Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 39.5 g. (0.24 mole) ethyl 4-aminobenzoate (free base), 140 ml. n-butanol and 47.1 g. (0.265 mole) bis-(2-chloroethyl)-amine hydrochloride is heated at reflux temperature for 36 hours, then 16.8 g. (0.12 mole) powdered anhydrous potassium carbonate are added thereto followed by further heating for 80 hours. The hot reaction mixture is then suction filtered, the filter cake is washed with some hot butanol and the combined filtrates are cooled. After standing overnight, the solid product obtained is filtered off with suction, washed twice with 50 ml. amounts of diethyl ether and dried. Yield: 33.4 g. (64% of theory) of yellow crystals which are recrystallised from ethanol/diethyl ether (2:1 v/v) to give 28.45 g. (55% of theory) of the desired product in the form of an almost colourless hydrochloride; m.p. 176°-178° C. The product is hydroscopic.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].CN1CCOCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[C:15]1([CH2:14][O:21][C:22]([NH:24][CH2:25][CH2:26][NH:27][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCCNC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CN(C)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 49.6 %

Procedure:
A solution of dimethylcarbamoyl chloride (1.39 g) in diethyl ether (15 ml) was added dropwise to a stirred solution of NMM (1.57 g) and 2-benzyloxycarbonylaminoethylamine (3.02 g) in diethyl ether (110 ml). The mixture was stirred for four hours and allowed to stand for two days. After evaporation of the ether the residual solid was partitioned between 10% aqueous citric acid and ethyl acetate. The ethyl acetate extracts were washed with 10% aqueous citric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and then dried (Na2SO4) and evaporated to give a solid (1.7 g). A sample crystallised from ethyl acetate/patroleum ether (bp 60°-80°) m.p. 81°-82°.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(Nc2ccccc2)CC1=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), aniline (30 g), triethylamine (0.8 g) and toluene (45 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 2 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain 2-allyl-3-methyl-4-anilino-2-cyclopentenone (22 g). Yield, 97%. nD20 1.5880.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.IC1C=C2C(C(N)=CC=N2)=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)CCC>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccnc2cc(I)ccc12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Nc1ccnc2cc(I)ccc12
Solvent: CCCCO
Product: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Temperature: 120 °C

Procedure:
4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.; Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives. Khim. Geterotsikl. Soedin. (1980), Issue 7, 972–5] and 4-phenoxyaniline (6.38 g, 34 mmol) in butanol (75 ml) were heated at gentle reflux (120° C.) overnight (18 hrs). On cooling the resultant precipitate was collected by filtration and washed with acetonitrile (2×50 ml). The resultant solid was suspended in chloroform (500 ml) and 2N sodium carbonate solution (300 ml) and heated at 75° C. for 45 mins. On cooling the resultant precipitate was collected by filtration, washed with water (2×50 ml) and dried to yield the product as a pale brown solid. (9.95 g, 66%) δH [2H6] DMSO 8.35(3H,m), 8.20(1H,s), 8.10(1H,d), 7.85(1H,s), 7.35(4H,m), 7.15(4H,d), 6.75(1H,d).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH:17]=[C:16]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])[CH:15]=[N:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:16]1[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cn1cc(C(CN)C2CCOCC2)cn1
Product: Cn1cc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=382.0, tR (minutes, Method E)=0.52
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[NH2:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>CN(C=O)C>[CH:13]1([C:18]([NH:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (8.5 g) was added to a solution of cyclopentanecarboxylic acid (5.2 mL) in DMF (40 mL). The resulting mixture was stirred for 1 h and cooled in an ice bath. Ethyl 2-amino-3-mercaptopropanoate hydrochloride (8.88 g) was added, followed by triethylamine (10 mL). The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing the product were combined and evaporated to give the subtitled compound as a white solid. Yield 7.7 g.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 3-fluoronitrobenzene (3.53 g, 25 mmol) and 2-methoxyphenol (3.72 g, 30 mmol) in anhydrous N,N-dimethylformamide (25 mL) under nitrogen was treated with anhydrous potassium carbonate (7.6 g, 55 mmol) and heated to 110° C. for 65 h, then cooled to room temperature. The solution was diluted with dichloromethane (50 ml) and treated with DOWEX® 550A OH anion exchange resin (log) which had been washed dry with methanol. Stirring was continued for one hour, the mixture was filtered, and the filtrate concentrated in vacuo (exhaustively at end to remove DMF) to give 3-(2-methoxyphenoxy)nitrobenzene as a residue.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH:23](I)([CH3:25])[CH3:24]>>[CH:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CC(C)I
Product: CC(C)N1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using isopropyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.18 (d, 6H), 1.60-1.67 (m, 1H), 1.71-1.94 (m, 2H), 2.63-2.75 (m, 2H), 2.81-2.95 (m, 2H), 2.99-3.20 (m, 2H), 3.30-3.55 (m, 3H), 3.99-4.12 (m, 1H), 6.45 (d, J=7.4 Hz, 2H), 6.65 (t, J=7.3 Hz, 1H) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2.C(O)(=O)C(C(C(O)=O)O)[OH:37]>CCCCCC.CCOCC>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:37])=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 0.67 h
Yield: 38 %

Procedure:
56 ml (67 millimoles) of a 20% strength solution of diisobutylaluminum hydride in hexane were added to a solution of 10 g (32 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) in 120 ml of absolute ether. The mixture was stirred for a further 40 minutes, 150 ml of saturated tartaric acid solution were added dropwise and stirring was continued for a further hour. Thereafter, the mixture was extracted three times with ether and the combined ether phases were washed twice with water, dried over Na2SO4 and evaporated down. Recrystallization of the residue from isopropanol gave 3.8 g (38%) of the title compound of melting point 130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=O>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][O:18]3)=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)C1CCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c(C2CCCO2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added tetrahydrofuran-2-carbonylchloride (80 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and the reaction system was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.[NH2:36][OH:37]>C(O)C>[OH:37][NH:36][C:14]([C:13]1[C:8]2[N:7]=[C:6]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[N:5]([CH2:4][C:3]3[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:15]
Reactant: NO
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 87.3 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (0.60 g, 1.57 mmol) dissolved in ethanol (15 mL) and triethylamine (0.5 mL) was added hydroxylamine (0.14 g, 130 M%). After 24 h at reflux, the reaction was concentrated. The residue was redissolved in CH2Cl2 and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 4% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of N-hydroxy 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxamidine (0.57 g, 1.37 mmol, 87% yield). M.p. 214-216° C. 1H NMR (200 MHz, CD2Cl2): δ7.84 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.57 (m, 1H, H4′), 7.54 (dd, J=1.1, 8.2 Hz, 11H, H7), 7.30 (dd, J=7.7, 8.2 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.83 (m, 2H, H3″,5″), 6.61 (br, 2H, NH2), 5.39 (s, 2H, CH2PhF2).
Reaction SMILES: NC1C(Cl)=CC(C(NCCN(CC)CC)=O)=C(OC)C=1.[NH2:21][C:22]1[C:49]([Cl:50])=[CH:48][C:25]([C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][C@H:30]2[O:46][CH3:47])=[O:27])=[C:24]([O:51]C)[CH:23]=1>>[NH2:21][C:22]1[C:49]([Cl:50])=[CH:48][C:25]([C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[CH2:31][C@H:30]2[O:46][CH3:47])=[O:27])=[C:24]([OH:51])[CH:23]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Agent: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Product: CO[C@@H]1CN(CCCOc2ccc(F)cc2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)cc1O
Yield: 54 %

Procedure:
The general procedure of Preparation No. 1 was repeated except that the 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide utilized therein was replaced by cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-methoxybenzamide (2 g, 4.3 mmoles) [prepared according to the procedure described in published European patent application No. 76,530 (1983)]. The product was crystallized from 2-propanol to give the title product in 54% yield, mp. 146°-148° C.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18]/[CH:19]=[CH:20]\[CH3:21]>C(O)C>[C:2]([NH:5][C:6]([CH2:18]/[CH:19]=[CH:20]\[CH3:21])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: C/C=C\CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C/C=C\CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reaction time: 8 h
Yield: 98 %

Procedure:
4.37 g (190 mmol) of sodium metal were dissolved in 110 ml of anhydrous ethanol. 41.14 g (189.6 mmol) of diethyl acetamidomalonate dissolved in 270 ml of anhydrous ethanol were added and the mixture was heated under reflux for 10 minutes. 25.65 g (168 mmol) of (Z)-1-bromo-2-butene were added dropwise at room temperature and the mixture was stirred overnight, then evaporated to dryness under vacuum and the residue was partitioned between ethyl acetate and 0.1 M hydrochloric acid. The organic phase was washed with saturated sodium hydrogen carbonate solution followed by saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation the crude product was chromatographed on silica gel using 66% ethyl acetate in petroleum ether as eluent to obtain 44.69 g of diethyl (Z)-2-acetamido-2-(2-butenyl)malonate as a colourless oil;1H NMR (250 MHz, CDCl3) δ: 1.2 (t, 6H), 1.6 (d, 3H), 2.0 (s, 3H), 3.1 (d, 2H), 4.2 (q, 4H), 5.1(m, 1H), 5.6 (m, 1H), 6.7 (s, 1H).
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:31])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:31])[CH2:15][CH2:16]1
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 40 mg (0.1 mmol) of 3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-1α,3,8-triaza-spiro[4.5]dodecan-2,4-dione hydrochloride in 1.7 mL of anhydrous DCE were added successively 24 mg (0.1 mmol) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide and 17 μL (0.12 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 26 mg (0.125 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by Bond Elut (ethyl acetate to 5% methanol/DCM) to yield the 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide as a white solid (40 mg, 62.3%).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:34])([F:33])[C:20]([N:22]1[C:27]2[CH:28]=[C:29](I)[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1)=[O:21]>>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([C:20](=[O:21])[C:19]([F:33])([F:18])[F:34])[C:27]=4[CH:28]=3)([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)N(C(=O)C(F)(F)F)CCO3)O2

Procedure:
This compound was prepared by coupling rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (1.15 g or 5 mmol) with 4-(trifluoroacetyl)-3,4-dihydro-6-iodo-2H-1,4-benzoxazine (1.95 g or 5.5 mmol) under the conditions described in Example 15. The product was isolated by chromatography over the 40 fold amount of silica gel methylene chloride. It was crystallized from ether/hexane and recrystallized twice from methanol to give colorless crystals with m.p. 153°-155°.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH2:31](O)[CH2:32]C.C([B-](F)(F)F)=C.[K+].C(N(CC)CC)C>O>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([CH:31]=[CH2:32])=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CCCO
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: C=Cc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 1.00 g, 2.302 mmol) was added with n-propanol (20 mL), potassium vinyltrifluoroborate (854 mg, 3.0 eq.), dichloro-((bis-diphenylphosphino)ferrocenyl)palladium (217 mg, 0.1 eq.) and triethylamine (1.11 ml, 3.0 eq.) in order and the resultant was stirred at 60° C. for 4 hr. Upon the completion of the reaction, water was added to the reaction solution. The resulting precipitates were filtered and washed with distilled water, and the residues were dried to obtain the title compound (666 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:26](=[O:30])[NH:25][C:24]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[N:23][C:22]2=3)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:26](=[O:30])[NH:25][C:24]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[N:23][C:22]2=3)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C2OC(C)(C)OC12)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(O)C1O)OCC
Yield: 86.5 %

Procedure:
Compound 18.3 (850 mg, 1.62 mmol) was dissolved in 9 mL TFA and 1 mL water mixture, stirred for 1.5 h. The mixture was concentrated under reduced pressure, and the residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 18.4 (680 mg, 86.4% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11][C:32]#[N:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC#N)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.88 g (4.16 mmol) Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propyl ester were dissolved in 5 ml DMF and 306 mg (6.24 mmol) sodium cyanide were added. The mixture was stirred for 5 h at 60° C. The reaction mixture was poured into 50 ml water, the precipitate was filtered, washed with water and dried in vacuo. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1
Reactant: OC1CCNCC1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cnn(-c2ccc(C(c3ccc(Cl)cc3)N3CCC(O)CC3)c(Cl)c2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol), 4-hydroxypiperidine (0.02 mol) and sodiumbicarbonate (0.02 mol) in DMF (100 ml) was stirred for 16 hours at 80° C. The mixture was cooled. The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 0.070 g (±)-2-[3-chloro-4-[(4-chlorophenyl)(4-hydroxy-1-piperidinyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 119).