Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH:14][NH:15]C(OC)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[ClH:22]>>[ClH:22].[CH:1]1([NH:11][C:12](=[O:13])[NH:14][NH2:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NNC(=O)NC1CCCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NNC(=O)NC1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
8.13 Grams (0.031 mole) of methyl 3-[(1,2,3,4-tetrahydro-1-naphthyl)carbamoyl]carbazate is added in portions to 31 ml. of stirred 4N potassium hydroxide maintained at 75° C. to 80° C. The mixture is stirred at this temperature for 30 minutes, then cooled in an ice bath and acidified with 12N hydrochloric acid. The precipitate is filtered, washed with cold water and then 2-propanol. The dried product weighs 1.88 grams and has melting point 189° C. to 191° C. The filtrate is evaporated under reduced pressure and the residue boiled in ethanol and filtered hot. The filtrate is evaporated at reduced pressure. The residue is crystallized from ethanol to give an additional 1.30 grams of product, melting point 191° C. to 193° C. Recrystallization from water gives the analytical sample, melting point 196° C. to 198° C. Analysis calculated for C11H16N3OCl: C, 54.66; H, 6.67; N, 17.30. Found: C, 54.57; H, 6.69; N, 17.46.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Br[C:20]1[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Temperature: 60 °C
Yield: 70 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.44 g, 1.75 mmol) in acetonitrile (30 mL) was added 5-bromo-[1,3,4]thiadiazole-2-carbonitrile (0.6 g, 3.16 mmol) and potassium carbonate (0.73 g, 5.25 mmol). The suspension was heated at 60° C. for 6 hours. The mixture was cooled to 0° C., diluted with water and extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30-60% EtOAc/hexane) to give [6-(5-cyano-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.44 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 7.55 (d, J=2.21 Hz, 1H), 7.43 (d, J=1.62 Hz, 1H), 5.59 (dd, J=8.72, 2.73 Hz, 1H), 4.04 (q, J=6.92 Hz, 2H), 3.16 (dd, J=15.56, 2.94 Hz, 1H), 2.37-2.43 (m, 1H), 2.35 (s, 3H), 1.14 (t, J=7.17 Hz, 3H).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](OC)=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>O>[C:28]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:14][CH2:15]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COCCN
Reactant: COc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 51 %

Procedure:
A solution of 20.8 parts of 1-(diphenylmethyl)-4-(4-methoxy-3-nitrophenylmethyl)piperazine dihydrochloride in 50 parts of 2-methoxyethanamine is stirred and refluxed overnight. Water is added and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 11.6 parts (51%) of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-(2-methoxyethyl)-2-nitrobenzenamine; mp. 97.2° C.
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([O-])=[O:26])[CH3:22].[Na+].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:25](=[O:26])[CH:24]([O:28][CH2:29][CH3:30])[O:23][CH2:21][CH3:22]
Reactant: NCc1ccccc1Br
Reactant: CCOC(OCC)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C(=O)NCc1ccccc1Br
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (1.15 g, 6.00 mmol) was added to a mixture of 2-bromobenzylamine (0.744 g, 4.00 mmol), sodium 2,2-diethoxyacetate (0.816 g, 4.80 mmol), 1-hydroxybenzotriazole hydrate (0.919 g, 6.00 mmol) and Hunig's base (1.53 mL, 8.80 mmol) in DMF (10 mL) with stirring. After 18 hours at room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2 M HCl, saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated to a viscous colourless oil (1.02 g, 81%). LC-MS (1) Rt==2.23 min; m/z (ESI+) 316 & 318 (M+H+).
Reaction SMILES: [Na].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Br[CH:10]([OH:13])[CH2:11][CH3:12]>N>[OH:13][CH2:10][CH2:11][CH2:12][S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2]
Reactant: CCC(O)Br
Reactant: N[C@@H](CS)C(=O)O
Agent: N
Agent: [Na]
Product: N[C@@H](CSCCCO)C(=O)O
Yield: 190.1 %

Procedure:
The compound was prepared in a similar manner to that described by J. F. Carson, et al, J. Org. Chem., 1964, 29, 2203. To a solution of sodium (6.44 g, 0,281 mol) in liquid ammonia (300 mL) was added cysteine (15.0 g, 62.5 mmol) over a 30 minutes period until permanent discharge of blue. Bromopropanol (15,8 mL, 0.175 mol) was added dropwise over 1 hour. The ammonia was allowed to evaporate and the resulting solid was dissolved in 1M HCl and passed through a column of Dowex 50 (H+) (5×30 cm) eluting with 1N ammonium hydroxide. Lyopholyzation yielded 21.3 g of the title compound as a white solid. MS(CI) m/e 180 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ1.70-2.00 (m, 3H), 2.70 (t, J=7.5 Hz, 2H), 3.00-3.21 (m, 3H), 3.58-3.84 (m, 3H), 3.93 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 1.5 h

Procedure:
13.6 g of trans-4-(7-chloro-quinolin-4-ylamino)-cyclohexanol (Example 123, step 1) were dissolved in 100 ml of dimethyl sulphoxide and 68 ml of triethylamine and cooled to +10° C. under argon. A solution of 25.5 g of sulphur trioxide-pyridine complex in 100 ml of dimethyl sulphoxide was added dropwise in such a manner that the internal temperature did not exceed +15° C. After stirring for an additional 90 minutes, 800 ml of water were rapidly added dropwise. The emulsion obtained became a filterable suspension after vigourous stirring at +10° C. The filter material was recrystallized from ethanol-ether. Yield: 10.1 g (75%) of beige crystals; dec. 195° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C:15]([CH2:29][NH2:30])=[CH:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1COCC1>[CH2:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C:15]([CH2:29][NH:30][C:1](=[O:3])[CH3:2])=[CH:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCn1cc(CN)c2cc(-c3cccc(C)c3)ccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCn1cc(CNC(C)=O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Acetyl chloride (44 μl, 0.434 mmol) was added to a solution of (1-octyl-5-m-tolyl-1H-indol-3-yl)methanamine (220 mg, 0.628 mmol) and triethylamine (131 μl, 0.651 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to stir at room temp for 60 min, the precipitate formed was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography (silica gel, CH2Cl2) to give sulphonamide 23 in 65% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH2:13].[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=O)=[CH:21][N:20]=[C:19]([S:25][CH3:26])[N:18]=1)[CH3:15].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]=[CH:23][C:22]1[C:17]([NH:16][CH2:14][CH3:15])=[N:18][C:19]([S:25][CH3:26])=[N:20][CH:21]=1
Reactant: COc1cc(OC)c(F)c(N)c1F
Reactant: CCNc1nc(SC)ncc1C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCNc1nc(SC)ncc1C=Nc1c(F)c(OC)cc(OC)c1F

Procedure:
In a 500-mL round bottom flask, 3.00 g (15.86 mmol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 3.13 g (15.86 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 150 mL of toluene with 1.11 g (4.76 mmol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained 3 times from the finger, replenished with 100 mL of the solvent and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 7.19 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 369.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35](N2C=CN=C2)=[O:36])=[CH:5][CH:4]=1)#[N:2].[OH:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][N:14]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([C:35]([O:42][CH2:43][CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][C:46]2=[O:50])=[O:36])=[C:11]([CH3:34])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[C:13]1=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C1CCCN1CCO
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCN2CCCC2=O)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 74 %

Procedure:
The title compound is synthesized in analogy to Example 64 from Example 15A using N-(2-hydroxyethyl)-2-pyrrolidone instead of tert.-butyl-N-hydroxyethyl carbamate.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:25])=[C:10](\[CH3:24])/[CH:11]=[CH:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[Cl:23])=[CH:3]\[C:4]([OH:6])=O.C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH2:38]([NH2:40])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[C:9](/[F:25])=[C:10](\[CH3:24])/[CH:11]=[CH:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[Cl:23])[CH3:39]
Reactant: CCN
Reactant: COc1cc(Cl)c(/C=C/C(C)=C(F)/C=C/C(C)=C/C(=O)O)c(Cl)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCNC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1Cl

Procedure:
In a manner similar to that described in Example 26, 385 mg. (1 mmole) of (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-nonatetraenoic acid were suspended in 15 ml. of dry benzene and treated with oxalyl chloride and dimethylformamide, followed by dry ethylamine. Work-up as described in Example 26 afforded N-ethyl (2E,4E,6Z,8E)-3,7-diemthyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-2,4,6,8-nonatetraenamide.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)=[CH:21][C:16]2=[N:15][N:14]=1.C(O)(C)C.O>CC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:23][C:24](=[O:26])[CH2:25]3)=[CH:21][C:16]2=[N:15][N:14]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C1CC(c2cc3nnc(-c4ccccc4F)n3[nH]c2=O)C1

Procedure:
8N Chromic acid was added to a solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.36 g, 1.2 mmol) in acetone (50 ml) dropwise, until excess was present (red colour remained). The reaction was then stirred for 2 hours before isopropanol was added until the blue colour remained and no excess chromic acid was present. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (4×50 ml), organic layers were combined, washed with brine (50 ml), dried (MgSO4), filtered and concentrated to give the desired product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO) δ 3.41 (2H, s), 3.43 (2H, s), 3.73-3.78 (1H, m), 7.42-7.50 (2H, m), 7.64-7.72 (1H, m), 7.83-7.88 (1H, m), 8.38 (1H, s); MS (ES+) m/e 299 [MH]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:11]2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2cc(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(OC)ccc12
Temperature: 40 °C
Reaction time: 0.3 h
Yield: 100.3 %

Procedure:
0.384 g (12 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 2.4 g (11.7 mmol) of 6-methoxy-3-methoxycarbonyl-1H-indole in 60 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hours, 1.98 g (12 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 5 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.9 g of a brown residue which is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate (65/35 by volume)]. After concentrating the fractions under reduced pressure, 2.5 g of 6-methoxy-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 162° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22].Br[CH2:29][CH2:30][Cl:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:31][CH2:30][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: ClCCBr
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OCCCl)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
The suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (50 mg, 0.14 mmol), 1-bromo-2-chloroethane (0.015 ml, 0.15 mmol), and potassium carbonate (23 mg, 0.17 mmol) in DMF (5 mL) was stirred for 3 days at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×20 mL) and brine (1×20 mL) and was dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was washed with hexane and dried to give 48 mg of 2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as light brown solid (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([OH:34])=[O:33])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.[OH-].[Na+:39]>CO>[Na+:39].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([O-:34])=[O:33])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)[O-])cccc3c2)cc1
Temperature: 25 °C

Procedure:
A mechanically stirred suspension of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid (166 g, 0.31 mol) in methanol (500 mL) was treated with 1N sodium hydroxide (327 mL). The resulting solution was stirred at room temperature. The mixture was stirred 1 h and the resulting solid was collected by filtration, washed with acetone, hexane and then dried to give 151 g of the product as a white solid. 1H NMR (DMSO-d6): 9.04 (d, J=9 Hz, 1H), 8.00 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.72 (d, J=7 Hz, 1H), 7.66-7.61 (m, 5H), 7.53 (dd, J=7, 9 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 6.88 (d, J=9 Hz, 2H), 4.85 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([C:8](OCC)=[O:9])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CO)CC1
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
1-tert-Butyl 4-ethyl azepane-1,4-dicarboxylate (3.3 g, 12 mmol, US Publication No. 2006/229289) was dissolved in THF (100 mL) and cooled in an ice bath. LiAlH4 (12 mL, 12 mmol) was added slowly and stirred for 30 minutes. Water (˜3 mL) was added slowly, followed by Na2SO4. The reaction was filtered and concentrated to afford crude tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate (2.8 g, 100%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.C(Cl)Cl.CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:14]3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(NC3CCCNC3)cc2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: c1cn(-c2ccc(NC3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
3-[(4-(Imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol) was dissolved in DMF and then treated with 5-chloromethyl-1,3-benzodioxole (1.0 eq.), K2CO3 (2.5 eq.) and NaI (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. Filtration of the mixture and evaporation of the solvent in vacuo gave a crude product (411 mg). Flash column chromatography on silical gel with 1–2.5% methanol in methylene chloride afforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (110 mg), 1H NMR(CDCl3) 7.70 (s, 1), 7.10 (m, 4), 6.80 (s, 1), 6.70 (m, 2), 6.60 (d, 2), 5.90 (s, 2), 4.30 (m, 1), 3.60 (m, 1), 3.40 (AB q, 2), 2.70 (m, 1), 2.40 (m, 3), 1.50–1.80 (m, 4) ppm.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[Ce].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH:2]([CH2:3][CH3:4])[CH3:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCC
Reactant: c1ccccc1
Agent: [Ce]
Product: CCC(C)c1ccccc1

Procedure:
When benzene was reacted with 1-butene at 130° C. using a cerium-exchanged Linde 13X zeolite catalyst, 2-phenyl butane was obtained with 97.3% selectivity without SO2. Upon addition of SO2, the selectivity increased to greater than 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:36][CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:36]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.3 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (94 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH:18]=[CH:19]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccc2c(ccn2-c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 5-methoxyindole (40 mg, 0.302 mmol) similar to example 1b and was isolated as white powder (14 mg, 28%). 1H NMR (CDCl3): 8.91 (s, 1H), 8.70 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 8.01 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 7.92 (dd, J=6.9 and 1.5 Hz, 1H), 7.87 (m, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.61 (ddd, J=8.4, 6.9 and 1.2 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.97 (dd, J=9.0 and 2.4 Hz, 1H), 3.88 (s, 3H).