Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl.S(=O)(=O)(O)O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([N+:24]([O-:26])=[O:25])=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4methyl-2,6-dioxo-1-(2H)-pyrimidinyl]-benzoate in 30 ml of methylene chloride at room temperature is treated with stirring with 2.0 ml of 100% nitric acid. The solution is then treated with 5 drops of concentrated sulphuric acid and stirred for 48 hours at room temperature. The reaction mixture is poured into 150 ml of ice/water, diluted with 100 ml of ethyl acetate and washed four times with 150 ml of water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-5-nitro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 202°-205° C., is obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.O.CN([CH:21]=[O:22])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[O:16][CH2:15][O:14][C:11]2=[CH:12][C:13]=1[CH:21]=[O:22]
Reactant: COc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1C=O)OCO2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of phosphorous oxychloride (3.0 ml, 0.033 mol) in DMF (10 ml) was added a solution of 1-methoxy-3,4-methylenedioxybenzene (2.0 g, 0.013 mol) in DMF (2 ml) at 0° C. After stirring at 60° C. for 18 h the mixture was cooled to 0° C. and then poured into water (500 ml). The precipitate was filtered and dried. The title compound was collected as a yellow solid (2.20 g, 92%).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:36][O:35][C:33]1[CH:32]=[C:11]([CH:12]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=[C:9]([O:8][CH3:7])[CH:34]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Reactant: CC(=O)CCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C=C(C)CCc2ccccc2)cc(OC)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 3,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel (400 g.) and elution with benzene. Yield: 10 g. as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1
Yield: 45.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from dichloromethane-hexane to give 0.19 g of crystals, m.p. 219°-221° C. Anal. Calc'd for C28H22N2O2 : C,80.4; H,5.3; N,6.7. Found: C,79.6; H,5.5; N,6.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[S:30][C:29]([C:31]([NH2:33])=[O:32])=[N:28][N:27]=1>CN(C=O)C>[C:31]([C:29]1[S:30][C:26]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:27][N:28]=1)(=[O:32])[NH2:33]
Reactant: NC(=O)c1nnc(Cl)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(N)=O)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.2 mmol) in anhydrous DMF (8 mL) was added cesium carbonate (8 mmol) and 5-chloro-1,3,4-thiadiazole-2-carboxamide (3.2 mmol). The resulting mixture was stirred at room temperature overnight then quenched with crushed ice. The pH was adjusted to 2 with 6M HCl and the mixture extracted with EtOAc (2×200 mL). The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-75% EtOAc in hexane) to give ethyl 2-(6-(5-carbamoyl-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:28])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:11]=2)[CH:9]=1.CCN(C(C)C)C(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Cl:28][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)[N:11]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A solution of methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate hydrochloride (0.500 g, 1.29 mmol) in THF (20 mL) was added DIPEA (2 mL) and cyclopropyl carbonyl chloride (0.201 g, 1.9 mmol) under nitrogen atmosphere. The reaction mass was stirred at RT for 2-4 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.41-7.54 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.79 (d, 1H), 8.71 (m, H); MS (m/z): 456.97 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[NH2:16][N:17]1[C:25]2[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O>CCOC(C)=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][N:17]2[NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1)=[O:14]
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Reactant: Nn1ccc2c(F)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2c(F)cccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.3 %

Procedure:
A suspension of 2-(pyridine-2-yl)-pyrimidine-5-carbonyl chloride (0.44 g) in EtOAc (20 mL) is added portion wise to a mixture of 1-amino-4-fluoroindole (0.30 g) and K2CO3 (0.276 g) in EtOAc (10 mL)/water (20 mL) and the resulting mixture is stirred at rt for 24 h. The aqueous phase is separated and extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried (MgSO4), filtered and concentration in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.115 g, 17%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 6.65 (d, 1H), 6.89-6.95 (q, 1H), 7.16-7.23 (m, 1H), 7.32-7.35 (d, 1H), 7.57 (d, 1H), 7.57-7.64 (m, 1H), 8.02-8.08 (t, 1H), 8.50-8.52 (d, 1H), 8.82-8.83 (d, 1H), 9.49 (s, 2H), 12.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C[CH2:10][N:11](CC)CC.CN>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-bath cooled solution of 4,6-dichloropyrimidine (3 g, 20 mmol) in THF (5 mL), NEt3 (5.6 mL, 40 mmol) was added followed by slow addition of N-methylamine (2 M in THF, 10 mL, 20 mmol). The mixture was warmed to RT and stirred overnight. The mixture was concentrated in-vacuo, the residue suspended in Et2O and solid collected to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:7][OH:8])[CH2:5][OH:6].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1COCC1>[Si:9]([O:6][CH2:5][C:4](=[CH2:3])[CH2:7][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a dry flask containing sodium hydride (2.270 g, 56.75 mmol) in THF (150 mL) under N2 at 0° C. was added slowly 2-methylenepropane-1,3-diol (5 g, 56.75 mmol). The reaction was warmed to room temperature and stirred 45 min. TBS-Cl (8.55 g, 56.75 mmol) was added in one batch and stirring was continued for another 45 min, until complete by TLC. To the reaction was added water and the mixture was extracted three times with EtOAc and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated at −10-15° C. Silica gel chromatography (20%-50% EtOAc/Hex) afforded the title compound (11.36 g, 99%) as a clear oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1)(=[O:4])=[O:3].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:21])=[O:13])=[CH:11][C:6]=2[O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A mixture of 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol) and sulfamic acid (0.223 g, 2.299 mmol) in acetic acid (8 ml) was cooled to 0° C., and a solution of sodium chlorite (0.378 g, 4.18 mmol) in water (3 ml) was added. The resulting yellow mixture was allowed to warm to RT and stirred for 2 hours. Additional sulfamic acid (0.081 g, 0.836 mmol) and sodium chlorite (0.133 g, 1.463 mmol) in water (2 ml) were added over 1 hour. The reaction mixture was diluted with water (15 ml), and the precipitate was collected by filtration, washed with water and dried to obtain 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.521 g, 1.820 mmol, 87% yield, MS/ESI+ 286.9 [MH]+). This product was employed in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:17][OH:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: NO
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The title compound was prepared by reacting 4′-hydroxy[1,1′-biphenyl]-4-carbaldehyde (1.03 mmol) with hydroxylamine hydrochloride (140 mg, 2 mmol) according to Method C to yield 193 mg (79%, over two steps) of yellowish solid: mp 207-210° C.; 1H NMR (DMSO-d6): δ 6.85 (2H, d, J=8.37 Hz), 7.53 (2H, d, J=8.39 Hz), 7.62 (4H, s), 8.15 (1H, s), 9.62 (1H, s), 11.21 (1H, s); MS (ESI) m/z 212 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1cccc(CN)c1OC
Solvent: CCN(CC)CC
Product: COc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1OC

Procedure:
2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,3-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: C1COCCN1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCOCC1
Yield: 12.8 %

Procedure:
Prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloro ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C (200 mg, 0.39 mmol) and morpholine (0.102 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.08 (brs, 1H), 8.56 (s, 1H), 7.58-7.65 (m, 2H), 7.38-7.43 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 4.00 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:26])[CH2:23][CH2:24][OH:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 270.2 %

Procedure:
(S)-1-Trityloxy-2,4-butanediol (1.64 g, 4.7 mmol) and imidazole (0.321 g, 4.715 mmol) were dissolved in DMF (20 ml) and the solution was cooled to 0° C. To the solution was dropped tert-butyldimethylsilyl chloride (0.5 ml, 1.44 mmol, 50% in toluene). After stirring for 1 hour, again to the solution was dropped tert-butyldimethylsilyl chloride (0.5 ml, 1.44 mmol) and the solution was stirred for 1 hour. Further tert-butyldimethylsilyl chloride (0.6 ml, 1.73 mmol) was added to the solution and the solution was stirred over night at room temperature. After dilution with toluene (100 ml), the solution was washed with water (100 ml) twice and saturated brine once, dried on magnesium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (1.80 g, yield 82.6%).
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:57][CH2:58]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([O:4][CH2:3][CH:2]3[CH2:5][CH2:6][CH2:7][NH:1]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of prolinol (0.0243 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH-CHCl3) to afford the title compound E22 as an off-white solid (0.35 g, quantitative). mp 84-86° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/%B=0/60, 10/60,25/80, 40/80, 45/60, 50/60; 268 nm, Rt 24.67 min, 99.59% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH2:13][C:12](=O)[N:11]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1.B(F)(F)F.C(OCC)C>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH2:12][CH2:13]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1
Agent: B#B
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(CNN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Reducing 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine using a mixture of diborane in tetrahydrofuran and boron trifluoride in diethyl ether to afford 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylamino)piperazine followed by dehydrogenating to afford the desired 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)piperazine.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[C@H:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Product: CO[C@@H](C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(R)-(+)-Methoxyphenylacetic acid was coupled with 4-aminomethyl benzonitrile (CAS No: 10406-25-4) according to general procedure C to give (R)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-acetamide as an off-white solid. MS 281.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5](=O)[C:4]=2[CH:3]=1.C[Mg]Cl.[C:22]([OH:25])(=O)[CH3:23]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6]([OH:17])([CH3:5])[C:22]([OH:25])([CH3:23])[C:14]=2[CH:15]=1
Reactant: CC(=O)O
Reactant: O=C1C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2-c2ccc(Br)cc2C1(C)O
Reaction time: 8 h

Procedure:
34.3 g (94 mmol) of 2,7-dibromophenanthrene-9,10-quinone were suspended in 600 ml of dry THF at −10° C. under argon, and 141 ml (282 mmol) of methylmagnesium chloride (2 molar solution in THF) were added dropwise at such a rate that the internal temperature did not exceed 0° C. The mixture was subsequently stirred overnight at room temperature. 50 ml of glacial acetic acid were added to the batch with ice cooling, and the mixture was diluted with ethyl acetate. After washing twice with saturated sodium chloride solution, the mixture was dried over sodium sulfate, and the solvents were removed, giving 43.4 g of the product, which was employed without further purification for the next step.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CON(C)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1CCCCC1>[C:26]1([C:25](=[O:32])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
Place lithium diisopropylamide (10 mL of a 1.5M solution in cyclohexane) and tetrahydrofuran (40 mL) under an argon atmosphere and cool to 0° C. Add, by dropwise addition, phenylacetylene (1.65 mL, 15 mmol). Remove the cooling bath and stir for 30 minutes as room temperature. Cool the yellow solution to 0° C. and add, by dropwise addition, N-methoxy-N-methylbenzamide (3.04 mL, 20 mmol). Remove the cooling bath and stir for 30 minutes at room temperature. Pour onto ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Purify by silica gel chromatography (2% ethyl acetate/hexane) then purify further by distillation (2×) to yield 1.9 g of the title compound; bp 210° C. in vacuo.