Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([O:35]CC)=[O:34])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)c(F)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4cc(F)c(F)c(F)c4)CC3)c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A mixture of 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluoro-phenoxy)ethyl]piperidine-4-carboxylate in 50 cm3 of dioxane, 50 cm3 of methanol and 4.4 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 18 hours. A further 4.4 cm3 of aqueous 5N sodium hydroxide solution were added to the reaction mixture, which was stirred for 6 hours in the region of 70° C. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (1.1 kPa) at a temperature in the region of 5° C. The residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 4 cm; height 20 cm), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 60-cm3 fractions. Fractions 8 to 19 were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and oven-dried under reduced pressure (10 kPa) at about 50° C. 0.59 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at about 120° C.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+]>O>[OH:15][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN1C(=O)COc2cc(N)ccc21
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)COc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a cooled (0° C.) solution of 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one (10.0 g, 56 mmol) in water (80 mL) was added concentrated sulfuric acid (17 mL). After stirring at 0° C. for 10 min, a solution of sodium nitrite (4.1 g, 59 mmol) in water (10 mL) was added dropwise. After stirring for 0.5 h, the reaction mixture was added dropwise to a solution of cupric sulfate (50 g) in water (300 mL) at reflux. Once the addition was complete, the reaction mixture was allowed to cool to ambient temperature and was extracted with ethyl acetate (5×200 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by trituration with ice-cold ethyl acetate (25 mL) and the solid was collected by vacuum filtration, air-dried and dried under high vacuum to afford 7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (3.22 g, 32%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.45 (dd, J=8.7, 2.6 Hz, 1H), 6.40 (d, J=2.6 Hz, 1H), 4.56 (s, 2H), 3.21 (s, 3H); MS (ES+) m/z 180.1 (M+1).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Br:11][CH:12]([CH3:21])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(O)C>[BrH:11].[CH2:1]([NH:7][C:8]1[S:9][C:12]([CH3:21])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: NC(=S)NCc1ccco1
Solvent: CCO
Product: Br
Product: Cc1sc(NCc2ccco2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
N-furfurylthiourea (0.82 grams, 0.005 moles) and α-bromopropiophenone (1.07 grams, 0.005 moles, Aldrich Chem. Co.) in 11 ml absolute ethanol were heated to reflux temperature under nitrogen for 3 hours. After cooling to room temperature, the solvent was removed under vacuum to give a thick brown oil, which was triturated with five 35 ml portions of refluxing ethyl acetate. The ethyl acetate was reduced in volume to about 25 ml and cooled to room temperature. The precipitated solids were filtered, washed with ethyl acetate and vacuum dried over phosphorous pentoxide, yielding 0.585 grams (33%) of 2-furfurylamino-5-methyl-4-phenyl-thiazole hydrobromide, m.p. 150°-153° C.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=[C:13]2[F:16])=[CH:4][CH:3]=1.[CH2:26]([O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:13]1[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=1)=[CH:4][CH:3]=[C:2]([C:36]1[CH:37]=[N:38][C:33]([O:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=1)[CH:15]=2
Reactant: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(Br)ccc12
Reactant: CCCCCCOc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(-c3ccc(OCCCCCC)nc3)ccc12

Procedure:
From 7-bromo-9-fluoro-2-octyloxyphenanthrene by reaction with 6-hexyloxypyridine-3-boronic acid, sodium carbonate and tetrakis(triphenylphosphine)palladium(0) in toluene/ethanol/H2O.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:30]1[CH:35]=[C:34]([O:36]C)[C:33]([O:38]CC2C=CC=CC=2)=[C:32]([O:46]C)[CH:31]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[CH3:29][CH:22]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([OH:8])=[C:10]([C:30]3[CH:35]=[C:34]([OH:36])[C:33]([OH:38])=[C:32]([OH:46])[CH:31]=3)[O:11]2)=[CH:16][CH:15]=1
Reactant: COc1cc(-c2oc3cc(CCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)CCCC(C)CCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirring solution of 47 (0.028 g, 0.05 mmol) in dichloromethane (1 ml) under argon at 0° C. was added boron tribromide (1.0M in DCM, 0.7 ml, 14 eq). The reaction was then warmed to room temperature and stirred for 23 hours. The mixture was then cooled to 0° C., methanol (1 ml) added heated to reflux for 2 hours. The reaction was then cooled and concentrated in vacuo to give a solid that was chromatographed (silica gel, DCM:methanol, 19:1) to give 9g* (0.008g, 37%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc2ccccc12

Procedure:
Following General Procedure B′ and using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 69°-73° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:42]([OH:44])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][C@H:36]([CH3:40])[CH2:35]1)=[CH:30][C:29]2=[O:41])[CH3:23].C(N(C(C)C)C(C)C)C.CNC>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:42]([N:7]([CH3:8])[CH3:6])=[O:44])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][C@H:36]([CH3:40])[CH2:35]1)=[CH:30][C:29]2=[O:41])[CH3:23]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (2.38 g, 3.96 mmol) was added portionwise to 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (0.88 g, 2.64 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.380 mL, 7.92 mmol) suspended in DCM (15 mL) at 10° C. under nitrogen. The resulting mixture was stirred at RT for 2 hrs. Dimethylamine (3.96 mL, 7.92 mmol) was then added at 10° C. and the resulting mixture was stirred at RT overnight. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 0 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a foam which crystallised from ethyl acetate, the solid was collected by filtration and dried to a constant weight in a vacuum oven to afford 8-(1-hydroxyethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (0.800 g, 84%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.C(#N)C>[Pt].CO>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C1CCNCC1
Agent: [Pt]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: Nc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.9 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (1.05 g, 5.00 mmol), piperidine (0.592 ml, 6.00 mmol), diisopropylethylamine (1.31 ml, 7.50 mmol) and acetonitrile (10 ml) was refluxed for 8 hours. Methanol (10 ml) and 10% platinum on activated carbon (0.10 g) were added to the residue obtained by evaporation of the solvent of the reaction mixture under reduced pressure, and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (1.11 g, 91%) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[N:5]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:18].[CH2:1]([O:3][C:4](=[O:17])[N:5]([N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[Cl:18])[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)N(c1ccncc1)n1cccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(c1ccncc1)n1cccc1Cl
Product: Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 64.6 %

Procedure:
To a solution of N-(4-pyridinyl)-N-(1H-pyrrol-1-yl)carbamic acid ethyl ester (9 g) in 100 ml of anhydrous tetrahydrofuran warmed to 50° C. was slowly dropped a solution of N-chlorosuccinimide (5.2 g) in 75 ml of anhydrous tetrahydrofuran. After stirring seven hours at 50° C., the reaction mixture was cooled, stirred with an aqueous solution of sodium bisulfite and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 11.5 g of an oil. This oil was purified by HPLC (silica, 20% ethyl acetate in dichloromethane) to give 3.8 g of the desired product as a solid. This material was converted to the hydrochloride salt and twice recrystallized from isopropanol-ether to give 3.3 g of crystals, m.p. 139°-140° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:8]=2[NH:9][C:10](=[O:13])[CH2:11][N:12]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6]1[NH:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:7]1=2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)=NCC(=O)N2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)NCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(3,4-dichloro-benzyl)-7,8-dimethoxy-1,3-dihydro-benzo[e][1,4]diazepin-2-one (0.48 g, 1.17 mmol) in glacial acetic acid (1.67 ml) and methanol (9.4 ml) was stirred at 0° C. under nitrogen. Sodium cyanoborohydride (0.148 g, 2.23 mmol) was added portionwise and the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 2 h. Water (17 ml) was added dropwise and the product was extracted with dichloromethane, washed with aqueous 1N ammonia. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under vacuum. The resulting yellow oil crystallized under HV (0.19 g, 41%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:9]=2)[N:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.C[Sn](C)(C)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[OH2:62].CC#N>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[C:25]1([S:22]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([NH:11][C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]([OH:20])=[O:62])=[O:21])[CH:9]=[C:10]3[C:2]([C:33]3[S:37][CH:36]=[N:35][CH:34]=3)=[CH:3]2)(=[O:23])=[O:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Reactant: C[Sn](C)(C)c1cncs1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)Nc1cnc2c(c1)c(-c1cncs1)cn2S(=O)(=O)c1ccccc1
Temperature: 85 °C
Yield: 38 %

Procedure:
A mixture of bromide 43 (50 mg, 0.104 mmol), 5-(trimethylstannyl)thiazole (51.1 mg, 0.21 mmol), PdCl2(MeCN)2 (2.67 mg, 10 μmol), and P(o-tolyl)3 (6.27 mg, 21 μmol) in toluene (5 mL) was heated in darkness at 85° C. overnight and then refluxed for 2 d. The mixture was concentrated and the product isolated by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 44 (20 mg, 38%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.30 (dd, J=4.5, 2.0 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 7.44-7.50 (m, 2H), 7.61-7.63 (m, 1H), 7.80 (s, 1H), 7.98 (d, J=1.4 Hz, 1H), 8.00 (s, 2H), 8.42 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H), 8.70 (s, 1H). MS (ES) m/z 505 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH2:4][CH2:3]1.[C:18](O)(=[O:20])[CH3:19]>C1(C)C(C)=CC=CC=1>[C:18]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)[CH2:4][CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC1(C)CC(C2CCC(O)CC2)CC(C)(C)N1
Reactant: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)OC1CCC(C2CC(C)(C)NC(C)(C)C2)CC1

Procedure:
7 parts of 4-(4'-hydroxycyclohexyl)-2,2,6,6-tetramethylpiperidine were dissolved in xylene by warming 1.7 parts of acetic acid and 0.5 part of tetra-n-butyl-ortho-titanate were added and the solution allowed to stir and reflux for 48 hours. Water was continuously removed from the reaction. The xylene was removed under reduced pressure and the residue treated with 0.5 part carbon, 0.5 part sodium carbonate and water. The mixture was stirred and heated at reflux for 1 hour. The mixture was then filtered and the filtrate extracted with ether. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled under reduced pressure to yield the desired product boiling at 114°-7°C/0.1mm and having the following elemental analysis:
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([N:23]=[C:24]=[S:25])=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7]>O1CCCC1>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[C:17]([CH3:26])=[CH:18][C:19]([NH:23][C:24](=[S:25])[N:3]([CH2:1][CH3:2])[CH3:4])=[C:20]([CH3:22])[CH:21]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:5])[CH3:7]
Reactant: CCNC
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N=C=S
Solvent: C1CCOC1
Product: CCN(C)C(=S)Nc1cc(C)c(Oc2cccc(C(C)(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylmethylamine (450 mg) is added dropwise to a solution of 1-{[3-(1,1-dimethylethyl)phenyl]oxy}-4-isothiocyanato-2,5-dimethylbenzene (1.9 g) in tetrahydrofuran (6 ml) at 0° C. The reaction mixture obtained is stirred at room temperature for 1 h and then concentrated and triturated with heptane. The title product is obtained in the form of a white precipitate.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Br)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CNC.O.[C:35](OCC)(=O)[CH3:36]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:36][CH2:35][CH2:26][C:25]5=[O:28])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(CBr)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: CNC
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole (170 mg) obtained in Example 374, a 2 M solution (2.2 ml) of dimethylamine in tetrahydrofuran and dimethylformamide (5 ml) was stirred at room temperature for 2 hr. Then water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by Chromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (35 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[OH-].[Na+].O.Cl>CCO>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (300 mg, 0.990 mmol) in EtOH (10 ml), 2M NaOH (0.495 ml, 0.990 mmol) was added dropwise over 1 minute. After stirring at RT for 30 minutes the reaction mixture was poured into water (30 ml) and the pH was adjusted to pH 4 by addition of 1M HCl.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2].[Br:16][CH2:17][CH2:18]O.S(=O)(=O)(O)O>O>[Br:16][CH2:17][CH2:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: OCCBr
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)OCCBr
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 2-isopropyl-4-nitro-benzoic acid (0.23 g, 1.10 mmol), 2-bromoethanol (1.0 mL, 14.1 mmol) and conc. sulfuric acid (0.2 mL) was heated at 80° C. overnight. The mixture was cooled to r.t., diluted with water and extracted twice with ethyl acetate. The organic phase was washed with sat. sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica (60-120 mesh), eluting with 7% ethyl acetate/petroleum ether, to afford 2-isopropyl-4-nitro-benzoic acid 2-bromo-ethyl ester (0.24 g, 69%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].Br[C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.CCO>COCCOC>[NH2:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: COCCOC
Product: NCCc1ccc(-c2cccc(C(N)=O)c2)cc1

Procedure:
The title compound was prepared from 3-(aminocarbonyl)-phenyl boronic acid and 4-bromophenethylamine. according to the procedure described for intermediate I-VII-1 with the exceptions that 4:1 PhMe/EtOH was sued as organic solvent (instead of DME) and the chromatographic purification step was omitted. LC/MS (method E) 0.53 min; m/z 241 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(OC(=O)C)(=O)C>>[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:31][CH:32]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(C=O)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(C=Cc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-acetoxybenzoyl)benzaldehyde (537 mg) was added acetic anhydride (0.5 ml) and the mixture was stirred at 140° C for 2 hours. This reaction mixture was concentrated and the residue was washed with n-hexane-diethyl ether and dried to provide 653 mg of yellow powder.