Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.C(NC(C)C)(C)C.C(Cl)CCl.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[C:40]([NH:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](O)=[O:54])=[C:49]([F:56])[CH:48]=3)=[C:41]([Cl:44])[CH:42]=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[C:40]([NH:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](=[O:54])[NH:4][CH2:1][CH2:2][CH3:3])=[C:49]([F:56])[CH:48]=3)=[C:41]([Cl:44])[CH:42]=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(C(=O)O)c(F)c3)c2CC1
Reactant: CCCN
Agent: On1nnc2ccccc21
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCNC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Add a solution of n-propylamine (6.3 mg, 0.11 mmol) in anhydrous THF (0.5 mL), HOBT (14.5 mg, 0.11 mmol), a solution of diisopropylamine (27.7 mg, 0.21 mmol) in anhydrous THF (0.5 mL) and EDC (20.5 mg, 6.11 mmol) to a mixture of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (48.1 mg, 0.11 mmol) in anhydrous THF (1.4 mL) at room temperature. Stir overnight at room temperature and partition the mixture between EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (12 g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a thick colorless oil (37.1 mg, 71%). MS (ES+) m/z: 490.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:6][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:17][C:16]3[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=3)=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Temperature: 65 °C
Yield: 75.2 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (4.68 g, 30 mmol), 4-fluorobenzyl bromide (17.0 g, 90 mmol) and potassium carbonate (8.3 g, 60 mmol) in THF:water (1:1, 100 mL) was heated at 65° C. for 48 h. After cooling to room temperature the mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation gave a residue which was crystallised from ether:heptane to afford the title compound (8.4 g, 75%) as a white solid. MS: m/e=372.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccco1
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Product: Clc1ccc(-c2cn(-c3ccco3)cn2)cc1
Yield: 1.7 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-(4-chlorophenyl)-1H-imidazole (125 mg, 0.7 mmol) and 2-bromofuran, to prepare the desired 4-(4-chlorophenyl)-1-(furan-2-yl)-1H-imidazole (3 mg, 0.12, yield 1.7%) as a brownish solid. The HPLC purity of the final product was 95.84%. LC-MS [M+H] 245 (C13H9ClN2O+H expected 245.04). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-:41].[Ca+2].[Cl-]>C(O)(C(F)(F)F)=O>[ClH:41].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1-c1ncncc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: [Cl-]
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ncncc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 220 mg (0.41 mmol) of (2S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-o-tolylpyrimidin-5-yl)propanoate in TFA (2.1 mL), protected from the atmosphere by a calcium chloride-filled drying tube was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo at less than 40° C. and the resulting orange oil was redissolved in toluene twice and evaporated to give the title compound as a white powder, 195 mg, 99% yield.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[CH3:19][C:20]1[C:21]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:33]2[CH2:34][CH2:35][N:30]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:23][N:22]=3)[CH2:31][CH2:32]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C(C)C)cc2)CC1
Yield: 30.7 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (490 mg) described in Preparation Example 51, the title compound (292 mg) was obtained.
Reaction SMILES: CC([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[CH:9][C:10](C(C3C=CC=CC=3C#N)=O)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)C.[C:30](O)(=O)[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=O)O.[CH2:43](O)[CH3:44]>[OH-].[Na+].C(OCC)(=O)C>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:34]([C:32]3[CH:31]=[CH:30][CH:44]=[CH:43][C:37]=3[C:38]([OH:40])=[O:39])=[O:36])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCO
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(=O)c3ccccc3C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1C(=O)c1ccc2[nH]ncc2c1

Procedure:
A solution of 2-({1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}carbonyl)benzonitrile in ethanol (2.0 mL) and 20% aqueous sodium hydroxide solution (2.0 mL) was refluxed for 30 min. Solid citric acid was added to pH 3-4. The reaction mixture was diluted with ethyl acetate, dried (sodium sulfate), filtered and concentrated in vacuo to give 0.19 g (>100% crude yield) of 2-(1H-indazol-5-ylcarbonyl)benzoic acid. NMR analysis confirmed the concurrent loss of the triisopropylsilyl protecting group during this step. The crude acid was used without further purification for the next step. 1H NMR (400 MHz, d4-MeOH): 8.14 (m, 1H), 8.10 (m, 1H), 8.05 (m, 1H), 7.75 (m, 3H), 7.63 (d, 1H), 7.57 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][CH:10]([CH3:26])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:9])[CH3:26])[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22]1
Reactant: OCCCCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 6-chloro-1-hexanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 347.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])[CH:64]=[CH2:65].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:65]=[CH:64]/[CH2:63][NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Reactant: C=CCNC(=O)NC(C)(C)CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=O)NC(C)(C)CO)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To an acetonitrile solution (5.4 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (0.48 g, 0.539 mmol) were added N-allyl-N′-(2-hydroxy-1,1-dimethylethyl)urea (223 mg, 1.29 mmol), palladium(II) acetate (24 mg, 0.108 mmol), tri-O-tolylphosphine (66 mg, 0.216 mmol) and triethylamine (273 mg, 2.69 mmol), and the mixture was stirred at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform and then chloroform:methanol=50:1) to obtain the title compound (210 mg, 40%) as a pale yellow amorphous compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([OH:10])=O)=[CH:4][S:3]1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:34]([O:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH2:50])[C:48](=[O:51])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46])(=[O:36])[NH2:35].C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[C:34]([O:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH:50][C:8](=[O:10])[CH2:7][C:5]3[NH:6][C:2](=[O:1])[S:3][CH:4]=3)[C:48](=[O:51])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46])(=[O:36])[NH2:35]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)Cc1csc(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)[nH]3)[C@H]2SC1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
To a mixture of 2-oxo-2,3-dihydrothiazol-4-ylacetic acid (0.4 g.) and N-hydroxysuccinimide (0.3 g.) in tetrahydrofuran (15 ml.) was added N,N'-dicyclohexylcarbodiimide (0.52 g.) with stirring at room temperature, and the mixture was further stirred for 2 hours at the same temperature. Thus obtained solution was added to a solution of 3-carbamoyloxymethyl-7-amino-3-cephem-4-carboxylic acid (0.816 g.) and trimethylsilylacetamide (0.27 g.) in ethyl acetate (30 ml.) at room temperature, and the mixture was stirred for 16 hours at the same temperature. After the reaction, the reaction mixture was cooled to at -20° C., and then water (20 ml.) was added thereto. After stirring the mixture sufficiently, the mixture was filtered, and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(2-oxo-2,3-dihydrothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (60 mg.).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.4 %

Procedure:
A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[C:11]1([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[N:3][NH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2cnncc2c1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=NNC(c2ccccc2)c2ccccc21

Procedure:
A solution of 4 g of phthalazine in 50 ml of tetrahydrofuran is added dropwise at room temperature to a solution of phenyl-magnesium bromide (prepared from 6 g of bromobenzene and 1 g of magnesium in 30 ml of tetrahydrofuran). The reaction mixture is held at reflux for 6 hrs. After cooling the mixture is treated with a saturated aqueous solution of ammonium chloride and extracted 3 times with diethyl ether. The organic phases are combined, dried and subsequently triturated with pentane. 2.32 g of not quite pure 1-phenyl-1,2-dihydro-phthalazine are isolated as a yellowish solid, m.p. 79° C.
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16][OH:17])[CH:10]=1.[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]#[CH:34])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]3[O:17][N:16]=[C:15]([C:11]4[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=4)[CH:34]=3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: ON=Cc1cccnc1
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Temperature: 50 °C
Yield: 55.3 %

Procedure:
N-Chlorosuccinimide (1.09 g, 8.19 mmol) was added to a 6° C. solution of 3-pyridinecarboxaldehyde oxime (1.00 g, 8.19 mmol) in tetrahydrofuran (THF) (25 mL). The solution was heated at 50° C. for 2 h. 4-Chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part D of Example 3, 1.96 g, 6.55 mmol) and triethylamine (1.70 mL, 12.3 mmol) were added to the reaction, which was heated at 50° C. for 17 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous layer was extracted multiple times with dichloromethane and chloroform. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 1:1 to 1:4 hexanes/ethyl acetate) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.52 g).
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][C:21]1[C:22]([O:32][CH3:33])=[N:23][C:24]([CH:27](OC)[O:28]C)=[CH:25][CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>O1CCCC1>[Si:2]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[N:23][C:22]=1[O:32][CH3:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1nc(C(OC)OC)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
1 M hydrochloric acid (40 mL) was added to a solution of 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5.47 g) in tetrahydrofuran (40 mL), and the mixture was stirred at 60° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-carbaldehyde (3.2 g, 73%) as a colorless oil.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18](OCC)=[O:19]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[CH:1]1([N:7]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC=O
Reactant: CC1(C)CC(NC2CCCCC2)CC(C)(C)N1
Agent: [Ti]
Solvent: CCCCO
Product: CC1(C)CC(N(C=O)C2CCCCC2)CC(C)(C)N1

Procedure:
80 g of 4-(N-cyclohexylamino)-2,2,6,6-tetramethylpiperidine and 32 g of tetrabutyl orthotitanate in 175 ml of ethyl formate were refluxed for 11 hours. Fractional distillation gave a fraction of boiling point 143°-144° C. under 0.4 mmHg. After solidification, this fraction was recrystallized from n-hexane. 4-(N-cyclohexyl-N-formylamino)-2,2,6,6-tetramethylpiperidine was isolated as a colorless solid of melting point 105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH2:32][C:33]([O:35]CC)=O.[NH2:39][CH2:40][CH2:41][OH:42]>C(O)C>[OH:42][CH2:41][CH2:40][NH:39][C:33]([C:32]1[S:22][C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:13]3[CH2:14][C:15](=[O:17])[NH:16][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:28]=[CH:27][C:11]=4[N:12]=3)[CH:19]=2)=[N:23][C:31]=1[CH3:30])=[O:35]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NCCO
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CCO
Product: Cc1nc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)sc1C(=O)NCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (78 mg, 0.2 mmol) and ethyl 4-chloro-3-oxo-butanoate (164 mg, 1.0 mmol) in ethanol (4 mL) was heated at reflux for 24 h. The solution was cooled to 0° C. and stirred for 0.5 h. The crystals were isolated by filtration and subsequently suspended in 2-amino-ethanol (4 mL). The mixture was stirred at 70° C. for 4 h, cooled to 23° C., and partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4 and evaporated in vacuum and the residue was triturated with ethyl acetate to give the title compound as light yellow solid (37 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (27.9 g, 104.7 mmol) in CH2Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[S:4].[CH3:19][I:20]>CC(C)=O>[IH:20].[CH3:19][S:4][C:3](=[N:2][CH3:1])[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CNC(=S)Nc1cc(C)ccc1N1CCOCC1
Reactant: CI
Solvent: CC(C)=O
Product: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of 1-methyl-3-(5-methyl-2-morpholinophenyl)thiourea (6.4 g) and methyl iodide (3.8 g) in acetone (60 ml) was heated at reflux for 4 hours to give 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide as a pale yellow solid (m.p. 160°-161° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:19])[CH3:18].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:19][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH3:18]
Reactant: CCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanol and DBU in THF. ES-MS m/e (%): 332 (M+H+, 100).