Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([Si:11]([CH3:33])([CH3:32])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])[CH3:15])([CH3:10])[CH3:9].[N:34]1([C:38]([C:40]2[CH:41]=[CH:42][C:43](Cl)=[N:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1>C(#N)C>[N:34]1([C:38]([C:40]2[CH:41]=[CH:42][C:43]([O:31][C:29]3[CH:28]=[C:19]([CH:18]=[C:17]([O:16][C@@H:14]([CH3:15])[CH2:13][O:12][Si:11]([C:8]([CH3:9])([CH3:10])[CH3:7])([CH3:33])[CH3:32])[CH:30]=3)[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])=[N:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2nccs2)c1
Temperature: 160 °C

Procedure:
Potassium carbonate (0.14 g, 0.98 mmol) was added to a mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide (200 mg, 0.49 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (96 mg, 0.49 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 4 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL), brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound. (0.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].C([O-])([O-])=O.[Na+].[Na+].[Cl:16][C:17]1[C:18]([Cl:26])=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([Cl:26])[CH:19]=2)[C:7]=1[NH2:8]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Nc1c(Br)cncc1Br
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1c(Br)cncc1-c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,5-dibromo-4-amino-pyridine 1 (4.0 g, 15.87 mmol), Pd(PPh3)4 (0.91 g, 0.78 mmol) and aqueous solution of Na2CO3 (23.8 ml, 2M) in toluene (80 ml) is added to a solution of dichlorobenzene boronic acid (6.23 g, 46.4 mmole) in ethanol (24 ml). The mixture is refluxed for 14 h., diluted with ethyl acetate and washed with saturated NH4Cl solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel to give 2.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[S:24](Cl)(=[O:26])=[O:25])[CH2:12][CH2:13][CH3:14]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:24]([C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:15]=1[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:25])=[O:26]
Reactant: CCCCc1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-n-butylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.35 g) and THF (6 ml). Recrystallization from ethyl acetate and hexanes provided 0.24 g (56%) of a yellow solid, m.p. 124.5-126° C.
Reaction SMILES: C(C1C=CC=CC=1[N:9]1[C:13]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]1)#N.FC(F)(F)C(=O)CC(C1OC=CC=1)=[O:28].O.NN>C(O)C>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH:13]1[NH:9][NH:10][C:11]([C:19]([F:22])([F:21])[F:20])([OH:28])[CH2:12]1
Reactant: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: NN
Solvent: CCO
Solvent: O
Product: OC1(C(F)(F)F)CC(c2ccco2)NN1

Procedure:
Part B: 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole: To a solution of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2.06 g, 10 mmol) in ethanol (mL) was added hydrazine monohydrate (0.46 g, 10 mmol). The resulting mixture was refluxed for 16 hours and dried under vacuum to give 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline in almost quantitative yield. 1H NMR (CDCl3) δ7.48 (d, J=1.9 Hz, 1H), 6.63 (d, J=3.7 Hz, 1H), 6.47 (dd, J=3.7 Hz, J=1.9 Hz, 1H), 6.16 (s, 1H), 3.48 (d, J=17.9 Hz, 1H), 3.18 (d, J=17.9 Hz, 1H); 19F NMR (CDCl3): δ−81.47; ESMS(+): 221 (M+H, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH2:21]([C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[CH3:22]
Reactant: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (13 g) and vinylboronic acid pinacol ester (10 g) were added toluene (90 mL) and water (4.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in ethanol (90 mL), 5% palladium carbon-ethylenediamine complex (2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (20 mL), 4N hydrogen chloride/ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the precipitate was collected by filtration to give the title compound (5 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][O:17][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(COCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
Sodium hydride (60% suspension in oil, 4.9 mg, 0.11 mmol) was added in small portions to a cooled (0° C.) solution of 4-tert-butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 0.057 mmol) in dry DMF (0.2 mL). The suspension was stirred vigorously at 0° C. for 15 min followed by addition of 4-chlorobenzyl bromide (14 mg, 0.066 mmol). After stirring for 45 min at 0° C., the reaction mixture was warmed to rt. When TLC showed complete consumption of the starting material, the reaction mixture was partioned between ethyl acetate (5 mL) and water (2 mL). The aqueous phase was further extracted with ethyl acetate (5 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 1% methanol in dichloromethane, gave 4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 0.013 mmol, 22%). LC-MS (LCT2) m/z 477 [M+Na+], Rt 8.74 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=1)(=O)=O.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C(=CC(=CC=1)C)C)C>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.O.C(O)(C)(C)C>[C:33]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:30]4[C:25]([CH:24]=[C:23]5[C:18]=3[CH:19]=[CH:20][CH:21]=[CH:22]5)=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:9][CH:8]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Oc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: c1ccc(-c2ccc(-c3c4ccccc4cc4ccccc34)c3ccccc23)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Under the nitrogen atmosphere, 4-(anthracen-9-yl)naphthalen-1-yl trifluoromethane sulfonate (30.0 g) as the sixteenth intermediate compound, phenylboronic acid (12.1 g), Pd(PPh3)4 (2.3 g), potassium phosphate (28.1 g), and a mixture solvent of pseudo cumene, t-butyl alcohol, and water (150 ml) (pseudo cumene/t-butyl alcohol/water=8/1/1 (volume ratio)) were added to a flask and refluxed for 5.5 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with water to terminate the reaction. It was then extracted with toluene. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (solvent: heptane/toluene mixture solvent). At that time, with reference to the method described in “Guideline for Experiments of Organic Chemistry (1)—Method of handling substance and separation and purification method”—published by Kagaku-Dojin Publishing Company, INC., page 94, the target compound was eluted by gradually increasing the ratio of toluene in the eluent. The crude product obtained by removing the solvent by distillation under reduced pressure was washed with heptane, followed with methanol to give 9-(4-phenylnaphthalen-1-yl)anthracene (24.1 g) as a seventeenth intermediate compound. The scheme is shown in the following “Reaction 28”.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:21](=[O:23])[NH2:22])([CH2:15][C:16](OCC)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16](=[O:17])[NH:22][C:21]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(N)=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Reaction time: 6 h
Yield: 88.5 %

Procedure:
(R)-diethyl 2-t-butyloxycarbonylamino-2-carbamoylsuccinate (590 mg) obtained in Example 15 was dissolved in acetone (6 mL) and water (6 mL), the solution was added with potassium carbonate (295 mg), the mixture was stirred for 6 hours, 1 mol/L hydrochloric acid was poured to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (450 mg, yield: 88%) as colorless crystals. Optical rotation [α]D25 was −39.1° (c 0.50, ethanol). 1H NMR (CDCl3) δ (ppm): 8.50 (1H, br), 5.99 (1H, br), 4.32 (2H, q, J=7.2 Hz), 3.16 (2H, m), 1.44 (9H, s), 1.30 (3H, t, J=7.2 Hz)
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[C:40]([NH2:44])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([NH:44][CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:22][CH2:23][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=3[CH2:30]2)=[CH:7][CH:6]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CC(C)(C)N
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCNC(C)(C)C)cc2)c1
Yield: 16.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and tert-butylamine (6.8 mg) according to an analogous synthetic method to Example 806, the title compound (4.6 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:18])[C:5]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:18])[C:5]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[C:6]([C:10]=1[N+:19]([O-:21])=[O:20])[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)C(=O)Nc1c(O)cc(Br)cc1C(=O)O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1c(O)cc(Br)c([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-(2,2-dimethylpropionylamino)-3-hydroxybenzoic acid (I-220) was dissolved in acetic acid (3 ml), then fuming nitric acid (22 μl, 0.52 mmol) was added at room temperature. After stirring at room temperature for 1 hour, the solvent was evaporated away under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The organic layer was again washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated away and the resulting residue was subjected to column chromatography with silica gel, and the fraction with hexane:ethyl acetate=3:1 gave 5-bromo-2-(2,2-dimethylpropionylamino)-3-hydroxy-6-nitrobenzoic acid (61 mg, 36) and the entitled compound (22 mg, 13%).
Reaction SMILES: [CH:1]([C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[CH2:5][OH:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH:1]([C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:16])([CH3:15])[CH3:17])=[C:10]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1)[CH2:5][OH:6])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature with stirring, to a solution of 5.65 g of 2(R)-isopropyl-3-(3-hydroxy-4-tert-butyl-phenyl)-propanol in 100 ml of dimethylformamide there are added 11 g of caesium carbonate and, dropwise, a solution of 3.2 ml of benzyl bromide in 20 ml of dimethylformamide. The reaction mixture is stirred at room temperature for a further 16 hours and then concentrated by evaporation, and the residue is partitioned between diethyl ether and water. The organic phases are concentrated by evaporation and the residue is purified by FC (90 g of silica gel, dichloromethane/hexane=9:1), yielding the title compound: Rf (dichloromethane/hexane=9:1)=0.44.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:15])[CH2:10][O:11][N+:12]([O-:14])=[O:13])=O)(C)(C)C.CCOCC.[ClH:21].O1CCOCC1>>[ClH:21].[CH3:15][C@H:9]([NH2:8])[CH2:10][O:11][N+:12]([O-:14])=[O:13]
Reactant: C[C@@H](CO[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)CO[N+](=O)[O-]
Reaction time: 0.83 h

Procedure:
In 80 ml of 4N hydrochloric acid-dioxane were dissolved 4.52 g of (1S)-N-(t-butoxycarbonyl)-1-methyl-2-nitroxyethylamine, and the mixture was left to stand at room temperature for 1 hour and 50 minutes. To the mixture were added 160 ml of ether, and the crystals were collected by filtration and dried to obtain 3.02 g of the desired compound as colorless crystals.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])=[CH:42][CH:41]=1>CC#N>[NH2:53][CH2:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][CH:42]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccccc1-c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 32.7 %

Procedure:
Using the general alkylation procedure: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.194 g, 0.51 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.72 mmol) followed by 4′-bromomethyl-2-cyanobiphenyl (0.303 g, 1.11 mmol) and the resultant mixture heated to 60° C. for 25 h. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided a tan foam (79 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:42][CH2:41][C:17]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[N:26]=[C:27]5[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][N:28]5[CH:40]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:42][CH2:41][C:17]3([CH2:18][CH2:19][N:20]([C:23]([C:25]4[N:26]=[C:27]5[CH2:32][NH:31][CH2:30][CH2:29][N:28]5[CH:40]=4)=[O:24])[CH2:21][CH2:22]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cn2c(n1)CNCC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2.5 ml) was added to a cooled (0° C.) solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.86 mmol, 1.0 equiv.) in DCM (10 ml), and the mixture was stirred for 2 h at 25° C. When the reaction was complete (TLC monitoring), the solvent was removed in vacuo in order thus to yield the desired product in the form of a yellow solid. This was used directly in the next stage without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])[CH3:26]>CN1C(=O)CCC1.O>[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:20]2[N:19]=[C:18]([C:15]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:10]4=[N:17][CH:16]=3)[CH:23]=[CH:22][N:21]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]
Reactant: Clc1nccc(-c2cnc3c(OCc4ccccc4)cccn23)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.19 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.29 g) in NMP (1 mL) was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid separated, washed with water, and dried. The solid was titurated with hot EtOAc and filtered to provide 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (compound 8, 0.25 g), which was used without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH3:10]>C(OC(=O)C)C>[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH3:10]
Reactant: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 500 milliliter, neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotameter was charged with 50 milliliters of ethyl acetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 100 milliliters of ethylacetate was added and 10.0 grams of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) was added. The resulting emulsion was stirred for 17 hours; and the flask was purged with nitrogen until no COCl2 was detected and a suspension formed. The solid was removed by filtration and dried in a vacuum oven at 80° C. to 5.9 grams of white crystals of 5-[1-(2,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer. (Melting point 176°-179° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4](F)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([NH:17][CH:14]2[CH2:16][CH2:15]2)[CH:3]=1
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)cc1F
Reactant: NC1CC1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(Cl)c(Cl)cc1NC1CC1
Temperature: 105 °C

Procedure:
A solution of 4,5-dichloro-2-fluorobenzenesulphonamide (3 g) in dioxane (30 mL) to which cyclopropylamine (3 mL) has been added is heated at 100-110° C. in a hermetically closed vessel for 24 hours. The solvent and the excess of amine are removed by distillation under reduced pressure and the residue is dissolved in methanol (20 mL). The methanolic solution is cooled on an ice bath, and water (60 mL) is added. The precipitate obtained (the title product) is collected by filtration, washed with water and dried. It is used in the following Step without being otherwise purified.
Reaction SMILES: [CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].B(F)(F)F.CCOCC.[CH2:25](O)[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CC(C)CO
Reactant: CCc1cc2c(O)c(C(=O)O)cnc2s1
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1cc2c(O)c(C(=O)OCC(C)C)cnc2s1
Yield: 31 %

Procedure:
A mixture of 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylic acid (200 mg, 0.9 mmol) and boron trifluoride-ethyl ether (47%, 0.5 ml) in isobutyl alcohol (10 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to cool and concentrated to dryness. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with chloroform/ethyl acetate (3:1) to give 80 mg (31%) of the title compound as colorless crystals.