Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(C2=CCCCC2)cc1
Solvent: CCO
Product: Nc1ccc(C2=CCCCC2)cc1
Yield: 74.2 %

Procedure:
1-Cyclohex-1-enyl-4-nitrobenzene (11.7 g, 57.6 mmol) was dissolved in hot absolute ethanol (170 mL). Stannous chloride (65 g, 288 mmol) was added and the reaction mixture was stirred at reflux temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was added ethyl acetate (700 mL) and water (700 mL), and neutralised to pH 7 with sodium hydroxide (4 N). Ethyl acetate (150 mL) was added and the mixture was filtered through celite. The organic phase of the filtrate was washed with water and a saturated solution of sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was purified on silica (200 g) using ethyl acetate and heptane (1:4) as eluent to give 7.4 g of 4-(cyclohex-1-enyl)phenylamine.
Reaction SMILES: COB(OC)OC.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:27]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:26]=2[C:25]2[C:24]3[CH:23]=[C:22]([NH:33][CH:34]=O)[CH:21]=[CH:20][C:19]=3[N:18]([CH3:36])[C:17]=2[CH:16]=1.O1CCCC1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:27]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:26]=2[C:25]2[C:24]3[CH:23]=[C:22]([NH:33][CH3:34])[CH:21]=[CH:20][C:19]=3[N:18]([CH3:36])[C:17]=2[CH:16]=1
Reactant: Cn1c2ccc(NC=O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Agent: COB(OC)OC
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2C)C(=O)NC3=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Borane methylsulphide complex (0.074 mL, 0.78 mmol) and trimethylborate (0.089 mL, 0.78 mmol) were added at 0° C. under an atmosphere of nitrogen to a solution of amide (920) (0.105 g, 0.26 mmol) prepared as described in example 469 dry tetrahydrofuran (10 mL) After stirring at 0° C. for 30 min. the solution was allowed to warm to room temperature over 16 h. Methanol (200 mL) was added and the reaction mixture was stirred for 12 h. The solvent was removed under reduced pressure and the yellow residue was purificatied by column chromatography on silica, eluting with petroleum ether:ethyl acetate (100:0 to 0:100) to give (922) as a red solid (0.053 g, 45%), mp 293–296° C. 1H NMR δ [(CD3)2SO] 11.01 (br s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.69 (s, 1H), 7.57 (dd, J=7.1, 2.0 Hz, 1H), 7.42–7.52 (m, 4H), 7.02 (dd, J=8.8, 2.3 Hz, 1H), 5.61 (q, J=5.2 Hz, 1H), 3.90 (s, 3H), 2.81 (d, J=5.2 Hz, 3H). EIMS found: M+=389.0929, 391.0905. C22H16ClN3O2 requires 389.0931, 391.0902.
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]12)[CH:2]=[CH2:3].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH:8]2[N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:10](=[O:12])/[C:11]/1=[CH:29]\[N:30]([CH3:32])[CH3:31])[CH:2]=[CH2:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: C=CCc1cccc2c1CC1CC(=O)N(C(=O)OC(C)(C)C)C21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1cccc2c1CC1/C(=C/N(C)C)C(=O)N(C(=O)OC(C)(C)C)C21
Yield: 93 %

Procedure:
A solution of the tert-butyl 5-allyl-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Step 4, 0.21 g, 0.7 mmol) in tert-butoxybis(dimethylamino)methane (0.415 mL, 2.0 mmol) in toluene (3 ml) was heated at 110° C. overnight. The solution was diluted with ethyl acetate and washed twice with water, brine, dried over magnesium sulphate and concentrated to give tert-butyl (3Z)-5-allyl-3-(dimethylaminomethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D1 (colourless solid, 0.24 g, 97%). This compound was used without extra purification. LC-MS (Method C) RT 1.05 min, 369 (M+H+). This method was used to prepare compound D2 to D13 (table D).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][CH:22]=1>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:28])([CH3:29])[CH2:30][N:11]2[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]2=3)=[CH:25][CH:26]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (150 mg, 0.66 mmol) was dissolved in DMF (2 mL), sodium hydride (79 mg, 1.98 mmol) was added and the mixture was stirred at RT for 5 min. 2-(4-Fluoro-phenyl)-2-methyl-oxirane (201 mg, 1.32 mmol) was added dropwise into the reaction mixture and stirred at RT for 18 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (neutral alumina) Eluent: −2% MeOH in DCM followed by chiral HPLC to obtain 77 mg of 2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-propan-2-ol. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.4 (m, 2H), 7.2 (m, 2H), 7.0 (m, 3H), 5.08 (t, 1H), 4.3 (d, 1H), 4.15 (d, 1H), 3.65 (m, 1H), 3.5 (m, 2H), 3.3 (m, 1H), 2.90 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H), 1.62 (s, 3H). Separation by chiral HPLC provided diastereomers II-121a-b.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C1(C)C=CC(S([O:38][CH2:39][C@H:40]2[CH2:44]OC(C)(C)[O:41]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O.CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:44][C@H:40]([OH:41])[CH2:39][OH:38])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cccc(O)c2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cccc(OC[C@H](O)CO)c2)s1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-5-(3-hydroxyphenyl)thiophene-2-carboxamide (Example 144, 80 mg, 0.20 mmol), (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (70 mg, 0.24 mmol) and K2CO3 (84 mg, 0.61 mmol) in DMF (0.3 mL) was stirred and heated at 80° C. for 17 h. After cooling to rt, the mixture was diluted with water (˜5 mL) and extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine, dried over anhyd. Na2SO4, filtered, and concentrated under vacuum to afford a brown oil. This material was purified by reverse-phase Prep HPLC to isolate the major product which was dissolved in MeOH (˜3 mL) and 2 N aq HCl (0.3 mL) was added. The solution was warmed to 65° C. for 45 min then cooled to rt and concentrated under vacuum to remove most of the MeOH. The resulting heterogeneous mixture was diluted with water (˜2-3 mL) and stirred for 1 h. The resulting solid was collected by vacuum filtration, rinsed with water (˜5 mL), and air dried in funnel then under vacuum to afford 29 mg (30%) of an off-white solid as the title compound (Example 193). HPLC Ret. Time=2.90 min, LCMS [M+H]+ 467.29.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[C:28]([NH:1][CH:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(NC(C)=O)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-amino-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (550 mg, 1.46 mmoles, see Example 2) in dichloromethane (5.0 ml) and pyridine (0.5 ml) was treated with acetic anhydride (0.3 ml) and the reaction was allowed to stir at room temperature for 1 hour. The colorless reaction mixture was diluted with ethyl acetate and was washed with 5% citric acid, sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate and evaporated to provide a colorless foam. Crystallization from ether-hexanes provided the title compound as a colorless solid, melting point 154.5°-156° C.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH:14]([C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([CH3:27])=[C:18]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=1[CH3:36])=[O:15]>C1COCC1.O>[OH:15][CH:14]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)[C:16]1[C:24]2[O:23][C:22]([CH3:25])([CH3:26])[CH2:21][C:20]=2[C:19]([CH3:27])=[C:18]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=1[CH3:36]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2c(c(C(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of magnesium (198 mg, 8.13 mmol) and a catalytic amount of iodine was added dropwise under argon atmosphere a solution of 1-bromo-4-isopropylbenzene (1.62 g, 8.13 mmol) in THF (5 mL) under argon atmosphere at room temperature, and the reaction solution was heated until the color of iodine disappeared. To the reaction solution was added dropwise at room temperature a solution of N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 340 (860 mg, 2.71 mmol) in THF (5 mL) and the mixture was stirred for 1 hour. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to synthesize 1.15 g (yield: 97%) of the title compound. Amorphous powder.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:4]1(=[O:16])[N:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COC(=O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
A mixture of methyl 7-phthalimidohept-5-ynoate (1.9 g) and Lindlar catalyst (250 mg) in methanol (130 ml) was shaken under an atmosphere of hydrogen at 30 psi for 2.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel eluted with chloroform to give the title compound (1.59 g) as a low melting solid. m.p. 47°-49° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C)cn1

Procedure:
11.5 g of 2,5-dimethylpyridine-N-oxide in 5 ml of acetic acid were added dropwise to 18 ml of acetic anhydride pre-heated to 120°. The reaction solution was boiled under reflux for a further 45 minutes, concentrated by evaporation on a rotary evaporator, and distilled at 8 mm Hg/115°. 14.0 g of 2-acetoxymethyl-5-methylpyridine was obtained.
Reaction SMILES: C1(C2C=C3C(=NC=2C(OC)OC)N(C(OC2C=CC=CC=2)=O)CCC3)CC1.NC1C=C(OCCOC)C(C#N)=CN=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-].[C:54]([C:56]1[C:57]([O:83][CH2:84][CH2:85][O:86][CH3:87])=[CH:58][C:59]([NH:62][C:63]([N:65]2[C:74]3[C:69](=[CH:70][C:71]([CH:80]4[CH2:82][CH2:81]4)=[C:72]([CH:75](OC)[O:76]C)[N:73]=3)[CH2:68][CH2:67][CH2:66]2)=[O:64])=[N:60][CH:61]=1)#[N:55]>C1COCC1>[C:54]([C:56]1[C:57]([O:83][CH2:84][CH2:85][O:86][CH3:87])=[CH:58][C:59]([NH:62][C:63]([N:65]2[C:74]3[C:69](=[CH:70][C:71]([CH:80]4[CH2:82][CH2:81]4)=[C:72]([CH:75]=[O:76])[N:73]=3)[CH2:68][CH2:67][CH2:66]2)=[O:64])=[N:60][CH:61]=1)#[N:55]
Reactant: COCCOc1cc(NC(=O)N2CCCc3cc(C4CC4)c(C(OC)OC)nc32)ncc1C#N
Agent: COC(OC)c1nc2c(cc1C1CC1)CCCN2C(=O)Oc1ccccc1
Agent: COCCOc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)N2CCCc3cc(C4CC4)c(C=O)nc32)ncc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 6-cyclopropyl-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 51A, 52 mg, 0.141 mmol) and 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 30.0 mg, 0.155 mmol) in THF (1 ml) at −78° C. was slowly added LHMDS (1 M in THF, 0.311 ml, 0.311 mmol). The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was subjected to reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give a mixture of title compound and N-(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)-6-cyclopropyl-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide as an off-white powder. This material was dissolved in THF (2 ml) and H2O (2 ml), treated with conc. HCl (1.0 ml), the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and concentrated to give the title compound as a light brown powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].O.[I:16]Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:16])[C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Reactant: ClI
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(I)c1O
Reaction time: 2 h
Yield: 96 %

Procedure:
To the product from Example 1, Part A (4.5 g, 23.05 mmol) dissolved in MeOH (120 ml) and water (30 mL) was added iodine monochloride (1.155 ml, 23.05 mmol) drop wise over a period of 10 min. The mixture was stirred for 2 h and diluted into 1 L of water and allowed to stand overnight. The solid material was collected by filtration and washed 3×50 mL with water and dried under vacuum overnight to give a tan solid (7.14 g, 96%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:15]2[C:16]3[C:21](=[CH:20][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[CH:22]=[C:14]2[C:12]([N:9]2[CH2:8][CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:11][CH2:10]2)=[O:13])=[CH:39][CH:40]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 2-chloropyridine-5-boronic acid to afford the desired product as a colorless foam (33%). MS (ISP): 563.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:7]=1)[CH2:8][O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-2-chlorophenyl)methanol from the previous step (1 eq.) in DMF (0.25 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 3 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed further with aq. 10% HCl, sat. aq. NaHCO3, and brine. Concentration of the organic extracts in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([O:12][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
0.5 g (2.19 mmol) of 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetic acid is suspended in 5 ml of dichloromethane, 250 μgl (2.41 mmol) of benzyl alcohol and 0.5 g (2.45 mmol) of 1,3-dicyclohexylcarbodiimide in solution in 5 ml of dichloromethane are added. The mixture is kept stirred for 3 hours at room temperature, it is diluted with 20 ml of dichloromethane, filtered and evaporated. The residue is recrystallized from ethanol. 0.57 g of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([CH2:8][CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].Cl>CO>[NH2:30][CH:6]([C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: [BH3-]C#N
Reactant: CCOC(OCC)P(=O)(CCC(=O)c1ccc(Cl)cc1)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CCOC(OCC)P(=O)(CCC(N)c1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 25.4 g of ethyl 2-(4-chlorobenzoyl)ethyl(diethoxymethyl)phosphinate in 200 ml of methanol is added 52 g of ammonium acetate and 4.23 g of sodium cyanoborohydride. The mixture is stirred under an atmosphere of nitrogen at room temperature for a period of 3 days. The mixture is then acidified to pH 2 with the requisite amount of dilute hydrochloric acid and the methanol is evaporated under reduced pressure. The crude product is dissolved in 25 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then made alkaline to pH 12 with potassium hydroxide. The solution is then saturated with sodium chloride and extracted with 3×25 ml of dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated under reduced pressure to give ethyl 3-amino-3-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31P=45.9 ppm (CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH:11](OCC#N)=[O:12]>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2]([NH:1][CH:11]=[O:12])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1CO
Reactant: N#CCOC=O
Solvent: C1CCOC1
Product: O=CNc1cc(Cl)ccc1CO

Procedure:
A solution of 5.00 g of (2-amino-4-chlorophenyl)methanol, 2.73 g of cyanomethyl formate and 0.04 g of 4-N,N-dimethylaminopyridine in 50 ml of anhydrous tetrahydrofuran was stirred for 72 hours at 20° C. The solvent was then evaporated in vacuo and the residue was taken up in 50 ml of ethyl acetate. The solution was washed in succession twice with in each case 100 ml of 0.01 N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate and then concentrated by evaporation in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate/cyclohexane (2/1) as eluent. 1.41 g (24% of theory) of the title compound was thereby obtained in the form of slightly yellowish crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:51]=[CH:50][C:30]([C:31]([NH:33][C:34]2[C:35]([C:40]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=3)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=2)=[O:32])=[C:29](O)[CH:28]=1>>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]([C:35]2[C:34]([NH:33][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([S:26][CH3:25])=[CH:51][C:50]=3[O:12][CH2:11][C@@H:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:39][CH:38]=[CH:37][N:36]=2)=[O:41])=[N:44][CH:45]=1
Reactant: COc1ccc(CO[C@H](CO)CNC(=O)OC(C)(C)C)cc1OC
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Product: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)COc2cc(SC)ccc2C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)cc1OC
Yield: 71 %

Procedure:
Using a procedure analogous to Example 38-D, (2S)-3-(t-butoxycarbonylamino)-2-(3,4-dimethoxybenzyloxy)propanol and 3-[4-methylthio-2-(hydroxy)benzoylamino]-N-(5-chloro-pyridin-2-yl)pyridine-2-carboxamide gave the title compound as a solid (800 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[C:20]([C:29](O)=[O:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:20]3[C:19]([F:18])=[CH:24][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:22][N:21]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS 89402-28-8) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=433.3 [M+H]+.