Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[F:33][C:34]([F:38])([F:37])[CH2:35]I.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][N:30]([CH2:35][C:34]([F:38])([F:37])[F:33])[CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1
Reactant: FC(F)(F)CI
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCNCC6)cc5c4)n3c2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCN(CC(F)(F)F)CC6)cc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 21.2 %

Procedure:
A suspension of 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline (Example 27—see in Table below) (12 mg, 0.027 mmol), 1,1,1-trifluoro-2-iodoethane (56.9 mg, 0.271 mmol) and DIPEA (17.5 mg, 0.136 mmol) in DMF (1 mL) was sealed in a microwave vial and heated at 120° C. for 6 hours. The solvent was removed and the residue was purified by prep-HPLC to give the title compound as yellow solid (3 mg, yield 20%). [Method 1C]
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:33][CH2:34][CH3:35])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([O:22][CH2:23][CH2:24][CH2:25][O:26][PH:27]([C:29]([O:31][OH:32])=[O:30])=[O:28])[CH3:21])=[CH:4][CH:3]=1.[CH3:36]OC(P(Cl)(Cl)=O)=O.[OH-].[Na+]>>[CH:5]1([CH:8]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([O:22][CH2:23][CH2:24][CH2:25][O:26][PH:27]([C:29]([O:31][OH:32])=[O:30])=[O:28])[CH3:21])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)P(=O)(Cl)Cl
Reactant: CCCC(CCSCCCCCCCCC(C)OCCCO[PH](=O)C(=O)OO)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CCSCCCCCCCCC(C)OCCCO[PH](=O)C(=O)OO)C1CCCCC1
Yield: 71 %

Procedure:
1.70 g (81%) R,S-((3-(12-cyclohexyldodecylthio)-2-decyloxy)-propoxy)-hydroxy-phosphinyl-formic acid methyl ester (example 12.28) was obtained analogously to example 1 as a colourless oil from 0.55 g (3.10 mmol) 16 and 1.50 g (3.10 mmol) R,S-2-decyloxy-3-(12-cyclohexyldodecylthio)-1-propanol. Saponification of 1.50 g of this ester with sodium hydroxide solution (example 1) yielded 1.10 g (71%) 8 with a melting point of 105-107° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](=O)[CH2:23]Br)=[CH:20][CH:19]=1)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:23]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Product: CCOC(=O)c1cccc(-c2nc(-c3ccc(OCC)cc3)cs2)c1
Yield: 59 %

Procedure:
In the same manner as in Example 74, ethyl 3-thiocarbamoylbenzoate was reacted with 4-ethoxyphenacyl bromide to obtain ethyl 3-[4-(4-ethoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 59%. Pale yellow prisms. Melting point: 108 to 110° C.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[N:29][C:30]2[N:31]([N:33]=[C:34]([SH:36])[N:35]=2)[CH:32]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:30]4[N:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1cnc2nc(S)nn2c1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4ncc(C)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:26])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:7][C:8]1[C:9](=[O:26])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([OH:23])=[O:22])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2c(OCC(=O)OCC)cccc2oc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCOc1c(O)c2c(OCC(=O)O)cccc2oc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
25 ml of ethanol was added to 3.64 g (0.01 mol) of 3-hexyloxy-4-hydroxy-5-ethoxycarbonylmethoxy-2H-1-benzopyran-2-one, and 25 ml of an aqueous 1 mol/L sodium hydroxide solution was added under ice cooling, followed by continuous stirring at room temperature for 4 hours. The reaction solution was added to 26 ml of hydrochloric acid having a concentration of 1 mol/L, and after extracting twice with 50 ml of ethyl acetate, the extract was dried over magnesium sulfate. After filtering the ethyl acetate solution, the filtrate was concentrated under reduced pressure, and the resulting crude product was recrystallized from methanol to obtain 2.4 g of the titled compound (yield: 74%)
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[Br:16][C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:14]=1[Br:15]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 500 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCO)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g), 3-(4-hydroxyphenyl)propanol (2.50 g), potassium carbonate (3.40 g) and N,N-dimethylformamide (25 ml) was stirred for 14 hours at 60° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (4.46 g, yield 84%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 70-71° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[H][H]>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Yield: 98.9 %

Procedure:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (0.80 g, 2.070 mmol) was dissolved in EtOAc (120 ml) and hydrogenated using a flow hydrogenation apparatus (H Cube™, settings: full hydrogen, atmospheric pressure, 1 ml/min flow rate). The eluant was evaporated in vacuo to give the title compound as an orange gum (0.73 g, 99%). LCMS (formate) Rt 0.73 min, MH+ 357.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([OH:21])[CH2:19][CH3:20]>>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([O:21][CH2:18][CH2:19][CH3:20])=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1C=CCCC1
Reactant: CCCO
Product: CCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 2.4 g. (9.2 mmoles) of 2-chloro-9-(2-cyclohexenyl)-9H-adenine in 60 ml. of 1 N sodium n-propoxide in n-propanol was heated at reflux overnight under a nitrogen atmosphere. The reaction mixture was poured into ice-water containing sufficient acetic acid to neutralize the excess alkoxide. The mixture was evaporated in vacuo. The residue was dissolved into CHCl3 with stirring. The CHCl3 extracts were washed with water, dried with Na2SO4 and evaporated to give 2.35 g. (90%) of title product; m.p. 157°-159° C. IR(KBr): 3450, 3110, 1630, 1585, 1470, 1390, 1335 cm-1. UV: λmaxMeOH 266 nm (ε 13200). NMR(CDCl3): δ 1.03 (3H, t, 7 Hz), 1.80(8H, m). 4.15(2H, t, J=7 Hz), 5.03 (2H, m), 5.88(1H, m), 6.56(2H, m), 7.4(1H, s).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)cc1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: Cc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-methylbenzylamine (0.5 ml) as described above; yield: 0.071 g (24.6%);
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:29][O:30][CH3:31])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide (12.0 g, 35.0 mmol) and K2CO3 (24.0 g, 170 mmol) in 80 mL anhydrous THF was added chloromethyl methyl ether (4.0 mL, 52.7 mmol). The resultant heterogeneous solution was stirred for 60 minutes at ambient temperature and the solids were subsequently removed via filtration. The filtrate was then removed in vacuo and the residue was dissolved in EtOAc. The organics were washed with saturated Na2CO3, dried over MgSO4, and evaporated in vacuo to generate a brownish oil. The oil was finally triturated with hexanes and the resultant solid filtered to produce the desired product as a light yellowish solid (11.5 g, 86% yield): MS (ES) M+H expected 447.0, found 447.0.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1.[Mg].[Cl-].[NH4+]>CCOCC.C1COCC1>[F:15][C:10]1[CH:9]=[C:8]([CH:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCCC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(O)c1cc(F)cc(F)c1
Yield: 116 %

Procedure:
A solution of pentanal (19.0 g, 0.22 mol) in dry ether (75 ml) was added dropwise to a stirred solution of the Grignard reagent at room temperature, under dry nitrogen, prepared from 1-bromo-3,5-difluorobenzene (50.2 g, 0.26 mol) and magnesium (7.25 g, 0.30 mol) in dry THF (100 ml). The stirred mixture was heated under reflux for 2 h, cooled and a saturated solution of ammonium chloride (300 ml) was added. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a pale-orange liquid (51.1 g) which was distilled to yield a colourless liquid. Smaller quantities of crude product were purified by column chromatography (silica gel/dichloromethane) to yield a colourless liquid (92%).
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([CH:16]=O)[C:13]=2[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:19]O>C(O)=O>[C:16]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])#[N:19]
Reactant: COc1c(C=O)cc(C(=O)O)cc1C1CCC1
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C1CCC1
Yield: 89.4 %

Procedure:
3-cyclobutyl-5-formyl-4-methoxybenzoic acid (458 mg) was dissolved in formic acid (2.5 mL), and hydroxylamine hydrochloride (163 mg) was added to the solution, and then the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (404 mg) as a brown solid.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[C:1]1([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc2ccccc12
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 1-naphthylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.25 (s, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.98 (d, 1H, J=7.5 Hz), 7.84-7.89 (m, 2H), 7.45-7.62 (m, 5H), 5.03 (s, 2H). [M+H] calc'd for C17H14N2O2, 279; found 279.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[N:12](O)=[O:13]>>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2)=[O:13]
Reactant: O=NO
Reactant: Oc1cccc2ccncc12
Product: O=Nc1ccc(O)c2cnccc12

Procedure:
The 8-hydroxyisoquinoline is reacted with nitrous acid to form 5-nitroso-8-hydroxyisoquinoline. The nitrous acid is generated in situ by the action of mineral acid, such as hydrochloric, sulfuric, and the like, on sodium nitrite usually under cold temperature conditions.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:10]=1.[H-].[Na+]>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:14]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(O)CN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 41 step i) using 1-dimethylamino-2-propanol (80 mg), 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1 step ii) (0.25 g) and 60% sodium hydride (30 mg) in THF (2 mL) at room temperature for 2 d to give the subtitle compound as a pale yellow gum. Yield: 0.29 g.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOCCSc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCSc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-carbaldehyde (0.97 g, 3.10 mmol) in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL) was added sodium borohydride (0.07 g, 1.59 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. The reaction solution was concentrated under reduced pressure, the residue was diluted with ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=5/1) to give the title compound (0.94 g, yield 96%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17]([OH:19])=O)[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Br.Br.[S:23]1[C:27]2[CH2:28][CH:29]([NH2:32])[CH2:30][CH2:31][C:26]=2[N:25]=[C:24]1[NH2:33]>>[NH2:33][C:24]1[S:23][C:27]2[CH2:28][CH:29]([NH:32][C:17](=[O:19])[CH2:16][N:11]3[C:12]([CH3:15])=[CH:13][CH:14]=[C:9]([NH:8][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])[C:10]3=[O:20])[CH2:30][CH2:31][C:26]=2[N:25]=1
Reactant: CCCCS(=O)(=O)Nc1ccc(C)n(CC(=O)O)c1=O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: CCCCS(=O)(=O)Nc1ccc(C)n(CC(=O)NC2CCc3nc(N)sc3C2)c1=O

Procedure:
The title compound was prepared from 2-[3-[(butylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6). The product was recrystallized from methanol to give a pale brown solid compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>CO>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:15][N+:16]([O-:18])=[O:17])=[NH:19]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CO
Product: Cc1nc[nH]c1CSCCNC(=N)N[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.7 g.) and S-methyl-N-nitroisothiourea (1.45 g.) in methanol (35 ml.) was heated at 50°-60° for 2.5 hours and then set aside at room temperature for 48 hours. The crystalline product was filtered off and recrystallised from methanol to give N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-nitroguanidine, m.p. 184°-186°. (Found: C, 37.5; H, 5.7: N, 32.5; S, 12.5. C8H14N6O2S requires: C, 37.2; H, 5.5; N, 32.5; S, 12.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:28]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)cc(OCC=C(C)C)c1OC
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OCC=C(C)C)c1
Yield: 157.4 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy-5-prenyloxybenzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.39 g), thereby yielding 1.78 g(69%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10](=[O:27])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10](=[O:27])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][OH:22]
Reactant: O=Cc1ccccc1-c1cccc2c(-c3c(Cl)cccc3Cl)c(=O)ccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccn2c(-c3ccccc3CO)cccc2c1-c1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 2-[1-(2,6-dichlorophenyl)-2-oxo-2H-quinolizin-6-yl]benzaldehyde (Example 4, 8 mg) in methanol was added sodium borohydride (2 mg) at 0° C. and stirred for ½ hr. The mixture was concentrated and purified by silica gel (methylene chloride/acetone=1/2) to give the title compound (4 mg).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Reaction time: 0.5 h

Procedure:
A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151°; NMR δ (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 11H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z (−) 268 (M+), 266, 196, 194.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)([OH:8])[CH2:4][O:3]1>C(O)(C(F)(F)F)=O.CCO.[Pd]>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:5]([OH:8])([CH2:6][OH:7])[CH2:4][OH:3])=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCc1ccc(C#CC2(O)COC(C)(C)OC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(CCC(O)(CO)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A mixture of the product of Step B (0.03 g; 0.087 mmol) and 10% Pd/C (0.05 g) in 5% TFA in EtOH (10 ml) was stirred for 1 h under H2 (balloon) at room temperature, then filtered through a pad of Celite, washed with CH2Cl2 (2×10 ml). To combined filtrates were evaporated to dryness under reduced pressure and dried in vacuo for 1 h to give title compound (0.027 g; 99%) as a colourless solid. 1H-NMR (CDCl3) 7.05 (s, 4H); 3.66 (broad m, 7H); 2.61 (m, 2H); 2.51 (t, 2H, J=7.92 Hz); 1.73 (m 2H); 1.55 (t, 3H, J=6.93 Hz); 1.26 (m, 10H); 0.87 (t, 3H, J=6.93 Hz).