Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:16](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOCC
Reactant: Fc1cc(F)cc(C2(F)CCNC2)c1
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CCC(F)(c2cc(F)cc(F)c2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-(3,5-difluorophenyl)-3-fluoropyrrolidine (0.17 g, 0.85 mmol) in formic acid (2.45 mL) and aqueous formaldehyde (40%, 2.2 mL) was heated at 85° C. for 1 h. Water (100 mL) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5M, 20 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.12 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 128-129° C.; MS m/z (relative intensity, 70 eV) 215 (M+, bp), 194 (29), 193 (36), 151 (33), 57 (92).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([O:20]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[CH:27]=[CH:26][N:25]=[CH:24]1.C[O-].[Na+].C1(C)C=CC=CC=1>CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:40][C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][CH2:29][CH2:28][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH:32]=[CH:33]2)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(ccn2CCCn2ccnc2)c1
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(Nc1ccc2c(ccn2CCCn2ccnc2)c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A mixture of 27.9 g of ethyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate, 17.8 g of 1-[3-(imidazol-1-yl)propyl]-5-aminoindole, 8 g of sodium methylate and 600 ml of toluene was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, the crystals being separated were collected by filtration and washed with toluene. Thus obtained crystals were dissolved in 500 ml of chloroform, then 100 ml of water was added and the mixture was filtrated with Celite. The chloroform layer was taken by separation, after washed with water, the chloroform portion layer was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation to obtain brown oily product. This oily product was dissolved in methanol, further added n-hexane and the crystals being separated were collected by filtration, recrystallized from methanol and dried. There was obtained 31.8 g of 1-benzyl-6-chloro-2-{1-[3-(imidazol-1-yl)propyl]indol-5-ylamino-carbonyl}benzimidazole.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:27](=[O:29])[CH3:28])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-amine monohydrochloride (17.6 g) in pyridine (85 mL) was added acetic anhydride (12.6 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane/ethyl acetate to give the title compound (12.0 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42]([CH:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][N:36]([C:42]([CH:44]4[CH2:48][CH2:47][CH2:46][O:45]4)=[O:43])[CH2:37][CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(=O)C3CCCO3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 679.2 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([CH3:31])([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:33])[F:34])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.17 h

Procedure:
1.98 g (6.74 mmol) of [3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 218A and 1.51 g (7.42 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]-ethylamine from Example 1A are placed in 50 ml of DMF and treated with 1.09 g (8.09 mmol) of HOBt. After 10 mins' stirring, 1.68 g (8.76 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with 500 ml of water. Next, the resulting precipitate is suction-filtered, washed with water and dried under high vacuum. 2.41 g (75% of theory) of the target compound are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 50 parts of 4-nitroaniline, 40 parts of triethylamine and 525 parts of chloroform were fed, and then cooled to 5° C. or below. While the reaction solution obtained was kept at 5° C. or below, a solution prepared by dissolving 41 parts of methacrylic acid chloride in 30 parts of chloroform was dropwise added thereto. After its addition made dropwise was completed, the reaction solution was heated to room temperature, and, as it was, the reaction was carried out for 4 hours. After the reaction was completed, the organic phase formed was washed with 200 parts of ion-exchanged water. This organic phase was then dried with sodium sulfate, and thereafter the solvent was evaporated off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 22 parts of an intermediate N-(4-nitrophenyl)methacrylamide (yield: 31%).
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1)[NH2:2].[C:13](OCC)(OCC)(OCC)[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[N:7]2[C:3]([S:4][C:5]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=32)=[N:1][N:2]=1
Reactant: Cc1cccc2sc(NN)nc12
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1cccc2sc3nnc(C)n3c12
Temperature: 25 °C

Procedure:
A solution of 6.1 grams of 2-hydrazino-4-methylbenzothiazole (0.034 mole) and 6.4 grams of triethyl orthoacetate (0.04 mole) in 200 milliliters of xylene was brought to reflux temperature over a period of 5 hours and thereafter refluxed for 96 hours. The reaction mixture was then concentrated to one-fourth of the original volume and allowed to cool to room temperature. The 3,5-dimethyl-s-triazolo(3,4-b)benzothiazole product was separated by filtration, 4 grams, m.p., 196°-8° C.
Reaction SMILES: C[O:2][C:3]1(C(O)=O)[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.[C:18]([OH:21])(=[O:20])C.Br(O)(=O)=O>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:18]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COC1(C(=O)O)C=CC(c2ccccc2)=CC1
Agent: [O-][Br+2]([O-])O
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(O)cc1

Procedure:
A mixture of 25 of 4-methoxybiphenyl-4-carboxylic acid, 1 1 of acetic acid and 200 ml of 48% bromic acid was refluxed for 12-14 hours and then throwninto 2.5 l of water. After cooling, the resultant crystal was collected to obtain 4'-hydroxybiphenylcarboxylic acid.
Reaction SMILES: [O:1]=[C:2]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)[CH:3]([C:6]([O:8]CC)=O)[C:4]#[N:5].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)[CH:3]([C:6](=[O:8])[NH:21][C:20]1[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=1)[C:4]#[N:5]
Reactant: CCOC(=O)C(C#N)C(=O)c1ccc[nH]1
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: N#CC(C(=O)Nc1ccc(F)cc1)C(=O)c1ccc[nH]1
Temperature: 25 °C

Procedure:
A mixture of 1.1 g of β-oxo-α-ethoxycarbonyl-β-(2-pyrrolyl)-propionitrile, 1.5 g of 4-fluoroaniline and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue is purified to yield β-oxo-α-(4-fluorophenyl carbamoyl)-β-(2-pyrrolyl)-propionitrile of example 5.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:19]=[C:18]([C:20](C)(C)C)[CH:17]=[C:16]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)[C:15]=1[OH:30])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=C(C)C=C(C)C=1>[C:24]1([C:16]2[C:15]([O:30][P:2]3[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]3)=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:19]=[C:18]([CH3:20])[CH:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC(C)(C)c1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)COP(Cl)OC1
Solvent: CCN(CC)CC
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1cc(C2=CCCCC2)c(OP2OCC(C)(C)CO2)c(C(C)(C)C)c1
Yield: 57.1 %

Procedure:
4.85 g (29.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added drop-wise over a period of about 15 minutes to a solution of 6.6 g (27.0 mmol) of 6-(cyclohexen-1-yl)-2-tert-butyl-4-methylphenol (compound (102), Example 1) and 4.0 ml (29.0 mmol) of triethylamine in 25 ml of mesitylene (1,3,5-trimethylbenzene). The reaction mixture is then refluxed for 18 hours, cooled, filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from dry acetonitrile gives 5.8 g (57%) of 2-[6-(cyclohexen-1-yl)-2-tert-butyl-4-methyl-phenoxy]-5,5-dimethyl-1,3,2-dioxaphosphorinane, m.p. 97°-102° C. (compound (201), Table 2).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([OH:6])([CH3:5])[CH3:4].[H-].[Na+].[N+]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([O-])=O>CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[F:1][C:2]([F:8])([F:7])[C:3]([CH3:5])([CH3:4])[O:6][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)(Oc1ccc(C#N)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
Add 2-trifluoromethyl-2-propanol (3.4 g, 27 mmol) slowly to a slurry of sodium hydride (0.6 g, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add a solution of 4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL). Stir the resulting purple slurry at ambient temperature for 16 h, dilute with diethyl ether (100 mL) and wash with 5% aqueous HCl (30 mL). Separate the layers and extract the aqueous layer with diethyl ether (2×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (780 mg, 25%). GC-MS m/z: 229 (M+).
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1>O1CCCC1.COCCOC>[Cl:5][C:6]1[NH:7][CH:8]([CH2:3][CH3:4])[C:9]([F:13])=[C:10]([Cl:12])[N:11]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCC1NC(Cl)=NC(Cl)=C1F

Procedure:
To magnesium turnings (4.27 g) in tetrahydrofuran (56 ml) was added a solution of bromoethane (19 g) in THF (19 ml) over 5 hours. To this slurry at 0° C. was added a solution of the product of part (i) (24 g) in 1,2-dimethoxyethane (70 ml) over 1 hour. The reaction was quenched at 10° C. using glacial acetic acid (10 g) to give a solution of the title compound which was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:68](O)[CH2:69][OH:70]>C(OCC)(OCC)OCC.C(OCC)(=O)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[O:2]1[CH2:68][CH2:69][O:70][CH:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-formylphenyl)acetate (1.72 g, 9.66 mmol) was dissolved in ethylene glycol (2.3 mL) and triethyl orthoformate (1.8 mL). Tetrabutylammonium tribromide (0.048 g) added and the reaction stirred at RT for 1 hour. Further tetrabutylammonium tribromide (0.434 g) added and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-15% ethyl acetate in iso-hexane to afford impure methyl 2-(4-(1,3-dioxolan-2-yl)phenyl)acetate (0.84 g). This material was dissolved in THF (15 mL) and cooled to −78° C. A solution of lithium aluminium hydride (1.0 M in THF, 6.00 mL, 6.00 mmol) was added drop-wise. The reaction mixture was allowed to warm to RT over 18 hours. The mixture was sequentially treated with water (0.228 mL), 2M aqueous sodium hydroxide (0.228 mL) and water (3×0.228 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture was stirred at RT for 1 hour and then filtered through celite. The filter cake was washed with further ethyl acetate and the filtrates combined. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (0.315 g, 17%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=2.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Reactant: Cn1c(=O)c(N)c(N)c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2cccnc21
Temperature: 0 °C
Yield: 12.2 %

Procedure:
3-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.277 g, 1.0 mmol), TEA (0.10 g, 1.0 mmol), and HOBt (0.135 g, 1.0 mmol) were added sequentially to a stirred solution of 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (0.19 g, 1.0 mmol) in DMF (8 mL) at room temperature. The solution was cooled to 0° C. and EDCI (0.19 g, 1.0 mmol) was added. The resulting solution was allowed to stir, with warming to room temperature, for 17 h. The mixture was diluted with water (5 mL) and extracted with CH2Cl2, dried with MgSO4, and concentrated. The residue was purified by flash chromatography eluting with 5% MeOH in CH2Cl2 to give [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-[1,8]naphthyridin-3-ylcarbamoyl)-cyclohexyl]carbamic acid benzyl ester (55 mg, 12% yield), and 60 mg (32%) of unreacted diamine. 1H-NMR (CDCl3): δ 8.59 (m, 1H), 8.21 (m, 1H), 7.91 (m, 1H), 7.33 (m, 6H), 7.20 (dd, 1H, J=8.0, 4.8), 5.51 (m, 2H), 5.12 (m, 2H), 4.76 (m, 1H), 4.10 (m, 1H), 3.81 (s, 3H), 2.60 (m, 1H), 2.33 (m, 1H), 1.93–2.05 (m, 3H), 1.73 (m, 2H), 1.45 (m, 2H). MS: calculated for C24H27N5O4+H 450.2; found: 450.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[CH2:14][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17]O)=[C:4]([F:24])[CH:3]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[CH2:14][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17][Cl:27])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CCO)C(F)(F)F)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)CC(CCCl)C(F)(F)F)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 64 h

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-5-hydroxy-3-(trifluoromethyl)pentanamide (1.2 g, 3.2 mmol) in 100 ml methylene chloride, was added thionyl chloride (0.24 ml) in one portion via pipette. The solution turned brown. It was heated to 40°-50° C. for about 7 hours, kept at room temperature for 64 hours, heated to 40° C. for 3 hours, then stirred at room temperature for 18 hours. Then additional thionyl chloride (0.1 ml) was added and heating to 40° C. was resumed for about 4 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dried in vacuo (50° C.) and the resulting golden brown, semi-solid mixture was purified via flash chromatography (20 ml fractions, 2'×7' column, 1:9 ethyl acetate/hexanes) to yield a brown solid, m.p. of 57°-63° C.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1(O)[CH:23]2[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2>C1(C)C=CC=CC=1>[C:1]12([NH:14][CH2:15][C:16]3([CH:23]4[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]3[CH2:25]5)[CH2:24]4)[O:13]1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: NCC1(O)C2CC3CC(C2)CC1C3
Reactant: O=C1CCCCCCCCCCC1
Solvent: Cc1ccccc1
Product: C1CCCCCC2(CCCCC1)NCC1(O2)C2CC3CC(C2)CC1C3

Procedure:
Cyclododecanone (0.91 gram, 5 mmol) was added to a solution of 2-aminomethyl-2-hydroxyadamantane (0.90 gram, 5 mmol) in 30 ml toluene. After the mixture was refluxed (Dean-Stark separator) for 7 hours, the solvent was evaporated leaving derivative VIII as a brown oil which crystallized from isopropanol, Yield--1.08 gram melting point 241°-245° C. (white crystals from isopropanol).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].BrC1C=CC=C2C=1C1(COC3C=C4C(=CC1=3)CCO4)C(=O)N2C[C:35]1[O:36][C:37](C(F)(F)F)=[CH:38][CH:39]=1.O1C=CC(B(O)O)=C1.N1C=C(B(O)O)C=NC=1>>[O:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:35]1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: OB(O)c1ccoc1
Agent: OB(O)c1cncnc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 4.14, and making non-critical variations using 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)one, and 3-furanboronic acid to replace pyrimidine-5-boronic acid, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 2H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 2H), 6.45-6.38 (m, 1H), 6.23-6.16 (m, 1H), 6.07-5.97 (m, 1H), 5.97-5.80 (m, 2H), 4.75-4.50 (m, 2H), 3.30-3.22 (m, 3H); MS (ES+) m/z 362.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2C(=O)C(=O)c3cc(Cl)ccc32)cc1

Procedure:
5-chloro-N-(p-tolylsulfonyl)-isatin was prepared by the method of Example 3, Step B from 5-chloroisatin and p-tolylsulfonyl chloride.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][C:2]21[CH2:16][C:15](=[O:17])[NH:14][C:13]2=[O:18].[H-].[Na+].I[CH3:22].Cl>CN(C=O)C.O>[CH3:22][N:14]1[C:15](=[O:17])[CH2:16][C:2]2([CH2:3][N:4]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[C:5]3[CH2:1]2)[C:13]1=[O:18]
Reactant: CI
Reactant: O=C1CC2(Cc3cc4ccccc4n3C2)C(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CC2(Cc3cc4ccccc4n3C2)C1=O
Reaction time: 17 h

Procedure:
A solution of 1.96 g of 1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione [prepared as described in Example 11(iv)] in 10 ml of DMF was added dropwise to a stirred suspension of 330 mg of a 60% dispersion of sodium hydride in mineral oil in 10 ml of DMF. The mixture was treated with 1 ml of iodomethane and stirred for 17 hours. The mixture was diluted with water, neutralized with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with sodium chloride solution, dried and the solvent was removed by evaporation. Crystallization of the residue from ethyl acetate/n-hexane gave 1.81 g of 1',3'-dihydro-1-methylspiro-[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione of melting point 154°-156° C.