Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2
Reactant: CCCCCCCC(=O)N1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCN1CCc2cc(OC)ccc2C1

Procedure:
The amide prepared under (a) is dissolved in 50 ml of dry diethyl ether and added dropwise to a suspension of 1.0 g of lithium aluminum hydride in 100 ml of dry diethyl ether. The mixture is then heated under reflux for 3 hours, 5 ml of water is added cautiously to cause decomposition, with cooling, and inorganic material is filtered off. The oil remaining after removal of the solvent in vacuo is reac-ted further without purification.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:27]=[C:28]([C:30]4([CH3:33])[CH2:32][CH2:31]4)[CH:29]=3)=[O:23])=[C:17]([CH3:41])[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(OCC)(=O)C>ClCCl>[CH3:33][C:30]1([C:28]2[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]3[C:17]([CH3:41])=[N:16][C:15]([N:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[CH:20][CH:19]=3)=[O:23])[N:26]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[N:27]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2C)cc1
Reaction time: 0.5 h

Procedure:
Bubble gaseous hydrochloric acid through a solution of 4-(6-methyl-5-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (assume 2.74 mmol) in 1:1 ethyl acetate:dichloromethane (200 mL) for 3 min to ensure saturation. Allow the mixture to stand for 30 min then concentrate under reduced pressure to a white solid. Dissolve the solid in MeOH and load onto a 20 g Varian SCX column, rinsing with additional MeOH. Elute the free base with 1:1 2 M ammonia in MeOH:dichloromethane. Concentrate the solution under reduced pressure to give a white solid (1.21 g, 99% over 2 steps). LCMS(ES+): m/z=446 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])=[O:40].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39](=[O:40])[C:41]1[CH:49]=[CH:48][CH:47]=[C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[C:14]2[CH:15]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:17]=[CH:18][N:19]=2)=[O:45])[CH:42]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCOCCO)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (300 mg, 0.70 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL). This was followed by the addition of 3-(2-(2-hydroxyethoxy)ethylcarbamoyl)benzoic acid (302.2 mg, 1.19 mmol, 1.70 equiv) at room temperature. To this was added triethylamine (156 mg, 1.54 mmol, 2.20 equiv). To the mixture was added EDC.HCl (148.2 mg, 0.78 mmol, 1.10 equiv) at room temperature, followed by HOBT (104.4 mg, 0.77 mmol, 1.10 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 83.6 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.039 (t, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.63˜7.57 (m, 3H), 7.53˜7.50 (m, 2H), 7.47˜7.40 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 3.71˜3.58 (m, 8H), 3.43˜3.39 (m, 4H), 1.84˜1.81 (m, 6H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol) with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithium hydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for 38 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and collection by filtration to obtain 2.236 g (7.47 mmol, 81% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 300(M+1).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:21][NH2:22]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=2[C:1](=[O:6])[NH:22][NH:21]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Yield: 84.4 %

Procedure:
3,4,5,6-Tetrahydrophthalic anhydride (25 g, 0.164 mol) was dissolved in 40% aqueous acetic acid (500 ml) with sodium acetate trihydrate (26.8 g, 0.197 mol) and hydrazine hydrate (9.58 ml, 0.197 mol). The reaction mixture was heated under reflux overnight and then allowed to cool. The resulting solid was collected by filtration, washed with water and diethyl ether and dried in vacio to give the title-product (23 g, 84%), 1H NMR (250 MHz, d6-DMSO) δ1.64 (4 H, br s, 2 of CH2), 2.34 (4 H, br s, 2 of CH2), 11.30 (2 H, br s, 2 of NH); MS (ES+) m/e 167 [MH]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=O)[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2([CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][CH:10]([CH2:8][NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:19][CH2:20][CH2:21]2)=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccccc1)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(CN3CCCC(CNc4ccccc4)C3)CCC2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A solution of 202 (0.504 mmol, 200 mg) in Toluene (2 mL) at 0° C. was treated with 3.0 M Red-Al (3.5 equiv, 1.76 mmol) under Ar. The reaction mixture stirred for 12 h and returned to 25° C. The reaction mixture was then cooled to 0° C., quenched with 10% aqueous NaOH and extracted with EtOAc (3×25 mL). The organics were dried with NaCl(sat) and Na2SO4(s). The reaction mixture was purified by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, 2:1 hexane-EtOAc) which provided 203 (170 mg, 186 mg theoretical, 91%) as a colorless oil: Rf 0.61 (SiO2, 2:1 hexane-EtOAc); LRMS m/z 368 (M+, C23H29ClN2, requires 368).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cnccn1
Yield: 74 %

Procedure:
Pyrazinecarboxylic acid (3.7 g, 30 mmol), benzene (25 mL) and thionyl chloride (15 mL) were added into a 100 mL round bottom flask. The reaction mixture was heated under reflux for two hours after which time benzene and excess thionyl chloride were removed by distillation. The dark red crude pyrazinoyl chloride was purified by sublimation under vacuum at a bath temperature of 50°-60° C. to give colorless crystals that weighed 3.2 g (74% yield).
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH3:20])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>C(O)(C)(C)C>[CH2:21]([NH:25][C:4]([NH:18][CH2:19][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CCN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NCC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-ethyl-2-thiopseudourea hydroiodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and t-butanol (75 ml) was heated at 90°-95° C. for 172 hours to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine which was converted into its monofumarate salt (m.p. 159°-160° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=2[F:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1c(Cl)cccc1Br
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Yield: 92.9 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (11.8 g, 56.3 mmol) in dry diethyl ether (100 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 22.5 mL, 56.3 mmol). The mixture was stirred at −78° C. for 10 min after which a solution of 1-benzylpyrrolidin-3-one (10 g, 56.3 mmol) in dry diethyl ether (50 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous ammonium chloride solution (50%, 50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (isooctane/ethyl acetate, 1:1) gave the title compound (16 g). MS m/z (relative intensity, 70 eV) 305 (M+, 9), 214 (41), 133 (71), 132 (50), 91 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.FC(F)(F)C(O)=O.[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:41][CH2:42][CH:43]([CH2:46][NH:47][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:44][CH2:45]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: NCC1CCN(C(N)=NC(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2CCN(C(N)=NC(=O)OCc3ccccc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
97 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and 124.3 mg of [Amino-(4-aminomethyl-piperidin-1-yl)-methylene]-carbamic acid benzyl ester trifluoroacetic acid salt were dissolved in 5 ml of DMF. After cooling to 0° C. 136 mg of HATU and 106 mg of NEM were added. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column) (gradient acetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to 0:100). The fractions containing the product were evaporated and lyophilized.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium (II) dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene was used and treated in a manner similar to Example 3-(3) to give the target compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH4).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C1(N(C2CCCCC2)C)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:27][O:26][C:22](=[O:25])/[CH:23]=[CH:24]/[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C(=O)OC)cc1
Temperature: 130 °C

Procedure:
3-(4-Bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (525 mg, 1.47 mmol) was dissolved in 15 ml of dioxane and after addition of methyl acrylate (264 ul, 2.93 mmol), dicyclohexyl-methylamine (622 ul ml, 2.93 mmol) and Pd(PtBu3)2 (15 mg, 0.03 mmol) the mixture was heated for 5 min at 130° C. in a microwave oven. Then the mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with sat. NaHCO3— and NaCl-solution, and dried over Na2 SO4. Evaporation gave a yellow solid. The crude product was purified by recrystallization from diethylether to give a colorless solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=4)=[CH:30][N:25]3[N:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].O>ClCCl>[CH2:11]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:32]=[CH:33][C:34]([C:35]([O:1][N:2]5[C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=6[N:4]=[N:3]5)=[O:36])=[CH:38][CH:39]=4)=[CH:30][N:25]3[N:24]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Reactant: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)On5nnc6ccccc65)cc4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.4 %

Procedure:
To a solution of 1-hydroxybenzotriazole (1.67 g) and 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoic acid (4.2 g) in dichloromethane (170 ml) was added 1-ethyl-3-(31-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (2.95 g) and stirred for 6 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoyloxy]benzotriazole (2.456 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
To a stirred solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert.-butyl ester (10 g) in dimethylformamid (50 ml) at room temperature is added 1-bromomethyl-4-iodobenzene (15.5 g) and potassium carbonate (8.0 g). After 15 h of stirring, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (4:1 to 3:2 cyclohexane:ethyl acetate) to yield 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g). [M+H]=427; HPLC retention time 1.57 min (Method E).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1CCC(NC(C)=O)CC1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A solution of 4-acetamidopiperidine (20.7 g), sodium bicarbonate (10.6 g) and water (300 ml) was cooled to 0° C., and 17.7 g of ethyl chloroformate was added dropwise, with stirring. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature and was diluted with water and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 32.2 g (100%) of product.
Reaction SMILES: [CH:1](=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+].O>CO>[C:2]1([CH:1]2[C:8]3([C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[O:19]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)C12OC2c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-benzylidene-1,3-indandione (20 g) in methanol (200 ml) was added 30% hydrogen peroxide (19 ml). The suspension was cooled to 5° C. and 1 N sodium hydroxide (2.1 ml) was added dropwise at such a rate as to keep the temperature below 15 ° C. After completed addition, stirring was continued at room temperature for 30 minutes. The mixture was then poured into water (1.2 L). The resulting crystalline precipitate was collected by filtration, washed on the filter with water (3×100 ml) and dried under high vacuum at room temperature for 24 hours, affording 3-phenylspiro[oxirane-2,2'-indan]-1',3'-dione as a yellow solid (17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17](O)=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH:7]([C:17]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:18])[O:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:11][C:10]=2[CH:12]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)C1Oc2ccc(Cl)cc2Cc2cc(Cl)ccc2O1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(NCc1cccnc1)C1Oc2ccc(Cl)cc2Cc2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 15 g of 2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid was added 75 ml of thionyl chloride, and the heterogenous mixture was refluxed with occasional stirring until it became homogenous. The mixture was refluxed for an additional 2 hours after which the thionyl chloride was distilled off under reduced pressure affording a solid residue which was dissolved in 300 ml of dry benzene by warming on a steam bath. The benzene was distilled off under reduced pressure affording a white crystalline residue to which was added 500 ml of dry benzene. The mixture was stirred at room temperature until homogenous then 35 g of 3-aminomethylpyridine was added. After standing at room temperature for 2 hours the mixture was heated to reflux for an additional 3 hours, cooled to room temperature, poured into ice water and separated. Methanol was added to aid the solubility of the product in the organic layer. The organic layer was washed with water and distilled under reduced pressure resulting in a residue which was dried and recrystallized twice from methanol-acetone (1:1) to give the desired product, M.P. 225°-226°C.