Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1)=[O:2].[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[OH:2][CH2:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1
Reactant: O=CCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
the aldehyde (19) (0.303 gm., 1 mmol) was dissolved in absolute ethanol (5 mL) and sodium borohydride (0.05 gm., 1 mmol) was added at room temperature. After stirring for 30 min. the mixture was poured into 10 mL brine and extracted with CH2Cl2 (3×10 mL). The extracts were dried over MgSO4 and evaporated to dryness to yield the desired alcohol (20) (0.264 gm., 0.86 mmol, 86%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([N+]([O-])=O)=[CH:6][C:7]([CH3:11])=[N+:8]([O-:10])[CH:9]=1.[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1>>[Br:3][C:4]1[C:5]([O:19][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:11])=[N+:8]([O-:10])[CH:9]=1
Reactant: OCC1CC1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCC2CC2)c(Br)c[n+]1[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Powdered NaOH (3 g, 75 mmol) was added to a suspension of 5-bromo-2-methyl-4-nitropyridine 1-oxide (11.7 g, 50 mmol; CAN 62516-08-9) in cyclopropylmethanol (89 g, 100 mL, 1.23 mol). The mixture was stirred for 4 h at 80° C. After evaporation to dryness ethyl acetate (400 mL) and water (400 mL) were added. The layers were separated and the aqueous phase was extracted four more times with ethyl acetate (250 mL). The combined extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to a volume of 100 mL and heptane (100 mL) was added dropwise under stirring. The precipitate was collected washed with ethyl acetate/heptane 1/2 (3×20 mL) and dried in vacuo to give the title compound (10.4 g, 80%) as light brown solid; LC-MS (UV peak area, m/z) 100%, 258.0125 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[C:18]1(C)C=CC=C[CH:19]=1>>[CH2:18]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([CH2:4][CH2:3][CH2:2][Br:1])=[CH:6][CH:7]=1)[CH3:19]
Reactant: O=C(O)c1ccc(CCCBr)cc1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(CCCBr)cc1

Procedure:
100 g 4-(3-Bromo-propyl)-benzoic acid (JACS 65, 2281 (1943) , 400 ml of toluene and 80 ml of thionyl chloride were refluxed for 4 hours. The solvent and the thionyl chloride in excess were removed under reduced pressure and after addition of 400 ml of absolute ethanol to the residue the mixture was heated for one hour to the boiling point. It was evaporated under reduced pressure, the residue was taken up in benzene and washed neutral with a saturated NaHCO3 -solution. The organic phase was distilled off after drying with MgSO4. Boiling point0.1 : 105° - 107° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[CH:17](=O)[CH3:18].C([BH3-])#N.[Na+]>>[CH2:17]([NH:7][CH:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:16])[CH3:18]
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCNC(Cc1ccc(O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 9, a reaction was carried out using DL-tyrosine ethyl ester hydrochloride (983 mg), acetaldehyde (0.26 ml) and sodium cyanoborohydride (100 mg) and the reaction mixture was treated to afford the desired compound (515 mg) as a syrup which was allowed to stand to give crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1C1OCCO1
Yield: 77.2 %

Procedure:
To a 3 neck round bottom flask, fitted with a Dean-Stark apparatus, was added 5-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), ethane-1,2-diol (4.12 ml, 73.9 mmol), and p-toluenesulfonic acid (424 mg, 2.46 mmol). The resulting mixture was placed under nitrogen, dissolved in anhydrous toluene (100 ml) and heated under reflux for 18 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 solution (30 ml), brine (30 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (95:5) as the eluent to give the title compound (4.69 g, 77%). The structure was confirmed by 1H NMR.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]1.O>CS(C)=O>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]1
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 93.6 %

Procedure:
To a stirred mixture of cyanogen bromide (4.05 g, 0.038 moles) and potassium carbonate (6.2 g, 0.045 moles) in dimethylsulfoxide (75 ml) was added dropwise a solution of 5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11.0 g, 0.036 moles) free base of Example 111(b) in hot dimethylsulfoxide (75 ml). The reaction was stirred at ambient temperature for 28 hours and then poured into water. The product was extracted (dichloromethane), dried (MgSO4) and concentrated to yield 10.8 g of an oil which crystallized upon standing. The product was recrystallized twice from isopropyl alcohol-ether and once from isopropyl alcohol which yielded 3.8 g (33%) of the 4-(5-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 137°-139° C.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:17]([C:22]([NH:24][C@H:25]([C:35]([NH:37][CH3:38])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([S:4][CH:5]([CH:17]([C:22]([NH:24][C@H:25]([C:35]([NH:37][CH3:38])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O

Procedure:
A solution of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E3; 300 mg, 0.55 mmol) in 4.5% formic acid/methanol (6 ml) was added, under nitrogen, to a stirred suspension of palladium black (310 mg) in the same solvent (15 ml). After 90 min the mixture was filtered through kieselguhr and evaporated in vacuo. Column chromatography using reverse phase silica (30 g) and eluting with 25% aqueous methanol gave two single diastereoisomers of the title compound, as monohydrates.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[S:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccc3[nH]c(=S)n(Cc4ccccc4)c3c2)c1

Procedure:
Prepared according to the procedure for Example 24 from 1-benzyl-6-(3-nitrophenyl)-1,3-dihydro-2H-benzimidazole-2-one (0.1 g, 0.29 mmol) and Lawesson's reagent (0.13 g, 0.32 mmol). A yellow solid (0.025 g, 24%): mp 244-245° C.; 1H-NMR (DMSO-d6) δ13.08 (s, 1H), 8.43 (s, 1H), 8.20 (dd, 1H, J=8.2, 1.7 Hz), 8.12 (d, 1H, J=7.8 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=8.3 Hz), 7.25-7.43 (m, 6H), 5.62 (s, 2H); MS (ESI) m/z 360 [M−H]−; Anal. Calc. For C20H15ClN2S.0.2H2O: C, 65.81; H, 4.25; N, 11.51. Found: C, 65.56; H, 4.11; N, 11.29.
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH:20]3[O:24][CH2:23][CH2:22][O:21]3)[C:14]=2[F:25])=[CH:9][N:8]=[CH:7]1)(=O)=O.Cl.O1CCO[CH2:30][CH2:29]1>O1CCCC1>[O:24]1[CH2:23][CH2:22][O:21][CH:20]1[C:15]1[C:14]([F:25])=[C:13]([N:12]([CH2:29][CH3:30])[CH2:11][C:10]2[NH:6][CH:7]=[N:8][CH:9]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C1COCCO1
Reactant: CN(C)S(=O)(=O)n1cncc1CNc1ccc(F)c(C2OCCO2)c1F
Agent: Cl
Solvent: C1CCOC1
Product: CCN(Cc1cnc[nH]1)c1ccc(F)c(C2OCCO2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a stirred solution of 5-[(3-[1,3]dioxolan-2-yl-2,4-difluoro-phenylamino)-methyl]-imidazole-1-sulfonic acid dimethylamide (0.53 g, 1.27 mmol) in tetrahydrofuran (10 ml) was added a 4 N solution of hydrogen chloride in dioxane (3.87 ml, 15.5 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was then concentrated in vacuo and the residue taken up in dichloromethane/methanol (95:5) and washed with 1 N aq. sodium hydroxide solution. The layers were separated and the aqueous phase was back extracted twice with dichloromethane/methanol (95:5). The combined organic phases were washed with saturated brine, then dried over magensium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a colourless gum (225 mg, 57%); MS (ISP): 310.3 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-hydroxy-2-methylbenzoic acid (5 g, 33 mmol) and concentrated sulfuric acid (3 mL) in methanol (300 mL) was stirred at reflux for 48 hours. The mixture was cooled to room temperature and the pH was adjusted to 7 using solid sodium bicarbonate. Some methanol was evaporated and residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 5.3 g, 32 mmol (97%) of methyl 3-hydroxy-2-methylbenzoate. 1H NMR (400 MHz, CDCl3): 7.41 (d, 1H), 7.13-7.09 (m, 1H), 6.94 (d, 1H), 3.89 (s, 3H), 2.46 (s, 3H). MS (EI) for C9H10O3: 167 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15]C[O:13]2)=[C:4](Cl)[N:3]=1.[OH-:19].[NH4+]>Cl>[OH:13][CH:12]([CH2:17][CH2:16][OH:15])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(CC3CCOCO3)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Product: Nc1nc2c(ncn2CC(O)CCO)c(=O)[nH]1

Procedure:
4-(2-amino-6-chloropurin-9-yl)methyl-1,3-dioxane (prepared according to Example 5) was dissolved in hydrochloric acid (1 mol/l) and refluxed for four hours. The solution was made alkaline with diluted ammonium hydroxide and evaporated to dryness at reduced pressure. The residue was dissolved in water and purified with preparative HPLC on a reversed phase column (μ Bondapack C18)eluted with a mixture of methanol and water (1:3). The product obtained was a white crystalline solid. M.p. 226°-8° C. (dec) (uncorrected) UV spectra (hydrochloric acid 0.01 mol/l): λmax (nm) 277, 254 (ε=10700).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[C:6]([C:8]2(Cl)[NH:13][C:12]([NH2:14])=[N:11][CH:10]=[CH:9]2)[CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: NC1=NC=CC(Cl)(c2cc(Br)ccc2OCc2ccc([N+](=O)[O-])cc2)N1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2OCc2ccc([N+](=O)[O-])cc2)n1
Yield: 82 %

Procedure:
Following the method described in Example 4, 6-[5-bromo-2-(4-nitro-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (82% yield) as its hydrochloride salt. 1H NMR (DMSO-d6) δ 5.42 (s, 2H, CH2), 6.55 (s, 1H, Ar), 7.29 (d, 1H, J=9.4 Hz, Ar), 7.45 (d, 2H, J=8.8 Hz, Ar), 7.72-7.84 (m, 6H, Ar), 8.24 (d, 2H, J=8.7 Hz, Ar).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][NH2:45]>C(O)(C)C.C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:45][CH3:44])[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(Cl)c34)c(F)n2)cn1
Reactant: CN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CNc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To tert-butyl N-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (85, 75 mg, 0.12 mmol) in Isopropyl alcohol (0.80 mL) was added 2M methylamine in THF (0.6 ml). The resulting solution was stirred at 40° C. for 6 hours. The reaction was concentrated to give product (86, 70 mg, 94.2%). MS (ESI) [M+H+]+=620.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)=[CH:4][C:3]=2[O:2]1.Cl.[CH3:24][OH:25]>>[OH:25][C:24]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)[CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11]1
Reactant: CO
Reactant: CCCOc1ccc2c(c1)CCC2c1ccc2c(c1)OCO2
Agent: Cl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Yield: 94 %

Procedure:
To a solution of (1RS, 3RS)-3-[(2-methoxymethoxy)-4-methoxyphenyl)]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.075 g, 0.16 mmol) in methanol (5 ml) was added 4-5 drops of 6M-HCl and the mixture refluxed for 1.5 h under argon. The solvent was removed in vacuo and the product partitioned between EtOAc and water. The organic extract was washed with water then sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous) filtration and evaporation gave the title compound (0.064 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH2:30]O)[CH2:25]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][N:24]([CH3:23])[CH2:25]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN1CCCC(CO)C1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Reaction time: 18 h
Yield: 32.5 %

Procedure:
1,1′-Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride 1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](OC(OCC)N(C)C)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:19][CH2:18][N:17]2[CH2:16][CH2:15][N:14]3[CH2:13][CH2:12][N:11]([CH:20]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCCNCCNCC2)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: c1ccccc1
Product: c1ccc(CN2CCN3CCN4CCN(CC2)C34)cc1
Yield: 96 %

Procedure:
A solution of 1-benzyl-1,4,7,10-tetraazacyclododecane (4 g; 0.015 mol) and dimethylformamide diethylacetal (6.88 g; 0.0467 mol) in benzene (40 ml) is heated at 80 C. and the azeotropic mixture ethanol-benzene is distilled away. When the conversion is ended, the solvent is evaporated under reduced pressure and the final product is obtained as a yellow oil (4.0 g). Yield 96%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]#[CH:23])[CH2:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]#[C:23][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccn1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C(#Cc1ccccn1)CCN1CC=C(c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A solution of 2-bromopyridine (0.99 mL, 0.01 mol) and the alkyne prepared in Example 9, Step (a) (2.0 g, 0.0095 mol) in 20 mL of piperidine is degassed by bubbling in dry nitrogen for 15 minutes, and 0.03 g (1.4×10-4 mol) of palladium (II) acetate and 0.07 g, (2.8×10-4) of triphenylphosphine are added. The flask is flushed with nitrogen and the mixture is heated at 80° C. for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extraced with 25 mL of dichloromethane and the combined organic layers are washed with 25 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound; mp 87.5°-88.5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:6])[CH2:5][CH2:4]1.ClCCl.CS(O[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][S:20][C:21]=1[CH2:22]OS(C)(=O)=O)(=O)=O>O>[CH3:2][C:3]1([N:6]2[CH2:15][CH2:16][C:17]3[N:18]=[CH:19][S:20][C:21]=3[CH2:22]2)[CH2:5][CH2:4]1
Reactant: CC1(N)CC1
Reactant: CS(=O)(=O)OCCc1ncsc1COS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1(N2CCc3ncsc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p. 1815) (1.89 g) was added to dichloromethane (20 ml) containing 4-(2-methane-sulfonyloxyethyl)-5-methanesulfonyloxymethylthiazole (4.46 g) under ice cooling, and the mixture was stirred overnight at room temperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) was additionally added, and the mixture was stirred for 20 hours at room temperature and 5 hours under refluxing. Dichloromethane and water were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:49) to obtain the title compound (944 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccc(Cl)c(Cl)c4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccc(Cl)c(Cl)c4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 168 from 2-chloro-8-(3,4-dichlorobenzyl-amino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 259°-261° C.) and piperazine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([Cl:15])=[N:5][OH:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cc(C(F)(F)F)ccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 643 mg (3.10 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde oxime in 5 mL of dimethyl formamide (DMF) was added 456 mg (3.41 mmol) of N-chlorosuccinimide (see K.-C. Liu, B. R. Shelton, and R. K. Howe, J. Org. Chem. 1980, 45, 3916). The reaction mixture was stirred at room temperature overnight, and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation to give 675 mg (2.79 mmol) of pure white crystalline 2-fluoro-5-trifluoromethyl-N-hydroxybenzene-carboximidoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[NH:6][C:5]([CH3:9])=[N:4][S:3]1(=[O:11])=[O:10].P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:7]1[N:2]([CH3:1])[S:3](=[O:11])(=[O:10])[N:4]=[C:5]([CH3:9])[N:6]=1
Reactant: CC1=NS(=O)(=O)N(C)C(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Yield: 100 %

Procedure:
212 parts of 2,5-dimethyl-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide were introduced into a stirred mixture of 292 parts of phosphorus pentachloride and 1,400 parts of phosphorus oxychloride at room temperature, and the mixture was heated to 110° C. in the course of 30 minutes. The reaction mixture was stirred under reflux for 6 hours and thereafter concentrated under reduced pressure, giving 234 parts (100% of theory) of 3-chloro-2,5-dimethyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of: melting point 86°-90° C. (Compound No. 1) (NMR (60 MHz, CDCl3): CH3 -C 2.4δ, CH3 -N 3.68δ).