Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C([Li])CCC.[CH:16]1([CH:19]2[CH2:22][C:21](=[O:23])[CH2:20]2)[CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:16]1([CH:19]2[CH2:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][CH:9]=[O:10])([OH:23])[CH2:20]2)[CH2:18][CH2:17]1
Reactant: O=C1CC(C2CC2)C1
Reactant: O=CNc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1C1(O)CC(C2CC2)C1
Temperature: -100 °C
Reaction time: 2.5 h

Procedure:
In a sulfonation flask, 7.8 g (0.039 mol) N-(2-bromophenyl)form amide was dissolved in a mixture of 100 ml dry tetrahydrofuran. The solution was cooled to −100° C. and 60 ml (0.096 mol) of n-butyllithium solution (1.6M in hexane) was added over a period of 1 hour in such at manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 2.5 hours at −100° to −110° C., 5.3 g (0.048 mmol) of 3-cyclopropylcyclobutan-1-one (prepared as described in Example 7), dissolved in 30 ml of dry tetrahydrofuran, were added over a period of 30 minutes in such a manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 3 hours at −78° C., the temperature was elevated to 0° C. in ca. 30 minutes. Concentrated ammonium chloride solution and ethyl acetate were added and the organic phase was washed several times with water. After drying and evaporation of the solvent in a water jet vacuum, the crude material was obtained. Purification was achieved by flash chromatography over silica gel (eluant: hexane/ethyl acetate 1:1). Yield: 2.55 g (23% of theory) of N-[2-(3-cyclopropyl-1-hydroxycyclobutyl)-phenyl]formamide in the form of a resin.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:10]2[C@@:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([NH:7][O:8][CH2:9]2)[CH2:5][O:4]1>C(O)(=O)C.[Zn]>[NH2:7][C@@:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:5][O:4][C@H:3]([CH2:2][F:1])[C@H:10]1[CH2:9][OH:8]
Reactant: FC[C@H]1OC[C@]2(c3ccccc3F)NOC[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccccc2F)CO[C@H](CF)[C@H]1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
(3aR,4S,6aS)-4-(fluoromethyl)-6a-(2-fluorophenyl)hexahydrofuro[3,4-c]isoxazole (62.20 g, 257.14 mmol) was dissolved in acetic acid (540 mL) and the solution was cooled to 0° C. Zinc dust (168.14 g, 2571.4 mmol) was added over 15 mins. The reaction temperature rose from 8° C. to 16° C. The ice bath was removed after addition and the reaction mixture was allowed to warm up to RT. Internal temperature increased to 40° C. and gradually went down to 24° C. The reaction was stirred at RT for 16 h. The reaction mixture was filtered through celite, and washed with 1.5 L of EtOAc. The solvent was evaporated and the crude product was dissolved in chloroform (600 mL), and ammonia (28% aq., 240 mL) was added slowly using a dropping funnel. Internal temperature rose to 40° C. The layers were separated, and the aqueous layer was further extracted with chloroform (3×250 mL). The combined organic extracts were dried over anhydrous MgSO4 and evaporated to afford the title compound (63.00 g, 100%) which was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ ppm 2.39-2.86 (m, 4H) 3.81 (dd, J=11.87, 4.55 Hz, 1H) 3.94 (dd, J=9.09, 3.03 Hz, 1H) 4.07 (dd, J=12.13, 4.04 Hz, 1H) 4.25 (d, J=9.09 Hz, 1H) 4.40-4.68 (m, 3H) 7.09 (ddd, J=12.57, 8.15, 1.26 Hz, 1H) 7.17 (td, J=7.58, 1.26 Hz, 1H) 7.28-7.34 (m, 1H) 7.49 (td, J=8.08, 1.77 Hz, 1H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].S(=O)(=O)(O)O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([OH:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-acetamidobenzenesulphonyl chloride (400 g, 1.72 moles) was added with stirring a solution of sodium sulphite (431.7 g, 3.42 moles) in water (2 liters). A solution of 50% sodium hydroxide (240 ml) was added dropwise over 35 minutes using a cooling bath to keep the temperature below 30° C. The pH was thus maintained in the range 6.5-7.0. The mixture was stirred at room temperature for 2 hours and acidified by adding conc. sulphuric acid (170 ml) with ice-bath cooling. The precipitated white solid was filtered off, washed with water and dried at 50° C. The yield was 324.2 g (94%). This was used in the next stage without further purification.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C[C@@H]1COC(=O)N1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (1.4 mL) and (R)-4-methyloxazolidin-2-one (860 mg) described in Preparation Example 25, the title compound (0.9 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=O)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].ClCCl.C(N(CC)CC)C.P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+]>ClC1CC(C(C)C)CCC1(Cl)C>[CH3:1][O:2][C:3]([C:4]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[S:13](=[O:14])(=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]=1[C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=[O:35]
Reactant: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(=O)c1cc(OC)c2c(c1)OCO2
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(c2cc(OC)c3c(c2)OCO3)c2ccccc2S(=O)(=O)N1c1ccccc1C
Temperature: -60 °C
Reaction time: 18 h

Procedure:
To a dry 100-mL flask was added {[2-(7-methoxy-benzo[1,3]dioxole-5-carbonyl)-benzenesulfonyl]-o-tolyl-amino}-acetic acid methyl ester (2.0 g, 4.2 mmol), dry 4 angstrom molecular sieves (8 g), and Ti(TfO)2Cl2 (0.56 g, 0.48 mmol). The flask was cooled to −60° C. and dichloromethane (45 mL) was added. A solution of triethylamine (1.35 g, 9.73 mmol) in dichloromenthan (18 mL) was added. The mixture was warmed to 5° C. over 2 hours, followed by refrigeration at 0° C. for 18 hours. The mixture was poured in to 50-mL ammonium phosphate buffer solution (pH 7), stirred 20 minutes, and filtered. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to an oil. The oil was chromatographed on 150 g silica gel eluted with a mixture of ethyl acetate and hexane (40:60). The appropriate fractions were evaporated in vacuo, and the residue was evaporated to a foam, 1.02 g, 53%. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: CC([O-])=O.N1CCN=C1[NH:10][C:11]1[CH:12]=[C:13]([C:21]#[N:22])[C:14]2[N:18]=[CH:17][NH:16][C:15]=2[C:19]=1[CH3:20].S(=O)(=O)(O)O>>[NH2:10][C:11]1[CH:12]=[C:13]([C:21]#[N:22])[C:14]2[N:18]=[CH:17][NH:16][C:15]=2[C:19]=1[CH3:20]
Reactant: Cc1c(NC2=NCCN2)cc(C#N)c2nc[nH]c12
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
A comparison of the solubility of the presently claimed anhydrous monoacetate salt of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile and that of previously disclosed sulfuric acid salt and free base form is presented as Example 18.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:40][CH:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:38]3)=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH2:40][CH:39]([N:41]6[CH2:42][CH2:43][O:44][CH2:45][CH2:46]6)[CH2:38]5)=[CH:33][CH:32]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc(N3CC(N4CCOCC4)C3)cc2)OC1(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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc(N3CC(N4CCOCC4)C3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 3.6 %

Procedure:
To a 2-5 ml microwave vial, combined (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (85 mg, 0.23 mmol), 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)morpholine (100.15 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (26.89 mg, 0.02 mmol), 1M Sodium carbonate soln in water (0.7 ml) in dioxane (2.3 mL) and blown down with nitrogen. The reaction was irradiated for 20 mins at 150 C. The reaction was diluted with water, extracted with DCM, combined organics, dried (Na2SO4), filtered, concentrated. Residues were purified by silica gel column chromatography to yield the title compound (4.2 mg, 3.6%) as a free base.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9](=[O:12])[CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([OH:30])=[O:29].[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:16][C:14]([NH:13][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[C:9](=[O:12])[CH2:10][O:30][C:28](=[O:29])[C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[CH3:25])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A heterogeneous solution containing 3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester, 109, (9.89 g, 24.7 mmol), 2,6-dimethyl benzoic acid (4.45 g, 29.6 mmol), and KF (3.58 g, 61.8 mmol) in 250 mL of DMF is stirred at rt for 12 h. The solution is diluted with EtOAc, washed with water, saturated NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (hexane/EtOAc) yields 11.3 g of the desired product as a white solid.
Reaction SMILES: [C:1]([C:4]1([CH2:17][C:18]([OH:20])=O)[CH2:16][CH2:15][N:7]2[C:8]3[C:13]([CH:14]=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)(O)=[O:2].C(=O)([O-])[O-].[NH4+:25].[NH4+]>ClCCl.CO>[NH:25]1[C:18](=[O:20])[CH2:17][C:4]2([CH2:16][CH2:15][N:7]3[C:8]4[C:13]([CH:14]=[C:6]3[CH2:5]2)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]1=[O:2]
Reactant: [NH4+]
Reactant: O=C(O)CC1(C(=O)O)CCn2c(cc3ccccc32)C1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: O=C1CC2(CCn3c(cc4ccccc43)C2)C(=O)N1
Temperature: 200 °C
Yield: 68.8 %

Procedure:
A mixture of 100 mg of 8-carboxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetic acid and 69 mg of ammonium carbonate was heated at 200° C. for 1 hour. After cooling and chromatography on silica gel using dichloromethane/methanol (9:1) for the elution there were obtained 64 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)N1CCCC1)C(c1ccc(C(C)C)cc1)CO2
Temperature: 50 °C
Yield: 44.2 %

Procedure:
To a solution of 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate (353 mg, 0.75 mmol) obtained in Example 138 and pyrrolidine (0.076 mL, 0.9 mmol) in dimethylsulfoxide (5 mL) was added diisopropylethylamine (0.13 mL, 0.75 mmol) at room temperature, and the resulting mixture was heated at 50° C. and reacted for 16 hours. The reaction solution was cooled to room temperature and poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 130 mg (yield: 44%) of the title compound. Melting point: 186-188° C. (ethyl acetate-hexane).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=1.[F:19][C:20]([F:31])([C:27]([F:30])([F:29])[F:28])[C:21]([F:26])([F:25])[C:22](Cl)=[O:23]>COCCOC>[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:22](=[O:23])[C:21]([F:25])([F:26])[C:20]([F:19])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:11]=1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(O)c(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Sodium bicarbonate (51 g, 0.607 mol) was suspended in 1,2-dimethoxyethane (180 ml), and methyl(3-amino-4-hydroxyphenyl)acetate (58.26 g, 0.32 mol) was added, followed by a further quantity of 1,2-dimethoxyethane (75 ml). To this mixture was added, dropwise, a solution of heptafluorobutyryl chloride (112.5 g, 0.48 mol) in 1,2-dimethoxyethane (140 ml), at such a rate that the reaction temperature was maintained at 19-20° C. Once the addition was complete, the mixture was stirred at room temperature for 1½ hours. The reaction mixture was filtered and the solid was taken up in ethyl acetate and washed with saturated aqueous bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was taken up in acetone (450 ml) and water (450 ml) was added. The mixture was stirred for 1½ hours, during which time an oil separated. The aqueous acetone was decanted and a further quantity (250 ml) of water was added to the oil. The mixture was stirred for 1 hour, during which time the desired product crystallised; it was collected by filtration, washed with water and dried to give methyl(3-heptafluorobutyramido-4-hydroxyphenyl)acetate (87.0 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4=[O:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[BH4-].[Na+].O>C1COCC1.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH:26]4[OH:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12]1
Reactant: CC1(C)CCC(=O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 7-{6-[4-(5-hydroxypentyl)piperazin-1-yl]pyridin-2-yl}-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one are dissolved in 0.5 ml of THF and 1 ml of methanol, cooled to 0° C., and 4.5 mg (0.12 mmol) of sodium borohydride are added. The reaction mixture is stirred for 30 min, water is added, and the mixture is extracted with ethyl acetate, dried and evaporated. The crude product is purified by means of prep HPLC and subsequently converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11](=[S:13])[NH2:12])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(NNC(N)=S)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(NC(N)=S)c2ccc(OC)cc2)cc1
Yield: 33 %

Procedure:
A mixture of 2-(4-methoxyphenyl)hydrazinecarbothioamide (0.5 g, 2.53 mmol), 4-methoxybenzoyl chloride (541 mg, 3.17 mmol), and pyridine (0.256 mL, 3.17 mmol) intoluene (10 mL) was refluxed for 1 hour. After cooling, the solvent was removed under reduced pressure. diisopropyl ether and small amount of methanol was added to the residue and a generated precipitate was isolated by filtration, washed with methanol-diisopropyl ether, and dried in vacuo to give 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarbothioamide (277 mg, 33% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.O>CN(C=O)C>[N:19]1([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (6.0 g, 25mmol) dissolved in DMF (100 ml) was cooled to −5° C., added with anhydrous pottasium carbonate (5 g, 36 mmol) and benzimidazole (3.0 g, 35 mmol), stirred for 30 minutes and further stirred at room temperature for 15 hours. The reaction mixture was added with water (500 ml). The precipitated crystals were collected by filtration, washed with trace amount of acetone and dried to obtain 5.2 g (yield: 64%) of 2-(benzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine with melting point of 201° C.-203° C. as colorless crystals.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[H-].[Na+].[Br:13][C:14](Br)([F:16])[F:15].ClCCl>CN(C)C=O>[Br:13][C:14]([F:16])([F:15])[S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: FC(F)(Br)Br
Reactant: Sc1nc2ncccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(Br)Sc1nc2ncccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (2.0 g, 12 mol) in N,N-dimethylformamide is added dropwise to a mixture of sodium hydride (0.96 g, 0.024 mol) in N,N-dimethylformamide over 30 minutes. The resultant reaction mixture is treated with a solution of dibromodifluoromethane (2.52 g) in N,N-dimethylformamide, stirred at room temperature for 24 hours, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and dichloromethane followed by azeotropic removal of N,N-dimethylformamide (toluene) affords an oil. The oil is further purified by column chromatography using silica gel and a 20:1 ethyl acetate/hexanes solution to give the title product as a light yellow liquid (0.61 g, 17% yield).
Reaction SMILES: Cl.Cl.N1CCOC([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])C1.N1C=CC=CC=1.[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1NC)[CH3:43]>C1COCC1>[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:18]=1)=[O:12])[CH3:43]
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCN1CCC[C@@H]1NC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NC[C@H]2CCCN2CC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.18 mmol, 0.1 g) and 0.1 mL of pyridine in 2 mL of THF was added ((R)-1-ethyl-pyrrolidin-2-yl)-methylamine (0.4 mmol, 0.05 g). The mixture was shaken at room temperature, upon completion, the solvent was removed and the residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc afforded 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid ((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amide. LCMS: m/z 464.9. 1H NMR (400 MHz, CD3OD) δ 8.27 (1H, s), 7.42 (2H, d), 7.09 (2H, d), 4.44-4.40 (1H, m), 4.00-3.96 (1H, m), 3.80-3.68 (4H, m), 3.20-3.10 (4H, m), 2.34-2.28 (1H, m), 2.16-2.02 (5H, m), 1.84-1.80 (2H, m), 1.64-1.27 (13H, m), 0.83 (3H, t).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 97 %

Procedure:
A solution of 1.4 g (3.1 mmole) of 7-[3-t-butoxycarbonylamino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 25 ml of trifluoroacetic acid was stirred at room temperature until gas evolution ceased. The solvent was removed in vacuo and the residue dissolved in 1N sodium hydroxide. The solution was diluted to 100 ml with water and acidified to pH 5.5 with 6N hydrochloric acid. The precipitate was removed by filtration, washed with water, ethanol, and ethyl ether. The residue was dried in vacuo to give 1.05 g (97%) of the title compound; mp 290°-292° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1>>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc(Cl)c3)ccc12
Yield: 7.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (162 mg, 0.77 mmol) and 1-(bromo-methyl)-3-chlorobenzene (189 mg, 0.92 mmol) to provide 472 (20 mg, 8% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 8.46 (m, 1H), 8.06 (d, J=8.7, 1H), 7.42 (d, J=1.7, 1H), 7.36 (dd, J=4.7, 7.8, 1H), 7.26 (m, 3H), 7.21 (d, J=6.8, 1H), 6.90 (dd, J=2.0, 8.7, 1H), 6.23 (s, 2H), 5.65 (s, 2H).