Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[CH3:14][O-:15].[Na+]>C(Cl)Cl>[CH3:14][O:15][CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: C[O-]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Agent: [Na+]
Solvent: ClCCl
Product: COCC(O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (202 mg, 1.10 mmol), prepared in the previous step, in DCM (20 mL) was dissolved in sodium methoxide solution (10 mL, 5 mmol, 0.5 M). The mixture was stirred, heating to reflux under argon overnight and then cooled to ambient temperature and concentrated in vacuo. After addition of saturated ammonium chloride solution and extraction with ethyl acetate, the organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-50% ether) to afford the product.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22](=[C:29]1[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]1=[O:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:23]1([C@H:22]([CH:29]2[C:30](=[O:38])[O:31][C:32]([CH3:36])([CH3:37])[O:33][C:34]2=[O:35])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)OC(=O)C(=Cc2ccccc2)C(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(=O)C([C@H](C#Cc2ccccc2)c2ccccc2)C(=O)O1
Temperature: 0 °C
Yield: 65.8 %

Procedure:
A solution of copper (II) acetate monohydrate (20 mg, 0.10 mmol) in water (0.4 ml) was treated with sodium (L)-ascorbate (40 mg, 0.20 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 66.2 mg, 0.10 mmol) and phenylacetylene (0.55 ml, 5.0 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-benzylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (116 mg, 0.50 mmol). The reaction mixture was stirred vigorously at 0° C. for 66 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1→1:1) to give 110 mg of the pure title compound as a white solid. (yield: 64%)
Reaction SMILES: [C:1]12([CH2:9][CH:10]([NH:21]C(=O)OCC3C=CC=CC=3)[CH2:11][N:12]([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2>[OH-].[OH-].[Pd+2].CO>[NH2:21][CH:10]([CH2:9][C:1]12[CH2:2][CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH2:8]2)[CH2:11][N:12]([CH3:20])[C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: CN(CC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(CC(N)CC12CCC(CC1)CC2)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A mixture of benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-(N-methyl-N-tert-butoxycarbonylamino)propan-2-ylcarbamate (250 mg, 0.58 mmol) and Pd(OH)2 (20%, 60 mg) in 12 Ml of absolute of MeOH was hydrogenated under 20 psi H2 for 2 h. TLC (EtOAc/Petroleum ether=1:2) indicated the completion of reaction. The mixture was then filtered and evaporated to afford tert-butyl 2-amino-3-(bicyclo[2.2.2]octan-1-yl)propyl(methyl)carbamate (150 mg, 87%) as oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:35]([CH3:45])[CH3:34])=[O:44])[CH2:43][CH2:42]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H36N7O3SCl2 [(M+H)+] 656.1972, observed 656.1973.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[C:40]([O:39][C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:10]2[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=[C:9]2[CH2:7][CH3:8])=[CH:26][CH:27]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1[nH]c(CC)nc1C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
0.337 g of potassium t-butoxide was added to a solution of 0.68 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 37) in 7 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes. 1.04 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate was then added to the resulting solution, and the reaction mixture was stirred at room temperature for 4 hours. At the end of this time, it was mixed with ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.32 g of the title compound as a gum.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.FC(F)(F)C([NH:48][C@@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)=O>CS(C)=O.COC(C)(C)C>[NH2:48][C@@H:49]1[CH2:53][CH2:52][N:51]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[CH2:50]1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N[C@@H]1CCNC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 52 h
Yield: 65.3 %

Procedure:
A mixture of 939 mg (1.76 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 1.22 g (8.81 mmol) potassium carbonate and 770 mg (3.52 mmol) (R)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 20 ml dimethyl sulfoxide was stirred at 130° C. for 52 h. After cooling to room temperature the reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 670 mg (65%) of the title compound as a light brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O.ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[N+:19]=[N-:20])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
3,4,5-Trimethoxyaniline (1.83 g; 10 mmol) is added to a 100 mL flask containing water (20 mL) and HCl (conc. aqueous solution, 5 mL). The solution is chilled to 0° C. and a solution of sodium nitrite (830 mg; 12 mmol) in water (5 mL) is added. The solution is stirred at 0° C. for 30 minutes, and then a solution of sodium azide (1.3 g; 20 mmol) in water (5 mL) is added. After another 30 minutes of stirring, dichloromethane is added (20 mL) and the organic phase was collected and filtered through a plug of silica, dried over magnesium sulfate and the solvent was evaporated to give approximately two grams of 3,4,5-trimethoxyphenyl azide.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6](=[O:7])[N:5]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:4](=[O:13])[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH2:14][C:15]([OH:17])=[O:16])[C:6](=[O:7])[N:5]([CH2:8][C:9]([F:11])([F:10])[F:12])[C:4](=[O:13])[NH:3]1
Reactant: CC(C)(C)OC(=O)CC1(C)NC(=O)N(CC(F)(F)F)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC(=O)O)NC(=O)N(CC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 109.4 %

Procedure:
To a solution of Compound 26c (100 mg, 0.32 mmol) in DCM (1 mL) was added TFA (1 mL) and the reaction mixture stirred for 1 h. The mixture was concentrated under reduced pressure, co-evaporated with toluene under reduced pressure, then dried under high vacuum to give Compound 26a (89 mg, 100% yield). LCMS=0.9 min using analytical method (B), 255.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (br. s., 1H), 8.45 (s, 1H), 4.37-4.00 (m, 2H), 2.88 (d, J=16.8 Hz, 1H), 2.60 (d, J=17.1 Hz, 1H), 1.31 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:9]=2[CH:10]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (5 mL), sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added. After 20 min, β-bromophenetole (0.31 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by two column chromatographies (Biotage, 40S) with heptane/EtOAc (17:3) and (Biotage, 40M) with heptane/EtOAc (9:1) to give 0.41 g (76%) of a white solid: mp 135.5-137.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=4.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 6.93 (m, 1H), 6.77 (d, J=7.9 Hz, 2H), 4.42 (m, 2H), 4.17 (t, J=5.3 Hz, 2H), 3.70 (m, 4H), 3.09 (m, 2H), 2.89 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 1678, 1494, 1469, 1406, 1364, 1297, 1245, 1233, 1172, 1119, 1106, 941, 875, 758, 691 cm−1; MS (ES+) m/z 475 (M+H+), 498, 497, 348, 346, 255, 252, 169, 137, 121, 90; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.22; H, 6.00; N, 5.88.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:18]C(=O)OC)[CH:9]=1.C[O-].[Na+].CC(O)=O>CO>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:18])[CH:9]=1
Reactant: COC(=O)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[Si](C)(C)CCOCOc1cc(O)cc2ccccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
5.82 g (16.7 mmol) of carbonic acid methyl ester 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yl ester was dissolved in 100 ml of methanol and cooled down to 5° C.; 3.4 ml=3.30 g (18.4 mmol) of sodium methoxide (5.4 molar in MeOH) was added and the reaction mixture then warmed up to room temperature. After one hour, it was poured into crashed ice, the pH was adjusted to 5-6 with AcOH (1N) and the reaction mixture subsequently extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of n-heptane/MeCl2) to give 4.23 g of 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ol as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]2)=[CH:4][CH:3]=1.F[C:20](F)(F)S(OC)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][N:9]2[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.2 g, 8.9 mmol) and methyl trifluoromethanesulfonate (3 mL) was stirred at 80° C. for 40 min. The mixture was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=70/30→100/0) to give the title compound (1.6 g, 67%) as a pale-yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:15])(=O)[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1>O>[O:12]=[C:11]1[NH:13][C:6]([C:5]([Cl:3])=[O:15])=[CH:7][C:8](=[O:9])[NH:10]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: O
Product: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 13.13 ml (180 mmol) of thionyl chloride, and a water condenser, is placed 15.61 g (100 mmol) of orotic acid. Addition of the thionyl chloride is completed with heating to about 55° C. over the course of about 45 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl chloride (orotoyl chloride). This acyl chloride, 6.11 g (35 mmol), is put into a dry separatory funnel and combined with 50 mL of dry DCM for use in the next step of the reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1.Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:20][NH:19][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][C:9]=2[CH:15]=1)=[NH:17]
Reactant: N#Cc1ccc2[nH]c(-c3ccccn3)nc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]c(-c3ccccn3)nc2c1
Yield: 46 %

Procedure:
A mixture comprising 2-pyridin-2-yl-1H-benzimidazole-5-carbonitrile (110 g, 0.5 mmol), hydroxylamine hydrochloride (38.2 mg, 0.55 mmol), potassium carbonate (104 mg, 0.75 mmol) and methanol (10 mL) was heated at reflux for 2.5 hours and then concentrated to dryness. The residue was taken up and purified by preparative reverse phase HPLC. The combined pure fractions were lyophilized to provide N-hydroxy-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine (40 mg, 0.23 mmol); 1H-NMR (300 Mhz, DMSO-d6): 7.53-7.57 (m, 2H), 7.80 (d, 1H), 8.01-8.04 (m, 2H), 8.32 (d, 1H), 8.75 (d, 1H), 9.20 (b, 2H); MS (ESI), Calculated for C13H11N5O: 253.1, Found (MH+): 253.7.
Reaction SMILES: [ClH:1].[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH2:31](Br)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[ClH:1].[CH2:31]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:3][CH2:4]1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CBr
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)CN1CCN(C(=O)c2ccc3c(c2)CC(=O)N3)CC1
Reaction time: 6 h
Yield: 32.5 %

Procedure:
5-(1-Piperazinylcarbonyl)oxindol hydrochloride (1.0 g), 1.2 g of DBU, and 0.73 g of isobutyl bromide were suspended in 15 ml of acetonitrile and the suspension was reflexed for 6 hours. To the mixture were then added 0.6 ml of triethylamine and 0.73 g of isobutyl bromide and the mixture was further reflexed for 8 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was washed with a saturated saline solution and dried over sodium sulfate. The residue obtained after the solvent was distilled off was purified by silica-gel column chromatography (eluent: dichloromethane:methanol=20:1). The product was converted into the hydrochloride with acetone and hydrochloricacid, and recrystallized from a mixture of ethanol and methanol to give 0.39 g of 5-(4-isobutyl-1-piperazinylcarbonyl)oxindol hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH3:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:13])=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(C#N)cccc1C(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C#N)cccc1C(=O)CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 25 °C

Procedure:
To a solution of 3-(chloroacetyl)-2-methylbenzonitrile (1.7 g, 8.8 mmol) in THF (17.6 mL) was added (R)-4-N-boc-2-hydroxymethyl-piperazine (2.279 g, 10.54 mmol) and DIPEA (3.07 mL, 17.56 mmol) at rt. The reaction mixture was stirred at rt over the weekend. After concentration, the residue was partitioned between EtOAc and aqueous NaHCO3 (saturated). The aqueous layer was extracted with EtOAc (2×). The combined organic phase was washed with brine, dried over anhydrous MgSO4, and filtered. Concentration was followed by purification by prep TLC (silica gel; 10% MeOH/DCM) to give the title compound: LC/MS (M+1)+=374.14
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:22][CH3:21])=[O:24])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3-(N-methylaminocarbonyl)phenyl boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 111. NMR (CDCl3): 3.11 (3H, d), 4.34 (3H, s), 6.25 (1H, br), 7.56 (1H, m), 7.63-7.70 (2H, m), 7.84 (1H, d), 7.87 (1H, s), 7.90 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 8.27 (1H, s), 8.97 (1H, s). MS: MH+ 383.09 (100%)
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25](S(C)=O)[N:24]=3)=[C:20]([CH3:22])[N:21]=2)=[O:15])=[N:8][CH:7]=1)[CH3:5]>CO>[CH2:4]([C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([O:2][CH3:1])[N:24]=3)=[C:20]([CH3:22])[N:21]=2)=[O:15])=[N:8][CH:7]=1)[CH3:5]
Reactant: C[O-]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Agent: [Na+]
Solvent: CO
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(OC)n3)s2)o1
Reaction time: 18 h

Procedure:
Sodium methoxide (2M in MeOH, 0.115 ml, 0.23 mmol) is added to a stirred solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) (0.050 g, 0.115 mmol) in methanol (3 ml) at room temperature. After 18 hours, the solvent is removed and the residue is dissolved in DCM and washed with water. The product is extracted into 1M HCl and the aqueous extract is washed with DCM. The aqueous phase is then basified with aq. NaOH and the product is extracted into DCM. After drying MgSO4) the solvent is removed to give the titled compound.
Reaction SMILES: O[CH:2]([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].OC(CC)CCCCCCC=CCCCCC(O)=O.OC(CCC)CCCCCC=CCCCCC(O)=O>>[C:16]([OH:18])(=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:19]
Reactant: CC(O)CCCCCCCC=CCCCCC(=O)O
Agent: CCC(O)CCCCCCC=CCCCCC(=O)O
Agent: CCCC(O)CCCCCC=CCCCCC(=O)O
Product: CCCCCCCCC/C=C\CCCCC(=O)O

Procedure:
The total amount of 15-hydroxy-6-hexadecenoic acid, 14-hydroxy-6-hexadecenoic acid and 13-hydroxy-6-hexadecenoic acid obtained by the reaction was 460 mg, and the ratio was such that 15-hydroxy-6-hexadecenoic acid: 51.3%, 14-hydroxy-6-hexadecenoic acid: 35.5%, and 13-hydroxy-6-hexadecenoic acid: 13.2%, respectively.