Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])=[O:6].O.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of 43C (60 mg, 0.14 mmol) in THF (2 mL):water (1 mL) at 0° C. was treated with a 1 M solution of LiOH (0.17 mmol). The reaction was warmed to room temperature and stirred for 30 minutes. The solution was neutralized with 1 N HCl and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to afford 43D (42 mg, 76%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1>ClCCl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)CN
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Isobutylamine (16.2 mL, 163 mmol) was added dropwise to a 0° C. solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (approximately 74.1 mmol) in dichloromethane (350 mL). The reaction mixture was allowed to stir and warm to room temperature for 3 hours, then was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (300 mL). The aqueous layer was back-extracted with dichloromethane (2×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford 23.06 g of 7-bromo-N-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2Cl)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-6-methoxy-2-(4-methoxyphenyl)naphthalene (0.65 g, 2.18 mmol) with boron tribromide (6.5 mL of 1N solution) according to method D to yield 0.44 g (75%) of a white solid: mp>220° C.; 1H NMR (DMSO-d6): δ 6.86 (2H, d, J=8.33 Hz), 7.23–7.28 (2H, m), 7.30 (2H, d, J=8.32 Hz), 7.37 (1H, d, J=8.51 Hz), 7.72 (1H, d, J=8.55 Hz), 8.13 (1H, d, J=9.07 Hz); MS (ESI) m/z 269/271 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH:16]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH:17]([CH3:19])[CH3:18])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].CO>O1CCCC1>[OH:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:15][CH:16]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(CC(Cc1ccc2cccc(OCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cccc2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Reaction time: 23 h

Procedure:
A solution of 2.44 g of ethyl 2-tert-butoxycarbonylamino-4-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-5-methylhexanoate in 35 ml of tetrahydrofuran is admixed at room temperature with 0.25 g of lithium borohydride in portions. After 23 hours, 35 ml of methanol are added dropwise and the resulting mixture is concentrated by evaporation at 40° C. The residue is once more admixed with 35 ml of methanol and again concentrated by evaporation to dryness. The residue is admixed with ice/1N HCl and extracted with dichloromethane (3×)—the combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(O)cc2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
267 mg of 5-(4'-t-butyl-dimethylsilyloxy-5,6-dimethoxybiphenyl-3-ylmethyl)-pyrimidine-2,4-diamine (Example 2f)) are dissolved in 6 ml of tetrahydrofuran and treated with 361 mg of tetrabutylammonium fluoride trihydrate. The mixture is stirred at room temperature for 1hr. and subsequently concentrated. The residue is chromatographed on MCl-Gel CHP20P (Mitsubishi Corporation) with water/acetonitrile 4:1. 73 mg (36%) of 5-(4'-hydroxy-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a colourless solid. M.p. 233°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:15][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:5]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(O)CC3)n2)n1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(Oc4ccccc4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
To a solution of 4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)cyclohexan-1-ol (Example 424, 0.1 g, 0.272 mmol) in THF (4 mL) was added phenol (0.03 g, 0.272 mmol), triphenylphosphine (0.09 g, 0.327 mmol) and N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (0.08 g, 0.327 mmol). The reaction mixture was stirred at room temperature 16 h. The mixture was then concentrated and purified by preparative HPLC, Method D, to afford the title compound (0.010 g, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O.[NH2:12][NH2:13]>CN(C)C1C=CN=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][NH2:13])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chlorobenzhydrazide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][C:18](OCC)=[O:19])[CH:12]=[CH:13][C:14]=1[F:15]>N1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:6]=[C:5]3[NH:7][C:18](=[O:19])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)c1ccc(F)c(F)c1
Solvent: c1ccncc1
Product: Cc1cc2[nH]c(=O)cc(-c3ccc(F)c(F)c3)n2n1
Temperature: 25 °C
Yield: 64 %

Procedure:
3-Methylpyrazol-5-amine (670 mg) and ethyl 3-(3,4-difluorophenyl)-3-oxopropanoate (1.12 g) are stirred overnight in a pyridine (30 mL) solvent at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (821 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 10.80 (br, 1H), 8.01 (m, 1H), 7.54 (m, 1H), 7.30 (m, 1H), 6.45 (s, 1H), 5.88 (s, 1H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:22]1[CH2:24][CH2:23]1>[I-].[K+].O>[CH:22]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: BrC1CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxybenzaldehyde (1.20 g), potassium carbonate (2.04 g), potassium iodide (49.0 mg) and N,N-dimethylformamide (9.80 mL), bromocyclopropane (1.02 mL) was added and the mixture was stirred at 200° C. for 3 hours under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (510 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.FC(F)(F)S(O)(=O)=O.[F:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27]([F:34])[C:23]=1[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[C:12]([C:24](=[O:25])[C:23]3[C:27]([F:34])=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=3[F:21])[C:3]=12
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: N#Cc1cnc2[nH]ccc2c1Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc([N+](=O)[O-])c3F)c2c1Cl
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 13.1 %

Procedure:
In a vial, 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (50, 500 mg, 2.82 mmol) is cooled in an ice water bath, and trifluoromethanesulfonic acid (2.49 mL, 28.15 mmol) is added. The solution is stirred at 0-5° C. for 5 minutes, then 2,6-difluoro-3-nitro-benzoyl chloride (49, 748.5 mg, 3.38 mmol) is added. The reaction is stirred at 0-5° C. for 1 hour, then warmed to room temperature and stirred for 4 days. The reaction is quenched with 5 mL of methanol, and stirred at room temperature for 1 hour. The reaction is poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is washed with water, brine, dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 0-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (51, 134 mg).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)[C:25](=[O:35])[N:24]([CH3:36])[CH:23]=3)[C:17]=2[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[C:8]([C:10]([O:12]C)=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)(C)C.O>[C:1]([C:5]1[S:6][C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)[C:25](=[O:35])[N:24]([CH3:36])[CH:23]=3)[C:17]=2[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3ccncn3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylate (125d) (590 mg, 0.9 mmol) and lithium hydroxide (1090 mg, 45 mmol) in isopropyl alcohol (20 mL) and water (20 mL) was stirred at 25° C. for 5 h. The reaction mixture was concentrated to about 50% of the original volume and acidified to pH˜4 with 1M HCl (aq.). It was then extracted with CH2Cl2:MeOH(−7:1). The organic layers were combined, dried with anhydrous MgSO4, and concentrated to afford 125e, which was used in the next step without further purification. LCMS: (M+H)+ 635.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[CH:30]>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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:30]#[C:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[F:22])=[O:5])[CH3:2]
Reactant: C#Cc1ccccc1F
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccccc3F)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To 0.502 g (1.161 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 67 mg (0.060 mmole) tetrakis(triphenylphosphine)palladium(0), 22 mg (0.116 mmole) copper (I) iodide, 10 mL degassed toluene, 0.484 mL (3.48 mmole) degassed TEA, and 0.199 mL (1.74 mmole) 2-fluorophenylacetylene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 0.440 g (89%) of a crystalline solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=6.8 Hz), 4.26-4.38 (m, 2H), 5.83 (q, 1H, J=6.8 Hz), 7.08-7.15 (m, 2H), 7.18 (d, 1H J=2.4 Hz), 7.31-7.37 (m, 1H), 7.45 (d, 1H, J=2.4 Hz), 7.49-7.53 (m, 1H), 7.63 (s, 1H); (ES+) 425 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].C([O-])(=O)C.[K+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O.O>[NH2:1][C:2]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:26](=[O:27])[CH2:25][Cl:24])[C@H:13]([OH:18])[CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](N)[C@H](O)C2)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
(+/−)-3-amino-5-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-4-chlorobenzonitrile (prepared from Example 171D) (1.0 g, 3.75 mmol) and potassium acetate (0.736 g, 7.50 mmol) were dissolved in acetone (20 ml)+water (6 mL). The solution was cooled to 0° C. under nitrogen. Chloroacetic chloride (0.373 ml, 4.69 mmol) was added dropwise and the mixture stirred at 0° C. for 10 minutes, then at room temperature for 60 minutes. The reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed with brine and dried over MgSO4. MgSO4 was removed by filtration and volatiles evaporated in vacuum to afford (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (0.61 g,); The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O.ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)c1C
Temperature: 190 °C
Yield: 30 %

Procedure:
A mixture of 3.9 parts of 3,6-dichloro-4,5-dimethylpyridazine, 4.2 parts of 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassium carbonate was stirred and heated for 4 hours in an oil bath at 190° C. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (30%) of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine; mp. 194.5° C. (compound 217).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)[C:6]([O:9][CH2:10][CH3:11])=[N:7][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=2)O1.CCO.C(=O)(O)[O-].[Na+]>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.C1C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:5]2[N:4]=[C:3]([CH2:2][C:30]3[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=3)[CH:8]=[N:7][C:6]=2[O:9][CH2:10][CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: CCOc1ncc(CBr)nc1-c1cccc(OC(F)F)c1
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: c1ccccc1
Solvent: CCO
Product: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 125 °C
Yield: 53.2 %

Procedure:
Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), and sodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125° C. under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49 (q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=384.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=O)[C:12]([CH3:14])=[O:13].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12](=[O:13])[CH3:14]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=NNc1ccc(Cl)cc1Cl)C(C)=O
Yield: 85.1 %

Procedure:
A mixture of 2,4-dichlorophenylhydrazine (1.0 g, 4.7 mmol), ethyl pyruvate (0.53 mL, 4.7 mmol), triethylamine (0.65 mL, 4.7 mmol) and ethanol (5 mL) was heated at reflux overnight. The solvent was evaporated and the residue taken up in chloroform. The solution was washed with water and brine and dried over magnesium sulfate and concentrated, leaving an oil (1.1 g, 98%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:25]([C:19]1([NH:18][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:26])[NH2:27]
Reactant: NC(=O)C1(N)CCOCC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)C1(NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)CCOCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 4-aminotetrahydro-2H-pyran-4-carboxamide (CAN 1183378-09-7) as starting materials, MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:14])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CCO
Product: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture of 26 g of 2,5-dichloro-nitrobenzene, 400 ml of ethanol and 25 ml of ethylamine was refluxed for 24 hours while adding 5 ml of ethylamine at 6 hour intervals and the mixture was cooled and filtered. The orange needles were washed with a small amount of an ethanol-ether mixture and dried over P2O5 under vacuum to obtain 24.4 g (89% yield) of N-ethyl-4-chloro-2-nitro-aniline melting at 90°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.IC.[C:14](=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1F
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (30.8 g) in DMF (150 mL) was added iodomethane (17.5 mL) and powdered sodium hydrogencarbonate (23.5 g). The mixture was stirred for 18 hours and partitioned between ethyl acetate and brine. The organic phase was isolated, washed with dilute sodium bisulfite solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 7-20% ethyl acetate/hexanes.