Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][C:35]5([CH3:39])[CH2:38][O:37][CH2:36]5)=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.CC(C)([O-])C.[Na+].O>CC1CCCO1>[CH3:39][C:35]1([CH2:34][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:38][O:37][CH2:36]1
Reactant: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3n2)COC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(N4CCC(N)CC4)c3n2)COC1
Yield: 85.8 %

Procedure:
The compound, (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester (2 g, 3.68 mmol, 1 equivalent), sodium t-butoxide (1.77 g, 18.4 mmol, 5 equivalents), 2-methyltetrahydrofuran (30 mL, 15 volumes), and water (66 mL, 1 equivalent) were added to a 100 mL round bottom flask. The mixture was heated to reflux and held at reflux for 24–30 hours. At reaction completion, the mixture was cooled to 20–30° C. The reaction was quenched into a 20% citric acid solution (10 volumes) and stirred at 20–30° C. for 30–60 minutes. The citrate salt precipitated out of solution during this time. A 50% sodium hydroxide solution (˜1 weight equivalent) was charged to basify the reaction mixture (pH 10–12). The layers were separated at 30–40° C. The aqueous layer was washed with ethyl acetate (10 volumes) and then the combined organics were concentrated to low volume. Ethyl acetate (14 mL, 7 volumes) was charged and the slurry was allowed to granulate for 10–20 hours. The solids were filtered and 1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine (1.4 g, 86% yield) was isolated.
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]2[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.O.C(OCC)(=O)C>[Br:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:13]([CH3:19])([CH3:20])[CH2:12][CH:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
To a suspension of sodium hydride 60% w/w (0.30 g, 6.8 mmol) in 20 mL of DMF under argon atmosphere was added slowly ethanethiol 98% (0.5 mL, 6.8 mmol), and the resulting solution was stirred for 15 min. A solution of 6-bromo-4-isopropyl-1,1-dimethyl-7-methoxy-1,2-dihydronaphthalene (Compound 102, 600 mg, 1.9 mmol) in 3 mL of DMF was added, and the reaction mixture was refluxed for 5 h, then cooled to room temperature, acidified with 2N HCl, diluted with water andextracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to afford 0.57 g (100%) of the title compound as a dark brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:29])[N:14](C1C=CC(F)=CC=1C)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:29])[NH:14][C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Product: CC(C)(C)OC(=O)NC(=O)CCC#Cc1ccccn1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester 250 mg, 0.82 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.50 mmol, 61%) of 4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
The 3-tert-butoxycarbonylaminopyridine (2.0035 g, 10.32 mmol) was dissolved in THF (100 mL). The solution was cooled to −30° C. in a dry ice/acetonitrile bath, then t-BuLi (13 mL, 22.1 mmol) was added dropwise. After 1 h, 4-chlorophenyl isocyanate (1.911 g, 12.44 mmol) was added. The reaction mixture was warmed to 0° C. After 1.5 h, the reaction was warmed to room temperature. After 3 h at room temperature, the reaction was quenched with water (100 mL) and extracted with EtOAc (800 mL). The organic layer was washed with water (2×50 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography (350 g silica, 30% EtOAc/-CH2Cl2) to give the amide (1.284 g, 3.69 mmol, 36%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]1[C:20]([CH3:21])=[CH:19][C:18](S(C(F)(F)F)(=O)=O)=[C:17]([O:29][CH3:30])[CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.[C]=O.Cl>CN(C)C=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:9][CH:10]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:11]([O:13][CH3:14])=[O:12])=[C:17]([O:29][CH3:30])[CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ccccc1)c1cc(OC)c(S(=O)(=O)C(F)(F)F)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(C(NC(=O)c2ccccc2)C(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
A stirred mixture of methyl 2-benzamido-2-(3-methoxy-6-methyl-4-trifluoromethylsulphonylphenyl)acetate (0.3 g, 0.65 mmol) triethylamine (0.16 g, 1.6 mmol), palladium acetate (5 mg, 0.022 mmol) and 1,3-diphenylphosphinopropane (9 mg, 0.022 mmol) in dimethyformamide (3 ml) and methanol was saturated with carbon monoxide gas using a bubbler and then heated to 70° C. for 3 hours and overnight at room temperature under an atmosphere of carbon monoxide using a gas filled balloon. The mixture was acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (2×). The combined extracts were washed with a saturated solution of ammonium chloride, dried, filtered and evaporated to a solid. Chromatography on flash silica eluting with diethyl ether-hexane (3:2, 4:1) gave methyl 2-benzamido-2-(4-methoxycarbonyl-3-methoxy-6-methylphenyl)acetate as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=2)=[O:20])[CH2:15][CH2:16]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.9 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.40 g, 1.38 mmol), methyl 3-(4-aminophenyl)propanoate (0.30 g, 1.66 mmol), EDCI (0.26 g, 1.66 mmol) and HOBt (0.25 g, 1.66 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 50:50) to give the title compound (0.56 g, 91%) as a white amorphous.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][CH:4]([CH2:18][C:19]#[N:20])[CH2:3]1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[NH4+]>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][CH:4]([CH2:18][C:19]#[N:20])[CH2:3]1
Reactant: CN1CC(CC#N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(CC#N)C[C@@H]2c3cccc4c3C(CN4)C[C@H]21

Procedure:
A solution of 4.1 g. of 6-methyl-8-cyanomethyl-ergoline in 110 ml. of trifluoroacetic acid was stirred and cooled to 5° C. in a ice-waterbath. To the cold solution was added 2.5 g. of sodium borohydride, in 5 equal portions over 1 hour. The reaction mixture was added to 100 g. of ice and the pH of the aqueous reaction mixture was adjusted to 11 by the addition of ammonium hydroxide. The aqueous alkaline reaction mixture was extracted with chloroform. The combined organic extracts were washed with water, dried, and the solvent was evaporated therefrom to provide 2,3-dihydro-6-methyl-8-cyanomethylergoline, M.P. 100°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:46])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[S:29](=[O:41])(=[O:40])[NH:30][C:31](=[O:39])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[CH:17][CH:16]=3)[C:10]([CH2:42][CH2:43][CH2:44][CH3:45])=[N:9]2)[CH:7]=1.[C:47](Br)(=[O:50])[CH2:48][CH3:49]>CN(C1C=CN=CC=1)C>[CH2:42]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=3[S:29](=[O:40])(=[O:41])[NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:47](=[O:50])[CH2:48][CH3:49])[CH:3]=[CH:4][C:5]=2[Cl:46])[N:9]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 65 %

Procedure:
By the procedure of Example 69, 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-5'-ethylbiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) was reacted with propionyl bromide in the presence of DMAP. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2Cl2) afforded a 65% yield of the title compound as a cream-colored solid, mp 144°-146° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; m/e 734 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH2:7]2)[C:3]1=[O:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH2:7]2)[CH:3]1[OH:14]
Reactant: CC1=CC(C)CC2(CCC(C)C2=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1=CC(C)CC2(CCC(C)C2O)C1
Yield: 87 %

Procedure:
A mixture of 2,6,8 and 2,7,9-trimethylspiro[4,5]dec-7-en-1-one was reduced with LiAlH4 according to the general procedure (example 2, procedure 3) to give the title product in 87% yield as a mixture of isomers. The crude product was purified by bulb-to-bulb distillation (B.p.=82° C./0.02 mbar).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12](=[N:14][OH:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][C:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[O:15][N:14]=1
Reactant: COC(=O)c1ccc(C(C)=NO)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C)noc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
Methyl 3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate (250 mg, 1.19 mmole) is combined with triphenylphosphine (446 mg, 1.7 mmole) in 14 ml dry THF in a dry flask under nitrogen. The solution is treated slowly dropwise with N,N′-diethylazidodicarboxylate (268 mL, 1.7 mmole) in 10 ml dry THF. The reaction is stirred 4 h at rt. The volatiles are removed in vacuo and the residue is chromatographed over 30 g silica gel (230-400 mesh) eluting with 10% EtOAc/hexane. The appropriate fractions are combined and concentrated to provide 125 mg (55%) of methyl 3-methyl-1,2-benzisoxazole-6-carboxylate slightly contaminated (<10%) with methyl 4-acetyl-3-hydroxybenzoate. 1H NMR (CDCl3) δ 2.64, 4.00, 7.70, 8.01, 8.25 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C([BH3-])#N.[Na+]>CO.Cl>[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:16][NH:1][C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cc[nH]n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cc[nH]n2)cc1OC1CCCC1
Yield: 30.2 %

Procedure:
To a solution of 3-aminopyrazole (1.5 g, 0.018 mol) in 50 ml of methanol and 7.5 ml of 1N aqueous HCl was added 3-cyclopentyloxy-4-methoxybenzaldehyde (3.3 g, 0.015 mol) and 95% sodium cyanoborohydride (1.0 g, 0.015 mol). The solution was stirred at room temperature for 20 hours after which concentrated aqueous hydrochloric acid (Hcl) was added to pH 2. The solvent was evaporated at reduced pressure and the residue was extracted twice with 50 ml portions of ether. The ether extracts were discarded and the aqueous solution was brought to pH 10 with 5N aqueous NaOH. The mixture was extracted twice with 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated. The solid residue was triturated with ether to give the pure title compound (1.3 g, 30%), mp 106-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:34][CH3:35].C([O-])(=O)C.[Na+].O.[NH4+].[OH-]>C(OC(=O)C)(=O)C>[C:29]([N:18]1[CH2:19][CH2:20][CH2:21][C:22]2[C:23]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[C:9]3[C:10]4[CH:11]=[C:2]([Br:1])[C:3]([O:34][CH3:35])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:15]=2[C:16]1=[O:17])([CH3:30])([CH3:32])[CH3:31]
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 2.9 g of 3c in 30 ml of acetic anhydride and 3 g of sodium acetate was heated with stirring at 100° C. for ½ hr. The mixture was cooled to RT. Then, 100 ml of water was added and stirring was prolonged for 1 hr. The reaction mixture was neutralized by dropwise addition of cold conc. aq. NH4OH solution, the product was extracted with ethyl acetate and the organic layer was washed, dried and concentrated. The residue was treated with diisopropyl ether, to provide 2.2 g of 3d as white crystalline material; Mp 232-233° C.; MS-ESI: [M+1] 499.15 and 501.19. Rf (heptane/ethyl acetate 1/1) 0.50
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:49]=[CH:50][N:51]2[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][C:52]=12>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:50]4[N:51]5[CH2:56][CH2:55][NH:54][CH2:53][C:52]5=[N:48][CH:49]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cnc4n3CCNC4)cc3nccn23)cn1
Temperature: 95 °C
Yield: 25.8 %

Procedure:
To 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropyl-propanenitrile (Preparation M; 100 mg, 0.320 mmol) in dioxane (10 mL) was added K2CO3 (88.4 mg, 0.639 mmol), diacetoxypalladium (7.18 mg, 0.0320 mmol), triphenylphosphine (16.8 mg, 0.0639 mmol) and tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (107 mg, 0.480 mmol). The reaction was sealed and heated to 95° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (33 mg, 26% yield). MS (apci) m/z=400.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:14]=1>>[CH3:8][O:9][C:10]1[CH:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(OC)c(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid was added neat to tert-butyl 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylate and stirred at room temperature for 5 hours. TFA was evaporated, solid product azeotroped with toluene then placed under vacuum for 24 hours to yield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid. HPLC=3.07 min; MS: MH+=321
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([CH2:13][O:14][CH2:15][CH3:16])[NH:10][C:9](=[O:17])[CH:8]=1.[OH-].[Na+].S(=O)(=O)(O)O>O>[NH2:6][C:7]1[N:12]=[C:11]([CH2:13][O:14][CH2:15][CH3:16])[NH:10][C:9](=[O:17])[C:8]=1[N:1]=[O:4]
Reactant: CCOCc1nc(N)cc(=O)[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(N)c(N=O)c(=O)[nH]1

Procedure:
17.7 g (0.256 moles) of sodium nitrate are added to a solution of 39.5 g (0.233 mole) of 6-amino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 336 ml (0.336 mole) of 1 N sodium hydroxide. A solution of 17.9 ml (0.320 mole) of 96% sulphuric acid diluted in 179 ml of water is then added dropwise at between 0° and 5° C. The precipitate formed is isolated by filtration immediately after completion of the addition. The solid obtained is washed with cold water and then with ethyl ether. After drying, it is used in the next step without further purification. Yld: 46.2 (quantitative), m.p. 163°-165° C. An analytical sample was obtained by recrystallization from methanol.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[F:9][C:10]([F:27])([F:26])[CH2:11][N:12]=[C:13]([NH2:25])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:19]=1.C(Cl)(Cl)Cl.CO.N>C(#N)C>[F:27][C:10]([F:9])([F:26])[CH2:11][N:12]=[C:13]([NH2:25])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])[N:19]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: FC(F)(F)CN=C=S
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNC(=S)NCC(F)(F)F)cs1
Reaction time: 2 h

Procedure:
Trifluoroethylisothiocyanate (0.2 g.) in acetonitrile (6 ml.) was added to a solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-thiazole (0.5 g.) in acetonitrile (10 ml.), and the mixture was allowed to stand at room temperature for 2 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 85:15:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.). The residue was crystallised from ethyl acetate/light petroleum ether (b.p. 60°-80°) to give 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-[3-(2,2,2-trifluoroethyl)thioureido]butyl)thiazole. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=O) included the following resonances (δ):- 4.05 (2H, multiplet); 4.35 (2H, multiplet); 6.36 (1H, singlet).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1([CH:28]([F:30])[F:29])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.FC(F)C1(C(F)F)CNC2C=C(S(C3C=CC=CC=3)(=O)=O)C=CC=2[O:35]1.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC=CN=1>[Cu].ClCCl.C(OCC)(=O)C.O>[F:31][CH:2]([F:1])[C:3]1([CH:28]([F:29])[F:30])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:35])[C:6]2[CH:15]=[C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)N(c1ccccn1)CC(C(F)F)(C(F)F)O2
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCC(C(F)F)(C(F)F)O2
Agent: [Cu]
Agent: Brc1ccccn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C(F)F)(C(F)F)O2
Temperature: 200 °C

Procedure:
2-(2,2-bis(Difluoromethyl)-6-phenylsulfonyl-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine. A mixture of the product of step e. (1 g), potassium carbonate (0.41 g), copper bronze (0125 g,), and 2-bromopyridine (4.3 g) was stirred and heated at 200° C. for 18 hours. The cooled, dark mixture was stirred with water and ethyl acetate:dichloromethane. The mixture was filtered through diatomaceous earth, and the lower organic layer was separated. The organic phase was washed (water), dried, and evaporated. Chromatography, eluting ethyl acetate:hexane (gradient 40% to 60%) gave the pyridine as a pale yellow gum (0.29 g); NMR: 4.31 (s,2), 6.49 (t,2), 7.06 (t,1), 7.21 (d,1), 7.33 (d,1), 7.53 (d,1), 7.60 to 7.70 (m,3), 7.79 (t,1), 7.92 (d,2), 7.94 (s,1), 8.36 (d,1); MS: m/z=453(M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(Cl)ncc2Br)CC1
Yield: 63 %

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate to provide the title compound in 63% yield. 1H NMR (CDCl3, 400 MHz) 8.43 (s, 1H), 4.32 (d, 2H), 4.18 (m, 2H), 2.76 (m, 2H), 2.03 9 m, 1H), 1.80 (m, 2H), 1.46 (s, 9H), 1.34-1.26 (m, 2H); MS (ESI) m/z: Calc: 405.1 (M+). Found. 307.9 (M+-Boc+2).