Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:12])[C:6](F)=[C:5](F)[C:4](F)=[C:3](N)[C:2]=1F.[ClH:13].Cl.Cl.[CH3:16][CH2:17]OCC.[CH:21](O)([CH3:23])[CH3:22]>>[ClH:13].[ClH:13].[CH:16]1[C:2]2=[C:1]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH2:23][CH2:21][CH2:22][N:12]3[CH:17]=1
Reactant: CC(C)O
Reactant: CCOCC
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: c1cc2c3c(c1)ccn3CCC2

Procedure:
To convert the product to the corresponding dihydrochloride, the title base was dissolved in isopropanol. Isopropanolic hydrochloric acid and then ether were added to the solution. The resulting precipitate was filtered out. 250 mg of 2-[4-(4-hydroxybutoxy)phenyl]-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl)piperazin-1-yl)ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline 2 HCl 2 H2O having a melting point of 150° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=O.[CH2:9]([O:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13]=1[CH:14]=O)[CH3:10].[NH2:35][C:36]([NH2:38])=[O:37].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:14]([C:13]2[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:9][CH3:10])[NH:35][C:36](=[O:37])[NH:38][C:5]=1[CH3:7])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: NC(N)=O
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C1NC(=O)NC(C)=C1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-ethoxy-6-pentadecyl benzaldehyde (3 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20 mL) was heated to reflux (65-70° C.) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with 1N hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by flash column chromatography and recrystallized from hexane to get white crystalline solid of title compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([OH:14])(=[O:13])[CH2:9]C(O)=O.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:4]1([CH2:9][C:8]([OH:14])=[O:13])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC(=O)O
Reactant: O=C1CCSCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1(CC(=O)O)CCSCC1
Reaction time: 4 h

Procedure:
1-thiacyclohexan-4-one, (17.4 g), was added to malonic acid (17.1 g), and ammonium acetate, (23.1 g), in ethyl alcohol (300 ml.). This slurry was heated to give a solid mass which on further heating gave a suspension. Heating was continued for a further 4 hours at reflux and then filtered hot to give 4-amino-1-thiacyclohexan-4-yl acetic acid, [(14.17 g), m.p. 232°-235°(d), found C. 47.6; H, 7.5; N, 8.0; S, 18.6; C7H13NO2S requires C, 48.0; H, 7.5; N, 8.0; S, 18.3%].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29]C(=O)OC(C)(C)C)[CH2:26][O:25]C(C)(C)[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:38].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:29][C:21]([C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:38])[CH:4]=4)[O:12][N:11]=3)=[CH:37][C:17]=2[CH:18]=1)([CH2:22][OH:23])[CH2:26][OH:25]
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(Br)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: NC(CO)(CO)c1cc2cc(-c3noc(-c4ccc(Br)c(Cl)c4)n3)ccc2o1
Yield: 39 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 39% yield, as creamy solid. 1H-NMR (DMSO-d6) 8.31 (b, 2H); 8.05 (d, 1H, J=8.52 Hz); 8.00 (d, 1H, J=8.49 Hz); 7.94 (d, 1H, J=8.58 Hz); 7.68 (d, 1H, J=8.46 Hz); 6.91 (s, 1H); 4.88 (bs, 1H); 3.66 (bs, 2H); 3.58 (bs, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH3:26][O:27][C:28]([CH:30]1[CH2:33][NH:32][CH2:31]1)=[O:29].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:32]3[CH2:33][CH:30]([C:28]([O:27][CH3:26])=[O:29])[CH2:31]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 23.5 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where methylazetidine-3-carboxylate hydrochloride (0.25 g, 1.2 eq.), T3P (50% in EtOAc) (1.0 mL, 1.2 eq.) followed by DIPEA (0.48 mL, 2 eq.) were added. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2-3% Methanol in DCM) to give (Z)-methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylate (0.15 g, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([Cl:15])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:28]([C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([CH:37]=O)[CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])C.[OH-].[K+].Cl>C(O)C>[CH:39]1([N:27]2[C:26]3[CH:45]=[CH:46][C:23]([C:21]([OH:22])=[O:20])=[CH:24][C:25]=3[N:29]=[C:28]2[C:30]2[CH:31]=[C:32]3[C:33](=[CH:34][CH:35]=2)[N:36]=[C:12]([C:11]2[C:6]([C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:7][CH:8]=[C:9]([Cl:15])[CH:10]=2)[CH:13]=[CH:37]3)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CC(=O)c1cc(Cl)ccc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Cl)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
1-(4′-Chloro-4-chloro-biphen-2-yl)-ethanone (132 mg, 0.5 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 132 mg product.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:16][CH2:17][C:18]1[C:26]2[S:25](=[O:28])(=[O:27])[N:24]=[C:23]([C:29]3[C:30](=[O:47])[C@@:31]([CH2:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:40])[C:32]4[C:37]([C:38]=3[OH:39])=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:22][C:21]=2[S:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH3:44][C:43]([CH3:46])([CH3:45])[CH2:42][CH2:41][C@:31]1([CH3:40])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]([OH:39])=[C:29]([C:23]2[NH:22][C:21]3[S:20][CH:19]=[C:18]([CH2:17][NH:16][S:2]([NH:5][C:6](=[O:7])[O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)(=[O:4])=[O:3])[C:26]=3[S:25](=[O:28])(=[O:27])[N:24]=2)[C:30]1=[O:47]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)NC(=O)OCc4ccccc4)csc3N2)=C(O)c2ccccc21
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A solution of chlorosulfonylisocyanate (9 μL, 0.1 mmol) in 1 mL of dichloromethane was treated with benzyl alcohol (10 μL, 0.9 mmol), stirred for 30 minutes, treated with a solution of Example 186B (36 mg, 0.07 mmol) and triethylamine (40 μL, 0.3 mmol) in 1 mL of dichloromethane, stirred for 1.5 h, diluted with dichloromethane, washed with 1 N aqueous HCl and water, and concentrated in vacuo. The crude material was purified by chromatography on silica gel with a gradient of methanol in dichloromethane (0-3%) to afford the title compound (34 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.40 (td, J=12.9, 3.7 Hz, 1H), 0.72 (s, 9H), 0.81 (td, J=12.8, 4.6 Hz, 1H), 1.54 (s, 3H), 2.04 (m, 1H), 2.20 (m, 1H), 4.27 (d, J=5.5 Hz, 2H), 5.17 (s, 2H), 7.19 (s, 1H), 7.37 (m, 5H), 7.49 (m, 1H), 7.62 (s, 1H), 7.70 (d, J=3.7 Hz, 2H), 8.11 (d, J=7.7 Hz, 1H), 8.55 (t, J=6.3 Hz, 1H), 11.52 (s, 1H), 14.44 (s, 1H); MS (APCI−) m/z 685 (M−H)−, m/z 472 (M−[SO2NHCbz]−H)—.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=2)[NH:3]1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:27]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc2N1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)ccc2N1

Procedure:
A solution of 2,2,2-trichloroethyl (2-oxo-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.618 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.108 ml, 0.618 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (18.0 mg, 6.9%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[CH2:33](N(CC)CC)[CH3:34].C(I)C>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][CH2:33][CH3:34])=[CH:23][CH:24]=3)=[C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(N)cc3)c12
Solvent: ClCCl
Solvent: CCI
Solvent: CC#N
Product: CCNc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)OC)c23)cc1
Yield: 19.9 %

Procedure:
Put 29.2 mg (0.068 mmol) 6-({5-[4-aminophenyl]-6-phenylfuro[2,3-d]pyrimidin-4-yl}amino)-hexanoic acid methyl ester in 0.5 ml acetonitrile with 14 μl (0.102 mmol) triethylamine and add an excess of ethyl iodide in portions at 45° C. in closed apparatus over a period of 12 h. After cooling, dilute the reaction mixture with dichloromethane, wash successively with satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate by vacuum evaporation. After preparative RP-HPLC (gradient: acetonitrile/water), 6.2 mg of the target compound (19.9% of theor.) is isolated from the raw product mixture.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.Cl.[N:23]([O-])=[O:24].[Na+]>O>[NH2:13][C:12]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:7])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9](=[O:10])[C:11]=1[N:23]=[O:24]
Reactant: O=N[O-]
Reactant: CCCCn1c(N)cc(=O)n(CCCC)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)n(CCCC)c1=O
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a mixture of 1,3-di-n-butyl-6-amino-uracil g, 112.8 mmol), glacial acetic acid (10 ml), and 6N HCl (18.8 ml) in water (500 ml) was added dropwise a solution of sodium nitrite (7.78, g, 112.8 mmol) in water (30 ml) on ice bath. The reaction mixture was stirred for 30 min. The violet solid was collected by filtration and washed with water (2×20 ml), dried for 2 days at 60° C. in a vacuum oven to yield 6-amino-1,3-di-n-butyl-5-nitroso-uracil (24.99 g, 82.6%), m.p. 199°-205° C.; 1H NMR (CDCl3) δ0.97-1.01 (m, 6H, 2×CH3), 1.36-1.49 (m, 4H, 2×CH2), 1.62-1.74 (m, 4H, 2×CH2), 3.94 (t, J=7.8 Hz, 2H, N--CH2), 4.08 (t, J=7.5 Hz, 2H, N--CH2), 6.46 (br s, 2H, NH2). Anal. Calc'd for C12H20N4O3 : C, 53.72; H, 7.51; N, 20.88; Found: C, 54.37; H, 7.67; N, 20.65.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6](C(O)=O)=[C:5]2O.O=S(Cl)[Cl:20].C[N:23]([CH:25]=[O:26])C.N>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:25]([NH2:23])=[O:26])=[C:5]2[Cl:20]
Reactant: CN(C)C=O
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nnc(C(=O)O)c(O)c2cc1Br
Agent: N
Solvent: CC(C)=O
Product: COc1cc2nnc(C(N)=O)c(Cl)c2cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 1 L round bottom flask charged with 6-bromo-4-hydroxy-7-methoxycinnoline-3-carboxylic acid (Method 18) (14 g, 46.8 mmol) was added SOCl2 (342 ml) and DMF (1 ml). The resulting mixture was heated to reflux for 4 hours before being cooled to rt. The reaction mixture was conc. in vacuo to yield a residue which was suspended in acetone (˜400 ml). The suspension was cooled to 0° C. in an ice bath and conc. aqueous ammonia (50 ml, 1284 mmol) was added drop wise via an addition funnel and the resulting mixture was allowed to stir at 0° C. for an additional 15 minutes. A precipitate formed which was collected via vacuum filtration. The filter cake was washed with water (3×100 mL), acetone (3×50 mL), collected, and dried in vacuo to yield the title compound as an off white solid (14.00 g, 94%) which was used without further purification. 1H NMR: 8.55 (s, 1H), 8.40 (s, 1H), 8.05 (m, 2H), 4.10 (s, 3H); m/z: 317.
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][N:7]1[CH2:11][CH3:12])#[N:4].O1[CH:19]2[CH:14]1[C:15]([CH3:27])([CH3:26])[O:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=12>CS(C)=O>[C:3]([N:5]=[C:6]1[N:7]([CH2:11][CH3:12])[CH2:8][CH2:9][N:10]1[C:19]1[C:18]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:17]=2[O:16][C:15]([CH3:27])([CH3:26])[CH:14]=1)#[N:4]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CCN1CCNC1=NC#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 40 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
60% Dispersion of sodium hydride (0.40 g) in mineral oil was added in small portion at ambient temperature to a solution of 2-cyanoimino-1-ethylimidazolidine (1.38 g) in dimethyl sulfoxide (15 ml). The reaction mixture was stirred for 30 minutes at the same temperature, and 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.01 g) was added thereto. The reaction mixture was stirred overnight at the same temperature, heated for 1.5 hours at 40° C., and then poured into ice-water (50 ml). The forming precipitate was collected by filtration, and washed with water. The product was recrystallized from ethanol to give 4-(2-cyanoimino-3-ethylimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.36 g).
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([O:34]C)=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.O[Li].O.Cl>CC(C)=O>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(c2cccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc3C)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylate (˜0.26 mmol) was dissolved in acetone (3 mL) and water (3 mL) in a reaction tube. LiOH.H2O (25 mg, 60 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N HCl until pH 1-2. The volatiles were removed under reduced pressure. The residue was taken up in methylene chloride and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The solid was triturated with Et2O, then hexanes to 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylic acid. ESI-MS m/z 493.2 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2cccc(N3CCOCC3)c2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
526 mg (2.0 mmol) of 1-(benzyloxy)-3-bromobenzene, 209 μl (2.4 mmol) of morpholine, 283 mg (2.8 mmol) of sodium t-butoxide, 9 mg (0.005 mmol) of tris(dibenzylidine acetone)dipalladium(0) and 19 mg (0.015 mmol) of (±)-BINAP were placed in a flask, 5 ml of toluene was added thereto, and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and filtered through Cellite. The resulting filtrate was concentrated under a reduced pressure, and the residue was subjected to column chromatography using 30% ethyl acetate/hexane as an eluent to obtain 430 mg (yield 80%) of 4-(3-(benzyloxy)phenyl)morpholine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[N:3]1.Br[C:21]1[CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[Cl:26].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:26][C:25]1[S:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2cnnn2C)c(Cl)s1
Temperature: 110 °C
Yield: 31.7 %

Procedure:
A mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (2.0 g, 5.37 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (1.25 g, 4.9 mmol), Pd(PPh3)2Cl2 (171 mg, 0.244 mmol), TRIETHYLAMINE (0.68 ml, 4.89 mmol) and toluene (3 ml) was heated at 110° C. for 4 hr under N2. The reaction mixture was purified via column chromatography (silica, 50%-70% EtOAc in hexane) to give the title compound as a white solid (400 mg, 32%): LCMS (ES) m/z 258.2 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1)[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[CH:49][N:50]=[C:24]12)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[F:57][C:54]1[CH:55]=[CH:56][C:51]([CH:21]([OH:20])[CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:44][C:4](=[O:7])[O:5][N:3]=4)=[CH:35][CH:36]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:52][CH:53]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)c2ccc(F)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.94 g), sodium hydrogen carbonate (1.51 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-({4-[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate and 1 N hydrochloric acid, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.31 g, 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1.[CH3:34][I:35]>>[I-:35].[CH3:34][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:17]=1
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCCc2ccccn2)cc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCCc2cccc[n+]2C)cc1
Product: [I-]
Yield: 83 %

Procedure:
The title compound is prepared by the procedure of Example 28 using 1.0 g of product from Example 56 and 15.68 g of methyl iodide. The residue is recrystallized from methyl alcohol to give 1.09 g of the desired product as yellow crystals.