Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]2[N:4]([CH2:5][CH2:6][CH:7]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.[CH2:20]1[C:27]2[N:23]([C:24]([C:28](Cl)=[O:29])=[CH:25][CH:26]=2)[CH2:22][CH2:21]1>C(Cl)Cl>[CH2:20]1[C:27]2[N:23]([C:24]([C:28]([C:3]3[N:4]4[C:8](=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]=3[CH3:1])[CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5]4)=[O:29])=[CH:25][CH:26]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1c(C)cn2c1C(C(=O)OCC)CC2
Reactant: O=C(Cl)c1ccc2n1CCC2
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c(C(=O)c2ccc3n2CCC3)n2c1C(C(=O)OCC)CC2

Procedure:
To an ice-bath cooled solution of diethyl 6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate (2.0 g, 0.0075 m) in methylene chloride (25 ml) was added stannic chloride (2.6 ml, 0.0225 m) all at once. A solution of 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride (1.1 g, 0.0075 m) in methylene chloride (10 ml) was then added dropwise, and the resultant mixture stirred cold for two hours, then at ambient temperatures overnight. The reaction mixture was then quenched with excess ice-H2O and ether, the organic layer removed, washed well with water, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue. Trituration with either yielded 1.75 g of diethyl 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:10].[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.CCCCCCC>CO>[ClH:10].[NH2:9][C:8]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)[N:18]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A solution of pivaloylacetonitrile (750 g, 6.0 mol) and p-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. 1H NMR □CDCl3) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, 1H), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M++H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCOCCl
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(Cl)cc1C(=O)O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Sodium hydroxide (7.20 g, 180 mmol) was added to a solution of 5-chlorosalicylic acid (10.36 g, 60 mmol) in tetrahydrofuran (60 ml). (2-Methoxyethoxy)methyl chloride (15.1 ml, 132 mmol) was added to the mixture, and the mixture was stirred for 18 hours. 2N Aqueous sodium hydroxide (80 ml) was added to the reaction mixture, and the mixture was refluxed for 2 hours. The water layer was adjusted to pH=3 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane ethyl acetate=1:1) to give the title compound (12.8 g, 82%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.ClC1C(CO)=CC(F)=C(Cl)N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:11])[N:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1cnc(Cl)cc1Cl
Yield: 60 %

Procedure:
Compound 41A (2.5 g, 60%) was prepared from 4,6-dichloro-nicotinic acid (4.5 g, 23.4 mmol) using a procedure similar to the synthesis of 1A.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])C>CO>[C:8]1([C:6]([OH:7])=[O:5])[NH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: CCOC(=O)c1[nH]cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1[nH]cc2c1CCCC2

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 10.3 mmol) was added to a stirring, room temperature solution of 171 (0.3966 g, 2.05 mmol) in MeOH (5.1 mL, 0.4 M) under N2. The reaction was then heated to reflux for 20 minutes. A small amount of starting material remained. A large amount of undesired product along with only a small amount of desired product was observed by HPLC. The reaction was concentrated, redissolved in H2O, and extracted with EtOAc (1 mL). 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.0076 g (11.6%) of 172. 1H (CD3OD, 400 MHz): δ 5.62 (1H, s), 2.77 (2H, t, J=5.6 Hz), 2.52 (2H, t, J=5.4 Hz), 1.78-1.66 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.87, 129.69, 122.48, 120.57, 118.42, 24.74, 24.69, 24.35, 22.94 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 24.74, 24.69, 24.35, 22.94; CH carbons: 120.57 ppm. HPLC: 8.896 min.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:14]1[CH:15]=[C:16]([C:20]2(O)[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11].[N:28]([Si](C)(C)C)=[N+:29]=[N-:30].C(OCC)(=O)C>C(OCC)C.[Cl-].[NH4+]>[N:28]([C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=2)[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]1)=[N+:29]=[N-:30]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C=C1CCC(O)(c2cccc(C(C)(C)C)c2)CC1
Agent: FB(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CCC(N=[N+]=[N-])(c2cccc(C(C)(C)C)c2)CC1
Yield: 36.9 %

Procedure:
Borontrifluoride-etherate (2.0 mL, 15.7 mmol) was added to a solution of 1-(3-tert-butyl-phenyl)-4-methylene-cyclohexanol (3.60 g, 14.7 mmol) and azidotrimethylsilane (4.0 mL, 30.1 mmol) in diethyl ether (30 mL) and placed into a preheated oil bath at 45° C. After heating at reflux for 4 h, the solution was diluted with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 99:1, 49:1, and 24:1 hexanes:ethyl acetate as the eluant to yield 1.46 g (37% yield) of 1-(1-azido-4-methylene-cyclohexyl)-3-tert-butyl-benzene as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([O:20][S:33](=[O:35])(=[O:34])[N:32]([CH3:37])[CH3:31])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2OS(=O)(=O)N(C)C)c(C)c1
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a solution of {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-hydroxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.190 g, 0.46 mmol) in CH2Cl2 (4 mL) was added dimethylsulfamoylchloride (0.160 mL, 1.49 mmol), NEt3 (0.300 g, 2.16 mmol) and DMAP (catalytic) and the reaction mixture stirred for 48 h. The mixture was diluted with CH2Cl2 (30 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated. Purification by column chromatography on silica gel with saturated NH4OH in Et2O afforded {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-dimethylsulfamoyloxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.054 g, 23%) 1H NMR (CDCl3) δ 1.30-1.53 (m, 13H), 2.11 (s, 3H), 2.25 (s, 3H), 2.50-2.54 (m, 2H), 2.94-3.00 (m, 8H), 3.74 (s, 2H), 3.91 (s, 2H), 5.11 (br s, 1H), 7.16 (s, 1H), 7.23 (dd, 1H, J=6.6, 4.8 Hz), 7.72 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 8.51 (d, 1H, J=4.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1Cl.C(N(C(C)C)CC)(C)C.[CH:36]([NH:39][CH2:40][CH:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)([CH3:38])[CH3:37]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[CH2:40][NH:39][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)NCC1CCCN1
Reactant: Cn1c(Cl)c(Cl)c(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCC1CCCN1c1c(Cl)c(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Temperature: 150 °C

Procedure:
A microwave tube was charged with 5,6-dichloro-1-methyl-3-naphthalen-2-yl-1H-[4,4′]bipyridinyl-2-one (0.300 g, 0.8 mmol), diisopropylethylamine (2 eq.) and isopropyl-pyrrolidin-2-ylmethyl-amine (1 eq). The heterogeneous suspension was heated in the microwave at 150° C. for 10 min. The resulting brownish suspension was dissolved in DCM and the crude product was purified by flash chromatography using an ISCO combiflash system with a mixture 97/3 DCM/MeOH to give the title compound. MS (ES+): 487 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Li]CCCC.C(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([B:11]([OH:16])[OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1F
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Dissolve 2-Fluoro-4-bromobenzonitrile (200 g, 990 mmol, 1.00 eq.) and triisopropyl borate (228 g, 1188 mmol, 1.2 eq.) in 700 mL of THF and 1400 mL of toluene. Cool the mixture with a dry ice/acetone bath to an internal temperature of −75° C. Slowly add n-BuLi (396 mL of a 2.5 M solution in hexanes) over a period of 2 hours. After addition is complete, a light-red, thin slurry occurs. Let the solution stir at −74° C. for 15 minutes, allow the solution to warm to −20° C. and then quench with 1500 mL of 2.5 M HCl. Let the solution warm to RT. Separate layers, extract the aqueous layer with EtOAc, dry the combined organic phases with Na2SO4, filter and concentrate in vacuo to yield a light-brown solid. Triturate the solid with hexane and transfer to a scintered glass funnel. Rinse with hexane one more time to obtain a pale-yellow filtrate. Stir the light-brown solid with cold CH2Cl2 and filter. Rinse with a small volume of CH2Cl2 to yield an off-white solid and a brown filtrate. Dry the solid in a vacuum oven at 40° C. and dried to yield 112 g (679 mmol, 69%) of 3-fluoro-4-cyanophenylboronic acid as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([OH:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([O:17][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a suspension of NaH (60% in mineral oil, 78 mg, 1.95 mmol) in DMF (15 mL) at 0° C. was added a solution of 3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenol (57) (0.52 g, 1.86 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 10 min. 4-Fluorobenzaldehyde (0.47 g, 3.72 mmol) in DMF (3 mL) was added and the resulting mixture was heated at 70° C. for 36 h. Cooled to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.61 g (86%) of compound 58 as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.06 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.08-7.15 (m, 2H), 7.17-7.27 (m, 4H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 383 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:30][CH3:31].[Li+].[OH-]>>[CH2:33]([O:32][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:30][CH3:31])[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:25][C:26]1[C:27](=[O:33])[CH:28]=[CH:29][C:30](=O)[CH:31]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:29]2[C:30](=[CH:31][C:26]([Cl:25])=[C:27]([OH:33])[CH:28]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:16][CH:15]=2)[C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:24])[CH3:2]
Reactant: CCOC(=O)C=C(CC(=O)OCC)Nc1ccc(C(C)(C)C)cc1
Reactant: O=C1C=CC(=O)C(Cl)=C1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (b) Example 1 from 3-(4-tert-butylphenylamino)pent-2-enedioic acid diethyl ester (6.2 g, 18.6 mmol, see step (a) above) and 2-chloro-1,4-benzoquinone (3.1 g, 22 mmol). Yield 266 mg (3%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14][C:15]=1[F:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:17][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Cl
Yield: 97.9 %

Procedure:
0.05 g of dibenzoyl peroxide and then 6.1 g of N-bromosuccinimide are added to a mixture of 5 g of 3-chloro-4-fluorotoluene and 100 ml of CCl4 and the reaction mixture is refluxed for 12 hours. The insoluble material is filtered off and washed with CCl4. The filtrate is washed with water and with saturated NaCl solution, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum to give 7.5 g of the expected product in the form of an oil, which is used as such.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: NNCc1ccccc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2ccccc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 3.4 g of benzylhydrazine hydrochloride and 5.9 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-benzyl-1H-[1,2,4]triazole remains as colorless crystals of m.p. 166-168° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])=[N:7][N:6]=1)=O.Cl>CN(C=O)C.CO>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([CH2:3][OH:2])=[N:6][N:7]=1
Reactant: COC(=O)c1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(CO)c2c1
Yield: 97 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-carboxylic acid methyl ester (3.9 g, 10.3 mmoles), prepared as described in example 102, in DMF/CH3OH (30/50 ml) under N2 was portionwise added with NaBH (1.17 g, 30.9 mmoles) in 1.5 hours. The stirring went on for 2.5 hours. The mixture was cooled on ice and added with concentrated HCl up to pH<1, then dried, taken up in water and extracted three times with CH2Cl2, the organic phase was anhydrified and dried to give 3.5 g of the title compound (yield: 97%). m.p.: 190-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40].[H-].[Li+].[Cl:47][CH2:48][CH2:49][CH2:50]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:50][CH2:49][CH2:48][Cl:47])[CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]
Reactant: ClCCCI
Reactant: CC(C)Oc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)c(F)c1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.8 g, 2.72 mmol) prepared in example 73a was reacted with LiH (1.0 g, 125 mmol) and 1-chloro-3-iodo-propane (5.0 g, 24.5 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.67 g, 33.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8](O)[N:7]=[CH:6]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cnc(O)nc2cc1OC
Product: COc1cc2cnc(Cl)nc2cc1OC
Yield: 38 %

Procedure:
Phosphorus oxychloride (50 ml) was added to 5.0 g of the 6,7-dimethoxy-2-hydroxyquinazoline synthesized in Referential Example 89. They were heated and reacted for 8 hours under reflux. After allowing the reaction mixture to cool down, phosphorus oxychloride was distilled off under reduced pressure and the residue was dissolved in dichloromethane. After washing the dichloromethane solution once with a saturated aqueous solution of sodium bicarbonate, once with water and then once with saturated saline, the solution was dried with anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue was purified by column chromatography (silica gel; eluent: 50:1 mixed solvent of dichloromethane and methanol), thereby obtaining 2.1 g of the intended product as crystals (yield: 38%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[NH:25][C:24]2=[O:31]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[NH:25][C:24]3=[O:31])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)C(=O)NC3=O)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 5-amino-1H-isoindole-1,3(2H)-dione in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.44-1.54 (m, 2H), 1.78-1.86 (m, 2H), 3.77 (t, 2H), 7.06-7.31 (m, 6H), 7.36-7.52 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)[N:3]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N
Yield: 85 %

Procedure:
To a solution of 2-methyl-3-nitro-6-[1-(phenylmethyl)-3-pyrrolidinyl]pyridine (200 mg, 0.673 mmol) in ethanol (6 mL) and water (2 mL) was added ammonium chloride (17.99 mg, 0.336 mmol) and iron powder (113 mg, 2.018 mmol). The reaction mixture was heated at reflux under nitrogen for 1 hour. The reaction mixture was filtered through a pad of celite and the pad washed with ethyl acetate. The combined filtrate and washings were separated between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with water and brine, then dried over magnesium sulphate and evaporated in vacuo to give the title product (153 mg) as a pale brown gum. LCMS (2 min, formic) Rt 0.35 min, m/z (ES+) 268 (M+H).