Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)[CH3:28].[BH3-]C#N.[Na+].C(Cl)(Cl)Cl.CO>CCO>[CH3:12][C:10]1[CH:11]=[C:3]([CH2:2][NH:1][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[CH:4]=[C:5]2[C:9]=1[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cc(CN)cc2c1C(=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc(CNC(C)c2ccccc2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 6 h
Yield: 44 %

Procedure:
A mixture of 5-aminomethyl-7-methyl-2-(4-trifluoromethoxybenzoyl)-2,3-dihydro-isoindol-1-one (0.053 g, 0.15 mmol), acetophenone (0.036 g, 0.30 mmol), Ti(i-OPr)4 (1 mL), and NaBH3CN (0.1 g, 1.6 mmol) in EtOH (2 mL) was stirred for 6 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-5-[(1-phenyl-ethylamino)-methyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.38 (d, 3H), 1.64 (bs, 1H), 2.73 (s, 3H), 3.62 (dd, 2H), 3.82 (q, 1H), 4.21 (s, 2H), 4.75 (s, 2H), 7.08-7.39 (m, 11H). GC-MS: m/z 439 (M-15)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].Cl[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1.O>C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: COc1ccc2nccc(CCl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2nccc(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)c2c1
Yield: 34.7 %

Procedure:
0.1 g of sodium hydride (at 60%) is added to a solution of 0.65 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 40 ml of anhydrous THF, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 30 minutes. 0.47 g of 4-chloromethyl-6-methoxyquinoline dissolved in 10 ml of THF is added. The reaction medium is refluxed for 16 hours. After cooling, 100 ml of water and 75 ml of ethyl acetate are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The brown oil obtained is purified by flash chromatography (SiO2, EtOAc/cyclohexane, 50/50 by volume, as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.36 g of 5,5-dimethyl-1-(6-methoxyquinolin-4-yl-methyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(O)(=O)C.Cl>C(O)C>[O:6]([CH2:5][CH:4]=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(COc1ccccc1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=CCOc1ccccc1

Procedure:
0.84 g (4 mmol) of 69A, 5 mL of acetic acid, 2.5 mL of 1N aqueous hydrochloric acid and 20 mL of ethanol were mixed and heated under reflux under an argon atmosphere for 3 hours. Ethanol was evaporated. Then the resulting residue was dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and the solvent evaporated in vacuum. The crude product was obtained in almost quantitative yield.
Reaction SMILES: CC(OI1(O[C:20]([CH3:22])=[O:21])(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH2:26][S:27]([CH2:30][C@H:31]([NH-:43])[C:32](=[O:42])[NH:33][CH:34]2[CH:39](O)[CH2:38][CH2:37][CH2:36][CH:35]2[OH:41])(=[O:29])=[O:28])[CH2:25][CH2:24]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:23]1([CH2:26][S:27]([CH2:30][C@H:31]([NH:43][C:32]([N:33]2[CH2:22][CH2:20][O:21][CH2:35][CH2:34]2)=[O:42])[C:32](=[O:42])[NH:33][C:34]2[C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH:39]=2)(=[O:28])=[O:29])[CH2:24][CH2:25]1
Reactant: [NH-][C@@H](CS(=O)(=O)CC1CC1)C(=O)NC1C(O)CCCC1O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCC=C1NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dess Martin Periodinane (0.688 g, 1.62 mmol) was added to a solution of the [(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32 g) in DCM (10 mL) and the mixture was stirred at room temperature for 3 hours then treated with resin bound Na2S2O3 (1.5 mmol/g, 1.9 g) and stirred at room temperature for a further 24 hours. The reaction mixture was diluted with DCM (20 mL), then filtered. The filtrate was washed with a solution of 0.25 M Na2S2O3, then with saturated NaHCO3, then dried (MgSO4), and then evaporated under reduced pressure. The residue was subjected to column chromatography eluting with a mixture of ethyl acetate and heptane to give morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethyl]-amide. 1H NMR (CDCl3): 9.00 (s, 1H), 7.78 (t, 1H), 6.18 (d, 1H), 4.9 (m, 1H), 3.85 (m, 1H), 3.77–3.62 (m, 4H), 3.58–3.45 (dd, 1H), 3.48–3.36 (m, 4H), 3.0 (d, 2H), 2.55–2.42 (m, 4H), 2.08–1.97 (m, 2H), 1.2 (m, 1H), 0.8–0.7 (m, 2H), 0.6–0.4 (m, 2H). MS: 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:16](OC)=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A suspension of methyl 5-((3,4-dichlorophenyl)amino)pyrazine-2-carboxylate (0.53 g, 1.778 mmol) in THF (18 mL) was cooled at −78° C. and 1M solution of DIBAL-H (5.33 ml, 5.33 mmol) in toluene was added. The mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate concentrated. The residue was purified on silica gel using 40-100% ethyl acetate in hexanes. The desired fractions were concentrated to give (5-(3,4-dichlorophenylamino)pyrazin-2-yl)methanol as a yellow solid (0.293 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (1H, s), 8.02-8.34 (3H, m), 7.46-7.66 (2H, m), 5.36 (1H, t, J=5.77 Hz), 4.51 (2H, d, J=5.77 Hz). LCMS: R.T.=3.65; [M+H]+=269.96.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O-:13])(=[O:12])[CH3:11].[NH4+:14].C(O)(=O)CC(O)=O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH2:11][C:10]([OH:13])=[O:12])[NH2:14])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: O=C(O)CC(=O)O
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(F)cc1
Yield: 68.5 %

Procedure:
4-Fluorobenzaldehyde (10 g, 80 mmol), ammonium acetate (8.2487 g, 107 mmol) and malonic acid (8.3285 g, 80 mmol) were refluxed (slow) in absolute ethanol (60 mL) for 48 hours. White solid was filtered and purified by ethanol recrystallization to afford β-4-fluorophenyl-β-alanine (10.04 g, 54.8 mmol, 68.5%); MP: 216-217° C.; IR (KBr): 3160, 1606 cm−1; TLC: RF=0.41 (solvent 24), 0.42 (solvent 25); 1H NMR (D2O/K2CO3): δ 7.28-7.19 (m, 2H), 7.03-6.91 (m, 2H), 4.10 (t, J=7.39 Hz, 1H), 2.54-2.34 (m, 2H). Anal. Calcd for C9H10FNO2.5/3H2O: C, 50.70; H, 6.30; N, 6.57. Found: C, 50.34; H, 6.39; N, 6.30.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:19][NH2:20].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([Cl:15])[CH:17]=2)=[N:4][N:3]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: Cc1ccc(CN)cc1Cl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-chloro-4-methylbenzylamine were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby the title compound was obtained as a less polar compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:19]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][C:19]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[O:36][C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: I[Mg]CCCCCC1CCCCC1
Product: CC(C)(C)c1ccc(C(O)CCCCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using 5-cyclohexylpentylmagnesium iodide and N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like substance.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[O:11])[C:5]=1[OH:26])=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:11])[C:5]=1[OH:26]
Reactant: [N-]=[N+]=Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
To 0.14 g of 4-azido-3-hydroxy-N-para-phenoxyphenylpicolinamide (obtained from the compound of the Preparation Example according to the methods described in Examples a) to g)) dissolved in a mixture of ethanol/ethyl acetate, 1:2, there is added a spatula tip of 10% palladium on carbon. Hydrogenation is carried out at 20 bars pressure and ambient temperature for 4-5 hours. After filtration, concentration and chromatography of the residue in ethyl acetate, there is obtained 0.099 g of a white solid (MP : 197° C.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH2:36][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C=O)c2)C1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(CN3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-formyl-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (143 mg of 50% pure material, approx. 0.142 mmol) was dissolved in DCE (1.5 mL) and AcOH (0.15 mL). Morpholine (18.5 uL, 0.213 mmol) and sodium triacetoxyborohydride (75 mg, 0.355 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between dichloromethane and 10% aqueous NaHCO3. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were evaporated to dryness and the product (90 mg) was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC(CO)CC3)cc1OCC2
Yield: 48 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-piperidine methanol, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 372 as a white solid (69 mg, 48%). LCMS: RT=2.57 min, [M+H]+=410. 1H NMR 400 MHz (DMSO-d6) δ: 9.10 (1H, s), 7.90 (1H, s), 7.84 (1H, s), 6.32 (1H, s), 5.99-5.90 (1H, m), 4.54-4.44 (5H, m), 4.34 (2H, d, J=13.11 Hz), 3.28 (2H, t, J=5.64 Hz), 2.84 (2H, t, J=12.55 Hz), 1.71 (2H, d, J=13.74 Hz), 1.65 (1H, m), 1.49 (6H, d, J=6.60 Hz), 1.13 (2H, t, J=12.33 Hz)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11]>CCCCCCC>[C:2]([Cl:4])(=[O:3])[C:1]([O:11][CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)=CCO
Solvent: CCCCCCC
Product: CC(C)=CCOC(=O)C(=O)Cl
Reaction time: 2 h

Procedure:
A 1-liter eggplant type flask was charged with 25.4 g (0.20 mol) of oxalyl chloride and 250 ml of n-heptane, to which 21.5 (0.25 mol) of 3-methyl-2-buten-1-ol were added dropwise over 3 hours while bubbling nitrogen at room temperature, followed by stirring further for 2 hours. Thereafter, the reaction mixture was concentrated and distilled to obtain 11.6 g of 3-methyl-2-butenyl chlorooxalate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[C:10]1([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: NNc1ccccc1Br
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: O=C(C(=NNc1ccccc1Br)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione (2-bromophenyl)hydrazone was prepared from 2-bromophenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS m/z 379;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:12]([CH2:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:8][C:7]1[C:6]([CH3:11])=[CH:5][C:4]([S:12]([CH2:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(S(=O)(=O)CCCO)cc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(S(=O)(=O)CCCO)cc(C)c1N
Reaction time: 3 h

Procedure:
3-(3,5-Dimethyl-4-nitro-benzenesulfonyl)-propan-1-ol is dissolved in 15 mL of ethanol, Pd/C(5%) (55 mg) is added and the reaction mixture is stirred under hydrogen atmosphere (3 bar) for 3 h. The reaction mixture is filtered on a celite pad, the solvent is concentrated under vacuum to give the title compound. Yield: 1 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:7]2[C:29]([C:33]([O:35]CC)=[O:34])=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:7]2[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(OC(c4ccccc4)c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1b from 2-ethoxy-7-ethoxycarbonyl-1-[4-[α-(1H-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: C(C1C=C(OC)C(OC)=CC=1C(O)=O)C.Cl.CC(O)(C1C=C(OC)C(OC)=CC=1CC)CS(CC(C1C=C(OC)C(OC)=CC=1CC)(O)C)(=O)=O.[NH:52]([CH:59]=[C:60]([CH2:63][C:64]1[CH:69]=[C:68]([O:70][CH3:71])[C:67]([O:72][CH3:73])=[CH:66][C:65]=1[CH2:74][CH3:75])[C:61]#N)C1C=CC=CC=1.[NH2:76][C:77]([NH2:79])=[NH:78]>CO>[NH2:78][C:77]1[N:79]=[C:59]([NH2:52])[C:60]([CH2:63][C:64]2[CH:69]=[C:68]([O:70][CH3:71])[C:67]([O:72][CH3:73])=[CH:66][C:65]=2[CH2:74][CH3:75])=[CH:61][N:76]=1
Reactant: N=C(N)N
Reactant: CCc1cc(OC)c(OC)cc1CC(C#N)=CNc1ccccc1
Agent: CCc1cc(OC)c(OC)cc1C(=O)O
Agent: CCc1cc(OC)c(OC)cc1C(C)(O)CS(=O)(=O)CC(C)(O)c1cc(OC)c(OC)cc1CC
Agent: Cl
Solvent: CO
Product: CCc1cc(OC)c(OC)cc1Cc1cnc(N)nc1N

Procedure:
2-Ethyl-4,5-dimethoxybenzoic acid is esterified in methanol containing hydrochloric acid. The methyl ester is converted consecutively to methyl-α-(2-ethyl-4,5-dimethoxyacetophenone) sulphone, methyl-β-hydroxy-β-(2-ethyl-4,5-dimethoxyphenyl)ethyl sulphone, and β-anilino-α -(2-ethyl-4,5-dimethoxybenzyl) acrylonitrile according to Example 107. Following the procedure of Example 121 the β-anilino-α-(2-ethyl-4,5-dimethoxybenzyl) acrylonitrile is allowed to react with guanidine to give 2,4-diamino-5-(2'-ethyl-4',5'-dimethoxybenzyl)pyrimidine, m.p. 206°-207° C. after recrystallization from 60% to ethanol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH:38]=[C:37]([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH2:36][CH2:35]1>O1CCCC1.CN(C)C=O>[NH:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([C:37]2[CH2:38][CH2:39][N:34]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[C:24]=4[O:23][CH2:22][CH2:21][C:20]5=[O:25])[O:26][CH2:27]3)[CH2:35][CH:36]=2)=[CH:41]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCOc2c1ccc1c2OC(CN2CC=C(c3c[nH]c4ccccc34)CC2)CO1

Procedure:
To a mixture of [(2R)-7-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1.54 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethyl-formamide (20 mL) was added 0.91 g (4.61 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product. Evaporation of the product-containing fractions in vacuum gave 0.12 g (18%) of the (S)-enantiomer of the title compound as an off-white solid, m.p. 210° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[N:7]([CH2:8][CH2:9][CH2:10]O)[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.S(Cl)([Cl:19])=O.CN(C)C=O>ClCCl>[Cl:19][CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3][S:2]1(=[O:16])=[O:1]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S1(=O)Nc2ccccc2CN1CCCCl
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 3-(2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)propan-1-ol (1.0 g, 4.1 mmol) in dichloromethane (20 mL) was treated with thionyl chloride (0.91 mL, 12.3 mmol) and dimethylformamide (0.20 mL) and stirred at 23° C. for 16 hours. Additional thionyl chloride (0.30 mL, 4.1 mmol) was added and stirring was continued for an additional 4 hours. The reaction mixture was quenched by the addition of methanol (5 mL) and evaporated. Flash chromatography (SiO2, 3-40% ethyl acetate/hexanes) provided 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.85 g, 79%) as a yellow oil:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([I:21])[C:12]2[O:16][C:15]([N:17]([CH3:19])[CH3:18])=[N:14][C:13]=2[CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][N:17]([CH3:19])[C:15]1[O:16][C:12]2[C:11]([I:21])=[CH:10][C:9]([CH2:8][NH2:7])=[CH:20][C:13]=2[N:14]=1
Reactant: CN(C)c1nc2cc(CNC(=O)OC(C)(C)C)cc(I)c2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1nc2cc(CN)cc(I)c2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of Tert-butylN-{[2-(dimethylamino)-7-iodo-1,3-benzoxazol-5-yl]methyl}carbamate (120 mg, 0.29 mmol) in 4 ml of CH2Cl2 was added slowly 0.5 mL of trifluoroacetic acid and it was stirred at room temperature for 30 min. The excess of TFA was removed under vacuum. The product was purified by column chromatography (CH2Cl2/MeOH 9:1) yielding 64 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD) δ 7.46 (d, 1H, J=1.5 Hz, H-6); 7.30 (d, 1H, J=1.5 Hz, H-4); 4.12 (s, 2H, CH2); 3.23, 3.24 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 164.5 (C-2), 152.7 (C-7a), 144.6 (C-3a), 132.9 (C-5), 131.6 (C-6), 117.3 (C-4), 72.0 (C-7), 44.2 (CH2), 38.3 (CH3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].[Br:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[Br-:9].[CH2:14]([O:13][C:11](=[O:12])[CH2:10][SH:1]1[CH:5]=[CH:4][NH+:3]=[C:2]1[CH:6]([OH:8])[CH3:7])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CC(O)c1nccs1
Solvent: CC#N
Product: CCOC(=O)C[SH]1C=C[NH+]=C1C(C)O
Product: [Br-]
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A mixture of 1-(2-thiazolyl)ethanol (1.17 g, 8.67 mmole) and ethyl bromoacetate (1.32 g, 8.63 mmole) was heated at 48 C. for 18 hr. The reaction mixture was dissolved in acetonitrile (3 mL) and stored at 4 C. After 2 months the crystals which separated were filtered out and washed with 3:7 ether-acetonitrile to yield 2.028 g of the title compound, mp 101-103 C.