Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10](F)=[CH:9][N:8]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(COc1ncc(F)cn1)OCC
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1ncc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)cn1)OCC
Temperature: 190 °C
Reaction time: 14 h
Yield: 37.6 %

Procedure:
2-(2,2-Diethoxyethoxy)-5-fluoropyrimidine (168 mg, 0.73 mmol) and potassium tert-butoxide (93 mg, 0.83 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (80 mg, 0.33 mmol), and stirred at 190° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=1:2) to obtain 6-{[2-(2,2-diethoxyethoxy)pyrimidin-5-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (56 mg, yield: 37%) as a pale brown amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[N:13]1[C:18]2[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[NH:22][C:23](=[O:24])[C:17]=2[CH:16]=[N:15][CH:14]=1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[NH:22][C:23](=[O:24])[C:17]2[CH:16]=[N:15][CH:14]=[N:13][C:18]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C1Nc2ccccc2Nc2ncncc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2ncncc21

Procedure:
A solution of 3.16 g (0.028 mol) of chloroacetyl chloride in 8 ml of absolute dioxan and a solution of 2.82 g (0.028 mol) of dry triethylamine in 6 ml of absolute dioxan are added dropwise, simultaneously and as uniformly as possible, in the course of 20 minutes, at 60° to 70° C., to a suspension of 4.24 g (0.02 mol) of 5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 60 ml of absolute dioxan, while stirring. The mixture is heated under reflux for a further 4 hours; precipitated triethylamine hydrochloride is filtered off, and the filtrate is concentrated in vacuo. The residue is chromatographed on neutral silica gel, using chloroform; the eluate is evaporated and the residue therefrom is stirred with ether and, after filtration, recrystallized from ethanol; yield: 3.9 g, m.p. 196° C. (dec.), from isopropanol.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44](O)=O)=[CH:31][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[ClH:28].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44]2[NH:13][C:14]3[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=3[N:20]=2)=[CH:31][N:30]=1
Reactant: COc1cc2c(CC(=O)O)cnc(Cl)c2cc1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(Cl)c2cc1OC
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6M aqueous solution, 0.33 ml, 1.85 mmol) is added to a suspension of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrmidine-2,4-dione (0.327 g, 1.54 mmol), (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.414 g, 1.54 mmol) and 1-hydroxybenzotriazole (0.25 g, 1.85 mmol) in CH2Cl2 (2ml). Water (2 ml) is added, the biphasic mixture is shaken for 18 hours and the the resultant solid is collected by filtration. This intermediate is suspended in methanol (10 ml), 4M aqueous NaOH (5 ml) is added and the mixture heated to reflux for 4 hours. After evaporation of the methanol, the residue is acidified to pH2 with concentrated hydrochloric acid and the resultant solid collected by filtration and purified by preparative HPLC to afford 8-(1-chloro-6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride, [MH]+ 458.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12](OC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-:23]>CO.O>[O:23]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccccc3)cccc2[nH]1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccccc2n1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
132 (160 mg, 0.569 mmol) is dissolved in 5 ml of methanol and treated with a solution of LiOH (27.2 mg, 1.138 mmol) in 3 ml of water. The mixture is stirred at room temperature overnight. Since the reaction is not complete (TLC), additional LiOH (30 mg, 1.25 mmol) is added and the stirring is continued for additional 18 h. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:21][C@@H:22]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)(C)C>[C:16]([O:21][C@@H:22]([C:24]1[N:25]=[C:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:15]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][N:29]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1cc2nc(N3CCNCC3)oc2cn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-(1-piperazinyl)oxazolo[5,4-c]pyridine (775 mg, 3.8 mmol; J. Org. Chem. 1995, 60, 5721) in isopropanol (38 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 3% methanol/chloroform then 6→8% methanol/ethyl acetate, where used herein, the arrow symbol, →, indicates a gradient) to give 1.2 g (79%) of the title compound of Example 2, Step A as a pale yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.57 (s, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:50]=[CH:49][C:21]([O:22][CH:23]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:24]([C:28]2[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:26][CH3:27])=[CH:20][C:19]=1[C:51]#[N:52]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C@H:23]([O:22][C:21]2[CH:49]=[CH:50][C:18]([C:11]3[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=3)=[C:19]([C:51]#[N:52])[CH:20]=2)[C@@H:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:40][CH:41]=2)[CH2:25][CH2:26][CH3:27])=[CH:47][CH:46]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(Oc1ccc(Br)c(C#N)c1)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1ccc(-c2ccc(C)cc2)c(C#N)c1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a flask charged with Na2CO3 (2.0 M in water, 132 μL, 0.263 mmol), Pd(PPh3)4 (10.1 mg, 8.77 μmol) and (4-methylphenyl)boronic acid (36.5 mg, 0.175 mmol) was added a solution of the product from Step A (50 mg, 0.088 mmol) in DMF, then the mixture was stirred at 60° C. overnight. After cooling to RT, the mixture was purified by preparative reverse phase HPLC eluting with 50-100% acetonitrile/water+0.1% TFA to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.81 (d, J=8.5 Hz, 2H); 7.43 (d, J=7.5 Hz, 4H); 7.36 (t, J=8.5 Hz, 4H); 7.35 (d, J=8.5 Hz, 1H); 7.28 (d, J=3.0 Hz, 1H); 7.26 (d, J=8.0 Hz, 2H); 7.19 (dd, J=8.5, 2.5 Hz, 1H); 5.77 (d, J=7.0 Hz, 1H); 3.65-3.61 (m, 2H); 3.31 (m, 1H), 3.25 (s, 3H); 2.65 (t, J=6.5 Hz, 2H); 1.88-1.86 (m, 1H); 1.63-1.61 (m, 1H); 1.16-1.11 (m, 2H); 0.79 (t, J=7.0 Hz, 3H); LC1 1.27 min. (M+H)+ 581.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=CC=1>>[S:20]1[CH:14]=[C:19]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:18]=[CH:17]1
Reactant: Sc1ccccc1
Reactant: O=C(O)c1cccc2ccccc12
Product: O=C(c1ccsc1)c1cccc2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 1-naphthoic acid (8 g, 46.46 mmol), thiophenol (8 ml, 78.05 mmol) and polyphosphoric acid (80 g) was heated for 12 hours on water bath at 80° C. Reaction mixture was poured onto ice water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give oil, which was crystallized from methanol to give the desired compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: COc1cccc(C=O)c1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: COc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methoxybenzaldehyde (0.5 g, 3.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g 72%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOC(C)(C)C3)c2n1
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A solution of N2-butyl-9-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-8-methoxy-9H-purine-2,6-diamine (73 mg) in MeOH (2 mL) was treated with 4N HCl in 1,4-dioxane (1 mL) and was stirred for 4 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried. The solid was re-precipitated from ether/light petrol to give the title compound (37 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][NH2:12])[CH:6]=1)[CH3:2].O=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][C:17]#[N:18].Cl>C(O)C>[NH2:18][C:17]1[N:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:13])[N:12]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1
Reactant: CCOC(=O)c1cccc(NN)c1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(-n2nc(-c3ccccc3)cc2N)c1
Yield: 91.1 %

Procedure:
To a mixture of 3-hydrazinobenzoic acid ethyl ester (4.5 g, 25.0 mmol) and commercially available 3-oxo-3-phenylpropionitrile (5.5 g, 37.5 mmol) in ethanol (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated to reflux for 3 h. After removal of the solvent, the residue was washed with Et2O to afford ethyl 3-(5-amino-3-phenyl-1H-pyrazol-1-yl)benzoate (7 g, 2% yield, 2 steps) which was used in the next reaction without further purification.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[I:1]
Reactant: COc1ccc(C(=O)O)c(I)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1I

Procedure:
411 G. of 2-iodo-4-methoxy-benzoic acid, 4 l. methanol and 400 ml. of concentrated sulfuric acid are heated at reflux for 4 hours. The solution is then evaporated under reduced pressure, treated with water, and extracted with ether. The organic phase is then washed with aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution and subsequently dried over sodium sulfate. The solution is filtered, evaporated under reduced pressure and distilled. There is obtained the 2-iodo-4-methoxy-benzoic acid methyl ester, having a boiling point of 95°-98°/0.04 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:4]2[CH:5]=[C:6]3[C:11](=[C:2]([CH:27]=[O:28])[CH:3]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: Brc1cc(Cc2ccncc2)cc2cccnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Cc2ccncc2)cc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 8-bromo-6-(pyridine-4-ylmethyl)quinoline (1 eq.) in THF (0.13 M) was added, at −78° C., n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at −78° C. for a further 30 min before DMF (1.5 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>CC#N>[Cl:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:22]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccccc1NC(=O)CCCl
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-aminobenzamide (500 mg, 3.68 mmol) and triethylamine (NEt3) (450 mg, 4.41 mmol) in CH3CN (30 mL) was added 3-chloropropanoyl chloride (0.45 mL, 4.41 mmol) dropwise at room temperature. After stirring overnight, the reaction mixture was concentrated to give the desired product (800 mg) as solid, which was used for the next step without further purification. LC-MS: m/z 227 (M+H+).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]2[C:21]3[C:11]([CH2:12][C@@H:13]4[C@@H:18]([C:19]=3[CH:20]=1)[CH2:17][C@H:16]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][N:14]4[CH2:30]CC)=[CH:10][N:9]2[Si](C(C)(C)C)(C)C>>[CH2:27]([N:24]([CH2:25][CH3:26])[C:23]([NH:22][C@H:16]1[CH2:17][C@H:18]2[C@@H:13]([CH2:12][C:11]3[C:21]4[C:8](=[CH:7][C:6]([CH:1]([CH3:3])[CH3:2])=[CH:20][C:19]2=4)[NH:9][CH:10]=3)[N:14]([CH3:30])[CH2:15]1)=[O:29])[CH3:28]
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]21
Reactant: CC(C)I
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)C)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With isopropyl iodide and 3-(13-bromo-1-tert-butyldimethylsilyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][C:15]1([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)=[O:13])=[N-]>ClCCl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][C:15]2([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)C1CCC(C)(OC(=O)C=[N+]=[N-])CC1
Solvent: ClCCl
Product: CC(C)C1CCC(C)(OC(=O)C2CC2c2ccccc2)CC1

Procedure:
To a mixture of styrene (1.063 g, 10.2 mmol) and Rh2(4R-BNOX)4 (0.0050 g, 0.0058 mmol) in 3.0 mL of refluxing anhydrous dichloromethane was added, by syringe at room temperature, 1-menthyl diazoacetate (0.109 g, 0.485 mmol) in 3.0 mL of dichloromethane under nitrogen &nd at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina, and solvent was removed under reduced pressure. The residue was analyzed by capillary gas chromatography (SPB-5 column) for diastereomeric separation and enantiomeric purity. Similar procedures were followed for the cyclopropanation of 3,3-dimethyl-1-butene, ethyl vinyl ether, and dihydropyran.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[N:8]=[N:7]1)C.[OH-].[Li+].Cl>O1CCOCC1.O>[OH:28]/[N:27]=[C:19](/[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)\[CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35]
Reactant: CCOC(=O)Cn1cc(-c2ccc(C(C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(/C(CC(c2ccc(-c3cn(CC(=O)O)nn3)cc2)c2ccccc2C)=N/O)ccn1
Temperature: 120 °C

Procedure:
To a solution of (4-{4-[(−)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-[1,2,3]triazol-1-yl)-acetic acid ethyl ester (35 mg) in a mixture of dioxane (1 mL) and water (1 mL) was added lithium hydroxide (14 mg) and the reaction mixture heated by microwave irradiation to 120° C. for 20 min. The solution was adjusted to approximately pH 3 by using 1 M aqueous hydrochloric acid and then extracted over a sat. solution of brine (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol (100:0 to 90:10). Light yellow solid. MS (ESI−): m/z=454.1 ([M−H]−).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH:35]6[CH2:37][CH2:36]6)[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1.[CH:38]1(NC(C2C3C=C(C4C(C)=CN=C(NCCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1>>[ClH:24].[ClH:1].[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([CH3:38])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH:35]6[CH2:37][CH2:36]6)[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCN(C5CC5)CC4)ncc3Cl)cc12
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C3CC3)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[3-(1-cyclopropylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 490 [M(free base)+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].[CH:15]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13])[CH3:15]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1cc(OC)ccc1Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cc(OC)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid methyl ester (994 mg) was dissolved in THF and cooled to −78° C. Lithiumdiisopropylamide (2M in THF, 3.72 mL) was added drop wise and stirring was continued for 30 minutes. Iodomethane (879 mg, 0.39 mL) was added and stirring was continued for 30 minutes. The cooling bath was removed and the reaction was allowed to warm for 45 minutes. The mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate: heptane 1:3) to give the desired compound as a yellow oil (859 mg). 1H-NMR (□, CDCl3): 7.27 (d, 1H), 6.85 (d, 1H), 6.74 (dd, 1H), 4.17 (q, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][C@H:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][C@H:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: OC[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@H](CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-pyrrolidin-3-yl methanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.72 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 438 [M+H]