Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:8]1=2)C.[Cl:24]C(OC=C)=O>C1C=CC=CC=1>[ClH:24].[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH:7]1[C:8]2[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:9]=2[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]1=2
Reactant: C=COC(=O)Cl
Reactant: CN(C)CCCC1c2cc(I)ccc2C=Cc2ccc(I)cc21
Solvent: c1ccccc1
Product: CNCCCC1c2cc(I)ccc2C=Cc2ccc(I)cc21
Product: Cl
Reaction time: 0.25 h

Procedure:
N,N-Dimethyl-3-(3,7-diiodo-5H-dibenzo[a,d]cyclohepten-5-yl)propylamine (7.3 g., 0.014 mole) in 30 ml. of benzene is added dropwise to 1.6 g. (0.015 mole) of vinyl chloroformate in 25 ml. of benzene stirred in an ice bath. Upon completion of the addition, the mixture is stirred at 30° for 15 minutes, and at 50°, another 60 minutes. The clear, pale yellow supernatant is decanted from the residual gum, filtered, and evaporated in vacuo to a yellow oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:25](=[O:27])[C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:29][CH:28]=3)[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 4-fluorobenzoic acid (29 mg, 0.21 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered to afford 90 mg (97%) of N-biphenyl-4-yl-3-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 446.18 (M+1)+, 97.9%. 1H NMR: (CDCl3): δ 9.8 (s, 1H), 7.6 (m, 6H), 7.44 (m, 3H), 7.34 (t, 1H), 7.14 (t, 2H), 3.7 (m, 10H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:14][CH2:13][N:12]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:23]=[C:18]([CH2:17][N:15]3[CH2:14][CH2:13][N:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:11]([CH3:10])[CH2:16]3)[CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2cccc(-c3cc(C#N)ccn3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 93.4 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (0.416 g, 3 mmol) was added 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (1.499 g, 3.60 mmol) followed by K2CO3 (1.244 g, 9.00 mmol) and Pd(Ph3P)4 (0.139 g, 0.120 mmol) in 1,4-dioxane (15.00 mL) and water (5.00 mL). The mixture was heated in a microwave oven for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted once with EtOAc (3 mL). The combined organic layers were filtered, concentrated on Glas-Col, redissolved in hexane/DCM (3:1, 4 mL), loaded onto Redisep silica gel column (12 g) and purified with Combiflash chromatography. Fractions were collected and the solvent was removed under reduced pressure to afford 1.10 g (94%) of the title compound. LC-MS m/z 393 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 9.0 g. (0.019 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]>>[C:1](=[O:4])([O-:3])[O-:2].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6].[CH2:5]([N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]
Reactant: O=C=O
Reactant: [OH-]
Agent: CC[N+](CC)(CC)CC
Product: O=C([O-])[O-]

Procedure:
Process according to claim 4 wherein carbon dioxide is passed through aqueous tetraethylammonium hydroxide to a pH of 8.3 to form tetraethylammonium carbonate plus dissolved carbon dioxide; adding the said tetraethylammonium carbonate to an aqueous solution of nitrates of yttrium, barium, and copper in a Y:Ba:Cu atomic ratio of 1:2:3 at a pH of about 7.7-8.0, thereby to precipitate the said Y, Ba, and Cu as carbonates; recovering and drying the precipitate; calcining the dried precipitate at about 950° C. and cooling the calcined product to about 150° C. over 8 hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O
Temperature: 115 °C
Reaction time: 4 h

Procedure:
18.0 g (46.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in 200 ml of DMF. 13.3 g (92.8 mmol) of methyl 2-acetamidoacrylate, 2.82 g (9.28 mmol) of tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) of palladium acetate and 12.9 ml (92.8 mmol) of triethylamine were added to the obtained solution, and they were stirred at 115° C. for 4 hours. The solvent was evaporated, and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[Cl:15][C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][C:10]=1[S:13][CH3:14]
Reactant: CSc1ccc(Br)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Butyl lithium (15 ml, 1.9M in hexanes) was added over 40 min to a solution of the product from step b) (6.82 g) and triisopropylborate (8.0 ml) in THF (30 ml) at −78° C. and stirred for a further 1 h. 2M HCl (20 ml) was added, the mixture was warmed to 20° C. and extracted with ether (three times). The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound (1.82 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C=O.[C:11](O)(C(F)(F)F)=O>C(O)C>[CH2:11]1[NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: NCCn1cccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CCO
Product: c1cc2n(c1)CCNC2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a ethanol solution (20 ml) of 1-(2-aminoethyl)pyrrole (9 mmol) and 37% formaldehyde (9 mmol) was added TFA (0.5 ml) and the resulting reaction mixture was stirred at 50° C. for 15 minutes. It was then cooled to come to 25° C. and stirred at this temperature for 4 hrs. Solvent was removed under reduced pressure, residue was dissolved in ethyl acetate, basified with aqueous sodium carbonate solution, organic layer was separated and dried over sodium sulfate. Evaporation of the organic layer gave the crude 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine which was dissolved in dichloromethane (90 ml) at to it DIPEA (12.15 mmol) and boc anhydride (8.9 mmol) were added at 0° C. The resulting reaction mixture was stirred for 16 hrs at 25° C. Organic layer was washed with sodium carbonate, water and brine and finally dried over sodium sulfate. Evaporation of the organic layer gave the crude product which was purified by column chromatography (1% ethyl acetate in dichloromethane). (10% ethyl acetate in hexane).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][C:8]1=[O:18])(O)=[O:2].N1C2C(=CC=CC=2)C(=O)NC1=O.BrCC1C=CC=CC=1C(OC)=O.COC(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)=O.[N:70]1([C:76]2[N:81]=[CH:80][CH:79]=[CH:78][N:77]=2)[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>>[N:77]1[CH:78]=[CH:79][CH:80]=[N:81][C:76]=1[N:70]1[CH2:75][CH2:74][N:73]([C:1]([C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][C:8]2=[O:18])=[O:2])[CH2:72][CH2:71]1
Reactant: O=C(O)c1ccccc1Cn1c(=O)[nH]c(=O)c2ccccc21
Reactant: c1cnc(N2CCNCC2)nc1
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: COC(=O)c1ccccc1CBr
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: O=C(c1ccccc1Cn1c(=O)[nH]c(=O)c2ccccc21)N1CCN(c2ncccn2)CC1

Procedure:
The title compound was prepared from 1-(2-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from quinazoline-2,4(1H,3H)-dione and methyl 2-(bromomethyl)benzoate using a procedure similar to those used for compounds of Example 1 and 2), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to that described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.76 (s, 1H), 8.40 (d, J=4.8 Hz, 2H), 8.03-8.00 (m, 1H), 7.70-7.50 (m, 1H), 7.35-7.00 (m, 6H), 6.68 (t, J=4.8 Hz, 1H), 5.25 (s, 2H), 4.10-3.60 (m, 8H). MS: m/z 443.2 [M+H]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([CH:22]3[CH2:24][CH2:23]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH:22]1([C:12]2([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:7]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH2:24][CH2:23]1
Reactant: NC1=NC(c2cccc(Br)c2)(C2CC2)c2ccccc21
Reactant: OB(O)c1cncnc1
Solvent: CC(=O)O
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(C2CC2)c2ccccc21
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate (Scheme #15, O) and pyrimidine-5-ylboronic acid: 1H NMR (DMSO-d6) δ 9.19 (s, 1 H), 9.10 (s, 2 H), 8.02 (t, J=1.76 Hz, 1 H), 7.77 (t, J=8.03 Hz, 2 H), 7.64 (dd, J=7.78, 1.25 Hz, 1 H), 7.60-7.55 (m, 1 H), 7.47-7.37 (m, 3 H), 2.05-1.94 (m, 1 H), 1.87 (s, 3 H), 0.52-0.41 (m, 2 H), 0.28-0.17 (m, 1 H), −0.04-0.05 (m, 1 H); MS (ES) m/z 327 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)COCCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylmorpholine (CAN 59229-63-9) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.4 [MH+].
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH:18](Cl)C)([CH3:15])[CH3:14].[H-].[Na+].[CH3:26]N(C)C=O>>[CH:21]([N:16]([CH:13]([CH3:14])[CH3:15])[CH:17]([CH3:18])[CH2:26][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:22])[CH3:23]
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(Cl)CN(C(C)C)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N(C(C)C)C(C)CN1C(=O)C(=O)c2ccccc21
Temperature: 90 °C

Procedure:
To a solution of 4.16 g of isatin and 6.06 g of 2-diisopropylamino-1-methylethyl chloride hydrochloride in 80 ml of dry N,N-dimethylformamide was added 2.28 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature and heated at 90° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane and the precipitates were collected by filtration. The crystals were recrystallized from benzene-hexane to obtain 4.48 g of 1-(2-diisopropylaminopropyl)isatin having a melting point of 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-3-trifluoromethyl-benzene using the conditions described in Example 10C to provide 1-Chloro-2-nitro-4-(3-trifluoromethyl-benzyloxy)-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: O.C(=O)(O)[O-].[Na+].C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][C:12]=1[O:22][CH3:23])(=O)C.Cl>CO>[CH3:23][O:22][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[OH:10])[C:18](=[O:21])[CH2:17][CH2:16][CH2:15]2
Reactant: COc1cc2c(cc1OC(C)=O)C(=O)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.9 %

Procedure:
3.5 mL of water and then 3.5 mL of saturated aqueous sodium bicarbonate was added to 117 mg of 7-acetoxy-6-methoxytetralin- 1-one dissolved in 7 mL of methanol. The resulting solution was stirred under nitrogen at 25° C. for 17 hours. Thereafter the solution was acidified with aqueous hydrogen chloride and extracted five times with 6 mL portions of methylene chloride. The combined methylene chloride extracts were washed once with brine and dried over anhydrous magnesium sulfate. The dried extract was separated by filtration and the methylene chloride was removed from the filtrate by evaporation at reduced atmospheric pressure and gave 94 mg of 6-methoxy-7-hydroxytetralin-1-one having m.p. 151-152° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:8][CH:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate (190) (0.20 g, 0.53 mmol) was dissolved in THF and EtOH (1:1, 6 mL). To the above solution was added 1 N NaOH (2.5 mL) at room temperature. The reaction was heated at 70° C. with stirring for 0.5 h and then cooled at RT. Reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with chloroform and methanol (9:1 to 4:1) as an eluent to give 0.182 g of compound 191 as an off-white solid. mp 170-171° C. 1H NMR (300 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.25 (s, 1H), d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 4.62 (s, 2H), 2.22 (br s, 4H), 1.5 (br s, 8H). LCMS (ESI): m/z 375.08 (M+Na)+. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86; Found: C, 73.05; H, 6.74.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclopropyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.23 mmol of cyclopropylamine. LC/MS [8.78 min; 398 (M+1)]
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][OH:17].[N+]([O-])(O)=O>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:16]=[O:17]
Reactant: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 5-methyl-2-(p-nitrophenyl)-4-imidazole methanol (2.9 g, 0.012 mole) and 70% nitric acid (20 ml) is stirred at 50° C for 3 hours, followed by dilution with water and neutralization with base. The precipitated yellow solid is collected by filtration to yield 2.4 g (0.011 mole) of title product, dec >270° C.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:69]1[CH:74]=[CH:73][C:72]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[CH:71][CH:70]=1>CN(C=O)C>[CH3:25][C:24]([CH3:27])([O:23][C:21]([NH:1][C@H:2]([C:18]([N:78]1[CH2:79][CH2:80][N:75]([C:72]2[CH:73]=[CH:74][N:69]=[CH:70][CH:71]=2)[CH2:76][CH2:77]1)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:22])[CH3:26]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH:30]=[CH2:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C[C@@H]2CNCCO2)cc1Br
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a) (70 mg, 0.19 mmol) was dissolved in acetone (1.5 mL), treated with potassium carbonate (78 mg, 0.56 mmol) and allyl bromide (68 mg, 1.86 mmol) added. The resulting reaction was shaken at 55° C. for 16 hrs. The reaction was filtered and concentrated under a flow of nitrogen. The crude residue was dissolved in tetrahydrofuran (8 mL) with polymer supported diphenylphosphine (0.5 g) and shaken for 4 hrs. The reaction was then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.5 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 19 as a colorless oil (35 mg).