Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[NH2:19][CH2:20][CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:26]1[C:22]([CH2:21][CH2:20][NH:19][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)=[CH:23][N:24]=[CH:25]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCCc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ncc(CCNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.2 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and histamine hydrochloride (92 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (1 mg) and a syn-form compound (2 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(SCc2ccccc2)n1
Yield: 46.4 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-6-methylpyridine (1 g, 7.8 mmol), K2CO3 (1.62 g 11.75 mmol), benzylmercaptan (1.46 g 11.8 mmol) and DMSO (7.5 ml) at 150° C. for 4 h in sealed tube gave the title compound (780 mg, 47%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10](OC)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:16][NH2:17]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:16][NH2:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NN
Reactant: COC(=O)C(O)c1cc(F)cc(F)c1
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
5.0 g of methyl 3,5-difluorophenylhydroxyacetate (C2) are dissolved in 45.0 ml of 2-propanol. 1.32 ml of hydrazine hydrate are then added dropwise, and the reaction mixture is kept under reflux for 18 hours. The solution is subsequently evaporated to dryness, and the resultant residue is purified by flash chromatography on silica gel (gradient for elution: ethyl acetate/0-20.0% by vol. of methanol), giving 3.70 g of the title compound as colourless solid having a melting point of 119.3° C. (MS: 202.8 (MH+)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.[CH2:31]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([S:33]([CH2:31][CH3:32])(=[O:34])=[O:35])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with 1-ethanesulfonyl-piperazine to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. LR-MS: 621.2 [(M+H)+]
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH:37]=2)=[CH:32][CH:31]=1>N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:41][CH2:40][N:39]([C:18](=[O:20])[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:22][CH:21]=3)[CH2:38][CH:37]=2)=[CH:32][CH:31]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C(O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CC=C(c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 3.9 g of 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoic acid and thionyl chloride is allowed to reflux for 41/2 hours. After isolation, the acid chloride is dissolved in 100 ml pyridine and 4.0 g of 4-[4-chlorophenyl]-1,2,5,6-tetrahydropyridine is added. The reaction is stirred overnight and then partitioned between chloroform and aqueous sodium carbonate. The organic phase is dried and concentrated. The residue is crystallized from methylene chloride. The crystals are filtered, washed with ether, and dried to yield 2.99 g (57%) of 4-(4-chlorophenyl)-1,2,5,6-tetrahydro-1-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl]pyridine, of melting point 225°-226° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[Br:14]Br>>[Br:14][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C)c(N)c(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 50.0 g (0.413 mol) of 2,4-dimethylaniline in 1500 cm3 of glacial acetic acid 21.2 ml (65.6 g, 0.410 mol) of bromine was added dropwise while vigorously stirring for ca. 20 min. This mixture was stirred for 2 h at 40° C. The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air. Then, this white solid was added to a solution of 100 g of potassium hydroxide in 400 ml of water. This mixture was stirred for 30 min. The crude product was extracted with 3×100 ml of dichloromethane. The combined extract was dried over Na2SO4 and evaporated to dryness. Fractional distillation gave a yellowish liquid, bp 83-85° C./1 mm Hg. Yield 46.9 g (57%).
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:11]1[NH:12]C(=S)N2C=CC=C[C:15]=12>>[N:4]1[N:3]=[C:2]([S:1][CH2:15][C:11]#[N:12])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Sc1nnc2ccccn12
Reactant: S=c1[nH]cc2ccccn12
Product: N#CCSc1nnc2ccccn12
Yield: 52 %

Procedure:
Following the procedure of Example 3, and substituting 3-mercapto-1,2,4-triazolo[4,3-a]pyridine, prepared according to Example 2, for imidazo[1,5-a]pyridine-3(2H)-thione, the title compound is prepared in 52% yield. The compound, after recrystallization from a mixture of benzene-acetonitrile, melts at 121°-3° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([NH2:20])=[CH:14][C:15]([F:19])=[C:16]([F:18])[CH:17]=1)(C(C)(C)C)(C)C.CN(C=O)C.OOS([O-])=O.[K+].[F:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=1)[CH:38]=O>O>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]2[N:11]([CH2:10][CH2:9][OH:8])[C:38]([C:37]3[CH:36]=[N:35][CH:34]=[C:33]([F:32])[CH:40]=3)=[N:20][C:13]=2[CH:14]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCn1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluorobenzene-1,2-diamine (38; 0.09 g, 0.0003 mol) in the mixture of DMF (3 ml) and water (0.3 ml) was added OXONE® (0.218 g, 0.0004 mol) and followed by 5-fluoronicotinaldehyde (0.041 g, 0.0003 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated and diluted with cold water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product 2-[5,6-difluoro-2-(5-fluoropyridin-3-yl)-1H-benzimidazol-1-yl]ethanol as an off white solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.93 (s, 1H), 8.77 (m, 1H), 8.33 (m, 1H), 7.96 (m, 1H), 7.81 (m, 1H), 5.09-5.11 (t, J=5.2 Hz, 1H), 4.35-4.38 (t, J=5.0 Hz, 2H), 3.75-3.76 (m, 2H). LCMS (ES) m/e MS (M+1=294) Purity 99.33%.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=NC#N)[C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].C(NCC)C>C1COCC1>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(C=N2)CCCCC1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Crude 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (95.0 g; purity 78% HPLC area) in THF (250 mL) was treated with diethylamine (105 g) and refluxed with a concomitant addition of THF (3.35 L) until dissolved. The solvent was distilled off (2.5 L) during which a precipitate was formed. The flask was cooled to ambient temperature and the white precipitate was filtered, washed with ether and dried to give 58.0 g (61% yield) of purified 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidenecyanamide (purity>99% HPLC area).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5]([Cl:13])=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CON=C(C(=O)O)C(=O)CBr
Solvent: ClCCl
Product: CON=C(C(=O)Cl)C(=O)CBr
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
In 15 ml of methylene chloride was dissolved 2.02 g of 4-bromo-2-methoxyimino-3-oxobutyric acid, followed by addition of 2.06 g of phosphorus pentachloride in small portions at 0°-5° C. The mixture was stirred at the same temperature for 5 minutes and, then, at 20°-25° C. for 1 hour, after which it was concentrated under reduced pressure. To the residue was added 20 ml of hexane and the mixture was stirred for a while and allowed to stand. The supernatant was concentrated under reduced pressure to give 2.1 g of 4-bromo-2-methoxyimino-3-oxobutyryl chloride as oil. Yield 96%.
Reaction SMILES: Br[C:2]1[CH:19]=[N:18][C:5]2[N:6]=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[C:20]([C:22]1[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:12]([NH:11][C:7]1[N:8]=[C:9]([OH:10])[C:4]2[CH:3]=[C:2]([C:21]#[C:20][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:42][CH:43]=3)[CH:19]=[N:18][C:5]=2[N:6]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 2.0 g of 6-bromo-2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidine, 2.1 g of diethyl N-(4-ethynylbenzoyl)-L-glutamate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous chloride in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The solid which forms upon first cooling to room temperature is collected by filtration, and washed with cold acetonitrile to yield 1.91 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate which is sufficiently pure for further processing. Chromatography on silica gel with 5% methanol:methylene chloride showing the following physical properties. m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=7.20 Hz), 1.33 (t, 3H, J=7.20 Hz), 1.36 (s, 9H), 2.14-2.62 (m, 4H), 4.14 (q, 2H, J= 7.20 Hz), 4.27 (q, 2H, J=7.20 Hz), 4.79-4.86 (m, 1H), 7.30 (d, 1H, J=8.40 Hz), 7.63 (d, 2H, J=8.25 Hz), 7.86 (d, 2H, J=8.25 Hz), 8.51 (brs, 1H), 8.64 (d, 1H, J=2.40 Hz), 8.97 (d, 1H, J=2.40 Hz), 12.2 (brs, 1H); IR (KBr) 3330, 3290, 2970, 1730, 1655, 1590, 1530, 1440, 1370, 1260, 1140, 1020, 965, 925, 850, 810, and 760 cm-1 ; 13C-NMR (CDCl3, 75 MHz) delta 14.3, 27.1, 27.2, 30.7, 40.6, 52.7, 61.1, 62.0, 87.61, 92.71, 115.1, 117.3, 125.9, 127.4, 127.5, 132.0, 133.9, 138.7, 149.6, 157.8, 158.6, 160.5, 166.4, 172.1, 173.5, 180.8.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:38]=4[N:29]=[CH:30][CH:31]=[CH:32]5)(=[O:40])=[O:41])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-d hydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and quinoline-8-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1cc(Cl)cc(Cl)c1
Yield: 32.4 %

Procedure:
Prepared according to the procedure of Example 50 using 3,5-dichloro-benzaldehyde (0.88 g, 5.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (1.22 g, 5.0 mmol), acetic acid (0.24 g, 5.3 mmol), and sodium triacetoxyborohydride (1.12 mmol) to afford the product (0.65 g); m.p. 164-165° C. after recrystallization from ethanol.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][NH:22][C:8](=[O:9])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:20][CH2:19]1
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: NCC1CC1
Product: CC(C(=O)NCC1CC1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 380° C. and MS: m/e=279 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and cyclopropylmethylamine.
Reaction SMILES: Br.Br[C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[N:5][CH:4]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:6]1[C:7]2[N:8]([N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:3]=[CH:4][N:5]=1)[NH2:18]
Reactant: NN
Reactant: FC(F)(F)c1nc2cncc(Br)n2n1
Agent: Br
Solvent: O
Solvent: CCO
Product: NNc1nccn2nc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.15 mmol) of 5-bromo-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrazine hydrobromide in 2.5 mL of dry ethanol was treated dropwise with 0.799 mL (11.5 mmol) of hydrazine hydrate, and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated to dryness, and the residue was extracted with dichloromethane and then with tetrahydrofuran. The organic extracts were washed with saturated sodium bicarbonate aqueous solution, filtered, and concentrated. Purification of the residue by preparative HPLC (C18 reverse phase column, 10-60% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound as a yellow solid. LC-MS 219 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[C:12]([S:14]Cl)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12](=[O:13])[S:14][N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)SCl
Product: O=c1oc(-c2cccc(Cl)c2)ns1
Reaction time: 1.5 h

Procedure:
m-Chlorobenzamide (75 g. 0.48 mol) and chlorocarbonylsulfenyl chloride (79 g, 0.6 mol, 25% excess) were reacted as described in Example 2 for 1.5 hours. Volatile components were removed under reduced pressure. The dark brown oil was taken up in hot cyclohexane, and the mixture was filtered. Cooling resulted in separation of a dark orange solid. The solid, recrystallized twice from hot ethyl acetate, gave 64.21 g (0.316 mol, 65.8%) of off-white slid, m.p. 83°-84.5°.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH3:9].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].Cl>O>[C:33]([O:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:14][CH:15]=1)[CH3:9])(=[O:36])[CH2:34][CH3:35]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(=O)CC)cc2)nc1
Yield: 97 %

Procedure:
Into 20 ml of pyridine were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in the Preparation Example starting material compound (VI)] 70, and then 0.56 g (6 millimole) of propionic chloride was added thereto, to subject to reaction at 30 to 40° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, adjusted to pH 1 to 2 with 4N hydrochloric acid, and then extracted with 200 ml of toluene, followed by separation thereof. The organic phase was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After drying over anhydrous magnesium sulfate, the residue obtained by distilling the organic solvent off under reduced pressure was purified by silica gel column chromatography (eluent; toluene: ethyl acetate) to obtain 2.00 g (yield: 97%) of (+)-2-(4-(1-Propanoyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: C([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][CH:6]([O:10]CC)[O:7][CH2:8][CH3:9])C.C(OC(=O)C)(=O)C.[C:23](OCC)(=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=O>>[CH2:28]([O:27][CH:25]=[CH:24][CH:23]=[C:5]([C:4]([O:13][CH2:14][CH3:15])=[O:3])[C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH3:29]
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC=C(C(=O)OCC)C(=O)OCC
Reaction time: 16 h

Procedure:
To a stirred, refluxing solution of 1.0 g. of freshly fused zinc chloride in 220 g. (1.0 mole) of 1,1,3,3-tetraethoxypropane and 200 g. (1.96 moles) of acetic anhydride is added dropwise during 3 hr. 10 min. 91 g. (0.57 mole) of diethyl malonate. After addition is complete, the reaction mixture is refluxed for one-half hour after which time the lower boiling components of the reaction mixture are removed by distillation up to a vapor temperature of 120° C. (pot 130° C.). An additional 50 ml. of acetic anhydride are added and reflux is continued for 16 hr. Again, low boilers are removed and the desired product is isolated from the residue by vacuum distillation. There is obtained 120 g. (87%) of product as a yellow oil: b.p. 110°-128°/0.1-1.7 mm. ν (film) 1720 (C=O) and 1610 cm.-1 (C=O); δ(TMS,CDCL3) 7.47, 7.13, 6.25 (s, s, t, 1 H each, olefinic protons), 3.84-4.6 (m, 6H, ethyl methylene) and 1.35 (overlapping triplets, 9H, ethyl methyls).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O>>[OH:25][B:13]1[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[CH2:3][CH2:4]2)[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=Cc1ccccn1
Product: O=C(C[C@H]1CC[C@H](NCc2ccccn2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and picolinaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 438 (MH)+.