Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([N:1]2[C:16]([OH:17])=[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:25])[CH:21]=[N:2]2)[CH:8]=1)#[N:10]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2cc(C#N)ccn2)c1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (5.36 g, 40 mmol, PREPARATION 2), diethyl(ethoxymethylidene)propanedioate (8.64 g, 40 mmol) and K2CO3 (10.76 g, 80 mmol) in H2O (100 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt and filtered to afford the title compound (2.5 g, 24%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.19 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 7.38 (1H, dd, J=4.8, 1.6 Hz), 7.53 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.79 (1H, s). [M+H] Calc'd for C12H10N4O3, 259. Found, 259.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:25][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[N:20]([CH3:19])[CH3:30])=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:4][CH:3]=1
Reactant: Cc1cc(N=C=O)ccc1Oc1ncc(Cl)cn1
Reactant: CN(C)c1ccccc1C(N)=O
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2N(C)C)ccc1Oc1ncc(Cl)cn1

Procedure:
A solution of a mixture comprising 3.33 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl isocyanate, 2.1 g of 2-(dimethylamino)benzamide and 30 ml of toluene, was reacted at 100° C. for 4 hours.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:24]([OH:26])=O)=[N:11][C:12]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[C:13]([F:15])[CH:14]=1)=O)(C)(C)C.[NH2:27][C:28]1[C:29]([N:37]2[CH2:42][C@H:41]([CH3:43])[CH2:40][C@H:39]([NH:44]C(=O)OC(C)(C)C)[CH2:38]2)=[C:30]2[CH2:36][CH2:35][O:34][C:31]2=[N:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[C:10]([C:24]([NH:27][C:28]2[C:29]([N:37]3[CH2:42][C@H:41]([CH3:43])[CH2:40][C@H:39]([NH2:44])[CH2:38]3)=[C:30]3[CH2:36][CH2:35][O:34][C:31]3=[N:32][CH:33]=2)=[O:26])=[N:11][C:12]([C:16]2[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=2[F:22])=[C:13]([F:15])[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)c(F)cc3N)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a mixture of 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (16.1 mg, 0.0437 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (14.0 mg, 0.0402 mmol) and HATU (53.1 mg, 0.140 mmol), DMF (1.0 mL) was added followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.9 mg, 29%). LCMS calc. for C25H26F3N6O2 (M+H)+: m/z=499.2. found 499.2.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:14][CH2:15][C:16](=[O:23])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH3:24])[CH:7]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>C(O)C>[CH:18]([OH:20])=[O:19].[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:15]2[O:14][C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])=[CH:7][C:8]=3[CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:27]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Product: O=CO
Temperature: 25 °C
Yield: 30.6 %

Procedure:
To a solution of ethyl 2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.070 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (2.0 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration then purified by preparative HPLC to afford the titled compound as solid (0.016 g, y. 16%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>COCCOC.C(=O)([O-])O.[Na+]>[N+:9]([C:7]1[CH:8]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c([N+](=O)[O-])cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A stirred solution of 4-Bromo-2,6-dinitroaniline (3 g, 11.45 mmol) in 1,2-dimethoxyethane (83 ml) was purged with nitrogen for 15 min and treated with aqueous sodium hydrogen carbonate solution (1M, 22.8 ml) followed by pyridine 3-boronic acid (2.1 g, 17.17 mmol) and 1,1-bis-(diphenylphosphino)ferrocene palladium (II) chloride complex (0.94 g, 1.15 mmol). The resultant mixture was boiled under reflux in a nitrogen atmosphere for 18 h. After cooling to ambient temperature, the dark mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×250 ml). This was dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 30% to 100% ethyl acetate in 40-60 petroleum ether. The 2,6-Dinitro-4-pyridin-3-yl-aniline was obtained as a yellow solid (1.46 g, 49%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29]CC)=O)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.CN(C)C=O>[CH:1]1[C:14]2[C:13]3([CH2:16][N:23]4[CH2:24][CH2:25][CH:26]([CH:27]([C:25]5[CH:24]=[N:23][CH:33]=[CH:32][CH:26]=5)[OH:29])[CH2:32][CH2:33]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: OC(c1cccnc1)C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (21.8 g, 92.4 mmol) in toluene (160 mL) was treated with thionyl chloride (11.7 g, 99 mmol) and N,N-dimethylformamide (0.1 g). The resulting solution was heated to reflux temperature for 2 h, then was cooled to room temperature. The mixture was then treated dropwise with a solution of ethyl isonipecotate (31.1 g, 198 mmol) in toluene (20 mL), using an ice/water bath to keep the reaction temperature <35° C. Upon complete addition, the mixture was stirred for 1 h at room temperature, then was washed sequentially with 10% hydrochloric acid (40 mL), water (40 mL), 1N aqueous sodium hydroxide (40 mL), water (40 mL) and brine (40 mL). The aqueous washes were extracted with toluene (100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated to afford the title compound (33.0 g, 85.2 mmol, 92%) as an off-white solid. 1H NMR (d6-DMSO): δ 7.33-7.14 (m, 4H), 6.99 (m, 4H), 4.54 (br, 1H), 4.38 (s, 1H, H-C(10)), 4.09 (q, J=6.5 Hz, 2H, CH2CH3), 3.8 (br, 1H), 3.0-2.5 (br, 6H), 2.05-1.45 (br, 5H), 1.19 (t, J=6.5 Hz, 3H, CH2CH3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:13])[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:10]([CH2:11][C:6]([CH3:13])([CH3:5])[C:7]([OH:9])=[O:8])=[O:12])=[CH:17][CH:16]=1
Reactant: Clc1ccccc1
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Finely powdered aluminium chloride (29.35 g), 2,2-dimethylsuccinic anhydride (13.9 g) and chlorobenzene (45 ml) were mixed, then stirred and heated on a boiling-water bath for 1.5 hours. The resulting mixture was cooled to room temperature and then poured onto a mixture of ice and water containing a little hydrochloric acid. The resulting mixture was extracted with ether. The ethereal layer was shaken with 2N sodium hydroxide and the resulting aqueous layer washed with ether, acidified with concentrated hydrochloric acid and then extracted with ether. The ethereal layer was washed with water and brine, and finally dried over magnesium sulphate. Removal of the solvent in vacuo gave 13.9 g of 3-(4-chlorobenzoyl)-2,2-dimethylpropionic acid. I.R. (Nujol Mull): 1680 cm-1 (s), 1590 cm-1 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.N[C:33]([CH3:37])(C)[CH2:34]O.C[N:39]1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:33]4[CH2:37][CH2:34]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CN1CCOCC1
Reactant: CC(C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NC2CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37.1 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (49 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:14]([N:16]=[C:17](CC)[O-])#[N:15]>C(O)C>[C:14]([NH:16][CH:17]=[N:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:3][C:2]=1[CH3:1])#[N:15]
Reactant: Cc1cc(-c2c[nH]cn2)ccc1N
Reactant: CCC([O-])=NC#N
Solvent: CCO
Product: Cc1cc(-c2c[nH]cn2)ccc1N=CNC#N

Procedure:
A solution of 4-(3-Methyl-4-amino-phenyl)-1-H-imidazole (15.9 g) and N-Cyano-ethylformimidate (9 g) in ethanol (100 ml) was stirred overnight at room temperature. The solid which crystallized out was filtered off and dried to give 11.3 of the desired compound. M.p. 200°-202° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:18][NH2:19]>O1CCCC1.C(OCC)(=O)C>[CH3:17][N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:19][CH3:18])=[C:3]2[C:15]([CH3:16])=[N:14]1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 1.268 g (5 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 7.5 ml (15 mmol) of methylamine in tetrahydrofuran (2.0 molar solution) was stirred at room temperature overnight and refluxed for 2 hours. The solvent was removed to give a white solid. The solid was dissolved in ethyl acetate and the solution washed with H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent was removed to give a white solid. Crystallization from ethyl acetate gave 0.715 g of white solid; Mass spectrum (ES) 249.2 (M+H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 13.1 %

Procedure:
A mixture of methyl thiosalicylate (0.56 g, 3.4 mmol), 2-cyano-6-methoxypyridine (0.45 g, 3.4 mmol), triethylamine (0.70 ml, 5.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.12 g, 13%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
According to the general method of Example 5, 4-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combine. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.38-8.34 (m, 2H), 8.19 (d, J=8.2 Hz, 1H), 8.09 (t, J=5.6 Hz, 1H), 8.03-7.99 (m, 2H), 7.80 (d, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 4.55 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (q, J=6.2 Hz, 2H), 1.80 (m, 4H), 1.58 (m, 2H), 1.45 (q, J=7.5 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3283, 3100, 2957, 2870, 2782, 1670, 1606, 1528, 1347, 1311, 1162, 1092, 854, 746, 737, 686 cm−1; MS (EI) m/e 496.1902 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4*HCl*0.85H2O: C, 52.57; H, 5.64; N, 15.33. Found: C, 52.57; H, 5.46; N, 15.33.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](O)[CH3:8])(=[O:4])[CH:2]=[CH2:3].[C:10]([O:14][CH2:15][CH2:16][CH2:17]O)(=[O:13])[CH:11]=[CH2:12]>>[CH2:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4])=[O:13].[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)OCCCO
Reactant: C=CC(=O)OCC(C)O
Product: C=CC(=O)OCCCCCCOC(=O)C=C

Procedure:
HPA—an isomeric mixture of 2-hydroxypropyl acrylate and 3-hydroxypropyl acrylate (available as ROCRYL 430 from Rohm and Haas, Philadelphia, Pa.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([C:28]([O:30][CH3:31])=[O:29])[NH:19]1>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1Cc2ccccc2CN1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the title compound was prepared as a solid (mp=37-40° C.). The reaction was monitored by tlc (Rf=0.64 in 10% MeOH/DCM).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:14][C:15](OC(C)=O)=[O:16].OS(O)(=O)=O>O>[C:15]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cc(O)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.1 %

Procedure:
To 3,5-dihydroxybenzoic acid (20 g, 129 mmol) was added NaOH (15.6 g, 390 mmol) in 100 mL water. After the mixture was cooled to 0° C., Ac2O (13.2 g, 129 mmol) was added. The solution was stirred for 40 min and then acidified with 10% H2SO4 at 0° C. The precipitate was filtered and washed with cold water. The crude product was recrystallized from water to give 3-acetoxy-5-hydroxybenzoic acid (15.2 g, 60%). Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.96 (s, 1H), 7.40 (dd, 1H, J=1.5 Hz), 7.26 (dd, 1H, J=1.5 Hz), 6.86 (t, 1H, 2.1H), 2.27 (s, 3H); HRMS (EI+) found 196.0380 M+, calcd 196.0372 for C9H8O6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:11](=[O:12])[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)O
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrophenylisocyanate was reacted with tert-butanol to form (3-nitro-phenyl)-carbamic acid tert-butyl ester. This was reacted with benzyl 2-bromoacetate, then the tert-butyloxycarbonyl group was removed and the resulting (3-nitro-phenylamino)-acetic acid benzyl ester was reduced with aluminium amalgam to afford (3-amino-phenylamino)-acetic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO/D2O) 7.02-6.86 (3H, m), 6.23 (1H, d), 3.55 (2H, s), 2.83 (2H, m), 2.61 (1H, m), 1.88-1.19 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 59.09; H, 8.60; N, 9.41%. C37H57N5O8.3.0 mols H2O requires: C, 58.95; H, 8.42; N, 9.29%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH:26]1C2CC3C(=CC=CC=3)NC=2C=CC=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=4)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(CN3c4ccccc4Cc4ccccc43)coc2n1

Procedure:
N-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 9,10-dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]23[O:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:16][O:15]3)=[CH:10][CH:9]=1)#[CH:7].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([C:7]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[O:15][CH2:16][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:20][O:21]3)=[CH:12][CH:13]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C(C)(C)C)cc3)(OC1)OC2
Reaction time: 0.17 h

Procedure:
n-Butyllithium (0.79 ml of 1.6M solution, in hexane) was added to a stirred solution of 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane (0.25 g.) in dry tetrahydrofuran (15 ml) at 0°, under nitrogen. The reaction mixture was stirred at 0° for 10 minutes. t-Butyldimethylsilyl chloride (0.23 g.) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated in vacuo. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC), eluting with 2:3 dichloromethane: hexane saturated with ammonia. 1-[4-(2-t-Butyldimethylsilylethynyl)phenyl]-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane was obtained as pale yellow crystals (0.32 g.)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.CC(=O)OCC>CN1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc2[nH]nc(Br)c2cc1F
Agent: CN1CCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1nc(Br)c2cc(F)c(F)cc21

Procedure:
To a light brown suspension of 3-bromo-5,6-difluoro-1H-indazole (1.0 g, 4.29 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in N-methylpyrrolidine (20 mL) was added iodomethane (0.81 mL, 12.9 mmol) at room temperature. The resulting dark brown solution was stirred for 15 h at room temperature under nitrogen atmosphere by which time the TLC (2:1, Hex:EA, Rf=0.6, major and 0.4, minor) indicated the presence of the desired compound. The reaction was diluted with water (˜100 mL), the organic compound was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine solution. After drying over MgSO4, the filtrate was concentrated to obtain the crude light brown solid which was purified by chromatography using an ISCO (80 g) column eluting with hexanes (1 min), 0-15% EA in hexanes (2 min), 15-40% EA in hexanes (15 min) to obtain 746 mg (70%) of 3-bromo-5,6-difluoro-1-methyl-1H-indazole as a white solid and 186 mg (18%) of 3-bromo-5,6-difluoro-2-methyl-2H-indazole as a light yellow solid.