Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16]C.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:14])([CH3:13])[CH3:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16]
Reactant: COc1ccc2c(nnn2CC(C)(C)C)c1Br
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-bromo-1-(2,2-dimethylpropyl)-5-methoxy-1H-1,2,3-benzotriazole (1-5) (8.97 g, 30.1 mmol, 1.0 equiv.) in dichloromethane (150 ml) at 0° C., was added slowly a 1M solution of BBr3 (60.2 ml, 60.2 mmol, 2.0 equiv.) in dichloromethane. The reaction mixture was allowed to warm up to room temperature and was stirred for an additional 14 hours. LCMS showed completion. The reaction mixture was treated with water, neutralized to pH=7, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to give provide 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6). 1H NMR (500 MHz, CDCl3) 7.36 (d, 1H, J=9.0 Hz), 7.24 (d, 1H, J=9.0 Hz), 4.37 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.
Reaction SMILES: [CH2:1]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:18]([O-])(=O)C(C(CC([O-])=O)C([O-])=O)O>>[C:8]([O:10][CH3:18])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])CC(C(=O)[O-])C(O)C(=O)[O-]
Reactant: O=C(O)CCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCC(=O)OC

Procedure:
We compared the production of ω-hydroxy myristic acid and α,ω-tetradecanoic acid by a Candida tropicalis strain lacking CYP52A13, CYP52A14, CYP52A17, CYP52A18, FAO1, FAO1B, FAO2A, FAO2B, CYP52A12, CYP52A12B, ADH-A4, ADH-A4B, ADH-B4, ADH-B4B, ADH-A10 and ADH-B11 and with CYP52A17 added back under control of the isocitrate lyase promoter (DP428).
Reaction SMILES: [C:1]([N:4]([CH3:38])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[C:26](=[O:27])[C:25]3[S:28][C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)=[CH:30][C:24]=3[N:23]=[CH:22]2)=[CH:15][CH:14]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[S:28][C:25]3[C:26](=[O:27])[N:21]([CH2:20][CH2:19][C:16]4[CH:17]=[CH:18][C:13]([NH:5][N:4]([CH3:38])[C:1](=[O:3])[CH3:2])=[CH:14][CH:15]=4)[CH:22]=[N:23][C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(C)Nc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
tert-Butyl 2-acetyl-1-[4-[2-[6-(4-chlorophenyl) -4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]ethyl]phenyl]-2-methylhydrazinecarboxylate (356 mg) was dissolved in dichloromethane (6.5 ml), and trifluoroacetic acid (2.0 ml) was added. The reaction mixture was stirred at room temperature for 1.5 hr, and diluted with dichloromethane. The obtained diluted solution was washed with saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated crystals were washed with ethyl acetate-diisopropyl ether to give the title compound (287 mg) as colorless crystals.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:18]#[N:19].NN.O>C(O)C>[NH2:3][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:18]#[N:19]
Reactant: COCCOCOc1ccc(C#N)cc1/C=C/CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COCCOCOc1ccc(C#N)cc1/C=C/CN
Yield: 90 %

Procedure:
(E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile (3.1 g, 8.0 mmol) and NH2NH2 hydrate (0.96 mL, 20 mmol) in ethanol (100 mL) is refluxed for 1.5 hours. The mixture is concentrated, treated with aqueous NaOH, and extracted with CH2Cl2 (3×). The CH2Cl2 layer is dried and concentrated to obtain the product as a clear oil (1.9 g, 7.2 mmol). 1H NMR (CDCl3, 300 MHz) δ7.70 (d, 1H), 7.47 (dd, 1H), 7.22 (d, 1H), 6.75 (d, 1H), 6.34 (m, 1H), 5.35 (s, 2H), 3.80 (t, 2H), 3.50 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[C:13]([C:16](OC)=O)[C:12]=2[CH:20]=1.C(Cl)[Cl:22]>O1CCCC1>[Cl:22][CH2:16][C:13]1[C:12]2[CH:20]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[O:15][CH:14]=1
Reactant: ClCCl
Reactant: COC(=O)c1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[C:18](=[O:19])[NH:17][N:16]=[N:15]1)[CH2:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[C:18](=[O:19])[N:14]([CH2:11][CH2:12][CH3:13])[N:15]=[N:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCn1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 38 parts of 1-fluoro-4-nitrobenzene, 32 parts of 1,4-dihydro-1-propyl-5H-tetrazol-5-one, 14 parts of sodium carbonate and 200 parts of dimethyl sulfoxide was stirred and heated for 4 hours at 120° C. The reaction mixture was cooled and poured into water. The precipitated product was filtered off and crystallized from 2-propanol, yielding 46 parts (74%) of 1,4-dihydro-1-(4-nitrophenyl)-4-propyl-5H-tetrazol-5-one; mp. 91.1° C. (int. 31).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:45])[C:19]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30](=[O:44])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)=[O:20])=[O:14])=[CH:8][CH:7]=1.Cl.O>C(#N)C>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:45])[C:19]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30](=[O:44])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:27][CH2:28]2)=[O:20])=[O:14])=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(CCCC(=O)Nc1ccc(C2OCCO2)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CN(CCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-(1,3-dioxolan-2-yl)phenylcarbamoyl)propyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (98 mg, 0.16 mmol) in acetonitrile (2 mL) was added aqueous hydrochloric acid (3 M, 1.07 mL). The resulting dark orange solution was stirred at room temperature. Water was added and the resulting mixture was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccccn1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Yield: 29.4 %

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]pyridine (5.0 g) and 1-nitro-2,2-bis-methylthioethylene (5.28 g) in ethanol was heated under reflux for 3 hours. Concentration and chromatographic purification of the product on a column of silica gel with elution by iso-propyl alcohol-ethylacetate (1:5) gave 1-nitro-2-methylthio-2-[2-(2-pyridylmethylthio)ethylamino] ethylene (2.49g), m.p. 95.5°-96.5°.
Reaction SMILES: ClCC([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16])=O.Cl.O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16]
Reactant: O=C(CCl)NCc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCc1cc([N+](=O)[O-])ccc1O

Procedure:
12.2 g (0.056 mole) of chloroacetamido compound of step 1 is heated in 100 ml ethanol and 30 ml concentrated hydrochloric acid for 4 hours accompanied by refluxing. After dilution with water, it is neutralized with sodium bicarbonate and the precipitate is separated by suction, accompanied by rewashing with water. The residue is purified by means of reprecipitation. 3 g of the substance is dissolved hot in 25 ml water/5 ml glacial acetic acid. After cooling, it is filtrated and the filtrate is neutralized with ammonia. The pure amimomethyl compound separates out, it is isolated by means of suction and washed with water and isopropanol.
Reaction SMILES: O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]([C:59]([OH:61])=[O:60])[C:46]3[C:51](I)=[N:50][N:49]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[C:47]=3[N:48]=2)=[CH:39][C:38]=1[C:62]([O:64][CH3:65])=[O:63].CC1(C)C(C)(C)OB([C:74]2[CH:75]=[C:76]([CH:87]=[CH:88][CH:89]=2)[C:77]([O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)=[O:78])O1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:80]([O:79][C:77]([C:76]1[CH:75]=[C:74]([C:51]2[C:46]3[C:45]([C:59]([OH:61])=[O:60])=[CH:44][C:43]([C:40]4[CH:41]=[CH:42][C:37]([F:36])=[C:38]([C:62]([O:64][CH3:65])=[O:63])[CH:39]=4)=[N:48][C:47]=3[N:49]([CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[N:50]=2)[CH:89]=[CH:88][CH:87]=1)=[O:78])[C:81]1[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=1
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(C4CCCCO4)c3n2)ccc1F
Reactant: CC1(C)OB(c2cccc(C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4cccc(C(=O)OCc5ccccc5)c4)nn(C4CCCCO4)c3n2)ccc1F
Temperature: 95 °C
Yield: 72 %

Procedure:
The ligand sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulphonate hydrate (146 mg/0.3 mmol) and the catalyst PdCl2(dppf) (280 mg/0.36 mmol) are added successively, under argon, to a suspension of 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.7.] (1.5 g/3 mmol), benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [880157-10-8] (1.16 g/3.4 mmol) and potassium carbonate (828 mg/6.0 mmol) in 9.5 mL of DMF. The reaction mixture is heated at 95° C. for 1 h. It is run into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness. After purification by flash chromatography on silica (DCM/EtOH 0.1% TEA: 100/0 to 90/10), 1.31 g of a yellow solid are obtained (triethylamine salt; yield: 72%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][NH:16][C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][CH:31]=2)=[C:26]([CH3:39])[CH:25]=1)=[O:23]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:36]([C:33]5[CH:34]=[CH:35][C:30]([C:27]6[CH:28]=[CH:29][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][C:26]=6[CH3:39])=[CH:31][CH:32]=5)=[O:37])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Product: COC(=O)c1ccc(-c2ccc(C(=O)N3CCCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) and 4'-methoxycarbonyl-2'-methylbiphenyl-4-carboxylic acid (D41) using a procedure similar to that of Example 1 (46%).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.[C:21](#[N:23])[CH3:22]>>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([CH2:22][C:21]#[N:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC#N
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Product: N#CCC(=O)c1cccc(Oc2ccccc2)c1
Yield: 65 %

Procedure:
A solution of sodium methoxide (from 1.2 g sodium in 25 ml methanol) was added dropwise over 2 hours to a refluxing solution of methyl-3-phenoxybenzoate (11 g) in acetonitrile (100 ml) under a nitrogen atmosphere while distilling off methanol and excess acetonitrile. After complete removal of methanol the reaction mixture was poured onto ice-water (200 g) and acidified with 50% HCl. The solid was filtered off and dried to give the title compound (7.5 g, 65%) as a white solid of m.p. 95°-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([CH2:8][CH2:9]O)[CH:7]=1.[C:12](=O)([O-])[O-:13].[Cs+].[Cs+].BrCCl.[I-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]2[O:13][CH2:12][O:11][C:4]=2[CH:3]=1
Reactant: OCCc1cc(O)cc(Br)c1
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [Cs+]
Agent: [I-]
Product: CCc1cc(Br)cc2c1OCO2
Temperature: 74 °C
Reaction time: 1.5 h

Procedure:
A 2L, 3 neck round bottom flask was equipped with an overhead stirrer, heating mantle, condenser, and nitrogen inlet. The flask was flushed with nitrogen and charged with acetonitrile (700 mL), followed by 5-bromo-2,3-dihydroxyethylbenzene (54.5 g, assumed to be 0.25 mol), then anhydrous cesium carbonate (121 g, 0.37 mol) and bromochloromethane (57 g, 0.44 mol). The mixture was stirred and heated to reflux (˜74° C.). At that point, sodium iodide (5 g, 0.03 mol) was added, and the mixture was boiled for 90 minutes. The mixture was then cooled and filtered with suction. The filter cake was rinsed with acetonitrile, then the solvent was removed under vacuum. The residue was treated with water (700 mL), and the mixture was extracted twice with 400 mL portions of hexane. The hexane was removed under vacuum, then the residue (˜36 g) was distilled under high vacuum. The distillate, collected at a head temperature of 84° C. (0.8 mm Hg) weighed 24 g (0.10 mol, 41% for the two steps). The product thus obtained has NMR characteristics consistent with the title compound and is greater than 95% pure by gas chromatography.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[N:35]1C=CC=C[CH:36]=1.N.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[C:36]([C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)#[N:35]
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Reactant: c1ccncc1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2C#N)CC1

Procedure:
To a mixture of 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (645 mg) and pyridine (3.87 mL) was added cuprous cyanide (219 mg), followed by heating and refluxing for 5 hours. Cuprous cyanide (328 mg) was further added thereto, followed by heating and refluxing for 15 hours. The reaction mixture was left to be cooled, and then a mixed solvent (10:1:0.1) of chloroform:methanol:28% aqueous ammonia was added thereto. A saturated aqueous sodium hydrogen carbonate solution was further added thereto, followed by stirring, and then the insoluble matter was separated by filtration. The filtrate was subjected to liquid separation, and then the organic phase was dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-20:1:0.1) to obtain 3-{[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (68 mg) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH2:7][CH2:8][N:9]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)NCCC2=CCCCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CC2=NCCC3=C2CCCC3)cc1
Yield: 105.7 %

Procedure:
27.3 g (0.1 mol) of N-[2-(cyclohexen-1-yl)ethyl]-p-methoxyphenylacetamide and 91.4 g (0.596 mol) of phosphorus oxychloride in 230 ml of toluene were heated to 100° C. under argon for 30 min. The mixture was then evaporated in a rotary evaporator, and the residue (46 g) was washed twice with 70 ml of petroleum ether and then dissolved in 270 ml of dichloromethane. The solution was added to 270 ml of a 12% strength aqueous ammonia solution at 0° C. with vigorous stirring. The organic phase was washed with 90 ml of water, dried over sodium sulfate and evaporated, giving 27.0 g of a viscous yellow-brown oil, which was used immediately for the hydrogenation.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Clc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Reaction time: 3.33 h
Yield: 134.7 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 76.9 g (0.220 mole) of 1,2-diphenyl4-p-chlorophenylbutane-1,4-dione, 100 ml of xylene and 45 g (0.101 mole) of phosphorus pentasulfide. The autoclave was cooled with a Dry Ice-acetone bath and charged with 120 g (3.52 moles) of hydrogen sulfide. The autoclave was heated with stirring for 200 minutes at 155°-178° C. (1000-2000 psig). The autoclave was cooled and the hydrogen sulfide allowed to escape into a sodium hydroxide solution. The residue was stirred with 150 ml of absolute ethanol. Filtration and drying gave a crude product of 61.2 g (80.2%) m.p. 115°-117°. Recrystallization from 190 ml of toluene and 625 ml of ethanol gave 47.2 g (61.9%) of pure 2,3-diphenyl-5-p-chlorophenylthiophene, m.p. 121°-122° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1CCCCC1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CCCCC1Oc1cc(Cl)ncn1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
In 6.7 ml of tetrahydrofuran was suspended 0.18 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.42 g of 2-methylcyclohexanol (cis:trans=3:7) was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.55 g of 4-chloro-6-(2-methylcyclohexyloxy)pyrimidine as a mixture of cis and trans forms.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[C:17]([Cl:23])[CH:16]=[CH:15]3)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:22][C:20]1[C:19]2[N:18]=[C:17]([Cl:23])[CH:16]=[CH:15][C:14]=2[C:13]2[CH:24]=[CH:25][C:10]([CH2:9][OH:8])=[CH:11][C:12]=2[N:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1nc2cc(CO)ccc2c2ccc(Cl)nc12

Procedure:
A solution of 8-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq.) and TBAF (1.1 eq.) in THF was stiffed at ambient temperature overnight. The reaction was quenched with saturated NaHCO3. The two phases were separated, and the aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give (5-amino-3-chlorobenzo[f][1,7]naphthyridin-8-yl)methanol as a white solid.