Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([C:9]1[CH:23]=[C:22](I)[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:8].C(N(CC)CC)C>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:22]1[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=[C:9]([C:7]#[N:8])[CH:23]=1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: C=CC(=O)OC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cc(C#N)cc2ncn(-c3ccccc3)c12
Yield: 82.4 %

Procedure:
Methyl acrylate (0.27 ml, 3 mmol), 5-cyano-7-iodo-1-phenylbenzimidazole (346 mg, 1.0 mmol), triethylamine (0.28 ml, 2 mmol) palladium acetate (4.5 mg, 0.02 mmol), tri-o-tolylphosphine (16.1 mg, 0.05 mmol) and acetonitrile (5 ml) were combined in Reactivial™. The mixture was heated under reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (250 mg, 83%), m/z 304.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:22])[CH3:21]
Reactant: NC/C=C/c1ccc(C(O)Cc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC/C=C/c1ccc(C(O)Cc2ccccc2)cc1

Procedure:
1-[4-[(E)-3-Amino-1-propenyl]phenyl]-2-phenyl-1-ethanol (Compound No. 1-6) is treated with acetic anhydride in pyridine to give the titled compound (Compound No. 2-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C[C:12]1[N:17]=[C:16]([C:18](O)=O)[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cccc(C(=O)O)n1
Product: COc1ccc(C(O)c2cccc(C)n2)cc1

Procedure:
To a boiling solution of 50 g of 4-methoxybenzaldehyde in 50 ml of p-cymeme is added 11.2 g of 6-methylpicolinic acid. After heating for 3 hours, the reaction is cooled and extracted with 2N HCl. The acidic extracts are washed with ether, made basic with ammonia and extracted with ether. Concentration of the dried ether extracts gives 4-methoxyphenyl-(6-methyl-2-pyridyl)carbinol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39]([NH:41][C:42]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=S)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24](/[C:42](/[NH:44][C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:41]\[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (250 mg, 0.523 mmol0, N,N′-bis-tert-butoxycarbonylthiourea (158.8 mg, 0.575 mmol) and triethylamine (0.22 mL, 1.57 mmol) in 3 mL DMF was added mercuric chloride (170.2 mg, 0.63 mmol) at 0° C. The reaction was stirred for 3 h at 0° C. and then quenched with EtOAc. The reaction was filtered through CELITE. The filtrate was washed two times with water, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified on ISCO with MeOH—CH2Cl2 and re-purified on HPLC (40-90% CH3CN (0.1% TFA)/H2O (0.1% TFA)) to yield (Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.CCCCCC.[K+].[Br-]>O>[C:22]([C:19]1[CH:20]=[CH:21][C:13]2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:14]=2[CH:18]=1)([O:24][CH3:25])=[O:23]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-6-carbomethoxy-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 70% overall yield as a white solid, after trituration with hexane, IR (KBr) 3468, 2952, 1688, 1452, 1285, 1260, 765 cm-1 ; 1H NMR (CDCl3) δ 1.61 (br s, 1H plus HDO), 2.17-2.39 (m, 2H), 3.86 (s, 3H), 3.93 (t, J=5.7 Hz, 2H), 4.94 (dd, J=7.6, 5.5 Hz, 1H), 5.16 (s, 2H), 7.04 (d, J=8.4, 1H), 7.15-7.33 (m, 4H), 7.59 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.4, 1.8 Hz, 1H); MH+ at m/z=376; Anal. Calc'd for C19 H18ClNO5.0.1 H2O: C, 60.44; H, 4.86; N, 3.71. Found: C, 60.26; H, 4.60; N, 3.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6]=2[CH:20]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(C)c(=O)n2COCC[Si](C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2[nH]c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (26 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (5.0 mg, 0.08 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 10.3 mg (47%). 1H-NMR (CD3OD, 500 MHz) δ 7.44 (m, 1.5H), 7.35 (m, 0.5H), 7.14 (m, 1.5H), 7.06 (m, 0.5H), 6.90-7.20 (m, 1H), 6.78 (d, J=2.1 Hz, 0.6H), 6.68 (m, 0.3H), 4.99 (m, 1H), 3.35-3.52 (m, 5H), 3.30 (d, J=9.2 Hz, 1H), 2.55-3.00 (m, 6H), 2.05 (m, 2H), 1.30-1.50 (m, 3H). Mass spec.: 432.1 (MH)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])C.[Li+].[OH-].C1COCC1>O>[Cl:27][C:17]1[C:18]([O:25][CH3:26])=[CH:19][C:20]([O:23][CH3:24])=[C:21]([F:22])[C:16]=1[C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2cccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1F
Yield: 96.8 %

Procedure:
A mixture of 5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 176.2) (235 mg, 0.60 mmol), a 2 N aqueous solution of LiOH (3 mL) and THF (3 mL) was stirred for 20 h at rt, diluted with H2O and extracted with Et2O. The aqueous layer was acidified to pH 4 by addition of a 2 N aqueous solution of HCl. The resulting white precipitate was collected by vacuum filtration providing 210 mg of the title compound: ESI-MS: 362.1 [M+H]+; tR=4.24 min (System 1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CN(C)[CH:21]=[O:22]>>[OH:22][CH2:21][CH2:11][CH2:12][CH2:4][CH2:5][CH2:13][CH2:18][CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1c(-c2cccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.4 g of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g (0.06 mole) of 1-tetrahydropyranyloxy-8-bromooctoane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(3-pyridyl)-3-methylindole.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.ClC(OCC)=O.[NH3:29]>C(N(CC)CC)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([NH2:29])=[O:18])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: N
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)O)cn2)CC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC[C@H]1CC[C@H](c2ncc(C(N)=O)cn2)CC1
Temperature: 2 °C
Reaction time: 0.25 h

Procedure:
A solution of 13.85 g of trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylic acid, 260 ml of chloroform and 7.8 ml of triethylamine is cooled to 2° C. and treated with 5.32 ml of ethyl chloroformate. The mixture is stirred at 2° C. for 15 minutes and then a strong stream of ammonia gas is conducted in for 10 minutes (while cooling with an ice-bath). The resulting suspension is stirred at 20° C. for a further 1 hour and then evaporated in vacuo. The solid residue is stirred up with 210 ml of water for 45 minutes and then filtered off under suction and dried. There are obtained 9.6 g of crude trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxamide (m.p. 234°-235° C.) which can be purified by sublimation at 175° C./0.05 mmHg; m.p. 249.3°-250.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccccc1F
Reactant: ClCCCBr
Product: Fc1ccccc1OCCCCl

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:38])=[C:8]([CH3:37])[C:9]=1[C:10]([C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[C:14]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:13]=1)=[O:11].[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:30]=[CH:31][C:12]([C:10]([C:9]3[C:8]([CH3:37])=[C:7]([CH3:38])[O:6][C:5]=3[CH2:4][C:3]3[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=3[Br:1])=[O:11])=[CH:13][C:14]=2[CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=[O:19])=[O:18])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4Br)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 25 %

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-{4-[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.318 g, 0.487 mmol), magnesium iodide (0.132 g, 0.475 mmol) and acetic anhydride (3.8 mL) in ether. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 30% EtOAc/pet ether gave 0.083 g (25%) of the title compound as a solid, mp 79° C. 1H NMR (DMSO-d6) δ 1.27-1.33 (m, 2 H), 1.51-1.54 (m, 2 H), 1.63-1.73 (m, 4 H), 1.79 (s, 3 H), 2.17 (s, 3 H), 2.24 (s, 3 H), 2.93 (quintet, 1 H), 3.91 (s, 2 H), 7.13-7.17 (m, 2 H), 7.21 (d, 1 H), 7.30 (dt, 1 H), 7.51 (dd, 1 H), 7.55 (dd, 1 H), 7.60 (d, 1 H), 7.85 (d, 1 H), 7.90 (dd, 1 H), 8.14 (d, 1 H)13.8 (br s, 1 H). mass spectrum (-ESI) m/z 693/695 (M-H). Anal. Calcd. for C34H31BrO9S: C, 58.71; H, 4.49; N, 0.00. Found: C, 58.04; H, 4.52; N, 0.04.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1.O>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1
Reactant: COCCCCO
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCCCOc1cc[n+]([O-])c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
6.77 g (0.065 mol) of 4-methoxybutanol was dissolved in 60 ml of dimethyl sulfoxide to obtain a solution. 2.6 g (0.065 mol) of 60% sodium hydride was added to this solution at a room temperature in a nitrogen atmosphere. The obtained mixture was heated to 60° C., stirred for one hour and cooled to a room temperature. A solution of 4.66 g (0.032 mol) of 4-chloro-2-methylpyridine 1-oxide in 20 ml of dimethyl sulfoxide was dropwise added to a resulting mixture. The obtained mixture was stirred at 40° C. for one hour. After the completion of the reaction, 5 ml of water was added to the mixture and the obtained mixture was evaporated to dryness to remove the solvent. 150 ml of water was added to the residue. The obtained mixture was extracted with 200 ml of chloroform four times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 5.06 g of the title compound as an oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and p-tolyl-hydrazine according to example 43 gave the desired product. MS: M=407.3 (M+H)+
Reaction SMILES: [C:1]([CH:9]([CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[C:2]1([C:1]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccccc1
Yield: 92.1 %

Procedure:
A mixture of 2.30 g of compound G, 8.20 g of ammonium acetate and 8.43 g of ferric chloride hexahydrate in 50 cc of acetic acid was heated under reflux for 7 hours. After cooling, the insoluble materials were removed by filtration through Celite and the filtrate was distilled to remove the solvent. The residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 1.98 g of compound H. Yield: 92.1%.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCCCC2
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCC2

Procedure:
A mixture of 4.0 g of ethyl 4-hydroxy-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate and 25 ml of phosphorus oxychloride is refluxed under argon for 3 hours and then evaporated to dryness under reduced pressure. A solution of the residue in methylene chloride is treated with ice and water and basified with 10N sodium hydroxide. The layers are separated, the aqueous phase is re-extracted with methylene chloride; the combined organic extract is dried with magnesium sulfate, filtered, and the solvent is removed at reduced pressure to yield ethyl 4-chloro-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride (0.92 g, 4.2 mmol) in anhydrous THF (20 mL) added dropwise a solution of N,N-dimethylethylenediamine (0.44 mL, 4.0 mmol) in THF (20 mL). After stirring 30 min combined with a 1:1 mixture of ice and satd NaHCO3 (50 mL) and then extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to yield the title compound (0.40 g, 37%) as a pale yellow solid. 1H-NMR (CDCl3): δ 8.28 (1H, d), 7.96 (1H, dd), 7.63 (1H, d), 6.98 (1H, br s), 3.54 (2H, m), 2.56 (2H, t), 2.30 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)[NH:16][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)c1csc(NC=O)n1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NC(C(=O)OC(C)(C)C)c1csc(NC=O)n1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
In 100 ml of methylene chloride was dissolved 5.5 g (21.4 mmole) of 2-amino-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid tert-butyl ester, and 2.165 g (21.4 mmole) of triethylamine was added thereto. Then, the mixture was cooled to -45° C. and a solution of 2.92 g (21.4 mmole) of ethyl chlorooxalate dissolved in 10 ml of methylene chloride was added dropwise thereto for 10 minutes. Then, a cooling bath was removed, and the mixture was stirred for 30 minutes. After the mixture was washed with water, it was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 7.5 g of the oily title compound. (Yield: 98%)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:34])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:34])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(N3CCOCC3)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C=C(Nc2ccc(N3CCOCC3)cc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A solution of the compound (0.080 g, 0.17 mmol) of Example 42 in N,N-dimethylacetamide (3.0 mL) was stirred at 160° C. for 4 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water, tetrahydrofuran and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 22%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])(=[O:17])=[O:16])([O-:4])=[O:3].[N:25]1([CH2:34][C:35](O)=[O:36])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[N+:2]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:35](=[O:36])[CH2:34][N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:20][C:19]1=[O:24])(=[O:17])=[O:16])([O-:4])=[O:3]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 94.3 %

Procedure:
The title compound (980 mg, 94%) was synthesized by reaction of 1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperazin-2-one HCl salt (780 mg, 2 mmol) with (thymin-1-yl)-acetic acid (369 mg, 2 mmol) as per the procedure of example 64.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:11]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[O:22]=[C:21]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][CH2:20]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: NNc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1=NN(c2ccccc2)C(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a three neck flask equipped with a Dean-Stark trap, phenylhydrazine hydrochloride and diethyl 4-oxoheptanedioate (1 equiv.) were combined in Toluene (1.15 M). The suspension was stirred 48 h at reflux. The reaction mixture was cooled to rt and concentrated under vacuum to afford the desired material as a brown oil which was used as such in the next step.