Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:12][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(O)c(C(=O)O)cn1
Solvent: CC#N
Product: Cc1ncc(C(=O)O)c(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Commercially available 4-hydroxy-6-methyl-nicotinic acid (300 mg) was suspended in 3 ml of acetonitrile, and N-chlorosuccinimide (380 mg) was then added to the suspension. The resulting mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated under reflux for 45 minutes. After the disappearance of the materials had been confirmed, the reaction solution was cooled on ice, and the precipitate was then collected by filtration, so as to obtain the title compound (324 mg) as a solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C.[Pd]>[F:1][C:2]([F:24])([F:25])[CH:3]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(OC(=O)c1ccc(N)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
The reaction liquid was poured into water, and extracted with methylene chloride. The methylene chloride layer was washed with a diluted hydrochloric acid and water in this order. The organic layer thus recovered was distilled under a reduced pressure to remove the solvent, and subjected to purification by a silica gel chromatography (n-hexane:ethyl acetate=10:2) to obtain 2.1 g of p-nitrobenzoic acid 1,1,1-trifluoro-2-decyl ester. The ester was dissolved in 30 ml of ethanol, to which 0.21 g of 5 % Pd-C catalyst was added, and the solution was stirred overnight under hydrogen atmosphere, then the Pd-C catalyst was separated by filtration, and the ethanol was distilled off under a reduced pressure to obtain 2.0 g of p-amino-benzoic acid 1,1,1-trifluoro-2-decyl ester which was the desired compound of the reaction [1].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: NCCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Product: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: Cl.[NH2:2]O.[OH-].[Na+].C(OC=C[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C.NO.[CH2:21]([OH:23])[CH3:22]>O>[CH3:22][C:21]1[O:23][N:2]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NO
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cnoc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (52.6 g) was dissolved in water (150 ml) and stirred while an ice-cold solution of sodium hydroxide (30.28 g) in water (100 ml) was added. This solution was stirred for 15 minutes then absolute ethanol (600 ml) added and the solution stirred for a further 15 minutes. Ethyl ethoxymethyleneacetoacetate (128 g) was dissolved in absolute ethanol (100 ml) and added to the hydroxylamine solution. After stirring for 30 hours the solvents were removed on a rotary evaporator (bath at 45° C.). The clear oil was distilled at reduced pressure through a 15 cm Vigreaux column. Product collected as a clear oil at 50°-54° C./0.5 mm Hg.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)[S:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:17]1[CH2:16][N:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:11]=2)[CH2:18]1)(=[O:27])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (326.5 mg, 0.86 mmol) (obtained as described in Reference Example 12(3)) in dimethylformamide (16 ml) was added potassium thioacetate (780 mg, 5.41 mmol) at room temperature, and the reaction mixture was then stirred in an oil bath (80° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1) as the eluant to afford 3-acetylthio-1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidine (191 mg, yield 62%) as a brown syrup.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN(C=O)C.F[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)[CH:24]=1)[C:20]#[N:21]>CCOCC.[OH-].[Na+]>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[CH:24]=2)[C:20]#[N:21])=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cn1ccnc1Sc1cc(F)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccnc1Sc1cc(C#N)cc(Oc2ccc(I)cc2)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A mixture of NaH (60%, 312 mg, 7.8 mmol) in oil was rinsed with dry pentane by syringe (3×3 mL) and excess solvent removed under a steam of N2. Solid 4-iodophenol (1.72 g, 7.8 mmol) was added followed by 16 mL of DMF under ice-bath cooling which resulted in a vigorous evolution of gas. After 15 min, solid 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile (910 mg, 3.9 mmol) was added and the resulting mixture microwave heated at 160° C. for 10 min. After cooling to rt, the mixture was diluted with ether and 3 M aqueous NaOH and shaken. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting 1.8 g of residue was adsorbed to 4.5 g SiO2 from CH2Cl2 and subjected to MPLC on a 40 g column of SiO2 eluting with % EtOAc in hexanes (time): 33% (10 min), 35-50% (20 min ramp) which provided 1.60 g (95%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 6.82 (dd, 1H, J=2, 1 Hz), 6.90 (d, 2H, J=8 Hz), 7.13 (d, 1H, J=1 Hz), 7.26 (t, 1H, J=2 Hz), 7.37 (dd, 114, J=2, 1 Hz), 7.50 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 434.3 [C17H12IN3OS+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:16][CH2:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:17])[C:7]=2[CH:18]=1.[Se]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]=[CH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)c1cccnc1CC2
Agent: [Se]
Solvent: c1ccncc1
Product: COc1ccc2ccc3ncccc3c(=O)c2c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 2.3 g (9.6 mmol) of the product from Example 23 step 4, 1.85 g (16.6 mmol) of selenium dioxyde and 5 ml of pyridine is stirred at 120° C. for 6 hr. The whole is poured into excess petroleum ether and the solution is evaporated giving 0.55 g (24%) of enough pure title product as to prosecute with the synthesis.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:14]1([C:12]([NH:11][C@H:10]([C:9]([OH:25])=[O:8])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Yield: 92.7 %

Procedure:
The compound obtained in (1) (1.75 g) was dissolved in methanol (30 ml). 10% Pd-C (0.30 g) was added and the mixture was stirred vigorously at room temperature under atmospheric pressure of hydrogen for 1.5 h. The catalyst was filtered off and the filtrate was concentrated to give the product (1.2 g) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][C:5]([CH2:8][O:9]C(=O)C)=[CH:6][CH:7]=1.Cl>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1ccc(C)c(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CO)nc1-c1ccccn1

Procedure:
1.4 g (5.8 mmols) of 3-methyl-6-acetoxymethyl-2,2'-bipyridine are boiled under reflux for 30 minutes in a mixture of 20 ml of 10% sodium hydroxide solution and 15 ml of ethanol. After cooling, the mixture is acidified with hydrochloric acid and washed with twice 20 ml of ethyl acetate. The aqueous phase is rendered alkaline with potassium carbonate, and the reaction product is extracted with 40 ml of ethyl acetate. After drying over sodium sulfate and concentration in vacuo, the 3-methyl-6-hydroxymethyl-2,2'-bipyridine is crystallised from diethyl ether. Yield: 0.99 g (85% of theory); melting point 51°-53° C. UV absorption (in chloroform): λmax =281 nm (ε=9400).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][N:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
Heat a solution of 5,6-dichloro-nicotinic acid ethyl ester (TCI America) (4.43 g, 0.02 mol), piperazine-1-carboxylic acid tert-butyl ester (4.13 g, 0.022 mol) and DIEA (5.2 mL, 0.03 mol) in DMA at 110° C. for 5 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as an orange oil.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][CH2:7][NH2:8].Br[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C(O)=O.CCOCC>CC(O)C.C(O)C>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][NH:8][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:3]=[CH:4]1
Reactant: Brc1nccs1
Reactant: NCCc1cnc[nH]1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCO
Product: c1csc(NCCc2c[nH]cn2)n1

Procedure:
1.1 g (10 mmol) of histamine base and 1.6 g (10 mmol) of 2-bromothiazole are brought to reflux in 15 ml of 2-propanol for 96 h. The reaction mixture is concentrated under reduced pressure until an oily residue is obtained which is chromatographed on a column of silica gel with a mixture of chloroform and methanol (1, 5 and 20%) as eluent to provide an oil. The latter is taken up in absolute ethanol and is treated with oxalic acid (2 molar equivalents). Addition of ether gives the title compound in the dioxalate form which, after having been crystallized from 2-propanol, melts at 198°-199° C.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].S(=O)(=O)(O)O.O.[F:19][CH:20]([CH3:29])[C:21](=O)[CH2:22][C:23](OCC)=[O:24]>CO>[F:19][CH:20]([C:21]1[N:12]=[CH:10][NH:11][C:23](=[O:24])[CH:22]=1)[CH3:29]
Reactant: CCOC(=O)CC(=O)C(C)F
Reactant: N=CN
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(F)c1cc(=O)[nH]cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution in which 24.3 g of ethyl 4-fluoro-3-oxopentanoate had been dissolved in 330 ml of methanol were added 72.3 g of a 28 % sodium methoxide methanol solution and 15.6 g of formarnidine acetate, and the mixture was stirred at 50° C. for 3 hours. To the mixture was further added 7.81 g of formamidine acetate and after stirring the mixture at 50° C. for 4 hours, the mixture was cooled to 10° C. or lower. After cooling, 18.8 g of conc. sulfuric acid and 13.5 g of water were added to the reaction mixture. After stirring the mixture at 50° C. for 15 minutes, insolubles were removed by filtration and the filtrate was quantitated by the liquid chromatography internal standard method. As a result, 18.0 g of 6-(1-fluoroethyl)-4-pyrimidone was formed (yield: 84.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:43][CH2:44]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:44][CH2:43][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)[CH2:25][CH2:24]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 48 %

Procedure:
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethylester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}acetate (2.9 g, 10.0 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine dihydrochloride (4.3 g, 10 mmol), 2.8 g of product (brown oil) was isolated. Yield 48%; MS: 583 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[C:15]2[O:14][C:13]([C:16]3([CH3:21])OCC[O:17]3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].C1(S(O)(=O)=O)C=CC=CC=1>CC(C)=O>[C:16]([C:13]1[O:14][C:15]2[C:7]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1)(=[O:17])[CH3:21]
Reactant: CC(=O)OC(C)c1cccc2cc(C3(C)OCCO3)oc12
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)OC(C)c1cccc2cc(C(C)=O)oc12

Procedure:
Ca 30 g of crude 7-(1'-acetoxyethyl)-2-(2-methyl-1,3-dioxolan-2-yl) benzofuran were dissolved in 200 ml of acetone and 2 ml of a 33% aqueous solution of benzenesulphonic acid were added to the solution obtained. The resulting solution was heated under reflux for 3 hours, then cooled and evaporated to dryness under reduced pressure. The residual oil was dissolved in diethyl ether and the solution washed with water and with brine and then dried over anhydrous sodium sulphate. The sodium sulphate was then filtered off and the filtrate evaporated to dryness under reduced pressure. The product was purified by column chromatography on silica gel followed by crystallization from cyclohexane to give 2-acetyl-7-(1'-acetoxyethyl)benzofuran in the form of a cream crystalline solid of melting point 82°-83°C.
Reaction SMILES: Cl.C(O[C:5](=O)[CH:6]([CH2:8][SH:9])N)C.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH3:16].N(C(C)(C)C#N)=N[C:19](C)([CH3:22])[C:20]#N>O1CCOCC1>[CH:11]([S:9][CH:8]=[CH:6][CH2:5][CH2:20][CH2:19][CH3:22])=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCC
Reactant: CCOC(=O)C(N)CS
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC=CSC=CCCCC
Reaction time: 0.33 h

Procedure:
A mixture of 12.80 g (68.93 mmol) of DL-cysteine ethyl ester hydrochloride, 25.60 g (311.62 mmol) of 1-hexyne, and 50 mg of 2,2'-azobis-(2-methylpropionitrile) in 250 ml of absolute dioxane was stirred at 60°-65°. under inert gas atmosphere for 20 minutes. After cooling, most of the solvent was evaporated in vacuo. The residue was treated with 150 ml of 1 N sodium carbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with 3×50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 15.90 g (99%) of crude (ethyl 2-aminopropanoate-3-yl) (1-hexenyl) sulfide as a thick pale yellow oil which can be used without further purification in the next step. NMR spectroscopical studies showed that the product is approximately a 1:1 mixture of geometrical isomers.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].[CH2:14]([CH2:16][NH2:17])[OH:15]>O1CCOCC1>[NH3:17].[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][NH:17][CH2:16][CH2:14][OH:15]
Reactant: NCCO
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N
Product: OCCNCCC(F)(F)F
Yield: 111.6 %

Procedure:
3-bromo-1,1,1-trifluoropropane (5.5 ml, 51.65 mmol) in dioxane (50 ml) in the presence of potassium carbonate (14.15 g, 102.5 mmol) was reacted with ethanolamine (3.0 ml, 51 mmol) at 60° C. for 36 hours. The solvent was evaporated and the residue purified by chromatography on silica gel. Elution with dichloromethane:methanol (95:5) then increased polarity to dichloromethane:methanolic ammonia (95:5) yielded 2-((3,3,3-trifluoropropyl)amino)ethanol (4.47 g, 55% yield):
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.[NH4+].[OH-]>CO>[CH3:16][O:15][C:14]1[CH:13]=[C:12]2[C:7]([C:8]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[OH:4]
Reactant: COc1cc2ncnc(Nc3ccccc3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccccc3)c2cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-4-phenylamino-quinazoline (1.01 g, 3.27 mmol) (from Example 15, Step A, supra) in MeOH (30 mL) was added an aqueous solution of NH4OH (29%, 2.0 g, 31.4 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then heated at 100° C. for 1.5 hours. The mixture was then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 7-methoxy-4-phenylamino-quinazolin-6-ol as a white solid. (Yield 0.6 g, 69%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].COC1C=C(OC)C=CC=1C[NH:10][CH:11]1[C:20]2[CH2:19][S:18][N:17]=[C:16]([N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:15]3=[N:36][N:37]([CH2:39][C:40]4[C:45]([CH3:46])=[C:44]([O:47][CH3:48])[C:43]([CH3:49])=[CH:42][N:41]=4)[N:38]=[C:13]([C:14]=23)[CH2:12]1.N1C=CC=CC=1>ClCCl>[NH2:21][C:16]1[C:15]2[C:14]3[C:13](=[N:38][N:37]([CH2:39][C:40]4[C:45]([CH3:46])=[C:44]([O:47][CH3:48])[C:43]([CH3:49])=[CH:42][N:41]=4)[N:36]=2)[CH2:12][CH:11]([NH:10][C:1](=[O:3])[CH3:2])[C:20]=3[CH2:19][S:18][N:17]=1
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cnc(CN2N=C3CC(NC(C)=O)C4=C3C(=N2)C(N)=NSC4)c1C
Reaction time: 3 h
Yield: 76 %

Procedure:
Acetyl chloride (18 μL) was added dropwise to a mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (36 mg), pyridine (40 μL) and dehydrated dichloromethane (0.7 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for three hours. The reaction mixture was diluted with chloroform and then washed with a 0.2 N hydrochloric acid solution. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dichloromethane (1 mL) and 1,3-dimethoxybenzene (12 μL) were added to the resulting residue. Then, trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (15.6 mg, 76%) as a solid.
Reaction SMILES: Cl.CN.[N:4](CCO)(CCO)[CH2:5]CO.[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24]OCC)[S:20][C:19]1=[S:28])([OH:16])=[O:15]>C(O)C>[CH3:5][NH2:4].[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24][NH:4][CH3:5])[S:20][C:19]1=[S:28])([OH:16])=[O:15]
Reactant: OCCN(CCO)CCO
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNC=C1SC(=S)N(CC(=O)O)C1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of 0.68 g (0.010 mole) of methylamine hydrochloride and 5 ml of ethanol, which was neutralized with 1.0 g (0.010 mole) of triethanolamine, was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5ethoxymethylidenerhodanine and 10 ml of ethanol. The reaction was conducted at a temperature of 50° to 60° C. for 1 hour. The reaction mixture was concentrated and the resulting residue was recrystallized from ethanol to give 1.0 g of 3-carboxymethyl-5-methylaminomethylidenerhodanine methylamine salt (yield: 79.2 %).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:31]
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCCC2)n1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1

Procedure:
To a solution of 0.563 g (0.0017 mol) 5-bromo-3-cyclopentylmethoxy-2-pyrrolidin-1-yl-pyrazine in 4 mL methanol and 2 mL ethyl acetate was added 0.050 g PdCl2dppfCH2Cl2 and 0.48 mL (0.0035 mol) triethylamine and the mixture was stirred under an atmosphere of 70 bar carbon monoxide at 110° C. for 18 h in an autoclave. The solids were removed by filtration and the mother liquor was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with water (2×) dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1 to yield 0.423 g of the title compound as slightly yellow orange crystals melting at 69-70° C.