Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:26].[K+]>O>[O:26]=[C:12]1[C:13]2[CH:1]=[C:2]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
4-(2-Fluorenyl)-butan-2-one (4.72grams) was dissolvedin a mixture of 60 ml of pyridine and 5 ml of water, the mixture was heated at 60° C., and stirred. Potassium permanganate (6.8 grams) was added thereto little by little during 2 hours. When the addition was finished, the mixture was stirred for 2 hours more. The reaction solution was filtered, the filtrate was concentrated, and the resulting residue was dissolved in chlroform, the solution was washed with in the order of 10% hydrochloric acid, water, saturated sodium bicarbonate, and water, then dried with magensium sulfate, the solvent was evaporated therefrom, and the residue was recrystallized from ethanol to give 1.3 grams of 4-(9-oxo-2fluorenyl)-butan-2-one, yellow crystals, m.p. 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1
Reactant: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(Cl)c21
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(N3CCOCC3)c21
Temperature: 50 °C

Procedure:
2,4-Dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (20 mg, 0.066 mmol), triethylamine (18.44 μL, 0.132 mmol) and morpholine (5.75 μL, 0.066 mmol) were mixed in dichloromethane at room temperature and stirred over the weekend at 50° C. The solvent was removed in vacuo to give crude 2-chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] Found 354.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]O)[CH2:24][CH2:23]1.Cl.C(O)CCO>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH:25]([CH:28]=[CH:29][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[CH2:26][CH2:27]1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: OCCC1CCC(CCC2OCCCO2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: OCCCO
Product: Fc1cc(C=CC2CCC(CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A Grignard reagent prepared from 3-fluoro-4-trifluoromethoxybromobenzene (9.3 g, 38.7 mmol) and dried Mg (0.97 g 39.9 mmol) in a 50 ml ether solvent, was cooled down 0° C., followed by dropwise adding thereto, a 40 ml ether solution of the above 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol (6.3 g, 26.2 mmol), heating the mixture up to room temperature, stirring it for 3 hours, adding this reaction solution to 6N HCl (100 ml), extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over MgSO4, distilling off the solvent, adding toluene (150 ml) and Amberlist (3.0 g) to the residue, refluxing for 5 hours, while removing water formed by the reaction by means of Dean-Stark, adding trimethylene glycol (1.0 g, 13.1 mmol), further refluxing for one hour, filtering off Amberlist, distilling off the solvent, purifying the residue according to column chromatography treatment using ethyl acetate/toluene (1/2) as a developing solvent, on silica gel, and distilling off the solvent, to isolate 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene (5.5 g, 13.7 mmol). The yield of this product from 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol was 52.3%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCBr
Reactant: O=Cc1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc2cc(C=O)cnc2c1
Temperature: 60 °C
Yield: 30 %

Procedure:
To a solution of 7-hydroxyquinoline-3-carbaldehyde (1.3 g, 7.5 mmol) in DMF (30 mL) was added 1-bromo-heptane (5.37 g, 30 mmol, 4 eq.) and K2CO3 (2.0 g, 15 mmol, 2 eq.). The mixture was warmed to 60° C. over 3 h. Then, the reaction mixture was diluted (water), extracted (ethyl acetate), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (pet. ether:ethyl acetate, 10:1) to give 7-(heptyloxy)quinoline-3-carbaldehyde as yellow solid (610 mg, yield 30%). ESI-MS: 272 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N+:12]([O-:14])=[O:13])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1NCCCCl
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
A mixture of 43 parts of N-(3-chloropropyl)-2-nitrobenzenamine 47.8 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 30.3 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100° C. The reaction mixture is cooled and poured onto 1500 parts of water. The precipitated product is filtered off, washed with water and with 2,2'-oxybispropane and dried, yielding 64 parts (78.3%) of 5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one; mp. 220° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1>CCN(C(C)C)C(C)C.O>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:11][CH2:12]1
Reactant: OC1CCNCC1
Reactant: Cn1nc(Cl)ccc1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(N2CCC(O)CC2)ccc1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a slurry of 6-chloro-2-methylpyridazin-3(2H)-one (1 g, 6.94 mmol) in DIPEA (20 mL) was added piperidin-4-ol (0.84 g, 8.33 mmol) and the reaction mixture was stirred at 120° C. overnight. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3×30 mL) to remove impurities. The aqueous phase was concentrated to dryness to afford the title compound as a yellow solid (1.2 g, 83%). [LCMS: Rt=1.07 min, m/z 210.1 (M+H)+].
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 50.2 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 109 mg, 0.63 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.60 mmol), DIPEA (0.386 mL, 2.22 mmol) and DMA (4 mL) was sealed into a microwave tube and heated to 140° C. for 1 h in the microwave reactor. After cooling, to r.t., the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then the desired product was eluted from the column using 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give an orange gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (140 mg, 50%) as an orange solid; 1H NMR (CDCl3): 1.90-1.98 (2H, m), 2.05-2.12 (2H, m), 2.20 (6H, s), 3.15-3.23 (1H, m), 3.28 (2H, t), 3.69 (2H, dd), 3.96 (3H, s), 4.18 (4H, dt), 6.03 (1H, s), 6.87 (1H, d), 7.35 (1H, s), 7.97 (1H, s), 8.31 (1H, d), 9.02 (1H, s); m/z: ES+ MH+ 465.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(CC(=O)c2cnc(C)cn2)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)c2cnc(C)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)-1-(5-methyl-pyrazin-2-yl)-ethanone (370 mg, 1.3 mmol) in DMF (5 mL) was added slowly over 30 min to a suspension of NaH (50% in mineral oil, 96 mg, 1.9 mmol) in DMF (2 mL). After 30 min, methyl iodide (199 mg, 1.4 mmol) was added slowly, and the mixture was stirred for 2 d at r.t. The reaction mixture was taken up in ethyl acetate, and washed (water, brine). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated to give a residue, which was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20) to give the title compound (290 mg, 75%). 1H NMR (300 MHz, CDCl3) □ 9.08 (1H, s), 8.45 (1H, s), 7.11 (1H, d), 6.92 (1H, d), 6.73 (1H, dd), 5.53 (1H, q), 3.75 (3H, s), 2.61 (3H, s), 1.49 (3H, d); MS (m/e)=291.0 [MH+].
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Reaction time: 84.5 h

Procedure:
The reaction of Example 1 (reaction scale: 71.5 kg, 177.29 mol of bromophenyl pyrazole) was conducted with 0.1 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. The crude solid was dissolved in THF (9 L/Kg of bromophenyl pyrazole starting material), and the mixture was stirred in the presence of PS-PPh3 resin (Fluka, 3.0 wt %) at ambient temperature. After stirring for 84.5 h, the resin was removed by filtration, and the filtrate was passed sequentially through a Darco zeta pad cartridge, then a 1.2 μm Cuno polish filter. The palladium levels after the Darco pad filtration and after polish filtration were less than 10 ppm and less than 13 ppm, respectively. The filtrate was concentrated and its solute recrystallized from THF/acetone/water to afford 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing less than 10 ppm of palladium.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1>>[F:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: [F-]
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 220 °C

Procedure:
A mixture of 20 parts of anhydrous potassium fluoride, 20 parts of 4-chlorophthalic anhydride and 2 parts of Carbowax® m-peg 2000 catalyst was charged to a reaction vessel and heated at 220° C. for about 18 hours. The product was removed by distillation, then recrystallized from a chloroform-hexane solution to yield 8.13 parts of 4-fluorophthalic anhydride having a melting point of 76°-78° C. Following the procedure of Example 3B, the fluorophthalic anhydride is reacted with ammonia and the resultant mixture of ammonium salts of 4- and 5-fluorophthalamic acid is acidified to yield a mixture of 4-fluorophthalamic acid and 5-fluorophthalamic acid.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[S:13]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:14]1
Reactant: O=Cc1ccnc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1ccnc(-c2ccsc2)c1

Procedure:
2-(thiophen-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and thiophen-3-ylboronic acid (89 mg, 101.8 mg theoretical, 87.4%). LC-MS m/z 190.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([F:17])([F:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:16][C:10]([F:17])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
A mixture of 3-fluoro-phenol (9.8 g, 87.4 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (18.3 g, 89.6 mmol) and K2CO3 (13.3 g, 96.2 mmol) in 75 g of dimethylacetamide (DMAC) was heated to 100° C. for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 250 mL of H2O and 50 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) and dried over Na2SO4. The product (18.5 g, >98% purity by quant. HPLC, 77.8 mmol, 89% yield) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification or purified by fractionated distillation.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:31]=[CH:30][C:25]5[NH:26][C:27](=[S:29])[NH:28][C:24]=5[CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:32][S:29][C:27]1[NH:28][C:24]2[CH:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:15]4[O:14][CH2:13][CH2:12][N:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=[CH:2][CH:3]=5)[CH2:17][C:16]=4[CH:18]=3)[CH:31]=[CH:30][C:25]=2[N:26]=1
Reactant: S=c1[nH]c2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A suspension of 5-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-dihydro-2H-benzimidazole-2-thione (355 mg, 0.84 mmol), potassium carbonate (578 mg, 4.18 mmol), and methyl iodide (119 mg, 0.84 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 1 h. Ethyl acetate (100 mL) was added, and the organic layer was washed with water (2×20 mL), 5% aqueous lithium chloride (2×20 mL), and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (dichloromethane/methanol 95:5) provided the title Compound (220 mg, 60% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): 8.71 (d, 1H), 8.09 (m, 2H), 7.66 (m, 1H), 7.57-7.42 (m, 5H), 7.17 (d, 1H), 6.98 (d, 1H), 4.54 (s, 2H), 4.36 (m, 2H), 3.84 (m, 2H), 2.82 (s, 3H); MS (EI) for C26H22N4OS: 439 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[Br:15].[H-].[Na+].CI.[C:20]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Br:15][C:3]1[CH:4]=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][CH3:20]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4-amino-3-bromo-5-nitrobenzotrifluoride (5.25 g, 18.4 mmol) in DMF (40 mL) was added NaH (883 mg, 60% suspension in mineral oil, 22.1 mmol). After 30 min MeI (1.38 mL, 22.1 mmol) was added. The reaction mixture was allowed to stand at room temperature for 1 h, then was poured into a solution of saturated aqueous NaHCO3 and brine. The resulting suspension was extracted twice with CH2Cl2, and the combined extracts were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (5% EtOAc in hexanes, then 8% EtOAc in hexanes) provided the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.12 (br s, 1H), 7.86 (d, J=2.0 Hz, 1H), 6.47 (br s, 1H), 3.07 (d, J=5.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1)=[O:8].C(OCC)(OCC)OCC.[N-:34]=[N+:35]=[N-:36].[Na+].[C:38](O)(=O)C.Cl.N([O-])=O.[Na+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([N:1]3[CH:38]=[N:36][N:35]=[N:34]3)[CH:3]=2)=[O:8])=[CH:11][C:12]=1[C:17]([F:20])([F:18])[F:19]
Reactant: Nc1cccc(CNC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: O=C(NCc1cccc(-n2cnnn2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.5 %

Procedure:
To a round bottom flask was added urea 27 (100 mg, 0.29 mmol, 1.0 eq.), triethyl orthoformate (0.16 mL, 0.93 mmol, 6.4 eq.), sodium azide (25.0 mg, 0.36 mmol, 1.25 eq.), and acetic acid (0.26 ml, 4.64 mmol, 16.0 eq.). The reaction mixture was stirred at RT for 10 min. before heating to 75° C. for 1 h. The reaction was cooled to RT, and water (0.2 mL), 6N HCl (0.16 mL), and 25% aq. NaNO2 (0.064 mL). The mixture was then extracted with EtOAc, washed with brine and dried with Na2SO4. Concentration via rotary evaporation followed by silica gel column chromatography with 60:40 EtOAc: Hexanes afforded urea 28 as a yellow solid (7.5 mg, 6% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 397.0 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.40 (s, 1H), 9.24 (s, 1H), 8.30 (d, 1H), 7.82 (s, 1H), 7.79 (d, 1H), 7.62-7.42 (m, 4H), 7.10 (t, 1H), 4.40 (s, 2H) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CO.C(Cl)(Cl)Cl>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2ncnc(N)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g), sodium hydrogen carbonate (6.72 g) and pyridine (20 ml) was stirred under ice-cooling. To the mixture was added dropwise during 30 minutes methanesulfonyl chloride (4.58 g) under ice-cooling. The reaction mixture was stirred for an hour under ice-cooling and for 4 hours at ambient temperature. To the mixture was added ice-water. The resultant mixture was stirred for about five minutes and concentrated under reduced pressure. To the residue was added a mixture of chloroform and methanol. The mixture was stirred under heating. Insoluble materials were removed by filtration and then the filtrate was concentrated under reduced pressure to give crude crystals, to which was added a mixture of chloroform and methanol (4:1). The mixture was stirred under heating to give crystals, which were separated by filtration to give crystalline 4-amino-6-methanesulfonamidoquinazoline (1.45 g).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:11]
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1cc(C)c(C(C(=O)O)c2ccccc2)c(C)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3c(C)cc(C)cc3C)CC2)c1

Procedure:
Example 14 was prepared from mesityl(phenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 9: ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCC
Product: CCN(CC)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Diethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine, MS: 389 (MH+, 1Cl).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][N:17]=[C:18]=[S:19].CCOC(C)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:18]([NH:17][CH3:16])=[S:19])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 1-Boc-4-aminomethylpiperidine (642 mg, 3 mmol) in THF (8 ml), methyl isothiocyanate (241 mg, 3.3 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, purification was performed by silica gel column chromatography (Hex/AcOEt=1/4) to obtain 4-({[(methylamino)thioxomethyl]amino}methyl)piperidine carboxylic acid tert-butyl ester. The compound was identified by LC-MS.