Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C(F)(F)F.Cl.Cl.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18]2)=[N:14][C:15]=1[NH2:16].[Cl:30][C:31]([Cl:37])([Cl:36])[C:32](=N)OC>C(O)=O>[N:25]1([C:23]([C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:13]3[N:14]=[C:15]4[NH:16][C:32]([C:31]([Cl:37])([Cl:36])[Cl:30])=[N:9][C:10]4=[CH:11][CH:12]=3)[CH2:18]2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: O=CO
Solvent: OCC(F)(F)F
Product: O=C([C@@H]1CCCN(c2ccc3nc(C(Cl)(Cl)Cl)[nH]c3n2)C1)N1CCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Formic acid (2.8 mL) and trifluoroethanol (61 mL) were added to (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride. Methyl 2,2,2-trichloroacetimidate (1.65 mL) was added and the reaction mixture was stirred at 60° C. for 3 h. The mixture was used for the next step without further workup or purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][C:4]=1[F:15].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][C:4]=1[F:15])[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(CCN)c[nH]c2cc1F
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 0.75 grams (3.6 mmole) of the tryptamine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was prepared. Acetic anhydride (1.0 ml.) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvents then were removed in vacuo with moderate heating. The resulting crystalline residue was dissolved in a 1:1 mixture of warm ethyl acetate and chloroform. The solution was washed with water, then with sodium chloride solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The crystalline residue was boiled in benzene for a few minutes. The mixture was allowed to stand at room temperature for several hours, and the resulting product was collected by filtration and dried to obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, m.p. 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH2:34].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>C(Cl)Cl>[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH:34][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 29.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid (3,3-dimethyl-butyl)-amide (30.4 mg, 29.5%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[CH:15]=[C:14]2[C:10](C=C[NH:13]2)=[CH:9][CH:8]=1)#[N:6].Cl.CCO[C:20]([CH3:22])=[O:21]>>[CH:20]([C:22]1[C:10]2[C:14](=[CH:15][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[NH:13][N:1]=1)=[O:21]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=N[O-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc2c(C=O)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of NaNO2 (11.04 g, 160 mmol) in DI—H2O (200 mL) was added 6-cyanoindole (5.68 g, 40 mmol) in one portion slowly. The resulting suspension was stirred for 5 min at rt. 6N HCl (32 mL, 192 mmol) was added dropwise via a dropping funnel over 30 min and the pH was about 1. The resulting suspension was stirred for 4.5 h at rt before 400 mL of EtOAc was added. After stirring for additional 10 min to dissolve the precipitate, the two layers were separated and the aqueous layer was extracted with EtOAc (150 mL). Combined extracts were dried over Na2SO4. Removal of solvents afforded 6.864 g (100%) of title compound as brown (coffee color) solid. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H, NH), 10.22 (s, 1H, CHO), 8.38 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H). MS ESI 172.0 [M+H]+, calcd for [C9H5N3O+H]+ 172.0.
Reaction SMILES: [CH3:1]C[O-].[Na+].[S:5]1[CH:9]=[CH:8][C:7](C=O)=[CH:6]1.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:18]([O:17][C:15]([C:14](=[CH:1][C:9]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:13][C:12]([OH:21])=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1ccsc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)CC(=O)O
Yield: 56.8 %

Procedure:
Sodium ethylate (36.3 g, 0.53 mol) was added under vigorous stirring to a solution of 3-thiophenecarboxaldehyde (50 g, 0.44 mol) and diethyl succinate (116 g, 0.66 mol) in ethanol (1 L). The reaction mixture was refluxed for 8 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 500 mL of a saturated aqueous solution of NaHCO3, and aqueous layer shaken. The was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm; hexane/ethyl acetate mixture, 1:1). Fractions with the target product were collected and evaporated in vacuum to give 61 g (0.25 mol, 57%) of 3-(ethoxycarbonyl)-4-(2-thienyl)but-3-enoic acid as a light-brown oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH:14][CH3:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(O)=O>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N:14]([CH3:15])[S:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(NC)cnc3n2CC2CC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOc1ccc(Cc2nc3cc(N(C)S(=O)(=O)c4ccccc4)cnc3n2CC2CC2)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine (237.0 mg, 0.70 mmol) in acetonitrile (5 mL) at room temperature was added triethylamine (196 μL, 1.41 mmol) followed by benzenesulfonyl chloride (156 mL, 0.92 mmol). The mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved into EtOAc (10 ml) and Na2CO3 saturated aqueous solution (10 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (10 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC (C-18 column, 20 to 80% [0.1% AcOH in AcCN solution] in 0.1% AcOH aqueous solution) to provide 63 mg of the AcOH salt of the title compound N-[3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-N-methyl-benzenesulfonamide (17% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine). 1H-NMR (400 MHz, d3-MeOD): δ 0.37 (m, 2H), 0.42 (m, 2H), 1.10 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 3.31 (s, 3H), 3.99 (t, J=7.0 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.32 (s, 2H), 6.86 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.55 (m, 2H), 7.57 (m, 2H), 7.59 (m, 1H), 7.70 (m, 1H), 8.11 (d, J=2.2 Hz, 1H). MS (ESI) (M+H)+: 477.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=1.S(=O)(=O)(O)O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:19])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: NCc1ccc(C(=O)O)c(F)c1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CN)cc1F

Procedure:
4-Aminomethyl-2-fluorobenzoic acid hydrochloride (500 mg) was dissolved in methanol (10 mL), concentrated sulfuric acid (6 μL) was added, and the mixture was stirred with heating under reflux for 9 hr. After completion of the reaction, the solvent was evaporated, saturated aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (181 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@@H:12]1[C:27](=[O:28])[N:14]2[C:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12.C(OO)(=O)C.C(=O)([O-])O.[Na+]>CC(N(C)C)=O.C(#N)C>[CH3:19][C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH:11][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27](=[O:28])[N:14]2[C:15]=1[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.75 h

Procedure:
Phenylacetyl chloride (0.58 ml, 1.1 equiv.) was added to a stirred solution of t-butyl 7β-amino-3-methylceph-3-em-4-carboxylate (1.08 g, 4 mmole) in dimethylacetamide (2.5 ml) and acetonitrile (10 ml.) The mixture was stirred at ca. 25° for 45 minutes and the acetonitrile was removed in vacuo. Water (50 ml) and ethyl acetate (150 ml) were added and the organic phase was washed with water, 3% sodium hydrogen carbonate solution and water (50 ml of each), dried and evaporated. The residual colourless oil was dissolved in methylene chloride (10 ml) and cooled in an ice-bath while peracetic acid (40% w/v; 1.16 ml, 1.1 equiv.) was added dropwise. The solution was stirred at ca. 20° for 30 minutes and saturated sodium hydrogen carbonate solution (20 ml) was added. The organic phase was washed with water (50 ml), dried and evaporated to a white gelatinous solid, t.l.c. (acetone-methylene chloride; 1:4) Rf 0.49, 0.80, which was purified by chromatography on Kieselgel G (50g). Elution with acetonemethylene chloride (1:9) gave a pale yellow solid which was crystallised from acetone-light petroleum, b.p. 40°-60° (1:1; 10 ml) to give t-butyl 3-methyl-7β-phenylacetamidoceph-3-em-4-carboxylate, 1,1-dioxide (0.17 g, 11 %), m.p. 87 to 88°, [α]D + 36.5°, λmax. 259 nm (ε 8,150), νmax. (CHBr3) 3410 (NH), 1798 (acetidin-2-one), 1714 (CO2R) and 1680 and 1510 cm-1 (CONH), τ (CDCl3) 2.66 (5H,s; C6H5), 3.06 (1H,d, J 10.5 Hz; NH), 3.90 (1H,dd, J 10.5, 5Hz; C7 -H), 5.19 (1H,d, J 5 Hz; C6 -H), 6.09, 6.55 (2H, AB-q, J 18 Hz; C2 -H2), 6.34 (2H,s; C6H5CH2), 7.94 (3H,s; C3 -CH3), 8.49 (9H,s; CO2C(CH3)3). (Found: C, 56.9; 56.6; H, 5.8; 5.7; N, 6.3, 6.3; S, 7.4 C20H24N2O6S (420.5) requires C, 57.1; H, 5.75; N, 6.7; S, 7.6%). Further elution with acetone-methylene chloride (1:9) gave a white gelatinous solid which dissolved in acetone (10 ml) and reprecipitated by addition of light petroleum (b.p. 40°-60°; 10 ml) to give the title ester 1β-oxide (1.04 g, 67%), m.p. 181° to 182° (dec), [α]D + 164°, λmax. 265 nm (ε 7,900), νmax. (CHBr3) 3390 (NH), 1790 (azetidin-2-one), 1716 (CO2R), 1678 and 1510 (CONH) and 1050 cm-1 (S→O), τ (CDCl3 + 3 drops Me2SO-d6) 2.68 (5H,s; C6H5), 4.12 (1H,dd, J 9.5,4.5 Hz; C7 -H), 5.34 (1H,d, J 4.5 Hz; C6 -H), 6.37 (2H,s; C6H5CH2), 6.56 (2H,s; C2 -H2), 7.91 (3H,s; C3 -CH3), 8.47 (9H,s; CO2C(CH3)3) (Found: C, 60.0, 59.6; H, 6.1, 5.9; N, 6.7, 6.7; S, 7.8 C20H24N2O5S (404.5) requires C, 59.4; H, 6.0; N, 6.9; S, 7.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ccnc4ncc(=O)[nH]c34)c2)n(-c2ccccc2)n1
Yield: 29 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a yellow solid (57 mg, 29%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[OH:17])[CH:2]([CH2:4][OH:5])[OH:3].C(=O)([O-])O.[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O>[CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[O:17][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Under an argon atmosphere, 3-O-glyceryl ascorbic acid (54.1 g) obtained in Example 1 was stirred in DMSO (200 mL), and further, sodium hydrogen carbonate (18.5 g) was added and the mixture was stirred at room temperature for 30 minutes. Thereafter, octyl bromide (63.7 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 131 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-glyceryl-2-O-octyl ascorbic acid (48.0 g).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][NH2:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:19][CH:18]=1>CO>[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][NH:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:26][CH:27]=1
Reactant: NCCCn1cnc2ccccc21
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 9.8 grams of 1H-benzimidazole-1-propanamine and 12.16 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 400 ml of 95% methanol was refluxed for 17 hours. The solvent was then evaporated under reduced pressure and the residue was chromatographed on a silica gel column packed in chloroform and eluted with solutions containing increasing percentages of methanol in chloroform. The fractions eluted with 30% methanol were combined and the solvent evaporated under reduced pressure. The solid residue was triturated with ether and then separated and dried at reduced pressure and room temperature to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-propanamine melting at about 92°-96° C. This compound has the following structural formula: ##STR12##
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][C:28]=3[NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:20][CH:19]=2)=[C:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O.O>[CH3:17][CH:15]([S:12]([NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][C:28]=2[NH:29][S:30]([CH:33]([CH3:34])[CH3:35])(=[O:31])=[O:32])=[CH:22][CH:23]=1)(=[O:13])=[O:14])[CH3:16]
Reactant: COC(=O)c1cccc(NS(=O)(=O)C(C)C)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2c(NS(=O)(=O)C(C)C)cccc2C(=O)O)cc1

Procedure:
Heat the mixture of 6-(propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (46 mg, 0.08 mmol) and LiOH (30 mg, 1.25 mmol) in 3 ml of THF/Methanol/water (3/2/1, v/v/v) to 60 C for 3 h. Remove solvent and dissolve in water (35 mL). Wash with methylene chloride (2×20 mL). Neutralize the aq. solution to a pH between 2 and 3. Further purification with flash chromatography affords the title compound. MS (m/e): 521.1(M−1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.CCOCC.O>CS(C)=O>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC1CCCCN1
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CC1CCCCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
4-fluoro-3-(trifluoromethyl)benzonitrile (Combi-blocks, 50 g; 264.40 mmol) and 2-methylpiperidine (Acros, 156.08 mL; 1 321.98 mmol) in DMSO (500 mL) were heated at 100° C. under nitrogen for 12 h. After this time, Et2O and water were added to the reaction mixture and organic phase was washed with water, NaHCO3 and a saturated aqueous solution of NH4Cl successively. Organics were dried over MgSO4, evaporated under vacuum to give the title compound as a beige powder. 1H NMR (DMSO-d6) δ 8.19 (d, J=2 Hz, 1H), 8.12 (dd, J=8.4, 2 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 3.15-3.10 (m, 1H), 2.90-2.85 (m, 1H), 2.60-2.51 (m, 1H), 1.77-1.25 (m, 6H), 0.72 (d, J=6.0 Hz, 3H). LC/MS (Method B): 269.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]4)=[CH:20][C:19]=3[F:32])=[CH:14][CH:13]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[CH:20][C:19]=3[F:32])=[CH:16][CH:17]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4]
Reactant: COC(=O)C1(c2cc(F)c(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(F)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(-c3c(F)cc(C4(C(=O)O)CC4)cc3F)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
Powdered potassium hydroxide (91 mg, 1.62 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate (Intermediate 28-1; 142 mg, 0.32 mmol) in tert-butanol (10 mL). The resulting yellow cloudy suspension was stirred at 40° C. for 1 hour. The reaction mixture was quenched with acetic acid (0.149 mL, 2.60 mmol) in ethanol (2 mL) and the resulting solution stirred for a further 10 minutes before being evaporated to dryness. The resulting solid was partitioned between water (20 mL) and ethyl acetate (20 mL). An insoluble solid was filtered off. The organic layer was separated and the aqueous re-extracted with ethyl acetate (20 mL). The combined organics were evaporated in vacuo to give crude product as an off white solid. The crude solid was triturated with mixture of DCM (3 mL) and methanol (3 mL) to give a solid which was collected by filtration and dried under vacuum to give 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid (52.0 mg, 37.8%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN3CCN(C)CC3)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(Cl)cc3cc(C(=O)O)[nH]c23)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a solution of 30 mg (0.09 mmol) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (2.5 ml) at RT was added 6 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 10 mg (36%) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 306.2 (M−H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:19][C:20]([F:57])([F:56])[C:21]1[CH:22]=[C:23]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[CH2:24][N:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:28]2[N:33]=[C:34](S(C)(=O)=O)[N:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[C:27]=2[C:26]1=[O:48].[O:58]1CCO[CH2:60][CH2:59]1>>[C:59]([N:29]1[CH2:30][CH2:31][CH2:32][N:25]([CH2:24][C:23]2[CH:49]=[C:50]([C:52]([F:54])([F:53])[F:55])[CH:51]=[C:21]([C:20]([F:57])([F:19])[F:56])[CH:22]=2)[C:26](=[O:48])[C:27]2[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])=[N:35][C:34]([N:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[N:33][C:28]1=2)(=[O:58])[CH3:60]
Reactant: C1COCCO1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2nc(-c3ccccc3C)c3c(n2)N(C(C)=O)CCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
1-acetylpiperazine (23.1 mg), diisopropylethylamine (0.1 mL), and 1,4-dioxane (1 mL) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg). While heated, the mixture was refluxed for 5 hours. The solvent was removed and anhydrous acetic acid (0.5 mL) and pyridine (0.1 mL) were added, followed by stirring at 100° C. for 3 hours. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 10-acetyl-2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (90.2 mg, 91%).