Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:14][C:11]=2[NH:12][N:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C@@H:29]1[O:31][C@H:30]1[CH3:32]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:14][C:11]=2[N:12]([CH:29]([CH:30]([OH:31])[CH3:32])[CH3:28])[N:13]=1
Reactant: C[C@@H]1O[C@H]1C
Reactant: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)n[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)nn(C(C)C(C)O)c2s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
To a solution of ethyl 3-(2,4-difluorophenyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (200 mg, 0,649 mmol) and potassium carbonate (448 mg, 3.24 mmol) in N,N-dimethylformamide (6.5 mL) was added trans-dimethyloxirane (140 mg, 1.95 mmol). The reaction mixture was stirred at 100° C. for 18 hr. The mixture was cooled to ambient temperature. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (134 mg). LC-MS [M+1]=381.2.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:28](=[O:29])[N:14]2[C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[CH2:19]([C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:28](=[O:29])[N:14]2[C:15]=1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:20]
Reactant: C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 86 %

Procedure:
Hydrogen was bubbled through a suspension of 10%-palladium on carbon (3 g, 0.00282 g atoms) in dry ethyl acetate (100 ml.) for 30 minutes. A solution of t-butyl 7β-phenoxyacetamido-3-vinylceph-3-em-4-carboxylate (1.4 g., 3.36 mmole) in dry ethyl acetate (50 ml.) was added and the mixture was stirred for 21/2 hours in a hydrogen stream and filtered through a bed of kieselguhr. The filtrate was evaporated in vacuo to give the title ester as a white foam (1.21 g, 86.5%), [α]D23 + 55.4° (c 0.85; CHCl3), λmax. (EtOH) 263 nm(ε 8,100) and 268 nm (ε 8,450), inflexion at 273 nm (ε 7,600), νmax. (CHBr3) 3420(NH), 1782 (azetidin-2-one), 1715 (CO2R), and 1695 and 1525 cm.-1 (CONH), τ (CDCl3) 2.66 and 3.03 (2H and 3H, two m; C6H5O) 4.15 (1H, dd, J 9.5 and 5 Hz; C7 --H), 5.00 (1H, d, J 5 Hz; C6 --H) 5.45 (2H, s; C6H5OCH2), 6.51 and 6.73 (2H, AB-q, J 18 Hz; C2 --H2), 7.37 and 7.80 (2H, AB-part of ABX3 -system, JAX, JBX 7 Hz, JAB 13 Hz; C3 --CH2CH3), 8.47 (9 H, s; CO2C(CH3)3), 8.87 (3 H, t, J 7 Hz; CH2CH3) (Found: C, 60.1; H, 6.3; N, 6.7; S, 7.2. C21H26N2O5S (418.5) requires C, 60.25; H, 6.2; N, 6.8; S, 7.7%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:29][N:28]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=2[CH:15]=[O:16])[C@H:10]([CH2:25][CH3:26])[CH2:9]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:29][N:28]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:14]=2[CH2:15][OH:16])[C@H:10]([CH2:25][CH3:26])[CH2:9]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a mixture of 2-((2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-benzaldehyde (75 mg, 0.11 mmol) in MeOH (2.0 mL) is added sodium borohydride (6 mg, 0.17 mmol). The reaction mixture is stirred at room temperature for 15 minutes. After addition of saturated aqueous sodium hydrogen carbonate, and the mixture is extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give [2-((2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-methanol as a colorless oil (72 mg, 96%). ESI-MS m/z: 672 [M+1]+, Retention time 2.36 min (condition A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][C@H:37]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C(O)(=O)C>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 47.5 °C
Reaction time: 1.5 h

Procedure:
[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (50 mg, 0.103 mmol), tert-butyl L-glutaminate hydrochloride (30 mg, 0.124 mmol) and N-methylmorpholine (40 mg, 0.396 mmol) were dissolved in methylene chloride (1 ml). TBTU (40 mg, 0.125 mmol) was added and the mixture was stirred for 90 min. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was heated to 45-50° C. for 4 h. The reaction mixture was evaporated under reduced pressure. Toluene (5 ml) was added and evaporated. The residue was dissolved in methanol (1 ml). NaBH4 (30 mg, 0.793 mmol) was added and the mixture was stirred for 15 min. Acetic acid (50 mg, 0.83 mmol) was added and the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (35:65) as eluent. After freeze-drying 47 mg (74%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.72-2.16 (m, 4H), 2.81-2.95 (m, 2H), 4.08-4.20 (m, 1H), 4.26-4.31 (m, 1H), 4.50 (s, 2H), 4.65-4.78 (m, 1H), 5.03-5.08 (m, 1H), 6.68 (s, 1H), 6.89-7.44 (m, 14H), 8.29 (d, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:20][OH:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[CH2:30]([Br:33])[C:31]#[CH:32].C(N(CC)CC)C>ClCCl>[Br:33][CH2:30][C:31]1[O:21][N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[CH:32]=1
Reactant: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Reactant: C#CCBr
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(-c3cc(CBr)on3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (170 mg, 0.59 mmol) in dichloromethane (5 ml) cooled to 0° C., was added N-chlorosuccinimide (119 mg, 0.89 mmol) and the mixture allowed to warm to room temperature with stirring for 1 h. Propargyl bromide (8 μl, 0.65 mmol) and triethylamine (9 μl, 0.65 mmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 60-80% (v/v) dichloromethane in n-heptane to afford 3-(5-bromomethyl-isoxazol-3-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (150 mg, 0.37 mmol) as a yellow solid.
Reaction SMILES: CC1N=C(SC[C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:18])[CH:13]3N)[C:10]=2[C:19]([O:21]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:20])SN=1.C(N(CC)CC)C.S=C(SCC(O)=O)C>C(Cl)Cl>[O:18]=[C:12]1[N:11]2[CH:14]([S:15][CH2:16][CH:9]=[C:10]2[C:19]([OH:21])=[O:20])[CH2:13]1
Reactant: Cc1nsc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)n1
Agent: CC(=S)SCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCSC2CC(=O)N12
Reaction time: 3 h

Procedure:
0.01 mol. of 7-[D-2-amino-2-(2-thienyl)acetamido]-3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt (prepared by the procedure of Example 7, but substituting 3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in part b) is brought into solution with triethylamine in methylene chloride and 0.015 mol. of [(1-thioxoethyl)thio]acetic acid (prepared as described in U.S. Pat. No. 3,341,518) is added. The reaction mixture is permitted to stand for three hours and worked up according to the procedure of Example 7 to obtain 7-[D-2-[(2-thienyl)-2-[(1-thioxoethyl)amino]acetyl]amino]-3-[[3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: CC[C@@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A mixture of sodium triacetoxyborohydride (237 mg, 1.116 mmol) and (R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (131 mg, 0.837 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (260 mg, 93%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.[O:71]1CCN(CCN)CC1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:71])=[C:25]([NH:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: NCCN1CCOCC1
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 43 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 2-morpholinoethylamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (31) (the second stage yield: 43%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile instead of compound (1f).
Reaction SMILES: C([O:4][C:5]1([CH2:22][N:23]([CH:27]([CH3:29])[CH3:28])C(=O)C)[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1)(=O)C.Cl.C(O)C.[OH-].[Na+]>O>[OH:4][C:5]1([CH2:22][NH:23][CH:27]([CH3:28])[CH3:29])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: CCOC(=O)Nc1ccc2c(c1)OCC(CN(C(C)=O)C(C)C)(OC(C)=O)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Nc1ccc2c(c1)OCC(O)(CNC(C)C)CO2

Procedure:
3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin (4.1 g., 10 millimoles) is warmed five hours at 40°C. with 6 ml. of concentrated hydrochloric acid and 34 ml. of ethanol. The solution is cooled, taken to the basic side with sodium hydroxide, diluted with water, and extracted with diethyl ether to give 3-hydroxy-3-isopropylaminomethyl-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[S:14]([O-:17])([O-:16])=[O:15].[Na+:18].[Na+]>C(O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][S:14]([O-:17])(=[O:16])=[O:15])=[CH:6][CH:7]=1)([O-:13])=[O:12].[Na+:18]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(NCCBr)cc1
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCS(=O)(=O)[O-])cc1
Yield: 86 %

Procedure:
661 g (2.7 mol) of (2-bromoethyl)(4-nitrophenyl)amine (7) were partially dissolved in 3.7 L of 96% ethanol. At about 75-80° C., aqueous sodium sulfite solution (820 g, 6.5 mol of Na2SO3 in 2.4 L of water) was added. The mixture was stirred at reflux for 11 hours. The resulting mixture was filtered while boiling and the filtrate was allowed to cool. A yellow precipitate formed, which was filtered off by suction and washed with acetone. After drying, 623 g of product were isolated.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:25](=[O:26])[CH:24]2[CH:19]([CH:20]3[O:27][CH:23]2[CH2:22][CH2:21]3)[C:18]1=[O:28].C(N(CC)CC)C>ClCCl>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:26][C:25]1[CH:24]2[CH:19]([C:18](=[O:28])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])[CH:20]1[O:27][CH:23]2[CH2:22][CH2:21]1)=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)C3C4CCC(O4)C3C2=O)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of pivaloyl chloride (0.055 g, 0.57 mmol) in dichloromethane (2 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.12 g, 0.42 mmol) in dichloromethane (2 ml) at room temperature and the reaction mixture is stirred for 2 minutes. A solution of triethylamine (0.08 ml) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-5-oxo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-3-en-3-yl 2,2-dimethylpropionate as a colourless oil.
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12]C(=O)OC(C)(C)C)[CH:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1(/[CH:4]=[CH:5]/[C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(/C=C/C2CC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3, 350 mg, 1.34 mmol) in dichloromethane (10 mL) at 0° C., trifluoroacetic acid (1.5 mL, 1.34 mmol) was added and stirred at 25° C. for 16 h. The solvent was removed under reduced pressure and the mixture made basic with the residue with aqueous ammonia. Filtration and washing with diethyl ether provided (6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4) as a brown solid. Yield: 170 mg, 79%; MS (ESI) m/z 162.10 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 6.70 (brs, 2H), 6.32-6.27 (m, 2H), 6.17 (s, 1H), 1.60 (m, 1H), 0.84 (m, 2H), 0.55 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:10]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:7][CH:6]=3)=[CH:9][C:10]=2[C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)=[CH:18][CH:17]=1
Reactant: ClCCN1CCCC1
Reactant: O=C1CCc2cc(-c3cc(-c4ccc(O)cc4)oc3-c3ccncc3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-c3cc(-c4ccc(OCCN5CCCC5)cc4)oc3-c3ccncc3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
A solution of the product from Step 5 (0.18 g, 0.47 mmol) in dimethylformamide (3 ml) was treated at 0° C. with sodium hydride (0.021 g of a 60% suspension in mineral oil, 0.52 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and treated with another portion of sodium hydride (0.021 g of a 60% suspension in mineral oil, 0.52 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride salt (0.088 g, 0.52 mmol) and stirred at room temperature overnight. The reaction mixture was poured onto aqueous sodium bicarbonate solution and the mixture was applied to an SCX column eluting with methanol followed by a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.081 mg, 36%); MS(ES+) m/e 465 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(-c3cnn(C)c3)cnc2N)cc1C
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To methyl 4-(2-amino-5-bromopyridin-3-yl)-2-methylbenzoate (500 mg, 1.557 mmol) in 20 mL MW vial was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (421 mg, 2.024 mmol), PdCl2(dppf)DCM (114 mg, 0.156 mmol), DME (11.7 mL) and 2 M Na2CO3 solution (3.892 mL). The reaction mixture was heated at microwave synthesizer (12 min, 120° C.). The reaction mixture was diluted with EtOAc and washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH)/heptane to provide crude product which was triturated with ether to provide 400 mg of pure product in 80% yield. LCMS (m/z): 323.4 (MH+), 0.60 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN1C(=O)CCC1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:27][CH:26]=2)[S:11][C:12]=1[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(Cn2ccnc2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Compound 18 (880 mg, 2.00 mmol) was suspended in NMP (10 mL), and imidazole (408 mg, 6.00 mmol) was added thereto, followed by stirring at 65° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature and then poured into water, and the deposited precipitate was collected by filtration. The resulting precipitate was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 19 (538 mg, 63%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:20]1([O:28][CH3:29])[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH3:23][O:22][C:21]1[CH:24]=[C:25]([C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:26]=[CH:27][C:20]=1[O:28][CH3:29]
Reactant: COc1ccccc1OC
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a solution of 5-phenylvaleric acid (10 g, 56.1 mmol) in dichloromethane (70 mL) is added 2 M oxalyl chloride (33.5 mL, 67 mmol). The mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane (60 mL) and veratrole (11.6 g, 84 mmol) is added. The mixture is cooled in ice and aluminum chloride (7.4 g, 56.1 mmol) is added in portions over 10 minutes. The mixture is stirred for 3 hours warming to room temperature. The mixture is added to aqueous HCl and is extracted with dichloromethane. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (7:3 hexane:ethyl acetate) to give 1-(3,4-dimethoxyphenyl)-1-oxo-5-phenylpentane (5.5 g 33%), m.p. 56-8° C. 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.68-1.82 (m, 4H), 2.52-2.61 (t, 2H), 2.88-2.98 (t, 2H), 3.95 (s, 6H), 6.82-6.92 (m, 2H), 7.10-7.30 (m, 4H), 7.48-7.60 (m, 2H); MS (EI) m/e 298 (M+).