Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[H][H]>CO.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: [H][H]
Reactant: C=C(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:23]1([CH:28]=[CH:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:28]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:29][C:30]#[N:31])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CC=CC1CCCC1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a stirred suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 158 mg, 0.50 mmol) and 3-cyclopentylacrylonitrile (8, 122 mg, 1.0 mmol, 2.0 equiv) in dimethyl sulfoxide (DMSO, 1.0 mL, 14 mmol) at room temperature was added powder potassium carbonate (K2CO3, 10.4 mg, 0.075 mmol, 0.15 equiv). The reaction mixture was then stirred at room temperature for 5 h. The reaction mixture became a clear solution in 2 h. When LCMS showed the reaction was deemed complete, the reaction was quenched with water (H2O, 5 mL) and extracted with ethyl acetate (EtOAc, 3×15 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 172.6 mg, 210 mg theoretical, 82% yield) as a white solid. For 20: 1H NMR (CDCl3, 400 MHz) δ ppm 8.87 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.47 (d, 1H, J=3.9 Hz), 6.75 (d, 1H, J=3.9 Hz), 6.24 (s, 2H), 4.25 (m, 1H), 3.12 (dd, 1H, J=17.0, 8.7 Hz), 2.95 (dd, 1H, J=17.0, 3.9 Hz), 2.58 (m, 1H), 1.95 (m, 1H), 1.72-1.52 (m, 5H), 1.25 (m, 2H), 1.14 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)#[N:2].[OH:40]O.[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C(N)=O)cc34)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{N-[3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenyl]carbamoyl}piperidinecarboxylate in 3 mL of ethanol, was added 3 mL of 30% commercially available H2O2 solution followed by 0.280 mL of 6.0 N aqueous NaOH solution. Within 30 min, the formation of an abundant white precipitate was observed. The mixture was acidified using a 6.0 N aqueous solution of HCl. Upon addition of water (20 mL), the formation of a precipitate was observed. The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven overnight. The desired product was isolated as a pure white solid (0.277 g, 40% over 2 steps): ES-MS (m/z) 548 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (34.6 mg) with purity >90%: LCMS (pos) m/z 409.0, 411.0; HRMS m/z 407.9753 (calc. of monoisotopic mass for C14H14Cl2N2O4S2 gives 407.9772).
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([CH2:18]OS(C)(=O)=O)[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([SH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([S:37][CH2:18][C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=3)[N:17]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(SCc2nc(-c3ccncc3)no2)CC1
Reaction time: 1.67 h

Procedure:
t-BuOK (92 mg, 823 μmol) and methanesulfonic acid 3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl ester (Preparation 12, 150 mg, 588 μmol) were added to a stirred solution of 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (191 mg, 881 mol) in anhydrous THF (10 ml). After 100 min, the reaction mixture was diluted with Et2O, before being washed with NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated, then the residue was purified by column chromatography (IH-EtOAc, 3:2) to afford the title compound: RT=3.77 min; m/z (ES+)=377.2 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([C:12]2[N:13]=[C:14]([CH2:26][CH3:27])[C:15]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:16][C:17]=2[CH2:18][CH3:19])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[ClH:28].N([O-])=O.[Na+]>O.Cl[Cu]>[Cl:28][C:2]1[C:3]([C:12]2[N:13]=[C:14]([CH2:26][CH3:27])[C:15]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:16][C:17]=2[CH2:18][CH3:19])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cl
Reactant: CCc1nc(-c2cc3c(cc2N)CCCC3)c(CC)nc1NC(CC)CC
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(-c2cc3c(cc2Cl)CCCC3)c(CC)nc1NC(CC)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 5-(3-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (118 mg, 0.32 mmol), con. HCl (3.41 mL) and cooled with an ice bath for 30 minutes. The solution was yellow. A cold solution of NaNO2 (22.4 mg, 0.325 mmol) in H2O (0.64 mL) was added and the mixture stirred at 0° C. for 30 minutes. A light precipitate was observed. A cold CuCl (38.2 mg, 0.386 mmol) solution in con. HCl (0.853 mL) was added and the mixture continued to stir at 0° C. for 20 minutes. The reaction turned dark. The cooling bath was removed, and after stirring at ambient temperature for 2 hours the color lightened and gas evolution was observed. The reaction was then heated to 60° C. for 20 minutes. More gas evolution was observed. After heating the reaction became clumpy. It was cooled with an ice bath and basified with aq. NaOH. The reaction turned blue/green in color. The now basic reaction mixture was diluted with water, extracted three times with CH2Cl2, the organics were combined, dried with Na2SO4, filtered and concentrated to 110 mg of a crude brown oil. PREP TLC followed by silica gel chromatography (4.5 g) using toluene) gave 4.45 mg (4%) of 5-(3-chloro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine as a yellow oil. Rf 0.16 (toluene). OAMS supporting ions at: ESI+386.1. HRMS (ESI) calcd for C23H32N3CL+H1 386.2363, found 386.2358.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: OO
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.06 g, 8.86 mmol), an aqueous solution (7 ml) of sodium chlorite (0.460 g, 5.11 mmol) and aqueous hydrogen peroxide (0.502 ml, 30%) were added to an acetonitrile solution (10 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-methoxybenzaldehyde (0.409 g, 1.14 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.260 g, 0.691 mmol, 61%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([NH:1][CH2:2][C:3]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CCOC(=O)c1cc(CN)cc(C(=O)OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)OCC)c1
Yield: 35 %

Procedure:
To a stirring solution of crude diethyl 5-(aminomethyl)isophthalate in 30 mL of CH2Cl2 at 0° C. was added 1.2 mL of Et3N and 0.7 mL of MsCl. The ice bath was removed, and after 2 h at r.t. the solution was concentrated, and EtOAc and H2O were added. The organic layer was washed with brine, the aqueous layer was extracted with EtOAc, the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 901 mg of diethyl 5-(methylsulfonamidomethyl)isophthalate as a pale yellow solid in 35% yield.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH:22]=[CH:23][CH:24]=1.C(Cl)Cl.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:50](O)=[O:51]>C(N(CC)CC)C>[Cl:41][C:37]1[CH:36]=[C:35]([C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:50](=[O:51])[C:49]3[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:47]([O:46][CH3:45])[CH:48]=3)[CH2:31][CH2:30]2)=[O:28])[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
0.44 ml of diphenylphosphoryl azide and 0.545 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) were added to 10 ml of a methylene chloride solution containing 0.25 g of 3,4-dimethoxybenzoic acid and 0.38 ml of triethylamine, and the reaction mixture was stirred for 16 hours at room temperature. At the end of this time, the mixture was washed with 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure chromatography using two Lobar B columns eluted with mixtures of hexane and ethyl acetate ranging from 1:2 to 1:4 by volume, to give 0.682 g of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.O1CCCCC1[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:24]=[CH:25][C:2]([C:38]5[CH:37]=[N:36][N:35]([CH2:34][CH2:33][OH:32])[CH:39]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: OCCn1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Yield: 48 %

Procedure:
Following the procedure for 182, 9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 206 (0.056 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.33 (d, J=8.4, 1H), 8.24 (s, 1H), 8.07 (d, J=11.7, 2H), 7.95 (d, J=8.9, 1H), 7.41 (dd, J=8.4, 1.7, 1H), 7.28 (d, J=1.7, 1H), 5.91 (q, J=8.8, 2H), 4.91 (t, J=5.3, 1H), 4.54 (dd, J=10.8, 5.6, 4H), 4.16 (t, J=5.6, 2H), 3.87-3.69 (m, 2H). MS (ESI(+)): m/z 446.1 (M+H)
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-])=O)[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[H][H]>[Pd]>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH2:22])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(N)c1

Procedure:
A mixture of 0.05 moles of ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate in 100 ml. methanol containing 0.05 mole citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 2 atm. pressure and 27°C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl α-hydroxy-γ-(3-amino-4-cyclohexylphenyl)butyrate, isolated as the citrate salt.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:10]2=[CH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1.CN(C)[CH:20]=[O:21]>>[CH2:6]1[C:10]2=[C:11]([CH:20]=[O:21])[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1
Reactant: c1cc2c(cn1)cc1n2CCC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2n(c3ccncc13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To dimethylformamide (0.3 ml) was added phosphorus oxychloride (0.33 ml) dropwise at 0° C. The mixture was allowed to stir for 10 min at room temperature. A solution of 2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]indene (0.10 g 0.63 mMol) in 0.1 ml dimethylformamide was added and the mixture was stirred at room temperature for 3 h. The reaction was quenched with ice (ca 5 g) and the pH was adjusted to 9 by addition of 28% sodium hydroxide. The mixture was heated to reflux for 10 min. cooled to room temperature and extracted with ethyl acetate(3×5 ml) The combined organic extracts were dried with sodium sulfate and evaporated to dryness to yield the title compound (0.115 g, 97% Th). For analytical purposes a sample was recrystallised from ethyl acetate to afford slightly yellow crystals. mp 150-151° C. Found C, 70.94; H, 5.56; N, 14.97%; C11H10N2O requires C, 70.95; H, 5.41; N. 15.04%
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbamate (92 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (51 mg, 74%). 1HNMR (DMSO-d6) 400 MHz δ: 8.55 (s, 1H), 8.09-8.04 (m, 1H), 7.98-7.93 (m, 1H), 7.70 (br s, 1H), 7.48 (d, J=6.9 Hz, 2H), 7.39-7.06 (m, 10H), 6.94-6.87 (m, 1H), 6.78-6.65 (m, 1H), 1.44-1.08 (m, 13H). LCMS: 542 [M+H].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[CH3:1]
Reactant: CCN1CCC[C@H]1CN
Reactant: C[C@H]1CCCN1
Agent: CC=O
Product: CNCCN1CCC[C@@H]1C

Procedure:
By using (S)-2-methyl-pyrrolidine (250 mg) as a starting material, the title compound (0.34 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)[C:25]([OH:27])=[O:26])(=O)=O)CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:71][C:68]1[CH:69]=[CH:70][C:65]([C:62]2[CH:63]=[CH:64][C:59]([N:56]3[CH2:55][CH2:54][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:47])[CH3:48])[C:25]([OH:27])=[O:26])(=[O:51])=[O:52])[CH2:58][CH2:57]3)=[N:60][CH:61]=2)=[CH:66][CH:67]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Yield: 33 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluoro-phenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonyl methyl}-3-methylbutyryl)-oxazolidin-2-one (0.312 g), to give the title compound as a white solid (0.077 g, 33%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: C1COCCN1
Product: O=C(O)c1cc(Br)ccc1N1CCOCC1

Procedure:
The title compound was prepared according to the procedure described for example B step 1 from 5-Bromo-2-fluorobenzoic acid and morpholine except that the mixture was heated at 130° C. for 48 hours (77%, white solid), 1-H-NMR (300 MHz, CDCl3) δ=8.45 (d), 7.74 (dxd, 7.33 (d)
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[F:22][C:19]1[CH:18]=[C:14]2[C:13](=[CH:21][CH:20]=1)[N:12]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[NH:17][C:15]2=[O:16]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution of 2-amino-5-fluorobenzamide (13.0 g, 84 mmol) and triethylamine (16 mL, 110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediately a precipitate started forming. Stirring of the solution was continued for 5 hours at room temperature. The formed precipitate was collected by filtration and was washed twice with diethyl ether and dried at 50° C. in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxide solution (250 mL) and heated at reflux until a clear solution was obtained (3 hours). The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified to pH<1 with concentrated aqueous HCl. The formed precipitate was collected by filtration and washed twice with water, twice with methanol, and twice with diethyl ether. The solid was dried in an oven at 45° C. to yield 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (18.2 g, 80%) as a white solid.