Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1.[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH2:24][CH2:23]1.[O-]CC.[Na+]>>[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2/[CH:29]=[CH:20]/[C:11]2[N:12]=[C:13]3[S:19][CH:18]=[CH:17][N:14]3[C:15](=[O:16])[C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:5][CH:6]=2)[CH2:23][CH2:24]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)F)cc2)c1OCC1CC1
Yield: 39.2 %

Procedure:
The title compound was synthesized by condensation of Intermediate 14 (250 mg, 0.811 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (234 mg, 1.136 mmol) in presence of sodium ethoxide (110 mg, 1.623 mmol) according to the procedure of Example 23 to give 158 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.49-0.51 (m, 2H), 1.02-1.04 (m, 1H), 3.69 (m, 2H), 3.77 (s, 3H), 6.93-7.08 (m, 4H), 7.27-7.57 (m, 6H), 7.99 (br s, 1H), 8.15 (d, J=16.2 Hz, 1H); ESI-MS (m/z) 497.28 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][Br:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: Cc1c(Cl)cc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)cc(Cl)c1CBr
Yield: 87.8 %

Procedure:
Heat a solution of 5-bromo-1,3-dichloro-2-methylbenzene (97 mg, 0.40 mmol), N-bromosuccinimide (76 mg, 0.425 mmol) and benzoyl peroxide (16 mg, 0.06 mmol) in CCl4 (5 mL) to reflux for 3 hours under N2. Cool the reaction to room temperature and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 112 mg (87%) of the product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[CH:13][N:12]=1>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:10])[CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Product: Cc1cc(-c2nc3cc(Br)cnc3[nH]2)ccn1
Reaction time: 16 h

Procedure:
0.30 g 5-bromo-2,3-diaminopyridine and 0.212 g 2-methyl-pyridine-4-carboxylic acid were heated in 3 g polyphosphoric acid at 160° C. with stirring for 16 hrs. The mixture was diluted with water and insoluble components removed by filtration. Water was evaporated from the filtrate and the residue dispersed in pyridine. Again, insoluble components were removed by filtration and the filtrate evaporated. The obtained residue was washed thoroughly with water and dried.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(CCl)ccn2)s1

Procedure:
2-(4-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.883 g, 3.80 mmol) was stirred in anh CH2Cl2 (12 mL) under N2. Dimethylformamide (0.354 mL, 3.80 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.294 mL, 3.80 mmol). After 4 h the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ12.35 (bs, 1H), 8.40 (d, 1H, J=5.3 Hz), 8.28 (s, 1H), 7.20 (s, 1H), 7.12 (d, 1H, J=5.3 Hz), 4.82 (s, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>C(OCC)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1cccc(Br)c1

Procedure:
To a solution of phenol (2.3 g, 24.4 mmol) and triethylamine (3.2 g, 32 mmol) in diethyl ether (150 mL) was slowly added 3-bromobenzoyl chloride (5 g, 22.8 mmol) and the mixture was heated to reflux for about 1 hour. The mixture was cooled, filtered, and the filtrate was successively washed with water, 0.2N hydrochloric acid, and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was triturated with hexane and dried under vacuum to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 7.22 (m, 3H), 7.42 (m, 3H), 7.79 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 8.37 (br s, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C@H:6]1[C@H:11]([OH:12])[CH2:10][C@H:9]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:4].CC(C)=O.O.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>[OH-].[Na+]>[C:31]([O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:9]4[C@@:7]([CH2:24][CH2:23]3)([CH3:8])[C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[C@H:11]([OH:12])[CH2:10]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@@]21C
Reaction time: 0.17 h

Procedure:
17β-Methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol (13.1 g) was dissolved in aqueous sodium hydroxide solution (260 ml; 2 N), acetone (260 ml) and water (260 ml). Benzoyl chloride (6.5 ml) was added and the mixture stirred vigorously for 10 min.; a further 6.5 ml of benzoyl chloride was added and the mixture was stirred vigorously for a further 10 min. Water (5 l) was added and the precipitated product was filtered, washed with water and dissolved in dichloromethane. The dichloromethane solution was washed with water, dried (Na2SO4) and evaporated to give a white froth (6.8 g), which was crystallised from dichloromethane-ether-light petroleum to give impure product (6.0 g). Acidification of the aqueous mother liquors provided unreacted starting material (7.8 g), which was treated as above to give a further quantity of impure product (2.3 g). Recrystallisation of the combined products from dichloromethane-ether afforded an isomeric mixture of 17β-methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol 3-benzoates (4.68 g; 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:59][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=1>ClCCl>[C:64]([C:63]1[CH:66]=[CH:67][C:60]([NH:59][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:23])=[CH:61][CH:62]=1)#[N:65]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Reactant: N#Cc1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (example 1, steps 1 to 4) (1.0 g, 2.6 mmol) in dichloromethane (50 mL) was treated with N,N-diisopropyl ethyl amine (0.34 g, 2.6 mmol) and cooled to 0° C. Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2.4 g, 5.2 mmol) was added, and the mixture was stirred at 0° C. for 1 min. 4-Aminobenzonitrile (1.2 g, 10.4 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude was purified by flash chromatography (heptane/ethyl acetate gradient) yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (4-cyano-phenyl)-amide as a white solid, 0.18 g (14%), MS (ISP): m/e=482.0 (M−H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Cl)cc1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and 4-chlorobenzonitrile (1.55 g, 11.2 mmol) is heated at 120° C. The conversion of the 4-chlorobenzonitrile is complete after 12 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 1.1 g of the title-compound. Yield: 52%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N+:15]([O-:18])([OH:17])=[O:16].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>O>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[S:19](=[O:21])(=[O:20])([OH:23])[OH:22].[N+:15]([O-:18])([OH:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
A 4-chloro-3, 5-dinitrobenzotrifluoride product is prepared by adding 1 mole of 4-chloro-3-nitrobenzotrifluoride to a nitrating mixture containing 3.04 moles nitric acid, 10.13 moles sulfuric acid, (59.9 mole percent sulfuric acid) and 3.72 moles water based on the mixture formed by mixing 94 percent (by weight) sulfuric acid in water obtained from a reconcentration process for sulfuric acid with 98 percent (by weight) nitric acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][C:37]1([CH3:44])[NH:42][C:41](=[O:43])[CH2:40][NH:39][CH2:38]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:39]2[CH2:40][C:41](=[O:43])[NH:42][C:37]([CH3:44])([CH3:36])[CH2:38]2)=[CH:4][N:3]=1
Reactant: CC1(C)CNCC(=O)N1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(/C=C/CN4CC(=O)NC(C)(C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (60.0 mg, 0.125 mmol) and 6,6-dimethyl-piperazin-2-one (75.7 mg, 0.498 mmol) were reacted according to General Procedure B. The product was purified via flash chromatography to furnish the title compound as a yellow powder. (5.0 mg, 0.0084 mmol): LCMS (Conditions a): MH+=595.0, Rt=3.58 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 7.98 (m, 2H), 7.80 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.09 (dd, J=8.2, 1.56 Hz, 1H), 6.74 (d, J=16.0 Hz, 1H), 6.23 (m, 1H), 5.66 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.24 (m, 2H), 2.95 (s, 2H), 2.42 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23]>>[C:22]([C:25]1[CH:26]=[C:27]([C:2]2[C:14]3[C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[CH:7]=[N:6][C:5]=3[NH:4][N:3]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])[NH2:23]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(-c4cccc(C(N)=O)c4)c23)C1

Procedure:
The compound, tert-butyl 1-(3-carbamoylphenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate was prepared using tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate and 4-carbamoylphenylboronic acid as described in step-1 of general procedure U. The compound was obtained as a white solid (0.070 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ13.98 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.58 (m, 1H), 7.45 (s, 1H), 4.65 (s, 2H), 3.49 (m, 2H), 2.82 (m, 2H), 1.43 (s, 9H); LC-Mass [M+H]: 394.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl>C1COCC1>[CH2:24]([CH:21]1[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH:3]=[O:2])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH2:23][CH2:22]1)[CH2:25][CH3:26]
Reactant: CCCC1CCC(CCc2ccc(C3CCC(=COC)CC3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC1CCC(CCc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1

Procedure:
1-[4-(methoxymethylene)cyclohexyl]-4-[2-(4-propylcyclohexyl)ethyl]-benzene (1.23 g, 2.74 mmol) was refuxed by a mixture of THF and 2N HCl (10 ml) in a volume ratio of 4:1. After reaction termination, the resulting solution was diluted by distilled water (10 ml), extracted by ether extraction (5 ml×2 times), and washed by distilled water (5 ml×2 times). The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:60). The ratio of cis or trans-isomer of the obtained crystal was 1:5 with NMR analysis. The crystal was performed by fractional recrystallization with hexane to obtain pure trans-4-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}cyclohexane carbaldehyde (0.2 g, 18%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:25][NH:24][C:23]=1[NH2:34]>ClCCCl>[CH3:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:25][NH:24][C:23]=1[NH:34][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: Cc1ccccc1-c1n[nH]c(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccccc1-c1n[nH]c(NC(=O)CCCN2CCCC2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-pyrrolidin-1-yl-butyric acid (118.0 mg, 0.8 mmol, 1.5 eq) in 1,2-dichloroethane (3 mL), N,N′-carbonyldiimidazole (113.0 mg, 0.7 mmol, 1.4 eq) was added and the mixture was stirred at room temperature for 1 hour, then N,N-diisopropyl ethyl amine (87 μL, 0.5 mmol, 1.0 eq) was added and the mixture was stirred at room temperature for further 1 hour until complete dissolution of the suspension. 4-Methyl-5-o-tolyl-2H-pyrazol-3-ylamine (93.5 mg, 0.5 mmol, 1.0 eq) was added and the reaction was stirred for 18 hours, then at 50° C. for 1 day, until the conversion of the less stable ring nitrogen-acylated isomer to the title compound was observed (as monitored by LC-MS). The solvent was removed under reduced pressure, the crude was purified by SiO2 column to give 44.0 mg of the title compound (yield: 27%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)=[O:20])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCCCC(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 0 °C
Yield: 17.6 %

Procedure:
To 300 ml of methylene chloride was dissolved 10 g/82 mmol of 2,6-dimethylphenol, and the solution was cooled to 0° C. in sodium chloride-ice bath. After adding 49 g/368 mmol of anhydrous aluminum chloride, methylene chloride solution of 7.3 g/40 mmol of adipic dichloride was added dropwise to the mixture with thorough stirring while maintaining the temperature to not more than 5° C. The reaction mixture was added to 50 ml of ice containing conc. hydrochloric acid to decompose excessive anhydrous aluminum chloride, and the mixture was extracted twice with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystalized from toluene to obtain 2.5 g of 1,6-bis(3',5'-dimethyl-4'-hydroxyphenyl)hexane-1,6-dione. MS: 354 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[OH:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[O:22][C:26](=[O:28])[CH3:27])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (1.0 g, 2.8 mmol) obtained in Example 31 is dissolved in pyridine (3 ml), and thereto is added acetic anhydride (1.3 ml, 14 mmol), and the mixture is stirred at room temperature for 5 hours. To the reaction solution is added ethyl acetate (100 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (1.07 g), m.p. 107-126° C. (recrystallized from diethyl ether).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])(CC(C(=O)N[C@H](C(=O)NC)CC(C)C)CC(C)C)=[O:8].[N+:29]([C:32]1[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]([O:37][C:38](=[O:39])[C:33]=12)=O)([O-:31])=[O:30]>>[CH3:5][O:6][PH:7]([CH2:27][N:28]1[C:38](=[O:39])[C:33]2=[C:32]([N+:29]([O-:31])=[O:30])[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]1=[O:37])=[O:8]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CO[PH](=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
In a manner analogous to that described in Example 3(A), from 0.23 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.105 g of 3-nitrophthalic anhydride, there was obtained 0.105 g of [4-methyl-2-(methylcarbamoyl)butyl]carbamoyl]pentyl][(3-nitrophthalimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C:26]1[CH:25]=[N:24][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:27]=1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnn(C2CCN(C)CC2)c1
Yield: 79 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (216 mg, 1.2 mmol) to afford the desired product (304 mg, 76%) as a light orange solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.42 (d, J=0.6 Hz, 1H), 4.18-4.11 (m, 1H), 3.00 (d, J=11.4 Hz, 2H), 2.67 (s, 3H), 2.34 (s, 3H), 2.26-2.02 (m, 6H); ESI MS m/z 385 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[NH2:21])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl-].C([O:33][C:34](=O)[C:35](O)=[O:36])C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[C:13](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:21][C:34](=[O:33])[C:35]2=[O:36])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2N)cc1
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At a bath temperature of +40° C., under argon and with exclusion of moisture, 582 mg (2.3 mmol) of 4-(2-amino-4-nitrophenylamino)benzoic acid ethyl ester is combined with 488 mg (4.8 mmol) of triethylamine in 27 ml of dry tetrahydrofuran. A solution of 659 mg (4.8 mmol) of oxalic acid ethyl ester chloride and 8 ml of dry tetrahydrofuran is added dropwise to this batch and stirred for 2 hours at room temperature. The mixture is then combined with 0.2 ml of triethylamine and 0.1 ml of oxalic acid ethyl ester chloride, and agitated for one hour at room temperature. The batch is filtered, and the filtrate is concentrated and distributed in water/ethyl acetate. The organic phase is concentrated. The residue is refluxed for 2 hours at the bath temperature in 25 ml of 1N hydrochloric acid and 25 ml of ethanol. The thus-precipitated product is suctioned off, washed with water, and dried, yielding 220 mg of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)benzoic acid ethyl ester (further processed without purification).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([O:15][C:16]3[N:17]([CH3:27])[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:27][N:17]1[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:19][N:20]=[C:16]1[O:15][CH:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:28]#[N:29])[N:9]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(Oc1nnc(-c2ccncc2)n1C)c1nnn(-c2cccc(I)c2)n1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1nnn(-c2cccc(C#N)c2)n1

Procedure:
The title compound is prepared from 4-(5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.