Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH:11](I)([CH3:13])[CH3:12].[CH:15]([O:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C#CC1C=CC(O)=CC=1.C(C(C)=O)C(C)C>[OH:3][C:2]1[CH:4]=[CH:13][C:11]([CH:15]=[CH2:16])=[CH:12][CH:1]=1.[CH:15]([O:18][C:19]1[CH:21]=[CH:4][C:2]([CH:11]=[CH2:12])=[CH:1][CH:20]=1)([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: CC(C)OC(C)C
Reactant: CC(C)=O
Agent: C#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)C)cc1
Reaction time: 27 h

Procedure:
Into a reaction vessel were charged 30.0 parts of the same poly(p-vinylphenol) as that used in Example 1 and 120 parts of acetone. They were stirred to form a solution. Additionally charged were 29.6 parts of anhydrous potassium carbonate and 18.2 parts of isopropyl iodide. The temperature was elevated so that the mixture reached to the lo reflux state. Subsequently, the reflux state was kept for 27 hours. After adding methyl isobutyl ketone, the solution was washed with aqueous oxalic acid solution and then with ion-exchanged water. The organic layer after washing was concentrated to 71 parts, combined with 206 parts of propylene glycol monomethyl ether acetate and further concentrated to 88.6 parts. The solid content of the concentrate measured by weight-loss on heating was 31.92% by weight. By 1H-NMR measurement, it was confirmed that the resin after reaction was a copolymer In which 31.4% of hydroxyl groups in poly(p-vinylphenol) was converted to isopropyl ether. The resin was referred to as Resin RA.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]=[CH:7]1.[CH3:21][S:22]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=2)[CH:27]=1)(=[O:24])=[O:23].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[N:6]1([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=4)[CH:27]=3)=[O:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9][N:8]=[CH:7]1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To 1.03 g of 4-(2-imidazolinyl)amino-benzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 mg of DMAP and 1.06 g of DCC was added 5 ml of anhydrous pyridine. The resulting mixture was stirred overnight at room temperature. To the mixture was added 50 ml of acetone and the precipitate which was formed was collected by filtration. To the precipitate was added 40 ml of DMF. After stirring the precipitate which was formed was collected by filtration and 20 ml of water was added to the precipitate. The insolubles were removed by filtration. The filtrate was distilled under reduced pressure. To the residue was added 200 ml of acetone. The precipitate which was formed was collected by filtration to obtain 0.8 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dimethanesulfonate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH3:35][NH2:36]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([CH3:13])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 100 °C

Procedure:
3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40% Methylamine solution (50 mL) under nitrogen. The resulting suspension was heated in a sealed system at 100° C. for 4 h. After cooling to room temperature, the solution was evaporated to dryness. The crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine). Evaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether gave a solid which was filtered off and dried to give the title compound (12.5 g) as an off white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.Cl.[NH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CN
Reactant: CN(C)CCCOc1ccccc1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN=Cc1ccccc1OCCCN(C)C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A stirred solution of 15 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 10.2 g of glycine, ethyl ester, hydrochloride in 300 ml of ethanol is treated with 4.8 g of 85% potassium hydroxide and stirring continued for 3 hours at room temperature. Potassium chloride is filtered off, washed with ethanol, and the solvent is removed on a rotary evaporator (water bath temperature, 30°-35° C.). The residue is dissolved in ether, filtered, and the evaporation repeated to give 20.9 g of an oil. The material is stored in the cold.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:25][C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:25][C:15]2[N:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Heat a mixture of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (5 g, 15.3 mmol) in DMF (25 ml) to 40° C. Add cesium carbonate (10.4 g, 32.4 mmol) and 2-bromomethylpyridine hydrobromide (4.05 g, 16 mmol). Stir the mixture at 40° C. for 24 h. Add the mixture to water (250 mL) and stir for 1 h. Filter the solids and dry the collected material under vacuum. Add the solid to ethanol (25 mL) and reflux for 30 min. Cool the mixture to 22° C. and filter. Dry the solid under vacuum to constant weight to provide 4.8 g (75%) of the title compound. MS (m/z): 419 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 ml RB flask containing a solution of lauroyl chloride (19.38 g., 89 mM) in dry chloroform (200 ml) was cooled to 0° C. on an ice bath. A solution of N,N-dimethyl-1,3-propanediamine (10.40 g., 51 mM) and triethylamine (9.40 g., 93 mM) in dry chloroform (25ml) was added dropwise to the cold solution through an addition funnel, then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in an ethanol/water mixture (1:1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4×50 ml). The combined extracts were dried (MgSO4), concentrated, and the residue distilled under reduced pressure (bp 171° C., 10μ) to give 23.92 g. (68%) of the subject compound as an amber solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15](C)(C)C)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH:51]=[CH:52][C:53]=1[N+:54]([O-:56])=[O:55])[O:34]C1C2C(=CC(OC)=C(C(OC)=O)C=2)N=CC=1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33]([OH:34])[CH:51]=[CH:52][C:53]=1[N+:54]([O-:56])=[O:55]
Reactant: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OC
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Product: O=[N+]([O-])c1ccc(O)cc1F

Procedure:
Similar to the synthesis of compound 1a, from methyl 4-chloro-7-methoxyquinoline-6-carboxylate (300 mg), 3-fluoro-4-nitrophenol (225 mg), N,N-diisopropylethylamine (415 μL), and N-methylpyrrolidin-2-one (1.5 mL), compound 49a was yielded (112 mg, yield: 25%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Mg].CN([CH:14]=[O:15])C>C1COCC1.C(Cl)Cl>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Br:8])[CH:5]=1)[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc(Br)c1
Reaction time: 5 h

Procedure:
A mixture of 15.7 g (50 mmoles) of 1,3,5-tribromobenzene and 1.344 g (56 mmoles) of magnesium in 200 mL of THF was stirred 5 hrs. At room temperature 7.5 mL (100 mmoles) of DMF was then added at 0° and the reaction mixture was stirred overnight. Solvent was removed in vacuo at room temperature the residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of satd. sodium chloride soln. The organic phase was dried over anhyd. MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of methylene chloride, and applied on silica gel. Elution with 1:9 mixture of ether:hexane mixture containing 3% methylene chloride gave the desired 3,5-dibromobenzaldehyde as white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=CC#N
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: c1ccccc1
Product: N#CCCN1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of acrylonitrile (5.6 ml/85.1 mmol) and benzylpiperazine (5.0 g/28.3 mmol) in benzene (28 ml) was refluxed for 10 hours. After cooling down, the mixture was concentrated in vacuo and the residue was purified by column chromatography (NH2 gel/200-350 mesh/100 g/dichloromethane) to give a pale brown oil (5.5 g/85%).
Reaction SMILES: ClC1C=C(C)N=C(NC2C=C(N[C@@H]3CCCC[C@@H]3NC(=O)[O:27]C(C)(C)C)C=NC=2C#N)C=1.[C:33]([C:36]1[N:41]=[CH:40][C:39]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]2[NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:38][C:37]=1[NH:57][C:58]1[CH:63]=[CH:62][C:61](O)=[C:60]([CH3:65])[N:59]=1)(=[O:35])[NH2:34]>>[C:33]([C:36]1[N:41]=[CH:40][C:39]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]2[NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:38][C:37]=1[NH:57][C:58]1[CH:63]=[C:62]([OH:27])[CH:61]=[C:60]([CH3:65])[N:59]=1)(=[O:35])[NH2:34]
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1O
Reactant: Cc1cc(Cl)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Product: Cc1cc(O)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)n1

Procedure:
This example describes the conversion of (D13) to (E15) as shown in Scheme 3. tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4-hydroxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate was prepared from tert-butyl [(1S,2R)-2-({5-[(4-chloro-6-methylpyridin-2-yl)amino]-6-cyanopyridin-3-yl}amino)cyclohexyl]carbamate (PrepEx 1.7) using chemistry analogous to that described for the synthesis of tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(5-hydroxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (PrepEx 1.9). MS ESI calc'd. for C23H33N6O4 [M+H]+ 457. found 457.
Reaction SMILES: N[C:2]1[C:7](OC)=[C:6]([Cl:10])[CH:5]=[C:4](F)[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].[CH3:25][O:26]C(OC)N(C)C>>[Cl:10][C:6]1[CH:5]=[CH:4][C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: COC(OC)N(C)C
Product: COc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 47 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.5 g, 1.4 mmol) and dimethylformamide dimethylacetal (0.8 g, 7 mmol) was refluxed for 4 hr under a blanket of nitrogen. Excess reagent was removed in vacuo and product extracted with ether. Solvent was removed to afford a residue which was chromatographed on silica gel. Elution of the column with hexane-ethyl acetate (6:4) afforded the title compound (0.22 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl.O>[CH3:28][O:27][N:26]([CH3:25])[C:8]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 4-oxocyclohexanecarboxylic acid (4.2 g, 0.0293 mol) in CH2Cl2 (20 mL) was added oxalyl chloride (5.2 g, 0.44 mol) slowly, stirred at room temperature for 1 hour and concentrated, then 20 mL CH2Cl2 was added, followed by addition of Et3N (9 g, 0.116 mol) and N,O-dimethylhydroxylamine hydrochloride (3.5 g, 0.0359 mol). The reaction mixture was stirred for 2 hours, and then 100 mL water was added. The mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to give the desired product (2.1 g, 39% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:22]([CH2:29][CH2:30]N1CCNCC1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:37](O)([CH3:39])C>>[O:22]([CH2:29][CH2:30][CH:39]1[CH2:37][NH:11][CH2:3][CH2:4][N:5]1[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)O
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1OC
Product: COc1ccc(-c2ccc3ncnc(N4CCNCC4CCOc4ccccc4)c3n2)cc1OC
Temperature: 80 °C
Yield: 84 %

Procedure:
To a suspension of 4-chloro-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (120 mg, 0.398 mmol) in isopropanol (15 ml) was added 1-(2-phenoxyethyl)-piperazine (0.795 mmol, 164 mg). The suspension was stirred at 80° C., after which the suspension became a clear colourless solution. The solvents were evaporated in vacuo. The residue was redissolved in ethyl acetate and extracted with a NaOH solution (1 N). The combined organic layers were evaporated in vacuo and purified by silica gel column chromatography (the mobile phase being a mixture of methanol and dichloromethane in a ratio gradually ranging from 1:99 to 2:98), resulting in the title compound (157 mg, yield 84%) which was characterised by its mass spectrum as follows: MS (m/z): 472 ([M+H]+, 100).
Reaction SMILES: [OH-:1].[K+].Cl[C:4](Cl)(Cl)[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20]>>[Cl:14][C:7]1[CH:8]=[C:9]([Cl:13])[CH:10]=[C:11]([Cl:12])[C:6]=1[CH2:5][C:4]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:1]
Reactant: Clc1cc(Cl)c(CC(Cl)(Cl)Cl)c(Cl)c1
Reactant: CCCCO
Reactant: [OH-]
Agent: [K+]
Product: CCCCOC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A 9.0 g. portion of potassium hydroxide of the grade described in the examples above was combined with 50 ml. of butanol, and the mixture was stirred for 15 minutes. To it was added 5 g. of 1,1,1-trichloro-2-(2,4,6-trichlorophenyl)ethane, and the mixture was stirred under reflux at 115° for 7 hours. It was then cooled to ambient temperature overnight, and worked up substantially as described in Example 4 above to obtain 3.9 g. of product, 96% pure by vapor phase chromatography. The product was distilled at 155°-162° under 0.35 torr to obtain 3.4 g. of purified product.
Reaction SMILES: [B:1]([O-:4])([O-:3])[O-:2].[B:5]([O-:8])([O-:7])[O-:6].[B:9]([O-:12])([O-:11])[O-:10].B([O-])([O-])[O-].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Ba+2:30].[Cl-]>>[B:1]([OH:4])([O-:3])[O-:2].[B:5]([OH:8])([OH:7])[OH:6].[B:9]([OH:12])([OH:11])[OH:10].[Ba+2:30]
Reactant: [O-]B([O-])[O-]
Agent: [Ba+2]
Agent: [Cl-]
Agent: [NH4+]
Product: OB(O)O
Product: [O-]B([O-])O

Procedure:
Following the procedure of Example 5, but substituting ammoniumpentaborate with 5.26 g (0.02 mole) ammoniumtetraborate which upon reacting with 4.88 g (0.02 mole) bariumchloride provided bariumtriborate in good yield. The composition was proven by barium and boron analyses (determined as boric acid) and IR spectrum.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:7]=1[C:8]([C:10](=[CH:14][O:15][CH2:16][CH3:17])[C:11]([O-])=O)=[O:9].C([OH:26])C>>[Cl:5][C:6]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:7]=1[C:8]([C:10](=[CH:11][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:14]([O:15][CH2:16][CH3:17])=[O:26])=[O:9]
Reactant: CCO
Reactant: CCOC=C(C(=O)[O-])C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
4.5 g of cyclopropylamine are added dropwise to a solution of 24.9 g of ethyl(2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-acrylate in 80 ml of ethanol, while cooling with ice and stirring. When the exothermic reaction has subsided, stirring is continued at room temperature for 1 hour, the solvent is stripped off in vacuo and the residue is recrystallized from cyclohexane/petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate of melting point 89°-90° C. are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C@H:16]1[C@H:21]([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1.CC([O-])(C)C.[K+]>C1COCC1>[F:15][C@H:16]1[C@H:21]([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@H](F)C1
Temperature: 0 °C
Yield: 72 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.1 g, 1.0 eq, 10.1 mmol) and tert-butyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.1 g, 1.0 eq, 9.6 mmol) (see, e.g., WO 2012/016217) was taken in annhydrous THF (50 mL) and stirred at 0° C. KOtBu (1.9 g, 1.8 eq, 17.3 mmol) was added to the above solution at 0° C. and the heterogeneous mixture was warmed to room temperature. Then the reaction mixture was refluxed overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the crude mixture and partioned with aqueous saturated NaHCO3 (50 mL) solution. The layers were separated and the organic layer was washed with aqueous saturated NaHCO3 (50 mL) solution and brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated to leave a crude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:1 to 3:7) as eluent gave the product in 72% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[CH2:15](O)[CH3:16]>>[ClH:3].[NH2:5][CH:6]1[CH2:11][CH2:10][C:9]([CH2:15][CH3:16])([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1
Reactant: CCO
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CCC1(C(=O)O)CCC(N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (2.55 mL, 35 mmol) was added dropwise to absolute ethanol (100 mL) under a N2 atmosphere. The resulting solution was stirred at room temperature for 10 min then 4-amino-1-cyclohexanecarboxylic acid (4.29 g, 30 mmol, cis, trans mixture) was added as a solid. The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo, the residue dissolved in ethanol (25 mL) and this solution was slowly added to a flask containing rapidly stirred ether (700 mL). The precipitate that formed was collected by filtration and dried in vacuo to give 5.75 g, 92% as a white solid. MS (ion spray) 172 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23]=[S:24])[CH2:20][CH3:21]>C(OCCC)(=O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:23](=[S:24])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CCCN=C=S
Solvent: CCCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a slurry of 2-amino-5-iodobenzoic acid (20 g, 0.076 mol) in n-propyl acetate (63 mL) was added triethylamine (11.6 mL, 0.0.84 mol) followed by n-propyl isothiocyanate (8.7 mL, 0.084 mol) at room temperature. The resulting solution was heated to reflux and the water generated was removed in a Dean Stark trap. After 4 h, the reaction mixture was cooled to room temperature and filtered. The wetcake was washed with fresh n-propyl acetate and dried at 60° C. under vacuum. In this manner, 21.4 g of the title compound was obtained as a light tan solid. See Step 1A for 1H NMR data, the UV spectrum matched that of the material made previously.