Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:5]([O:4][C:2]([NH:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1(C(=O)O)CCCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of benzyl chloroformate (0.290 g, 1.1 mmol) in dioxane (2.5 cm3) was added dropwise to a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.2 g, 1.54 mmol) and sodium carbonate (0.490 g, 4.64 mmol) in water (5 cm3) at 0° C. Stirring was continued at room temperature overnight and the reaction mixture washed with ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (Na2SO4), filtered and the solvent removed to afford carbamate 21 (0.253 g, 62%) as an oil which solidified on standing. Carbamate 21 was shown to be a 70:30 mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the resonances at δ 5.31 and 7.29-7.40, assigned to the N—H protons of the major and minor conformers, respectively): mp 70-80° C. (lit.1 82-86° C., ethyl acetate, petroleum ether); δH (400 MHz; CDCl3; Me4Si) 1.83 (4H, br s, 2× cyclopentyl-H2), 2.04 (2H, br s, cyclopentyl-H2), 2.20-2.40 (2H, m, cyclopentyl-H2), 5.13 (2H, br s, OCH2Ph), 5.31 (0.7H, br s, N—H) and 7.29-7.40 (5.3H, m, Ph and N—H*); δC (100 MHz; CDCl3) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH2, OCH2Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO2) and 179.5 (quat., CO2H). * denotes resonance assigned to minor conformer.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].O>CC(CC)=O>[C:20]([C:19]1([C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:10][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[CH:5]=2)[CH2:2]1)(=[O:21])[CH3:22]
Reactant: Fc1ccc(CBr)c(CBr)c1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)C1(C(=O)OCc2ccccc2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.9 %

Procedure:
To 5 g of 1,2-bis-(bromomethyl)-4-fluoro-benzene in 100 ml of methylethylketone were added 14.7 g of potassium carbonate followed by 4.1 g of benzyl acetoacetate. The mixture was stirred for 16 h at ambient temperature. 100 ml of water were added. The phases were separated and the aqueous phase was extracted once with 50 ml of methylethylketone. The combined organic phases were evaporated to give 6.2 g of crude product as an oil. The crude product was crystallized from cold heptane and from cold methanol. Melt.p. 55° C. 1HNMR: δ=2.16 ppm (s, 3H); 3.50 ppm (AB, 2H); 3.53 ppm (AB, 2H); 5.22 (s, 2H); 6.88 ppm (m, 2H); 7.12 ppm (dd, 1H) 7.30-7.42 ppm (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][N:6]=[CH:5]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:14]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[N:6]1)(=[O:16])[CH3:15]
Reactant: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)n1ncc2cc(C)c([N+](=O)[O-])cc21
Reaction time: 15 h
Yield: 75 %

Procedure:
Five g (28,2 m-mol) of 5-methyl-6-nitro-1H-indazole (formula 24) prepared e.g. according to the method described by E. Nolting, Ber. Dtsch. Chem. Ges. 37 (1904) 2556 were added to a mixture of acetic acid (50 ml) and acetic anhydride (100 ml). After about 15 min the acetylated compound (formula 25) crystallized from the light-yellow colored solution in the form of elongated colorless needles. To complete crystallization, the solution was left to stand for a period of 45 min at room temperature and for a period of 15 hours in a refrigerator (4°). The crystal mass formed was filtered under suction, washed well with water and dried over P2O5 under vacuum. This yielded 4.6 g (yield 75%) of the formula 25 target product. By careful evaporation of the mother liquor and allowing to stand overnight in the refrigerator, an additional portion (0.90 g) of the target product was obtained. Total yield was 5.55 g (90%). The target product melts at 185°; ir (KBr): 1715 (ester carbonyl), 1582 (aromatic), 1530 cm-1 (NO2); pmr (CDCl3): δ 2.66 (s, 3, C5 --CH3), 2.82 (s, 3, N1 --CH3CO), 7.70 (s, 1, H4), 8.18 (s, 1, H7), 8.96 (s, 1, H3); ms (70 eV): m/e 219 (35%, M+), 177 (61%, M+ -keten), 160 (100%, M+ -keten-HO).
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]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[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]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 76.2 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example S-2, 0.18 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.15 g of the title compound as a solid, mp 183-185° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH2:18][CH2:17][CH:16]1[CH:15]([OH:20])[N:14]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:13]2=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCN1C(=O)C2CCCC(C1=O)N2C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CCN1C(=O)C2CCCC(C1O)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
3-[2-(2-Methoxy-phenyl)-ethyl]-2,4-dioxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 8, 0.77g, 1.82 mmol) was dissolved in methanol (18 mL). The mixture was cooled to 0° C., and NaBH4 (0.14 g, 3.64 mmol) was added in portions from the top. The reaction was stirred for 10 minutes and then carefully quenched with water. MeOH was removed under reduced pressure, and the residue was extracted with EtOAc. The combined organic layers were washed with 10% citric acid (5 mL), water (5 mL), saturated NaHCO3 (5 mL), and brine (5 mL), and finally passed over a short plug of Na2SO4. The solvents were evaporated to give Compound 9 (0.65 g, 83%, mixture of isomers) as a clear oil, which was of sufficiently good quality to be advanced to the next step without further purification. Rf=0.5 (50% EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]C2)[CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:57][CH2:58][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:60][CH2:61]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCN(CCOC2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCC2)CC1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMF (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-(2-(pyrrolidin-1-yl)ethoxy)piperidine (109) (0.133 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.287 g, 89% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.65-1.81 (6H, m), 1.87-1.96 (3H, m), 2.53-2.61 (3H, m), 2.65-2.72 (2H, m), 3.04-3.14 (1H, m), 3.38-3.57 (3H, m), 3.61 (2H, t), 3.97-4.06 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.21-7.33 (2H, m), 7.68-7.80 (3H, m), 8.43-8.48 (1H, m), 9.85-9.95 (1H, m); m/z (LC-MS, ESI+), RT=1.88 (M+H 479.5).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]=[C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH:11]=[CH:10]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:11]2[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9](=[O:8])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C1C=CCCc2ccccc21
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(C2CCc3ccccc3C(=O)C2)CC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A solution of 8 g of N-methylpiperazine in 80 ml of ethanol was added over 5 minutes to a solution of 6.32 g of 5-oxo-8,9-dihydro [5H] benzocycloheptene in 40 ml of ethanol and the mixture was stirred for 4 hours at 20° C and was then evaporated to dryness. The residue was taken up in 0.5 N hydrochloric acid and the solution was washed with ethyl acetate and made alkaline with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride and the extracts were dried and evaporated to dryness to obtain 8.8 g of 7-(4-methylpiperazin-1-yl)-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[C:15][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)[CH:8]=2)[O:3]1
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)cc1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
Nitrogen was bubbled for 15 min through a solution of 200 (0.877 mmol) of 2,2,4,4,7-pentamethyl-6-ethynylchroman (Compound 9) and 245.3 mg (0.888 mmol) of ethyl 4-iodobenzonate (Compound 97) in 2 ml of triethylamine. The mixture was then placed under an argon atmosphere and treated with a finely ground mixture of 50 mg (0.2625 mmol) of cuprous iodide and 100 mg (0.1425 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction vessel was then fitted with a reflux condenser and the mixture was heated at 55 degrees C. under argon for 72 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica, 5% ethyl acetate in hexane) to give the title compound as a yellow oil. PMR (CDCl3) : & 1.32 (12H, s), 1.37 (3H, t, J~7.0 Hz), 1.80 (2H, s) 2.40 (3H, s), 4.36 (2H, q, J~7.0 Hz), 6.66 (1H, s, 7.42 (1H, s), 7.54 (2H, d, J~8.6 Hz), 7.99 (2H, d, J~8.6 Hz). MS exact mass, m/e 376.2 038 (calcd. for C25H28O3, 376 2038).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])=O>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)cc3Cl)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 72 mg (0.269 mmol) of 2-bromo-1-(2,4-dichlorophenyl)ethanone were reacted according to the General Method 3. Yield: 43 mg (34% of theory)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[F:21][C:16]([F:22])([C:17]([F:18])([F:19])[F:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: FC(F)(F)C(F)(F)CCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: OCCCCCCCC(F)(F)C(F)(F)F
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
16 g of 1-benzyloxy-8,8,9,9,9-pentafluoro-nonane is dissolved in 700 ml of absolute methylene chloride, mixed with 18.4 ml of N,N-dimethylaniline at 0° C. and stirred for 5 minutes. Then, 26.4 g of aluminum trichloride is added in portions, and the reaction mixture is heated for 45 minutes to 50° C. For working-up, the batch is allowed to come to room temperature, it is stirred into 2N hydrochloric acid, extracted 3 times with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. 8.6 g of 8,8,9,9,9-pentafluoro-nonan-1-ol is obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21]S(C4C=CC(C)=CC=4)(=O)=O)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.O[CH2:33][C:34]1[N:38]=[CH:37][N:36]([CH3:39])[N:35]=1>>[CH3:1][O:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:33][C:34]4[N:38]=[CH:37][N:36]([CH3:39])[N:35]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: Cn1cnc(CO)n1
Reactant: COc1cc(-c2nnc3c4ccccc4c(OS(=O)(=O)c4ccc(C)cc4)nn23)no1
Product: COc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)no1

Procedure:
The title-compound was prepared from 3-(5-methoxyisoxazol-3-yl)-6-(4-toluenesulphonyloxy)-1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 118 part a) and 3-hydroxymethyl-1-methyl-1,2,4-triazole (prepared using the conditions of Itoh and Okongi, EP-A-421210) using the conditions given for in Example 98, 1H NMR (360 MHz, CDCl3) δ 3.96 (3H, s, CH3), 4.15 (3H, s, CH3), 5.72 (2H, s, CH2), 6.30 (1H, s, Ar—H), 7.79 (1H, m, Ar—H), 7.95 (1H, m, Ar—H), 8.07 (1H, s, Ar—H), 8.28 (1H, d, J=8.4 Hz, Ar—H), 8.68 (1H, d, J=8.4 Hz, Ar—H); MS (ES30) m/e 379 [MH]+; Anal. Found. C, 53.97; H, 3.73; N, 29.62. C17H14N8O3 requires C, 54.04; H, 3.48; N, 29.32%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(Cl)cc1

Procedure:
A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 189 g (1.2 mole) of 1-bromo-3-chloropropane, 249 g (1.8 mole) of anhydrous potassium carbonate, and 600 ml of acetone was stirred vigorously and heated to reflux for 16 hr under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration, and the acetone and excess bromochloropropane were removed by heating under reduced pressure. The residue was dissolved in petroleum ether, and the resulting solution was cooled in an ice-isopropyl alcohol bath to produce a white solid. The solid was collected by filtration and washed with cold petroleum ether. The filtrate was concentrated and cooled to yield two more crops of white crystals. The combined solids were dried under vacuum at ambient temperature to yield 107 g (87%) of white, flaky solid, m.p. 35°-36° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH3:18]
Reactant: CCI
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (5.0 g) in DMF (30 mL) was added potassium carbonate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of the title compound as a crude product, that was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:29][C:30](=[O:77])[C:31]1[CH:36]=[CH:35][C:34]([NH:37]C2CCCCC2)=[C:33]([NH:44][C:45](C2C=C3C(=CC=2)N=C(C2C(C4C=CC(Cl)=CC=4)=CC=C(C(N4CCCC4)=O)C=2)C=C3)=O)[CH:32]=1)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:45]5[NH:37][C:34]6[CH:35]=[CH:36][C:31]([C:30]([OH:29])=[O:77])=[CH:32][C:33]=6[N:44]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Reactant: O=C(O)c1ccc2nc(-c3ccccc3-c3ccc(Cl)cc3)ccc2c1
Product: O=C(O)c1ccc2[nH]c(-c3ccc4nc(-c5ccccc5-c5ccc(Cl)cc5)ccc4c3)nc2c1

Procedure:
The title compound was synthesized from Compound 353b in two steps as described for Compound 25 and 27 Q=ethyl, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2cc(C)sc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A solution of 3.7 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-methylbenzo[b]thiophene in 20 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 5 min. to form a clear solution. After stirring at room temperature for 1 hour, the solution is poured into an ice-cold solution of 10% sodium hydroxide. The organic materials are extracted 3 times with ether, dried and concentrated under vacuum. The reddish brown residue is purified by dissolving it in ether and passing it through an alumina column packed with ether. Elution with ether gives 2.1 g of 6,7-dichloro-5-methoxy-2-methylbenzo[b]thiophene as off-white crystals, mp. 113°-114°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[OH-].[Na+].Br[CH:20]([CH3:22])[CH3:21]>CC(C)=O>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][CH:20]([CH3:22])[CH3:21])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 8.4 mmole) in acetone (20 ml) was added sodium hydroxide (0.71 g, 17.6 mmole). After the sodium hydroxide had reacted, 2-bromopropane (1.08 g, 8.8 mmole) was added, and the reaction mixture was stirred for two hours. The mixture was concentrated in vacuo to an oil that was dissolved in diethyl ether (50 ml), washed with water (30 ml in two portions), dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. Chromatography on silica gel and recrystallization from aqueous methanol gave the title compound, m.p. 80°-82°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)(C)C>[Cl:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]([NH:14][NH2:15])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1cc(C(F)(F)F)c(Cl)cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.63 mmol) in isopropanol (20 mL) was added hydrazine monohydrate (2.021 mL, 41.7 mmol). The mixture was stirred at 70° C. for 16 h. The reaction was concentrated. The residue was taken up in ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated to give the title compound as a tan solid (0.94 g). LCMS m/z=212.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39 (s, 2H), 7.11 (s, 1H), 8.19 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([C:27]#[N:28])=[CH:16][N:15]=2)=[N:6]1.S(=O)(=O)(O)[OH:34]>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([C:27]([NH2:28])=[O:34])=[CH:16][N:15]=2)=[N:6]1
Reactant: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 5 °C
Reaction time: 24 h

Procedure:
20.7 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-carbonitrile (31-1, 0.049 mmol, 1 eq.) were added to ice bath cooled conc. sulfuric acid (1.84 mmol, 37.5 eq.) and stirred for five minutes at 5° C. and further 24 hours at room temperature. Ice was added to the suspension. The suspension was filtered off, washed with water and the filter cake was dried under vacuo at 50° C. to yield 23.0 mg (0.05 mmol, 106%) of the analytically pure target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][S:13][CH3:14]>CN(C)C=O>[CH3:12][S:13][CH2:14][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc([N+](=O)[O-])n1
Yield: 67.1 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 50 mg, 4.42 mmol) in anhydrous N,N-dimethylformamide (5 mL), a 60% dispersion of sodium hydride in mineral oil (230 mg, 5.75 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, chloro-methylsulfanyl-methane (555 mg, 5.75 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-methylsulfanylmethyl-3-nitro-1H-pyrazole (514 mg, 67%) as a white solid.