Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[Br:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(Br)c1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cccc(Br)c2)O3)nc1

Procedure:
2-(3-Bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 215 mg of 2-(3-bromophenyl)chroman-4,6-diol (Example 15(b)). The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8 Hz), 7.69 (m, 1H), 7.58-7.50 (m, 2H), 7.40 (m, 1H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.7 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.8 Hz), 4.97 (m, 1H), 2.36 (m, 1H), 1.94 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:22]#[N:23].C(N(CC)CC)C>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:18][C:19]2[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][C:26]=2[NH:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(NC2CCCCC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCCCC2)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of the acid chloride of 4-benzyloxybenzoic acid (2.56 g, 10.4 mmol) in dichloromethane (30 mL) and dimethylformamide (5 mL) was added dropwise to a solution of compound 4 (2.23 g, 10.4 mmol) and triethylamine (2.4 mL, 17.2 mmol) in dichloromethane (15 mL). After 1.5 h, 4-dimethylaminopyridine (0.12 g) was added. The reaction was stirred at rt for 18 h and then heated to 45° C. for 4 h. The reaction was cooled to rt and then extracted with 1 N KHSO4 (1×) and brine (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 10-20% ethyl acetate/hexanes (v/v)) to afford compound 11 as a slightly purple solid (2.08 g, 47%). ESI-MS m/e 426.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:13]#[N:14]>CN1C(=O)CCC1.O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]([CH3:11])[CH3:10])=[CH:8][C:2]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Combine 2-bromo-4-isopropyl aniline (7.5 g, 35 mmol) and copper (I) cyanide (3.76 g, 42 mmol) in NMP (30.0 mL) and heat at 200° C. for 2 hours. Cool to ambient temperature and dilute with water (300 mL). Extract with ethyl acetate to give 4.58 g of the crude product. Silica gel chromatography, eluting with methylene chloride, gives 3.20 g of the title compound as a red oil: mass spectrum (ion spray): m/z=161 (M+1); 1H NMR (300 MHz, DMSO-d6): δ 7.21 (m, 2H), 6.73 (d, 1H), 5.79 (s, 2H), 2.73 (quintet, 1H), 1.12 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=C(C#N)[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-:26].[Na+].Cl.[CH2:29]([OH:31])[CH3:30]>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:30]([C:29]([OH:26])=[O:31])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1

Procedure:
100 mg (0.293 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-cyano4-pyridyl)-2-pyrimidineamine are stirred in 15 ml of ethanol and 15 ml of 2N sodium hydroxide solution for 3 hours at 60°. After acidifying with 4N hydrochloric acid, N-(3-trifluoromethyl-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 241°-245°, FAB-MS: 361 (M+ +H).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[N:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccn(C)c(=O)n2)cc(C)c1I
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccn(C)c(=O)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)-1-methylpyrimidin-2(1H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.14 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5]C)=O.[Na].[C:11]1([N:17]2[C:21]([NH2:22])=[C:20]([CH:23]=O)[N:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[C:11]1([N:17]2[C:21]3[NH:22][C:3](=[O:5])[C:2]([C:1]([O:8][CH3:9])=[O:7])=[CH:23][C:20]=3[N:19]=[N:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1c(C=O)nnn1-c1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Reaction time: 18 h
Yield: 49.1 %

Procedure:
Dimethyl malonate (0.31 ml, 2.7 mmol) was added at room temperature to a stirred solution of sodium (0.065 g, 2.7 mmol) dissolved in dry methanol (8 ml) under nitrogen. A solution of 1-phenyl-4-formyl-5-amino-1,2,3-triazole (Bull. Soc. Chim. Belg., 1988, 97, 85-86) (0.50 g, 2.66 mmol) in dry methanol (4 ml) was added and the mixture was stirred for 18 h. The white suspension was diluted with water (50 ml) and the solids were collected and dissolved in dichloromethane-methanol (2:1, 100 ml). The solution was washed with aqueous citric acid (1 M, 50 ml), dried (Na2SO4), filtered and concentrated to give 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.353 g, 49%) as a white powder. δH (360 MHz; DMSO) 3.89 (3H, s), 7.56 (1H, t, J=7.5), 7.68 (2H, dd, J=7.5 and 7.5), 8.09 (2H, d, J=7.5), 8.92 (1H, s) and 12.67 (1H, br s); m/z (ES+) 271 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br.Br[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].[H-].[Na+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCBr
Reactant: O=[N+]([O-])c1cccc(-c2ncc[nH]2)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1ccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At rt and under N2, to a solution of 2-(3-nitrophenyl)-1H-imidazole (0.189 g, 1.00 mmol) and (2-bromoethyl)dimethylamine hydrobromide (0.280 g, 1.20 mmol) in anhydrous DMF (5 mL) was added NaH (60% in mineral oil, 160 mg, 4.0 mmol) in two portions with caution. The mixture was stirred at rt for 15 h. Water (0.3 mL) was added cautiously to quench the reaction. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=2.24 (s, 6H), 2.69 (t, J=7.2 Hz, 2H), 4.13 (d, J=6.8 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 8.04(dt, J=0.8, 8.0 Hz, 1H), 8.28 (dq, J=1.2, 8.4 Hz, 1H), 8.56 (t, J=1.6 Hz, 1H). MS (ES+): m/z 261.17 [MH+]. HPLC: tR=0.46 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCc1nc(-c2ccccc2)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCc1nc(-c2ccccc2)c(CBr)o1

Procedure:
5-Methyl-2-pentyl-4-phenyloxazole (4.25 g) was brominated with N-bromosuccinimide (3.4 g) in carbon tetrachloride in the presence of azobisisobutyronitrile (0.2 g). The procedure gave an oil of 5-bromomethyl-2-pentyl-4-phenyloxazole, yield 5.70 g (99.7%).
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([P:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([SH:16])=[S:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:1]1([S:16][P:14]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCCC1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: S=P(SC1CCCCC1)(C1CCCCC1)C1CCCCC1

Procedure:
Cyclohexylbromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain cyclohexyldicyclohexylphosphinodithioate, m.p. 82°-85° C, which on testing lasted 1250 hours* longer than the control. The average number of hours required to reach failure was 3.5 times that of the control.
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[OH:17])=[O:30].[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[OH:24])=[O:30]
Reactant: Oc1cccc(F)c1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(CCCCl)c1ccc(F)cc1O
Product: O=C(CCCCl)c1ccccc1O
Temperature: 130 °C
Reaction time: 18 h

Procedure:
To a cold boron trifluoride etherate (280 mmol) solution was added 3-fluorophenol or phenol (89 mmol) and 4-chlorobutyryl chloride (178 mmol). The resulting solution was stirred at 130° C. for 18 hours. The reaction mixture was cooled and poured into ice water (100 mL). After stirring for 10 minutes, the water mixture was extracted with ether (3×100 mL). The ether layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated to a residue to afford 4-chloro-1-(4-fluoro-2-hydroxyphenyl)butan-1-one and 4-chloro-1-(2-hydroxyphenyl)butan-1-one in 52%-67% yield, which was used in the following step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=S)=[N:7]1.[NH3:20]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:20])=[N:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[N:7]1
Reactant: OCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Product: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Yellow mercuric oxide (30.1 g.) was added quickly to a stirred solution of 1-(4-hydroxybutyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (10.4 g.) in methanolic ammonia (5 M; 340 ml.). After stirring for 3 hours at room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate evaporated to dryness in vacuo to give 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole, m.p. 105°-106° (yield 82%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:35][C:30]2C=[CH:32][CH:33]=[CH:34][C:29]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:35]2[CH2:32][CH2:33][CH2:34][CH2:29][CH2:30]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4.0 g of 4-iodobenzoic acid (16.13 mmol) in 40 ml of CH2Cl2 there are added 3.65 ml of diisopropylethylamine (20.97 mmol) and then, after 10 minutes, 5.18 g of TBTU (16.13 mmol). After stirring for 10 minutes more, 1.60 ml of piperidine (16.13 mmol) are added and the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is washed 3 times with water and then once with saturated NaCl. After drying (MgSO4) and evaporation under reduced pressure, the residue is chromatographed on silica (CH2Cl2/acetone 9/1) to yield the title product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C2C(=CC=CC=2)C=CN1[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#N.C(N1CCC(=O)CC1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:14][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1c2ccccc2C=CN1C(=O)c1ccccc1
Reactant: OC1(c2nccc3ccccc23)CCN(Cc2ccccc2)CC1
Agent: O=C1CCN(Cc2ccccc2)CC1
Product: O=C(OC1(c2nccc3ccccc23)CCN(Cc2ccccc2)CC1)c1ccccc1

Procedure:
A solution of 318 g. of 1-benzyl-4-(1-isoquinolyl)-piperidin-4-ol, obtainable by reacting 1-cyano-2-benzoyl-1,2-dihydroisoquinoline with 1-benzylpiperidin-4-one to give 1-benzyl-4-benzoyloxy-4-(1-isoquinolyl)-piperidine, which is subsequently hydrolyzed in 5 l. of methanol, is hydrogenated on 60 g. of 5% Pd-on-charcoal at 20° under 1 atmosphere of hydrogen. The mixture is filtered and the filtrate is evaporated to give 4-(1-isoquinolyl)-piperidin-4-ol, m.p. 138°-140°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)=[C:22]=[O:23].Cl>C(#N)C>[CH3:31][C:26]1[CH:25]=[C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:23])[CH:29]=[C:28]([CH3:30])[CH:27]=1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: Cc1cc(C)cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-isocyanato-3,5-dimethyl-benzene (0.17 mg, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3,5-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (280 mg, 67%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.4 min (96%); mp. 289-291° C. 1H NMR (DMSO-d6) δ 1.92-2.06 (m, 1H, CHH), 2.19 (s, 6H, CH3+CH3), 2.38 (qd, J=4.4, 13.1 Hz, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.80-3.02 (m, 1H, CHH), 4.17-4.58 (m, 4H, CH2+CH2), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 6.54 (s, 1H, Ar), 6.69 (t, J=5.9 Hz, 1H, Ar), 7.03 (s, 2H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.45 (s, 1H, NH), 10.98 (s, 1H, NH). 13C NMR (DMSO-d6) δ 21.12, 22.49, 31.20, 42.76, 47.10, 51.56, 115.54, 121.88, 122.78, 122.93, 126.91, 130.27, 137.49, 140.19, 142.38, 144.93, 155.21, 167.95, 170.99, 172.85; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.1H2O: C, 65.42; H, 5.78; N, 13.27. found: C, 65.15; H, 5.58; N, 13.18.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH2:16].[CH3:17][C:18]([CH3:20])=O>Cl>[CH2:17]([CH:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:8][CH2:9][CH:4](/[CH:1]=[CH:2]/[CH:3]=[O:16])[CH2:5][CH2:6]2)[CH2:11][CH2:12]1)[CH2:18][CH3:20]
Reactant: O
Reactant: CC(C)=O
Reactant: CCCC1CCC(C2CCCCC2)CC1
Agent: Cl
Product: CCCC1CCC(C2CCC(/C=C/C=O)CC2)CC1
Temperature: 25 °C

Procedure:
The resulting cyclohexane derivative was dissolved in a mixed solvent of acetone (80 ml) with 2N hydrochloric acid (8 ml), followed by heating the solution under reflux for 4 hours, cooling the reaction mixture down to room temperature after completion of the stirring, adding water, extracting with ether (50 ml), drying the organic layer over anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 3-(4-(4-propylcyclohexyl)cyclohexyl)-2E-propenal (3.1 g, 12 mmols). This product was used in the subsequent reaction without any purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.CN(C)C=O.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35].C(N(CC)CC)C>O>[CH3:32][CH:33]([CH3:37])[C:34]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:35]
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 26 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 5 mL N,N-dimethylformamide, 13.7 μL 2-methylpropanoyl chloride and 18.2 mL N,N-diethylethanamine was stirred at 23° C. overnight. Water was added and the solvents were removed. The residue was purified by chromatography to give 16 mg (26%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][CH:23]([CH3:25])[CH3:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1cccc(Cl)c1
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1cccc(Cl)c1

Procedure:
A solution of 2-(3-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (12 g.) and isopropyl-amine (120 cc.) in anhydrous toluene (200 cc.) is heated under reflux for 5 days. The reaction mixture is then evaporated to dryness under reduced pressure and the residue obtained is recrystallised from ethyl acetate (65 cc.). After drying, 2-(3-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one (11.6 g.), melting at 128° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CC(C)=[O:22]>>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:22])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Product: O=C(O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 77 %

Procedure:
To a cold solution of 4′-trifluoromethoxy-biphenyl-4-carbaldehyde (0.9 g, 3.38 mmol) in acetone (10 mL) the Jone's reagent was added slowly at 0° C. drop wise until reaction completes. Acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.7 g, 77%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 46.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-93, 0.350 g, 1.00 mmol), pivaloyl chloride (0.128 g, 1.0 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO c/6): δ 1.13 (s, 9H), 2.34 (s, 3H), 4.29 (d, J=6.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.58-7.61 (m, 2H), 7.82 (d, J=8.7 Hz, 1H), 8.01 (s, 1H), 8.18 (t, 1H), 12.58 (s, 1H); MS (m/z): 433.19 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:27])([F:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reactant: O=C(Cl)C(F)(F)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccccc2)c1F
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of DIEA (1.49 mL, 8.55 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (690 mg, 2.85 mmol), as prepared in the preceding step, in DCM (6 mL) was added a solution of 2,2-difluoro-2-phenylacetyl chloride (0.99 g, 5.20 mmol), as prepared according to the procedure of step 3 of Example 1, in DCM (3 mL). After stirring for 24 hours, the mixture was concentrated, and partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to give the title compound (1.04 g, 92% yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 8.49-8.43 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 6.68 (d, J=7.1 Hz, 2H), 7.55-7.49 (m, 3H), 4.35 (t, J=6.4 Hz, 2H), 3.37 (dt, J=6.3, 2.3 Hz, 2H), 2.01 (s, 3H).