Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([CH:18]=O)[S:15][C:13]=2[N:14]=1>>[Cl:8][C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([CH2:18][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[S:15][C:13]=2[N:14]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
N-Methylpiperazine was reacted with 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde via General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=1.[C:19](CC(Cl)=O)([CH3:22])([CH3:21])[CH3:20]>COCCOC>[CH3:20][C:19]([CH3:22])([CH3:21])[C:1]([NH:17][C:12]1[CH:11]=[C:10]([CH2:9][C:8]([O:7][CH3:6])=[O:18])[CH:15]=[CH:14][C:13]=1[OH:16])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(O)c(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydrogen carbonate (19 g, 0.23 mol) was suspended in 1,2-dimethoxyethane (180 ml), and methyl(3-amino-4-hydroxyphenyl)acetate [from step 4] (26.3 g, 0.145 mole) was added. To this mixture was added, dropwise, a solution of tert-butylacetyl chloride in 1,2-dimethoxyethane (45 ml), over 2 hours. Once the addition was complete, the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the inorganic solid washed with ethyl acetate (3×50 ml) and the filtrate and washings were combined and concentrated. Trituration of the product with hexane gave methyl [3-(2,2-dimethylpropionamido)-4-hydroxyphenyl]acetate (40.1 g) as an off-white solid, m.p. 112-113° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 80.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-butyl-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-2, 0.16 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.C(OC(=O)[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(C)(C)C>>[CH3:25][O:24][C:21]1[N:20]=[CH:19][C:18]([CH2:17][NH:16][C:26]2[N:27]=[CH:28][C:29]([C:32]([C:9]3[C:5]4[CH:4]=[N:3][CH:2]=[N:1][C:6]=4[NH:7][CH:8]=3)=[O:33])=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Reactant: c1ncc2cc[nH]c2n1
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1

Procedure:
{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-0008 was prepared in three steps from 7H-pyrrolo[2,3-d]pyrimidine 6 and (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 71 as shown in Scheme 13.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]1[C:21]2[CH2:20][CH:19]([CH2:22][NH2:23])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH:1]([NH:23][CH2:22][CH:19]1[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:21]=2[CH2:20]1)=[O:3]
Reactant: O=CO
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNCC1Cc2ccccc2Cc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of formic acid and acetic anhydride (1:1, 20 ml) is prepared at 0° to 10° C and added to 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine (15.0 g). The mixture is stirred for 1 hr. and then allowed to stand for 18 hr. Water (100 ml) and ice chips are are added. After stirring for 15 min., the mixture is rendered alkaline with dilute NaOH solution and extracted with ether. The extract is washed with water, dried (MgSO4) and concentrated to afford N-formyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, m.p. 109° - 111° C, δmaxCHCl3 3445, 3350, 1685 cm-1, after recrystallization from ether.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][N:28]1[CH:33](O)[CH3:34])=O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89]([OH:93])[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:64]1[C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:92]=[CH:91][CH:90]=[C:89]([O:93][CH2:34][CH2:33][N:28]3[CH2:27][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:88]=2)=[N:67][CH:66]=[N:65]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)N1CCNCC1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-(tert-butyloxycarbonyl)piperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (5–70% acetonitrile/water). The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.132 g, 52% yield) as the bis-trifluoroacetic acid salt. 1H NMR (D2O) δ 8.26 (s, 1H), 8.12 (s, 1H), 7.61 (d, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 6.90 (m, 1H), 4.35 (m, 2H), 3.62 (m, 6H), 3.52 (m, 4H). ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:37](N1C=CN=C1)([N:39]1C=CN=[CH:40]1)=O.CNC.C1COCC1>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([N:39]([CH3:40])[CH3:37])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6 (1.68 g, 3.43 mmol) in dry DMF (30 mL) was added carbonyldiimidazole (1.1 g, 6.86 mmol), and the reaction mixture was heated to 60° C. for 1 hr. The reaction mixture was cooled to 0° C. and a solution of dimethylamine in THF (2 M, 8.6 mL, 17.2 mmol) was added and stirred for 18 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was then rinsed sequentially with 10% citric acid (2×50 mL), water (2×50 mL), and brine (20 mL), then dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography using hexane-ethyl acetate (3:7) containing 1% acetic acid. Yield: 1.77 g, 100%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[N:17]#[C:18][NH2:19].O.NN>CC#N>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:19]\[C:18]#[N:17])=[CH:4][CH:3]=1
Reactant: S=c1ccccn1-c1ccc(I)cc1
Reactant: N#CN
Agent: NN
Solvent: CI
Solvent: CC#N
Solvent: O
Product: N#C/N=c1\ccccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (180 mg, 0.575 mmol) in CH3CN (15 mL), CH3I (0.50 mL, 8.0 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in CH3CN (5 mL). To the solution, cyanamide (200 mg, 4.76 mmol) and hydrazine monohydrate (0.100 mL, 2.06 mmol) were added. After being stirred at room temperature for 2 h, the mixture was purified by HPLC to give (E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[K+].O>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(/C=C/C(=O)OC)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)O)cc1OCC
Temperature: 70 °C

Procedure:
1.0 g (4.00 mmol) of methyl 3(E)-(3,4-diethoxyphenyl)acrylate is suspended in 30 ml of a 10% solution of potassium hydroxide in methanol. Thereafter, 2 ml of water are added and the mixture is heated to 70° C. for 3 hours. The reaction mixture is then cooled and is partitioned between diethyl ether and water, the organic phase is washed several times with saturated sodium chloride solution and the combined aqueous phases are adjusted to pH 4 with a 25% hydrochloric acid solution and are extracted several times with methylene chloride. The methylene chloride phases are combined, dried over magnesium sulfate, filtered and evaporated down. This gives 3(E)-(3,4-diethoxyphenyl)acrylic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].Cl.N([O-])=O.[Na+].[F:23][C:24]1[CH:30]=[CH:29][C:27](N)=[CH:26][C:25]=1[CH3:31]>O1CCOCC1.O.C(O)C>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:26][C:25]=1[CH3:31]
Reactant: Cc1cc(N)ccc1F
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(NC(=NO)c2nonc2NCCNS(C)(=O)=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N′-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (35 mg, 0.13 mmol) was stirred in 1,4-dioxane (2 mL) and 6 N hydrogen chloride solution (4 mL) was added. The solution was cooled to 0° C. and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred for 1 hour at 0° C. and evaporated. Dry 1,4-dioxane (2 mL) was added and the mixture evaporated two more times. A solution of 4-fluoro-3-methylaniline [Aldrich, product #559415] (25 mg, 0.20 mmol) in ethanol (2 mL) was added and the mixture was stirred for 1 hour. Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). LCMS calculated for C13H18FN6O4S (M+H): m/z=373.1. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=2)=[CH:7][CH:6]=1)O.[OH-:20].[Na+].[O:22]1[CH2:27][CH2:26][O:25][CH2:24]C1>CO>[CH2:16]([C:13]1[O:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:26]([O:25][CH3:24])[C:27]([OH:22])=[O:20])=[CH:10][CH:9]=2)=[N:15][N:14]=1)[CH3:17]
Reactant: C1COCCO1
Reactant: CCc1nnc(-c2ccc(C(O)C(Cl)(Cl)Cl)cc2)o1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCc1nnc(-c2ccc(C(OC)C(=O)O)cc2)o1
Temperature: 55 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol (2.0 g, 6.25 mmol) in anhydr 1,4-dioxane (12.5 mL) and anhydr MeOH (15 mL) was added a solution of NaOH (1.25 g, 31.3 mmol) in anhydr MeOH (15 mL). After stirring for 4 hrs at 55° C., the mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized with saturated aqueous NH4Cl, acidified carefully with 1 M HCl and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was triturated with Et2O to give 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyacetic acid as an off-white solid (1.2 g, 73% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:31][C:30]([Cl:33])=[CH:29]C=1)=O>CO.O>[Cl:33][C:30]1[CH:31]=[CH:3][C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:29]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the reactions described in examples 1.5 and 1.7 trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester (example 3.2) was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 354 (MH+, 1Cl).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][F:22])C1C=CC=CC=1.C(O)C.[C:26]([OH:29])(=[O:28])[CH3:27]>[Pd].CCOCC>[C:26]([OH:29])(=[O:28])[CH3:27].[C:26]([OH:29])(=[O:28])[CH3:27].[F:22][CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: FCC1CNCCN1
Reaction time: 72 h

Procedure:
A mixture of 1,4-dibenzyl-2-fluoromethyl-piperazine (0.47 g, 1.6 mmol), ethanol (20 mL), acetic acid (0.4 mL) and 10% palladium on carbon (0.2 g) was hydrogenated at 20° C. and 4 bar for 72 h. Solids were removed by filtration and the filtrate evaporated in vacuo to give a colourless solid. Trituration (twice) with ether gave the title compound (0.332 g) as a colourless solid. 1H NMR (DMSO-d6): 7.38-5.74 (4H, m), 4.40-4.27 (1H, m), 4.27-4.14 (1H, m), 2.94-2.69 (4H, m), 2.69-2.58 (1H, m), 2.58-2.52 (1H, m), 2.32 (1H, dd), 1.87 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][O:44][CH2:45][CH2:46][NH2:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:24]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methoxyethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.O>CC(C)=O>[Cl:1][C:2]1[C:3]([O:15][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: ICCOC1CCCCO1
Reactant: COC(=O)c1cc(O)c(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCCOC2CCCCO2)c(Cl)c([N+](=O)[O-])c1

Procedure:
6.84 g of methyl 4-chloro-3-hydroxy-5-nitro-benzoate were dissolved in acetone (150 ml), treated at RT in succession with 10.19 g of potassium carbonate and 11.19 g of 2-(2-iodo-ethoxy)-tetrahydro-pyran and the mixture was heated at reflux for 16 hours. Subsequently, the mixture was poured into water, extracted with ethyl acetate, the organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was flash chromatographed on silica gel with hexane/ether (2/1) as the eluent. There was thus obtained the desired methyl 4-chloro-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=S.ICC.[H-].[Na+].[N:28]#[C:29][NH2:30]>O1CCCC1>[C:29]([NH:30][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=1)=[N:2][CH3:1])#[N:28]
Reactant: N#CN
Reactant: CNC(=S)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CN=C(NC#N)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of 120 mg of N-methyl-6-nitro-spiro[2H-1benzopyran-2,1'-cyclohexane]-4-carbothioamide, 150 μl of iodoethane, and 3 ml of dried tetrahydrofuran was added 23 mg of sodium hydride (60%) with stirring and cooling with ice followed by refluxlng for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added thereto, followed by refluxing for 4 hours. Ice-water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: ethyl acetate:hexane=2:3) recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 90 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine having formula shown below.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=3)=[N:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]=[C:43]=[S:44])([CH3:35])[CH3:34]>ClCCl>[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:14]=[CH:15][N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:2])([F:24])[F:25])=[CH:10][CH:9]=3)[N:12]=2)=[CH:17][CH:18]=1)=[S:44])([CH3:35])[CH3:34]
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1NC(=S)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
In a 100 mL flask, to a solution of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl) methanamine hydrochloride (0.200 g, 0.598 mmol) in dichloromethane (5 mL) was added triethylamine (0.0720 g, 0.718 mmol) and 1-isopropyl-2-isothiocyanatobenzene (0.106 g, 0.598 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue purified by flash column chromatography eluting with 10-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to give the title compound as a white solid (0.145 g, 48%).
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13](=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:13])=[C:6]([F:12])[CH:5]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cc(Br)cc1F

Procedure:
Add iodomethane (2.0 ml, 32.1 mmol) dropwise to a suspension of 4-bromo-2,6-difluorophenol (5.90 g, 28.2 mmol) and potassium carbonate (4.40 g, 31.8 mmol) in acetone (50 ml) at room temperature while stirring vigorously. Heat the mixture under reflux overnight. Evaporate acetone and add dichloromethane. Filter through silica eluting the product with dichloromethane/EtOAc. Concentrate to yield the title compound.
Reaction SMILES: Cl.CN(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20](/[C:29](/[C:36]2[NH:41][C:40](=[O:42])[C:39]([CH3:43])=[CH:38][CH:37]=2)=[CH:30]\[CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:21]=[CH:22][C:23]=1[S:24][CH2:25][CH2:26][CH2:27][OH:28].CN(C)CCN>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:28][CH2:27][CH2:26][CH2:25][S:24][C:23]2[CH:22]=[CH:21][C:20](/[C:29](/[C:36]3[NH:41][C:40](=[O:42])[C:39]([CH3:43])=[CH:38][CH:37]=3)=[CH:30]\[CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:19][C:18]=2[Cl:17])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCO)c(Cl)c2)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCSc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(=O)[nH]3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
Triethylamine (148 μL), trimethylamine hydrochloride (50 mg) and 4-methylbenzenesulfonyl chloride (74 mg) were sequentially added to a solution of 6-[(E)-1-{3-chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-cyclopentylethenyl]-3-methylpyridin-2(1H)-one obtained in Example 1-22 (143 mg) in chloroform (5 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water and N,N-dimethylethylenediamine were added to the reaction solution, followed by extraction with chloroform. The organic layer was sequentially washed with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg, 18%) as a colorless amorphous.