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 1.25 h

Procedure:
The desired tetrachlorobenzoyl chloride is prepared by reacting the tetrachlorobenzoic acid with thionyl chloride. A six fold molar excess of thionyl chloride is slowly added to the acid. This mixture is heated to reflux and held at this temperature for 1.25 hours. The solution is then cooled and the excess thionyl chloride vacuum distilled off. The solution is further distilled under vacuum to yield the pure tetrachlorobenzoyl chloride in 92-93% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
To a solution of the methyl ester (Example 1) (12.5 g) in tetrahydrofuran (150 ml) and methanol (300 ml) was added 2N sodium hydroxide (78 ml). The reaction mixture was heated under reflux for 4 hours, then cooled. The volume was reduced in vacuo to approximately 100 ml. and the solution acidified with 5N hydrochloric acid. On cooling, the crystalline product was filtered off and dried in vacuo in the oven at 50° C. to give 1-(3-nitrobenzyl)indole-5-carboxylic acid (m.p. 251°-254° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[S:37])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 92%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(O)C>[C:1]([NH:4][C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: BrCCCCCCCCCCCCOC1CCCCO1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCCCCCCOC1CCCCO1)(NC(C)=O)C(=O)OCC
Yield: 39.2 %

Procedure:
Diethyl acetamidomalonate (6.996 g) and 3.189 g of sodium ethoxide were dissolved in 130 ml of dry ethanol and a solution of 10.698 g of 1-bromo-12-tetrahydropyranyloxydodecane in 200 ml of dry ethanol was added thereto. The mixture was refluxed under heating for 8 hours. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography to give 5.837 g of diethyl 2-acetamido-2-(12-tetrahydropyranyloxydodecyl)malonate.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.C(N(CC)CC)C.[OH:46][N:47]=[C:48](Cl)[CH3:49]>C(Cl)Cl>[CH3:49][C:48]1[CH2:38][CH:37]([CH2:36][O:35][C@H:32]2[CH2:31][CH2:30][C@H:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:46][N:47]=1
Reactant: CC(Cl)=NO
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution (40 mL) of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (2.7 g) and triethylamine (7.5 mL) in methylene chloride was added N-hydroxyethanimidoyl chloride (5 g) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 28%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.[OH-].[Li+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)[C:16]=1[N:29]1[CH2:30][CH2:31][C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Reactant: C1CCC2(C1)CCNC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(-c3ccccc3)nn2c(N2CCC3(CCCC3)C2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
(S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate was dissolved in NMP (1 mL) and combined with 2-azaspiro[4.4]nonane (8.72 mg, 0.070 mmol) and N,N-diisopropylethylamine (27 mg, 0.21 mmol). This mixture was stirred at rt for 24 h. A 1M lithium hydroxide solution (0.348 mL, 0.348 mmol) was added to the reaction mixture and it was heated at 50° C. for 4 h to complete the ester hydrolysis. The reaction mixture was concentrated in vacuo and purified by Biotage (4 g column, 0-10% MeOH/CH2Cl2 ramp) to give 11.1 mg (27% yield) of S)-2-(tert-butoxy)-2-(5-methyl-2-phenyl-7-(2-azaspiro[4.4]nonan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic (1:1 solvate with NMP) as a yellow waxy solid.