Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:16]>C[C@H](O)CC.CN(C=O)C>[C@@H:5]([O:16][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)([CH2:6][CH3:7])[CH3:4]
Reactant: O
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1nn2c(N)nnc2c(C)c1C
Temperature: 0 °C

Procedure:
(S)-Butan-2-ol (1.7 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (85 mg). The suspension formed was heated to 55° C. for 1.5 h and then admixed with portions of 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 100 mg), suspended in (S)-butan-2-ol (2 ml) and DMF (2 ml). After stirring at 55° C. for 1 h, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 105 mg of the title compound were isolated in sufficient purity. LC-MS rt: 0.81 min [M+H]+: 236.2 (met. b)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: Fc1ccc(CNc2cncc(-n3cnc4ccccc43)n2)cc1
Yield: 52.7 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (240 mg, 1.01 mmol) and benzimidazole (130 mg, 1.1 mmol) furnished the product (170 mg, 53%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1(C(=O)C(C#N)=CN(C)C)C=CC=CC=1.[N+]([O-])([O-])=O.OCCOC1C=CC(NC(N)=[NH2+])=CC=1.[OH-].[Na+]>>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2].[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C=C(C#N)C(=O)c1ccccc1
Agent: N#Cc1cnc(Nc2ccc(OCCO)cc2)nc1-c1ccccc1
Agent: NC(=[NH2+])Nc1ccc(OCCO)cc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Nc3ncc(C#N)c(-c4ccccc4)n3)cc2)cc1

Procedure:
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]pyrimidine-2-amine was prepared from 5-cyano-4-phenyl-N-[4-(2-hydroxy-ethoxy)phenyl]pyrimidine-2-amine (1.42 g,4.28 mmol) and 4-toluene-sulphonyl chloride (1.23 g, 6.4 mmol) as a yellow solid, m.p. 147°. δH (CDCl3) 8.67 (1H, s), 8.05-8.03 (2H, m), 7.83 (2H, dd, J 6.5, 1.8 Hz), 7.58-7.49 (6H, m), 7.35 (2H, dd, J 8.6, 0.9 Hz), 6.83 (2H, d, J 0.9 Hz), 4.38-4.36 (2H, m), 4.18-4.16 (2H, m) and 2.45 (3H, s). 5-cyano-4-phenyl-N-[4-(2-hydroxyethoxy)phenyl]pyrimidine-2-amine was prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.41 g, 7.0 mmol), 4-(2-hydroxy-ethoxy) phenylguanidinium nitrate (2.0 g, 7.7 mmol) and sodium hydroxide (340 mg, 8.4 mmol) to give a yellow solid (1.54 g), m.p. 151°. δH (CDCl) 8.67 (1H, s), 8.04 (2H, d, J 7.7 Hz), 7.58-7.52 (5H, m), 7.45 (1H, s), 6.95 (2H, dd, J 6.7,2.3 Hz), 4.12-4.09 (2H, m), 4.00-3.97 (2H, m) and 2.05-2.01 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1
Yield: 70 %

Procedure:
To a solution of 4-hydroxybenzoic acid (138 g, 1.00 mol) in methanol (1000 mL) was added concentrated sulfuric acid (20 mL), then the reaction heated at reflux for 20 h. The reaction mixture was concentrated to one half the original volume under reduced pressure then partitioned with ethyl acetate (1000 mL) and water (1000 mL). The organic layer was washed with 1 N aqueous sodium hydroxide (2×300 mL), water (300 mL), brine (300 mL) then dried (MgSO4). The solvent was removed under reduced pressure to give the ester as a white solid (106.62 g, 70%) after drying under vacuum at ambient temperature.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[C:24]([O:26]CC)=O>C(Cl)Cl.CO>[NH:14]1[CH:15]=[CH:16][N:12]=[C:13]1[CH2:17][N:18]1[C:19]2[CH:23]=[CH:22][NH:21][C:20]=2[C:24](=[O:26])[NH:9][C:10]1=[S:11]
Reactant: CCOC(=O)c1[nH]ccc1NCc1ncc[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2ncc[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Benzoyl isothiocyanate (0.19 mL, 1.41 mmol) was added to a stirred solution of ethyl 3-[(1H-imidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.3 g, 1.28 mmol) in CH2Cl2 (4 mL) and methanol (2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in ammonia (7N in methanol, 7 mL) and heated at 80° C. for 1 h. The crude product was filtrated and purified by preparative HPLC, obtaining 0.110 g, (35%) of the title compound as a white solid.
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([OH:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].BrCC1CC1.II>C1(CO)CC1>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([CH2:5][CH:6]2[CH2:2][CH2:7]2)(=[O:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: O=C(O)c1ccccc1
Agent: BrCC1CC1
Agent: II
Agent: OCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl)-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and Bromomethyl-cyclopropane (+catalytic amount I2) in 20 ml cyclopropyl methanol/20 ml water and obtained in 8% yield. MS (m/e): 273.1 (MH−, 100%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][CH2:33][C@@:34]1([CH2:48]CO)[CH2:38][N:37]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[C:36](=[O:47])[CH2:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C@@:34]1([CH2:48][CH2:1][Br:5])[CH2:38][N:37]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[C:36](=[O:47])[CH2:35]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H](c1ccccc1)N1C[C@](CCO)(COCc2ccccc2)CC1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@](CCBr)(COCc2ccccc2)CC1=O
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
Carbon tetrabromide (3.17 g, 9.56 mmol) and triphenylphosphine (2.51 g, 9.56 mmol) were sequentially added to a solution of (4R)-4-benzyloxymethyl-4-(2-hydroxyethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (3.22 g, 9.10 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→1:2) to give 3.18 g (84%) of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].C([Li])CCC.C1C[O:24][CH2:23]C1>>[CH3:12][C:8]1([CH3:13])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]2[CH:3]=[C:2]([CH:23]=[O:24])[CH:11]=[CH:10][C:9]1=2
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: [Li]CCCC
Product: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Temperature: -70 °C
Yield: 100 %

Procedure:
A flame dried round bottom flask was charged with 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphtalene (10 g, 37 mmol) and anhydrous THF (100 mL). This solution was cooled to −70° C. while stirring under a nitrogen blanket. To this solution was added 2.5 M n-butyl lithium (14.9 mL, 37 mmol). The reaction mixture was allowed to stir for 30 minutes at which time it was quenched via the addition of dimethylformamide (5.0 mL). The reaction was allowed to warm to RT where it stirred for 17 hours. The reaction was quenched by the addition of 1.0 N HCl (100 mL). The reaction mixture was extracted using ether. The organics were separated and dried over MgSO4 followed by concentrating to dryness. The resulting oil was dried under high vacuum to give a total of 8.2 g (100%) of crude oil. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:24])[C@@H:12]([OH:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O>CN(C)C=O>[OH:23][C@H:12]([C:11]([NH:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH:1][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:24])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of tert-butyl ((3S)-4-{[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-hydroxy-4-oxobutyl)carbamate (2.86 g) in N,N-dimethylformamide (30 ml) were added trityl chloride (3.48 g) and triethylamine (3.48 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave crude crystals, which were washed with ethyl acetate-diisopropyl ether (2:1) and collected by filtration to give tert-butyl ((3S)-3-hydroxy-4-{[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (3.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:34]O)[CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:34][O:24][C:23]([C:18]2([C:20]([O:22][CH2:34][CH:30]3[CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CCC1)(C(=O)OCC1CCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 30 as an off-white solid (HCl salt); 1H NMR (CDCl3) δ 1.32 (d, J=6.5 Hz, 3H), 1.85 (m, 8H), 2.05 (m, 4H), 2.69 (m, 2H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.10 (s, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1759, 1779 cm-1 (C=O); MS (ES) m/z 558 (MH+); [α]D25 -27° (c, 1.0, CHCl3). Anal. Calcd. for C30H36ClNO7 ·HCl: C, 60.61; H, 6.10; N, 2.36; Cl, 11.94. Found: C, 60.68; H, 6.30; N, 2.31; Cl, 11.71.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)/[C:13]#[N:14])=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]>ClCCCl>[S:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)/[C:13]#[N:14])=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: COc1ccc(/C=C(\C#N)c2ccc(NS(N)(=O)=O)cc2)cc1
Solvent: ClCCCl
Product: N#C/C(=C\c1ccc(O)cc1)c1ccc(NS(N)(=O)=O)cc1
Yield: 28.2 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 63 mg of (2Z)-2-[4-(N-sulfamoylamino)phenyl]-3-(4-methoxyphenyl)-prop-2-enenitrile was used in place of 4′-methoxy-2-biphenylacetonitrile, and 1,2-dichloroethane was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 2:1 mixture of chloroform and acetone as the developing solvent) to obtain 17 mg of (2Z)-2-[4-(sulfamoylamino)phenyl]-3-(4-hydroxyphenyl)prop-2-enenitrile.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (4.00 g) and dimethylformamide (69 ml) was added diisopropylethyl amine (4.81 ml), piperidine (1.50 ml) and sodium iodide (0.62 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 83°-85° C. for 7-8 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatogaphy (silica gel, 2% triethylamine/0-4% methanol/ethyl acetate) afforded 2.30 g of the product. Recrystallization from ether/pentane yielded 6,7-dihydro-3-phenyl-5-[3-(1-piperidinyl)-propyll-1,2-benzisoxazol-4(5H)-one, m.p. 91.5°-93.5° C.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([CH3:14])=[O:13]>CCO>[C:4]1(/[CH:3]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 788.8 %

Procedure:
A solution of aq. NaOH solution (2 N, 125 mL) in EtOH (250 mL) was added to a mixture of benzaldehyde (26.5 g, 25 mmol) in acetone (9.2 mL, 13 mmol). The reaction mixture was stirred for 4 h at ambient temperature and the resulting yellow precipitate was filtered, washed with H2O, recrystallized from EtOAc and dried in vacuo to obtain NW275 as a yellow solid (23.1 g, 79%). mp: 106-107° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.78 (d, 3J=16.0 Hz, 2H, Hvin), 7.66-7.64 (m, 4H, HAr), 7.46-7.44 (m, 6H, HAr), 7.12 (d, 3J=16.0 Hz, 2H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 189.3 (C), 143.7 (CH), 135.2 (C), 130.9 (CH), 129.4 (CH), 128.8 (CH), 125.8 (CH). MS (EI) m/z: 234.2 (M+). Anal. calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 87.03; H, 6.03%.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:6]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH:13]=1.[ClH:27]>C1(C)C=CC=CC=1>[Cl:27][CH2:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:6]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH:13]=1
Reactant: Cl
Reactant: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CO)cc21
Solvent: Cc1ccccc1
Product: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CCl)cc21
Temperature: 25 °C

Procedure:
A mixture of 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (1.25 g, 3.41 mmol) (example 10c) and 12N HCl (8.5 mL) in toluene (35 mL) was heated at reflux for 1 hour. The solution was cooled to room temperature and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. To the residue obtained (3-[5-chloromethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde) (example 10e), diluted in dimethylformamide (35 mL), were added potassium carbonate (3.49 g, 25.25 mmol) then dimethylamine hydrochloride (1.47 g, 18.04 mmol). The mixture was stirred at room temperature for 3 hours. Water was added and the layers separated. The mixture was extracted with ethyl acetate and the organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (10% methanol in dichloromethane) to afford 742 mg of 3-(5-Dimethylaminomethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde. 56% yield. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 6H), 2.30 (s, 6H), 3.47 (s, 2H), 4.25 (s, 2H), 7.06 (s, 1H), 7.16 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.90 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 10.03 (s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(Cl)c4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3)c2O1
Yield: 57.2 %

Procedure:
Treatment of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.24 mmol) with sodium azide (0.93 g, 14.3 mmol) generally according to the procedure described for Intermediate 98 provided 0.41 g of (±)-2-(azidomethyl)-5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (100 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.31 g (50%) of (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 195° C. (dec); Anal. calcd for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 51.59; H, 4.21; N, 4.02.
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(N(CC)CC)C>[C:20]([O:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COC1Nc2c(ccc(C)c2OC(C)=O)C(=O)N2CCCC12
Reaction time: 0.25 h

Procedure:
49.3 mg of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was suspended in 0.5 ml of 1:1 mixture of triethylamine and acetic anhydride and stirred at 0° to 5° C. for 15 minutes under a stream of nitrogen gas. Thus, 30 mg of 2,3,5,10,11,11a-hexahydro-9-acetoxy-11-methoxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained was a colorless powdery product. Recrystallization of the resulting product from acetone-ligroin gave a colorless needle-like crystal having a melting point of 147° to 149.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:43])=[C:16]4[C:41](=[O:42])[C:22]5[C:23]([OH:40])=[CH:24][C:25]6[C@@:32]7([CH3:34])[O:33][C@H:28]([C@@H:29]([OH:39])[C@H:30]([N:36]([CH3:38])[CH3:37])[C@H:31]7[OH:35])[O:27][C:26]=6[C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[C@@H:12](C(O)=O)[C@:11]([OH:48])([CH3:47])[CH2:10]2)[C@H:5]([O:49][CH3:50])[C@@:4]([O:52][CH3:53])([CH3:51])[C@H:3]1[O:54][CH3:55].C(Cl)(Cl)Cl.CCO>CN(C=O)C.CO>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:43])=[C:16]4[C:41](=[O:42])[C:22]5[C:21](=[C:26]6[O:27][C@@H:28]7[O:33][C@@:32]([CH3:34])([C@H:31]([OH:35])[C@@H:30]([N:36]([CH3:38])[CH3:37])[C@@H:29]7[OH:39])[C:25]6=[CH:24][C:23]=5[OH:40])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH2:12][C@:11]([OH:48])([CH3:47])[CH2:10]2)[C@H:5]([O:49][CH3:50])[C@@:4]([O:52][CH3:53])([CH3:51])[C@H:3]1[O:54][CH3:55]
Reactant: CO[C@H]1[C@H](O[C@H]2C[C@](C)(O)[C@H](C(=O)O)c3cc4c(c(O)c32)C(=O)c2c(O)cc3c(c2C4=O)O[C@@H]2O[C@@]3(C)[C@H](O)[C@@H](N(C)C)[C@@H]2O)O[C@@H](C)[C@H](OC)[C@@]1(C)OC
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CO[C@H]1[C@H](O[C@H]2C[C@](C)(O)Cc3cc4c(c(O)c32)C(=O)c2c(O)cc3c(c2C4=O)O[C@@H]2O[C@@]3(C)[C@H](O)[C@@H](N(C)C)[C@@H]2O)O[C@@H](C)[C@H](OC)[C@@]1(C)OC
Reaction time: 8 h

Procedure:
A solution of 12.3 g of nogalamycinic acid in a mixture of 20 ml of DMF and 50 ml of CH3OH was prepared by heating. After the solution had stood at room temperature overnight, it was put on 500 g of silica and eluted with CHCl3 --MeOH starting with 99:1 and gradually increasing the concentration of CH3OH until a ratio of 4:1 was reached. The elution was followed by thin layer chromatography (tlc) (CHCl3 --MeOH--H2O; 78:20:2) and collecting those fractions containing only nogamycin (Rf 0.5). A total of 3.9 g was obtained. One and one-half grams was recrystallized from acetone-CH3OH (85:15). Obtained: 259 mg, mp 210°-215° C.; αD +273° (C 0.923, CHCl3); uv (EtOH) λmax nm 236 (ε51,700), 259 (ε25,850), 290 (ε10,050) and 478 (ε16,100); ir (Nujol) 3500, 1670, 1630, 1575, 1295, 1230, 1110, 1055, 1005, 920, 890, 838, 778, 762 and 724 cm-1 ; mass spectrum m/e 729; 'H NMR (d7 -DMF) 1.14, 1.23, 1.37, 1.69 (12 H, 4 CH3C), δ2.07-2.38, 2.83-3.0 (m, 4 H, 2 CH2), 2.42 [s, 6 H, (CH3)2N], δ3.13, 3.42, 3.52 (3 S, 9 H, 3 CH3O), 3.3-4.2 (m, CHO, CHN), 4.95 (m, 1 H, benzylic CHO), δ5.32 (d, 1 H, anomeric), δ5.68 (1 H, anomeric) δ7.16, 7.32 (2s, 2 H, aromatic); 13C NMR (CDCl3) δ15.2, 18.3, 24.2, 30.4 (4 CH3C), 30.8 (CH2), δ41.5 [(CH3)2N], δ44.1 (CH2) δ48.7, 59.0, 61.4 (3 CH3O), δ66.4-88.6 (CO and CN), δ96.79 and 99.81 (anomeric), δ113.1-161.4 (aromatic), δ179.7 and 190.8 (carbonyl). Anal. calcd. for C37H47NO14 : C, 60.96; H, 6.55; N, 1.92. Found: C, 58.55; H, 6.42; N, 1.94.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc(Cl)c[n+]([O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cc(Cl)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-chloropyridine 1-oxide (90 mg, crude) in DCM (3 mL) was added TFA (1.5 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford the crude title product, which was used directly in the next step without further purification (80 mg, crude). MS (ESI) m/z 173.1 [M+H]+.