Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2csc(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc(C)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.19 g), sodium hydrogen carbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.47 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.43 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.93 g, 87%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:61]3[CH:62]=[N:57][CH:58]=[N:59][CH:60]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]2=3)[CH2:27][CH2:26][O:25]4)[C:5]1=[O:18]
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1cncnc1
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (16%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5 (M+1).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].C(ON=O)(C)(C)C>C(O)(=O)C.C1COCC1>[CH3:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[CH3:8])[C:15]1[C:14](=[C:23]3[C:18](=[CH:17][CH:16]=1)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13][S:10]2(=[O:12])=[O:11]
Reactant: Cc1cc(N)c(S(=O)(=O)Nc2cccc3cccnc23)cc1C
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C)S(=O)(=O)Nc1c-2ccc2cccnc12
Temperature: 0 °C
Yield: 7.3 %

Procedure:
2-Amino-4,5-dimethyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 164) (100 mg, 0.31 mmol) was suspended in acetic acid: THF (1:1) (2 ml) and cooled to 0° C. Tert-butylnitrite (54 μl, 0.46 mmol) was added and the reaction was slowly warmed to 5° C. over 3 h. The reaction was quenched with water (4 ml) and the resulting solution was concentrated in vacuo. The residue was dissolved in EtOAc (10 ml) and washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (7 mg, 7%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.34 g, 1.1 mmol) and phenylboronic acid (0.16 g, 1.4 mmol) in 1,4-dioxane (10 mL) was added a 1 N solution of sodium carbonate in water (1.5 mL, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.057 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-50% ethyl acetate/hexanes) to give the desired product (0.23 g, 68%). LCMS calculated for C14H12N5OS (M+H)+: m/z=298.1. Found: 298.0.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2cccc(C)n2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2nc(CO)c(Br)c(=O)n12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A heterogeneous mixture of (3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4.2444 g, 13.64 mmol), concd. HCl (3.87 mL, 46.4 mmol), and 1,4-dioxane (39.0 mL) was heated with stirring at 70° C. After 3 h, the mixture was cooled to rt and the mixture was concd under reduced pressure. The residue was diluted with water (100 mL) and the pH adjusted to 10 with 28% ammonium hydroxide (10 mL). The precipitate was filtered, washed with water (200 mL), and dried under high vacuum to give 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (1 H, dd, J=8.8, 6.8 Hz), 7.49 (1 H, dd, J=9.0, 0.8 Hz), 7.01-7.06 (1 H, m), 5.24 (1 H, t, J=6.1 Hz), 4.52 (2 H, d, J=6.3 Hz), 2.96 (3 H, s); Mass Spectrum (ESI) m/e=268.9 [M+1 (79Br)] and 271.0 [M+1 (81Br)].
Reaction SMILES: [O:1]=[C:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([CH2:31][CH3:32])[C:6](=[O:30])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][C:10](=[O:29])[C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.Cl>>[OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([CH2:31][CH3:32])[C@@H:6]([OH:30])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][C@H:10]([OH:29])[C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1
Reactant: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)C(=O)C[C@@H]23)[C@@]2(C)CCC(=O)C[C@@H]12
Agent: Cl
Product: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)[C@@H](O)C[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of the triketo ester 8 (0.1 g, 0.22 mmol) in CH2Cl2 (8 ml) tert-butylamine-borane complex (0.1 g, 1.12 mmol) was added and the reaction was refluxed overnight. The reaction was cooled to room temperature 3N HCl was added and the resulting mixture was stirred for 30 min. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (10 ml), water (10 ml), was dried over anhydrous sodium sulfate and evaporated to dryness. The residue, in which the 7-ketone was not reduced, was dissolved in a mixture 1:4 v/v of H2O/THF (5 ml) and NaBH4 was added at 0° C. The mixture was stirred at room temperature for 30 min, then water (5 ml) and 3N HCl (5 ml) were added. The mixture was extracted with EtOAc (4×30 ml), the combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue, which consist of at least 2 components, was purified by flash chromatography, using from 1 to 4% MeOH in CHCl3 to yield 0.036 g (0.08 mmol, 36%) of the desired compound 9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[N+:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[C:39]=1[NH2:45])([O-:37])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)CCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([N+:35]([O-:37])=[O:36])[C:39]=1[NH2:45])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCCC(=O)Nc1cccc([N+](=O)[O-])c1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of 9 g of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (prepared from 4-(methylamino)butyric acid and BOC anhydride) in 159 mL DCM were added 14.2 mL of DIPEA, 8 g of HOBt and 9.1 g of EDC. After stirring for 5 min 6.1 g of 3-nitro-benzene-1,2-diamine were added and the mixture was stirred for 4 days at rt. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC using EtOAc/heptane 1/4 to 3/1 yielded 5.2 g of [3-(2-Amino-3-nitro-phenylcarbamoyl)-propyl]methyl-carbamic acid tert-butyl ester as orange foam.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:54])[C@H:14]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:39][CH2:38]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](S(CC[Si](C)(C)C)(=O)=O)[N:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+]>C(#N)C>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:54])[C@H:14]([NH:34][C:35]([N:37]3[CH2:38][CH2:39][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:41][CH2:42]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(N[C@H](Cc1ccc2[nH]ncc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Yield: 62.6 %

Procedure:
A solution of (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]bipiperidinyl-1′-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide (568 mg, 0.73 mmol) and cesium fluoride (1.11 g, 7.31 mmol) was heated at 80° C. in acetonitrile (50 mL) for 4.5 h. The reaction mixture was concentrated and the residue was subjected to flash column chromatography (methylene chloride/methanol/triethylamine, 94:5:1) to give 280 mg (63% yield) of the title compound as a white solid with 98.2% ee as determined by HPLC analysis using a Chirocel OD column with 20% B (A=ethanol, B=0.05% diethylamine in hexanes) as eluent (Retention times: 9.51 min for title compound and 15.9 min for S-enantiomer). 1H-NMR (CD3OD, 500 MHz) δ 8.04 (s, 0.75H), 8.03 (s, 0.25H), 7.67 (s, 0.75H), 7.65 (s, 0.25H), 7.56 (d, J=8.5 Hz, 0.75H), 7.51 (d, J=8.5 Hz, 0.25H), 7.41 (d, J=8.5 Hz, 0.75H), 7.31 (d, J=8.5 Hz, 0.25H), 7.19-7.12 (m, 2H), 6.97-6.94 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 5.08-5.05 (m, 1H), 4.60-4.53 (m, 1H), 4.48-4.40 (m, 1H), 4.37 (s, 1.5H), 4.26 (s, 0.5H), 4.24-4.14 (m, 2H), 4.06-3.97 (m, 1H), 3.15 (d, J=7.9 Hz, 1.5H), 3.12-3.05 (m, 0.5H), 2.94-2.86 (m, 3H), 2.57-2.51 (m, 1.5H), 2.47-2.42 (m, 1H), 2.37-2.33 (m, 0.75H), 2.03-2.02 (m, 1.5H), 1.87-1.75 (m, 3.75H), 1.73-1.68 (m, 2H), 1.67-1.54 (m, 3H), 1.53-1.44 (m, 4H), 1.43-1.34 (m, 2H), 1.30-1.26 (m, 1H), 0.83-0.77 (m, 0.75H), −0.16 to −0.24 (m, 0.75H). Mass spec.: 613 (MH)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:16][CH2:17][O-].[Na+].[CH2:20]([C:28]1[CH:33]=[CH:32][C:31](CCO)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.CO>C(O)C>[C:1]([NH:4][C:5]([CH2:26][C:25]#[C:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:17][CH3:16])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc(CCO)cc1
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCCCC#CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl acetamidomalonate (3.327 g) and 1.137 g of sodium ethylate were dissolved in 50 ml of dry ethanol and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. A solution of 4.000 g of the compound of (3) above in 30 ml of dry ethanol was added thereto and the mixture was refluxed for 15 hours. Methanol (50 ml) was added to the reaction mixture and the insoluble matters were removed. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography to give 3.236 g of diethyl 2-acetamido-2-(2-pentadecynyl)malonate.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-])=O)=[C:18]([NH2:20])[CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(O)C.[Pd]>[NH2:20][C:18]1[CH:19]=[C:14]([C:10]2([CH3:13])[CH:9]3[CH:11]2[CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8]3)[CH:15]=[CH:16][C:17]=1[NH2:21]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
To a solution of 5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenylamine (Preparation 47, 360 mg, 1.14 mmol) in ethanol (15 ml) was added 10% palladium on carbon (50 mg). The mixture was placed under an atmosphere of hydrogen (50 psi, 345 kPa) and heated at 50° C. for 16 hours. The mixture was then cooled and filtered through Celite™, washing with ethanol. The filtrate was concentrated in vacuo to give the crude title compound (328 mg, 100%) as a yellow oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[C:21]([F:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:28][C:21]1[CH:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[C:23]([O:25][CH3:26])[C:22]=1[F:27]
Reactant: OB(O)c1cncnc1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(F)c1F
Product: COc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc(F)c1F
Yield: 14 %

Procedure:
The title compound was synthesized as described for Example 45 in 14% yield starting from 1-(3-Bromophenyl)-1-(3,4-difluoro-5-methoxyphenyl)-4-fluoro-1H-isoindol-3-amine (714 mg, 1.60 mmol) and pyrimidine-5-boronic acid (237 mg, 1.92 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@H:10]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.[ClH:44]>C(COC)OC.C(O)(C)C>[ClH:44].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([O:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C@H:10]3[C@H:11]([O:15][C:16](=[O:24])[C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9]3)=[O:43])=[CH:28][CH:29]=2)=[O:42])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(O)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Agent: Cl
Solvent: COCCOC
Solvent: CC(C)O
Product: O=C(N[C@@H]1CNCCC[C@H]1OC(=O)c1ccc(O)cc1)c1ccc(OC(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
56 mg (3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylic acid tert-butyl ester was dissolved in 2 ml dimethoxyethane and 2 ml isopropanol (i-Pr-OH); after cooling to 0° C. the solution was slowly saturated with HCl-gas and stored in a refrigerator for 24 h. The solvent was completely removed in vacuo; the product was triturated with diethylether; the resulting suspension was stirred for several hours. The solvent was decanted and stirring was continued overnight after addition of another portion of fresh solvent. The product was filtered, washed with several portions of diethylether and dried in vacuo (0.1 mbar) at 50° C. 40 mg (85% yield) 4-Hydroxy-benzoic acid (3R,4R)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepan-4-yl ester hydrochloride (1:1) was obtained as a yellow powder
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:12])=[CH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[CH3:13][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:12])=[CH:9][CH:10]([OH:11])[CH3:13])=[CH:6][CH:7]=1
Reactant: O=CC=C(Cl)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C=C(Cl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a cooled (-78° C.) solution of 3-(4-chlorophenyl)-3-chloroacrolein (2.0 g, 10.4 mmol, obtained according to Hauptmann et al, Tetrahedron Lett. 1968, 1317) in dry THF (30 mL) was added dropwise a 3M solution of methylmagnesium bromide in THF (3.47 mL, 10.4 mmol). After the addition was complete, the reaction mixture was stirred at -78° C. for 0.5 h. Next, saturated aqueous NH4Cl solution was added and the mixture was concentrated. The resulting aqueous residue was extracted with CHCl3, dried, filtered, concentrated and purified by flash chromatography to give 4-(4-chlorophenyl)-4-chloro-3-buten-2-ol (1.54 g, 71%) as a colourless oil: 1H NMR (300 MHz, CDCl3) δ (TMS) 7.51 (dt, Jt =2.6, Jd =8.6, 2H, arom), 7.33 (dt, Jt =2.6, Jd =8.6, 2H, arom), 6.18 (d, J=7.5, 1H, =CH), 4.93 (quint, J=6.4, 1H, CHOH), 1.39 (d, J=6.4, 3H, CHCH3).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C=CC3C=CC=CC=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.CO.O=[O+][O-].[CH:32]([O:37][CH3:38])([O:35][CH3:36])OC>C(Cl)Cl>[CH3:38][O:37][CH:32]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1)[O:35][CH3:36]
Reactant: COC(OC)OC
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1nn(COCC[Si](C)(C)C)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole [Example 14, step (i)] (1.28 g, 2.69 mmol) in CH2Cl2 (40mL)/MeOH (40 mL) was stirred at −78° C. The reaction was treated with ozone until a blue color persisted, and then was purged with argon. Methyl sulfide (4 mL) was added, and the reaction stirred 4 h while warming to r.t. Concentration in vacuo gave a crude mixture of acetal and aldehyde, which was converted completely to the acetal by stirring in trimethyl orthoformate (10 mL) with Amberlyst 15(wet) acidic ion-exchange resin (0.8 g) for 1 h. The resin was removed by filtration, and the solution was concentrated in vacuo. Purification by silica gel chromatography gave 1.11 g (92%) of 3-(1,1-dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.48 (dd, 1H, J=8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H), 3.53 (t, 2H, J=8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J=8.4 Hz), −0.06 (s, 9H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([C@H:10]([CH2:17][CH3:18])[C@@H:11](C)[CH2:12][N:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.N[C@H]([C:25](O)=[O:26])CCSC>CS(O)(=O)=O>[CH3:14][N:13]([CH3:15])[CH2:12][C@H:11]([O:26][CH3:25])[C@@H:10]([C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=1)[CH2:17][CH3:18]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Reactant: CSCC[C@H](N)C(=O)O
Agent: CS(=O)(=O)O
Agent: Cl
Product: CC[C@H](c1cccc(O)c1)[C@H](CN(C)C)OC
Temperature: 77.5 °C
Reaction time: 18 h
Yield: 105.3 %

Procedure:
In 28 mL of methanesulfonic acid, (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine HCl (6.0 g, 0.022 moles) is dissolved, and methionine (4.7 g, 0.031 moles) is added to the solution. The reaction is stirred at the temperature of 75-80° C. for 16-20 hours. It is then cooled to 15-25° C. and the following is added: purified water (20 mL), slowly at this temperature. The pH is brought to the value of 10-11 by means of the addition of 28% NaOH (about 35 mL), maintaining the temperature below 50° C. Then, ethyl acetate (30 mL) is added to the mixture. The mixture is then stirred for 30 minutes and the organic phase is separated. The organic phase, with dark color, is filtered over a silica panel and washed with 30 mL of ethyl acetate. A yellowish transparent solution is obtained. The solvent is removed under vacuum, obtaining about 5.5 g of oil which, left at ambient temperature, solidifies.