Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]([CH3:33])[CH2:10][N:11]1[C:23]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Br[C:35]1[CH:36]=[CH:37][C:38]2[NH:39][C:40]3[C:45]([C:46]=2[CH:47]=1)=[CH:44][C:43](Br)=[CH:42][CH:41]=3.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:8][CH:9]([CH3:33])[CH2:10][N:11]1[C:12]2[CH:13]=[CH:14][C:15]([C:35]3[CH:36]=[CH:37][C:38]4[NH:39][C:40]5[C:45]([C:46]=4[CH:47]=3)=[CH:44][C:43]([C:20]3[CH:21]=[CH:22][C:23]4[N:11]([CH2:10][CH:9]([CH3:33])[CH3:8])[C:12]6[C:17]([C:18]=4[CH:19]=3)=[CH:16][CH:15]=[CH:14][CH:13]=6)=[CH:42][CH:41]=5)=[CH:16][C:7]=2[C:1]2[C:6]1=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CC(C)Cn1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c2ccccc2c2cc(-c3ccc4[nH]c5ccc(-c6ccc7c(c6)c6ccccc6n7CC(C)C)cc5c4c3)ccc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
Toluene (10 ml) and H2O (1 ml) were added into a mixture of 4 (0.25 g, 0.72 mmol), 3,6-dibromocarbazole (0.12 g, 0.36 mmol), Pd(PPh3)4 (0.04 g, 0.036 mmol) and Na2CO3 (0.37 g, 3.6 mmol). The reaction mixture was stirred at 90° C. for 12 hours, cooled to room temperature, and then extracted with methylene chloride. The organic extracts were combined, washed with water, and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexane/methylene chloride 9:1 to 2:1 (v/v) as the eluent to yield 7 (0.27 g, 61%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ (ppm) 8.49-8.44 (d, 4H), 8.21-8.19 (d, 2H), 8.10 (s, broad, 1H), 7.86-7.81 (m, 4H), 7.57-7.42 (m, 8H), 7.27-7.24 (m, 2H), 7.30-7.23 (m, 2H), 4.15-4.10 (m, 4H), 2.45-2.38 (m, 2H), 1.03-0.99 (m, 12H), 4.16-4.14 (d, 4H), 2.46-2.43 (m, 2H), 1.04-1.02 (d, 12H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[N:13]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.2 ml of 3-chloro-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 172 mg of expected product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=O)[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2].C([O-])(=O)C.[Na+].Cl.[CH3:32][O:33][NH2:34].O>C(O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=[N:34][O:33][CH3:32])[CH2:19][CH2:20][CH2:21]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: CON
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=NOC)CCC3)cc2c1
Temperature: 65 °C
Yield: 81.3 %

Procedure:
To a solution of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-formyl-cyclobutyl)-2-methylsulfanyl-acetamide (125 mg) in ethanol (10 ml) was added sodium acetate (50 mg) and O-methyl hydroxylamine hydrochloride (44 mg), at room temperature. The mixture was heated to 65° C. during 1 hour. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate (2×10 ml). The organic phase was washed with sat. aq NaCl solution, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. Purification by flash chromatography (ethyl acetate/cyclohexane, 1/1) gave 2-(3-ethynyl-quinolin-6-yloxy)-N-[1-(methoxyimino-methyl)-cyclobutyl]-2-methylsulfanyl-acetamide (110 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]([C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1)([CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[C:12]([CH3:27])[CH:11]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:33]([C:31]1[S:32][C:28]([C:4]([CH2:5][CH:6]=[CH2:7])([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH3:27])[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)=[C:14]([CH3:16])[CH:15]=2)[CH2:1][CH:2]=[CH2:3])=[CH:29][CH:30]=1)=[O:34]
Reactant: COC(=O)CCN
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Yield: 69.7 %

Procedure:
To a mixture of 5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carboxylic acid (0.1695 g, 0.338 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.0533 g, 0.382 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.0561 g, 0.415 mmol) in DMF (3.5 mL) is added N, N-diisopropylethylamine (0.175 mL, 1.00 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.0836 g, 0.436 mmol) and stirred overnight. The reaction mixture is poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 3-({5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.138 g, 70%) as a white foam. MS (ES): 584.3 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]1([CH:44]=O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:44][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3cccc4ccccc34)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.5 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (150 mg, 0.34 mmol) in anhydrous DCE (3 mL) were added 1-naphtaldehyde (Fluka, 70 μL, 0.51 mmol) and sodium triacetoxyborohydride (110 mg, 0.51 mmol). The reaction mixture was stirred at rt for 72 hrs. The solvent was removed under reduced pressure. The residue was taken up with an aqueous solution of NaOH (2 mL, 1N) and extracted with Et2O (6 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (pentane/DCM (2/3)) gave 72 mg (36%) of the title compound as a yellow oil. HPLC, Rt: 6.2 min (purity: 100%). 1H NMR (CDCl3) δ: 7.91-7.80 (m, 3H), 7.54-7.27 (m, 11H), 7.17 (d, J=7.9 Hz, 2H), 7.08 (m, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.20 (s, 2H), 4.70 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.69 (s, 6H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]=2[CH3:36])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C1C=[N:41]C2N(O)N=NC=2C=1.[OH-].[NH4+].C(Cl)CCl>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:22]2[C:21]([CH3:36])=[C:20]([C:7]3[C:8]4[C:9]5[C:14](=[CH:13][C:12]([C:17]([NH2:41])=[O:18])=[CH:11][CH:10]=5)[NH:15][C:16]=4[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=3)[CH:25]=[CH:24][CH:23]=2)=[O:35])=[CH:33][CH:32]=1
Reactant: On1nnc2cccnc21
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(N)=O)ccc3c12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 32.2 %

Procedure:
A mixture of 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid (Example 23-1, 30 mg, 0.062 mmol) and HOAT (12.72 mg, 0.093 mmol) in THF (0.4 mL) was treated with 28% aqueous ammonium hydroxide (0.052 mL, 0.374 mmol) and EDC (23.89 mg, 0.125 mmol) and the mixture was stirred at rt. After 22.5 h, the mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was treated with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1,7-dicarboxamide as an off-white solid (9.6 mg, 29%). 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J=1.3 Hz, 1 H) 8.03-8.08 (m, 2 H) 8.01 (d, J=7.9 Hz, 1 H) 7.51-7.55 (m, 1 H) 7.41-7.48 (m, 2 H) 7.29 (dd, J=7.5, 1.3 Hz, 1 H) 7.24 (t, J=8.8 Hz, 2 H) 7.08-7.12 (m, 2 H) 1.98 (s, 3 H). Mass spectrum m/z 481.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+].I[CH3:21]>CN(C=O)C.CCCCCCC>[CH3:21][N:7]1[C:8]2[C:13](=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: Cn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (234 mg, 1 mmol) was dissolved in DMF (2 ml). NaH (32 mg, 1.4 mmol) was added as a suspension in heptane (0.5 ml) and the mixture was stirred at room temperature for 10 min. Iodomethane (170 mg, 1.2 mmol) was added drop-wise and the solution was left stirring for 1 h. During this reaction, hydrolysis occurred. The reaction mixture was quenched with H2O (2 ml) and washed with EtOAc (3×1 ml). The aqueous layer was acidified to pH 1 with conc. HCl until a white precipitate formed and extracted with EtOAc (3×1 ml). These organic layer were combined, dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23]([NH:48][S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid (80 mg, 0.23 mmol) is dissolved in dry THF (3.0 mL) and 1,1′-carbonyl diimidazole (84 mg, 0.52 mmol) is added into it. The mixture is stirred for 30 min at room temperature and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (73 mg, 0.46 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.07 mL, 0.46 mmol) is added. The mixture is again stirred for 8 heat room temperature. 1.0 M HCl aqueous solution (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 55% EtOAc in Hexanes affords 66 mg (59%) of N-[3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionyl]-benzenesulfonamide. LCMS (ESMS): m/z 486.05 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.ClCCl.B(Br)(Br)[Br:32].O>CCOC(C)=O>[Br:32][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cccc(CNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Into a 1-neck round-bottom flask were added 2-[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]ethanol (0.20 g, 0.52 mmol) and dichloromethane (“DCM”, 5 mL). To the reaction mixture was added a solution of boron tribromide in methylene chloride (1.6 mL, 1.6 mmol, 1.0 M) at 0° C. The resulting mixture was allowed to warm up to rt and stirred overnight. The resulted mixture was cooled in a dry ice bath when water (10 mL) was added. The mixture was allowed to warm up to rt and EtOAc was added. The aqueous layer was extracted with EtOAc twice. The organic layers were combined and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a light brown powder (34 mg, 20%). LCMS for C19H19BrClN4O (M+H)+: m/z=371.1, 373.1. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 9.11 (s, 1H), 7.95 (s, 1H), 7.74 (t, J=6.1 Hz, 1H), 7.42 (m, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.03 (dd, J=8.7, 7.6 Hz, 1H), 6.71 (dd, J=11.5, 7.6 Hz, 1H), 6.69 (s, 1H), 6.58 (dd, J=8.0, 2.3 Hz, 1H), 4.56 (m, 2H), 3.50 (m, 2H), 2.56 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:10]([F:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[C:10]([F:20])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(F)c(CNC(=O)C(C)(C)C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)NCc1c(F)ccc(C(=O)O)c1Cl
Yield: 74.9 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-4-fluoro-3-(pivalamidomethyl)benzoate (350 mg, 1.16 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (93 mg, 2.32 mmol) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.55 (br s, 1H), 7.78 (m, 2H), 7.32-7.26 (t, J=8.7 Hz, 1H), 4.38 (d, J=4.5 Hz, 2H), 1.07 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[N:3]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1ccnc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cc1ccnc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 14) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[C:25]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2cccc(OCCNCC(O)COc3ccc(CCOCC4CC4)cc3)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1>ClC1C=CC=CC=1Cl>[N:5]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: Clc1ccccc1Cl
Product: O=C=Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 175 °C
Reaction time: 0.67 h
Yield: 98 %

Procedure:
200 g of phosgene are dissolved in 650 g of o-dichlorobenzene at 5° C. A hot solution of 44.6 g (≈0.2 mol) of 1-amino-anthraquinone in o-dichlorobenzene is added dropwise to the phosgene solution in the course of 90 minutes. During this addition, the temperature in the reaction mixture is allowed to rise slowly up to 25° C. and a stream of phosgene is continuously passed through the reaction mixture. A yellow product precipitates. The mixture is then heated to 175° C. in the course of a further 90 minutes whilst passing a stream of phosgene through, whereupon a clear solution forms. After 40 minutes at 175° C., the stream of phosgene is discontinued and nitrogen is passed through the reaction mixture. After a further 60 minutes, the mixture is cooled and, from 120° C., the solvent is distilled off under reduced pressure. The crystalline residue which remains (53 g, still contains small amounts of o-dichlorobenzene) consists of 1-isocyanato-anthraquinone to the extent of 92.1% (NCO titration according to the method in Houben-Weyl, volume 2 (1953), page 557), which corresponds to a yield of 98%. C15H7NO3 calculated: 72.29% C. 2.83% H 5.62% N; found: 72.2 72.3 2.7 2.8 5.5 5.6.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:10]([C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[N+:10]([C:13]1[C:18]([O:19][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ncccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCCOc1cccnc1[N+](=O)[O-]
Yield: 76 %

Procedure:
This compound was prepared from ethyl 4-bromobutyrate 2 and 2-nitro-3-pyridinol (39) via the procedure of Step (A), supra. Following flash chromatography (silica gel; 1.5% methanol/methylene chloride eluant) a dilute sodium bicarbonate wash of an ether solution of the product was necessary to remove traces of starting phenol. The product (40) was obtained in 76% yield as a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([Mg]Cl)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.Cl>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[OH:8])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Reactant: O=CC1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydropyran-4-carboxaldehyde (16.0 g, 0.14 mol) in tetrahydrofuran (60 ml) is added dropwise over 1 hour to a 1 M solution of 3,5-dimethoxyphenylmagnesium chloride in tetrahydrofuran (140 ml), maintaining the reaction at or below reflux by external cooling. Once the addition is complete, and the exotherm has subsided, the reaction mixture is allowed to stir at room temperature overnight. A solution of dilute aqueous hydrochloric acid (300 ml) is added carefully and the reaction mixture is extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated in vacuo. Purification by column chromatography on silica gel gives (3,5-dimethoxyphenyl) (tetrahydropyran-4-yl)methanol as a cream solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[O:10]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])C.[CH3:17]CCCCCC>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[O:10]=[C:11]1[CH2:13][C:14]([CH3:16])([CH3:15])[CH:2]([C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([CH3:17])=[CH:5]1
Reactant: CCCCCCC
Reactant: CC(=O)C=C(C)C
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(C)=CC(=O)CC1(C)C
Reaction time: 24 h
Yield: 27 %

Procedure:
A mixture of 1020 ml (1041 g, 8.00 mol) of ethyl acetoacetate, 960 ml (824 g, 8.40 mol) of mesityl oxide, 1000 ml of heptane, 600 ml of toluene, and 175 g of zinc chloride was heated at reflux in a 5000 ml round bottom flask while stirring. The flask was equipped with a Dean-Stark trap and drying tube. After 24 h, an additional 25 g of zinc chloride was added and refluxing continued for 36 h. After cooling, the reaction mixture was washed with 1500 ml of water, 5% sodium bicarbonate solution (2×1000 ml), and another 1500 ml of water. Removal of solvent by evaporation yielded 979 g of crude product. Distillation of the crude product provided 453.5 g of the desired ester which represents 27.0% yield. Distillation was at 124°-5° C. (3.0 torr).