Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH:21]4[CH2:22][CH2:23][CH:17]3[CH2:18][O:19][CH2:20]4)[CH:13]=[C:12]([N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CC(O)C.ClCCl.[Pd]>[CH:25]12[N:24]([C:12]3[CH:13]=[C:14]([N:16]4[CH:21]5[CH2:22][CH2:23][CH:17]4[CH2:18][O:19][CH2:20]5)[N:15]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:11]=3)[CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 4 h
Yield: 86.1 %

Procedure:
In a 250 mL round-bottomed flask was placed 8,8′-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane) (37, 246 mg, 0.581 mmol) in 2-propanol (3 mL) and dichloromethane (3 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 4 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (40-60%). Collected fractions were concentrated to give the title compound (197 mg, 0.5 mmol, 86%) as a light yellow solid. For [M+H]+ mass error=0.2 mDa or 0.46 ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[C:4]([C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6])=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=CN(C)C)C(=O)C1CC1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
3-Cyclopropyl-3-oxo-propionic acid methyl ester (1.25 g, 8.79 mmol) was dissovled in 6.25 mL of CHCl3 and 1.17 mL (8.79 mmol) of dimethylformamide dimethyl acetal was added. The mixture was heated to 60° C. in a sealed vessel overnight. The mixuture was then cooled and concentrated to provide 1.67 g of 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:61])[N:24]([C@@H:26]([C:38](=[O:60])[N:39]([C@H:41]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]([CH3:52])[CH3:51])=[O:43])[CH3:40])[CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH3:25])[CH:18]=1)C)(C)(C)C>ClCCl>[CH2:53]([C@@H:41]([N:39]([CH3:40])[C:38]([C@H:26]([N:24]([CH3:25])[C:23](=[O:61])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][NH:14][CH3:13])[CH:18]=1)[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:60])[C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[CH2:49][N:50]([CH3:51])[CH3:52])=[O:43])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(C(=O)N(C)[C@H](Cc2ccc3ccccc3c2)C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N2CCC[C@H]2CN(C)C)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.1 %

Procedure:
At 0° C., trifluoroacetic acid (7 ml) was added to a solution of N-(3-[N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]benzyl}-N-methylcarbamic acid tert-butyl ester (523 mg, 0.70 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 25 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (90 ml), and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 436 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@H:23]([C:25]([O:27]C)=O)[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:42]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@H:23]([C:25]([NH2:42])=[O:27])[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 94.9 %

Procedure:
In a sealed tube a solution of methyl(2S,5S,7R)-8-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 23, 80 mg, 0.136 mmol) in 7 M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated to dryness and the crude was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (74.4 mg, 0.129 mmol, 95% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H) 7.61 (s, 2H) 7.15-7.28 (m, 2H) 6.84-6.97 (m, 2H) 6.78 (t, 1H) 4.63 (d, 1H) 4.34 (d, 1H) 4.08-4.22 (m, 1H) 3.48-3.55 (m, 1H) 3.33-3.42 (m, 1H) 2.93 (s, 3H) 2.76 (t, 1H) 2.65 (br. s., 1H) 2.31 (s, 3H) 2.01-2.16 (m, 1H) 1.38-1.85 (m, 7H); HPLC: Rt=4.91 mins; MS: m/z=575 [M+H]+ and 597 [M+Na]+.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1CCCN1c1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCCN1c1cccc(CBr)n1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A stirred solution of 1-(6-hydroxymethylpyridin-2-yl)pyrrolidin-2-one (10.19 g, 53.01 mmol), in dichloromethane (600 mL), was treated with triphenylphosphine (15.29 g, 58.31 mmol) followed by carbon tetrabromide (15.66 g, 58.31 mmol), stirred for 1 h, concentrated in vacuo and purified by column chromatography (SiO2; EtOAc:hexane (1:1)) to give the title compound (10.19 g) as a white solid also containing triphenylphosphine oxide as an impurity; NMR δH (400 MHz, d6-DMSO) inter alia 8.22 (1H, d, J 8.5 Hz), 7.81 (1H, t, J 7.5 Hz), 7.28 (1H, d, J 7.5 Hz), 4.63 (2H, s), 3.98 (2H, t, J 7.0 Hz), 2.58 (2H, t, J 8.0 Hz) and 2.08-2.00 (2H, m); (M+H)+ 255, 257.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:12]3[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:11]=3[C:10]=2[C:35]#[N:36])[CH:5]=[CH:4][C:3]=1[N:37]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]1.O.C(=O)(O)[O-:52].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:12]3[N:24]=[CH:25][NH:26][C:11]=3[C:10]=2[C:35]([NH2:36])=[O:52])[CH:5]=[CH:4][C:3]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)cc2Cl)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)c(Cl)c2)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 95 °C

Procedure:
To a solution of the product of Example 18C (100 mg, 0.14 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, water (3 mL) was added, and the mixture was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.62 (s, 1 H), 11.85 (s, 1 H), 9.62 (s, 1 H), 8.69 (s, 2 H), 8.61 (s, 1 H), 7.85 (br, 1 H), 7.58 (m, 1 H), 7.55 (m, 1 H), 7.52 (d, J=2.4 Hz, 1 H), 7.42-7.37 (m, 1 H), 7.15 (dd, J=9, 2.4 Hz, 1 H), 6.85 (d, J=9 Hz, 1 H), 4.74 (s, 2 H), 3.27 (m, 4 H), 2.08-1.70 (m, 4 H). MS: 530 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N:20]=[C:21]=[S:22])(=O)C1C=CC=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:21]([NH2:20])=[S:22])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCNC(N)=S
Yield: 84.9 %

Procedure:
To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanamine (WO 0007985: 24.4 g) in THF (300 mL) was added benzoyl isothiocyanate (22.7 g), and the mixture was mixed for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol (150 mL). To the resulting solution were added potassium carbonate (5.0 g) and water (50 mL), and the mixture was mixed for 2 hours. The insolubles were filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, sequentially washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (27.7 g) as a colorless oily matter.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:7](=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:1]([C:3]1[C:11]2[C:7](=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc2c(-c3ccccc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2c(-c3ccccc3)onc12
Reaction time: 2.5 h

Procedure:
To a solution of 12.2 g (0.054 mole) of 7-ethyl-3-phenyl-2,1-benzisoxazole in 60 ml of carbon tetrachloride was added 10.5 g (0.059 mole) of N-bromosuccinimide and 0.1 g of dibenzoylperoxide. The stirred reaction mixture was heated at reflux under flood light illumination and an argon atmosphere for 2.5 hr. The cooled reaction mixture was filtered and the filter cake was washed with 40 ml of carbon tetrachloride. The combined filtrates were washed with three 100 ml portions of 10% sodium bicarbonate, twice with 100 ml portions of water and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was treated with charcoal and filtered. The filtrate was concentrated to give 16.2 g (98%) of slightly impure title compound as a light brown oil that solidified upon standing. A sample was recrystallized from diethyl ether-petroleum ether (30°-60° C.) to give yellow crystals, m.p. 73°-77° C.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][N:38]([CH2:41][C:42](O)=[O:43])[C:37](=[O:45])[N:36]=1)=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:42](=[O:43])[CH2:41][N:38]2[CH:39]=[CH:40][C:35]([NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])=[N:36][C:37]2=[O:45])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1ccn(CC(=O)O)c(=O)n1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(2-methylthioethoxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.72 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.01 (t, 1H), 4.82 (s, 1.2H), 4.71 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.26 (t, 2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H), 2.73 (t, 2H), 2.11 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][N:16]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc3ncc(C=O)n3c2)cn1
Yield: 55.55 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methoxypyrimidin-5-ylboronic acid. Yield: 55.55%; 1H NMR (DMSO-d6; 300 MHz): δ 10.01 (s, 1H), 9.62 (s, 1H), 9.00 (s, 2H), 8.59 (s, 1H), 8.04-8.05 (m, 2H), 3.99 (s, 3H); MS: m/z 254 (M+1)+.
Reaction SMILES: C(O[C:4](=[O:8])[O:5][CH2:6][CH3:7])C.[NH:9](CCO)[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][N:9]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]
Reactant: CCOC(=O)OCC
Reactant: OCCNCCO
Product: O=C1OCCN1CCO

Procedure:
This compound was prepared from diethylcarbonate and diethanolamine in accordance with the method of E. K. Drechsel in the Journal of Organic Chemistry 22 (1957), page 851. A clear, slightly colored liquid having a boiling point of 154° was obtained.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:25][C:26]1[C:31](O)=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:31]3[C:30]([F:33])=[C:29]([F:34])[C:28]([F:35])=[C:27]([F:36])[C:26]=3[F:25])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
100 g of 4-octyloxybiphenyl-4′carboxylic acid and 62 g of pentafluorophenol are introduced into 1 liter of dichloromethane. Agitation is carried out for 15 minutes and 69.6 g of N,N′-dicyclohexylcarbodiimide in solution in 500 ml of dichloromethane is added over 15 minutes. The dark beige suspension is agitated for 20 hours at ambient temperature. The dicyclohexylurea is filtered and the filtrate is concentrated. Distillation to constant volume is carried out by the regular addition of ethanol up to the vapour temperature of 74° C. The reaction medium is cooled down to ambient temperature, followed by agitating for one hour, filtering then washing with ethanol. After drying, 145.7 g of sought product is obtained in the form of crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A solution of N,N-diisopropylamine (909 mg, 1.25 mL, 9 mmol) in tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (3.6 mL, 9 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of tetrahydro-pyran-2-carboxylic acid methyl ester (864 mg, 6 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 minutes. Acetaldehyde (792 mg, 1.0 mL, 18 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.28 g) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 189.3 [M+H], Tr=1.23 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][O:19][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CCO)CC2)COC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(CCOCc3ccccc3)CC2)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15.1 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[1-(2-hydroxyethyl)cyclopropylmethyl]-1,3-oxazolidine are dissolved in 50 ml of tetrahydrofuran, and 14.2 g of a potassium hydride suspension (20% in oil) are added at 0° C. The mixture is stirred at 0° C. for 1 h and 6.3 ml of benzyl bromide are then added dropwise, while stirring. After 90 min., 100 ml of water are slowly added to the reaction mixture and the aqueous phase is extracted with diethyl ether. This gives the title compound: Rf (A)=0.8; FAB-MS: (M+H)+ =390.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([O:11][C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][N:5]=[CH:4]3)[CH2:13]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: O=Cc1ccccc1Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(O[C@@H]2CCC[C@H](NCc3ccccc3Cl)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of the cis-3-[(4-methyl-1H-indazol-5-yl) oxy]cyclohexanamine (100 mg, 0.407 mmol) obtained in Example 411 in methanol (5 ml) were added 2-chlorobenzaldehyde (46 μl, 0.407 mmol) and acetic acid (23 μl, 0.407 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. Then, acetic acid (46 μl, 0.814 mmol) and sodium cyanoborohydride (28 mg, 0.447 mmol) were added thereto and stirred for 2 hours and a half. Subsequently, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain cis-N-(2-chlorobenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 66%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: OC1C=CCC1
Reactant: CC(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
2-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[C:9]32)=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][C:12]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[C:9]32)=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccc(Cl)cc3c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CN2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.7 g of 10-chloro-N,N-diethyl-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide are suspended in 65 ml of tetrahydrofuran under argon, whereupon 150 mg of lithium borohydride are added thereto, the mixture is stirred at room temperature for 4 hours, an additional 75 mg of lithium borohydride are added thereto and the mixture is stirred further until the reaction finishes. The reaction mixture is poured into 300 ml of ice-water, whereby the product crystallizes out. The crude product is chromatographed on silica gel. By recrystallization from toluene, there is obtained 10-chloro-N,N-diethyl-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide of m.p. 192°-194° (toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-chloro-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (DMSO-d6): 11.31 (s, 1H), 9.02 (d, J=2.4, 1H), 8.96 (d, J=9.3, 1H), 8.31 (d, J=2.4, 1H), 8.24-8.20 (m, 1H), 7.73-7.69 (m, 1H), 7.54 (d, J=8.4, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:18][CH2:16][CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CCN
Product: CCNCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 248.