Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[C:18]1([C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:26]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:25][CH2:26][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH2:8])=[CH:16][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: CC(C)O
Product: NCCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
N-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)ethylamine (1.3 g) and 3,3,3-triphenylpropanol (1.4 g) were coupled by the method of example 5. The product (1.4 g) was dissolved in 15 mL isopropanol containing 1.0 g HCl, and stirred 3 hr at room temperature. A precipitate formed, which was collected and recrystallized from ethanol-ether to provide the hydrochloride salt of the title compound as a white solid, mp 163°-165° C., in 66% yield. Anal. calcd. for C29H29NO·HCl·0.75 H2O: C, 76.13; H, 6.94; N, 3.06. Found: C, 75.99; H, 6.81; N, 3.02.
Reaction SMILES: [F:1][CH:2]1[CH:11](OC)[NH:10][C:9](=O)[C:8]2[N:7]=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]1=2.P(Cl)(Cl)([Cl:19])=O>C(#N)C>[Cl:19][C:9]1[N:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[N:7]=[CH:6][C:5]([C:15]#[N:16])=[CH:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1NC(=O)c2ncc(C#N)cc2C1F
Solvent: CC#N
Product: N#Cc1cnc2c(Cl)ncc(F)c2c1
Temperature: 75 °C
Yield: 56.3 %

Procedure:
A pressure bottle was charged with 5-fluoro-6-methoxy-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (step 3, 2.27 g, 10.26 mmol), acetonitrile (41 ml) and phosphorus oxychloride (Aldrich, 3.35 ml, 35.9 mmol). The bottle was sealed and the reaction mixture was heated to 75° C. overnight. The reaction mixture was concentrated and the crude material was purified by silica gel chromatography (gradient 0-20% (10 MeOH in DCM)/DCM to afford the title compound (1.2 g, 5.78 mmol, 56.3% yield) as a white solid. MS m/z=208 [M+H]+. Calculated for C9H3ClFN3: 207.0
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:27][NH2:28].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:27][NH:28][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 0.08 h

Procedure:
Mix propane-2-sulfonic acid [2-(4′-formyl-biphenyl-4-yl)-thiophen-3-yl]-amide (0.16 mmol) in 1,2-dichloroethane (2 ml) and add methylamine 2N in THF (0.16 ml, 0.32 mmol) at room temperature. Stir the resulting solution for 5 min before adding Na(OAc)3BH (0.32 mmol). Stir the mixture at room temperature for 16 h. Analyze by LC/MS for final product. Add saturated NaHCO3 aqueous solution and dichloromethane and filter the mixture through hydrophobic filter. Evaporate the filtrate and apply the residue to SCX cartridge, elute with MeOH/DCM to remove non-basic materials, followed by 2N NH3 in MeOH to give a crude product. Purify by flash chromatography (Silica gel-Dichloromethane/Methanol 7:1)to yield the title compound. MS (ES−): 399(M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(Cl)Cl>[CH2:16]([N:18]([CH2:19][CH3:20])[C:7]([C:6]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8])[CH3:17]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoylchloride in 250 ml. of methylene chloride is treated at 0°-20° C with a solution of 11 g. (0.15 mol.) of diethylamine in 100 ml. of methylene chloride. The solution is kept at 20°-25° C for 2 hrs., the solvent is evaporated and the residue triturated with water. Recrystallization from methanol affords 4-(N,N-diethylcarbamoyl)-1,2-dinitrobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:20]([CH3:21])[CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (150 g, 335 mmol) obtained in Step 3 was dissolved in dimethylformamide (500 ml), imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (56 g, 369 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous ammonium chloride solution and saturated brine, and dried over sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 1:2) to give 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (173 g, yield 92%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][C:6]2=[C:9]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1Cc2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (26.9 mg, 0.055 mmol) is dissolved in 1 mL of anhydrous THF, and then 400 uL of 1.5 M DIBAL-H in toluene is added dropwise. After the reaction mixture is stirred at room temperature overnight, additional 800 uL of 1.5 M DIBAL-His added to the solution. The reaction mixture is stirred at room temperature for 24 hours, and then quenched with NH4Cl aqueous solution. After routine workup, the mixture is purified by a semi-preparative HPLC to give 3.0 mg of pure product as while solids. MS (ESI) m/z 476.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.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>[Br:8][C:6]1[CH:5]=[C:4]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:3]=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc(-c2nc3ccccc3s2)c1
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(-c2cccnc2)cc(-c2nc3ccccc3s2)c1

Procedure:
4.74 g (12.8 mmol) of 2-(3,5-dibromophenyl)benzo[d]thiazole) according to Synthesis Example 5, 1.89 g (15.4 mmol) of pyridine-3-boronic acid, 0.44 g (3 mol %) of tetrakis(triphenylphosphine)palladium (0), and 5.31 g (38.4 mmol) of potassium carbonate were dissolved in 50 ml of tetrahydrofuran/H2O mixed in a volume ratio of 4/1. The solution was reacted at 80° C. for 12 hours. The acquired reactant was extracted with ethyl acetate and treated under reduced pressure to remove the solvent. The extract was separated through a column and dried, obtaining 2.54 g (Y=54%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Br:10]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]=[CH:6][C:5]([CH2:8][Br:10])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 4-bromo-3-fluorotoluene (10 g, 0.053 moles) in carbon tetrachloride (100 ml) is added with N-bromosuccinimide, (NBS; 14 g, 0.08 moles). The mixture is refluxed, added with dibenzoyl peroxide (100 mg, 0.4 mmoles), refluxed for 1 hour, then cooled at room temperature and extracted with water. The aqueous phase is discarded, the organic phase is washed with brine, dried over sodium sulfate and concentrated under vacuum to give an oil (16 g) which is subjected to chromatography on a silica gel column (150 g), eluting with hexane, to afford the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1.CCCCCC>[CH3:12][C:3]1[CH:4]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C(C)(C)C)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)ccc1B(O)O
Temperature: -5 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
The obtained 1-bromo-2-methyl-4-(t-butyl)benzene (10.70 g, 47.1 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling at −5° C., solution of n-butyllithium in n-hexane (1.65 M, 31.40 mL) was dropped, and reaction solution was stirred for 1 hour, then, triisopropyl borate (14.10 mL, 61.3 mmol) was dropped, and stirred for 1 hour. Temperature was elevated up to room temperature, then, reaction solution was stirred for 1 hour, then, hydrochloric acid (0.5 M, 30 mL) was added, and reaction solution was stirred for 3 hours. Resulting solid was filtered, and dried under reduced pressure to obtain the desired 2-methyl-4-(t-butyl)phenylboronic acid (7.00 g, 36.4 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:8]3[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]=3[OH:23])[S:13][N:14]=2)=[CH:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2snc(-c3ccc(F)cc3)c2c1O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(F)cc3)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-Fluoro-phenyl)-4-hydroxy-7-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 360.1 (M−1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[NH4+].[OH-].CO>C(Cl)Cl>[NH2:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN)c3)nc12

Procedure:
1-[2-(3-Aminomethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3-aminomethylphenyl)boronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 75 mg (48%) of a pale brown solid. MP 176-178° C., M+H=309.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:18]
Reactant: NN
Reactant: Cn1c(=O)c2c(Cl)nccc2n(C)c1=O
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2c(NN)nccc2n(C)c1=O
Yield: 93.1 %

Procedure:
0.69 g of Compound 17 and 0.31 g of hydrazine hydrate were added to 20 ml of methanol and the solution was heated under reflux for 24 hr. The solvent was distilled off to give 0.63 g of 5-hydrazino-1,3-dimethylpyrido[4,3-d]pyrimidine-2,4-dione (Compound 18).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.OS(O)(=O)=O>>[NH:5]1[CH:6]=[CH:7][CH2:2][CH2:3][CH:4]1[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][N:5]=1
Reactant: OC1CCNCC1
Agent: O=S(=O)(O)O
Product: C1=CNC(c2ccccn2)CC1

Procedure:
2-(Piperidinyl)pyridines 83 are prepared as described in Scheme 22. Strong base, such as n-BuLi, in a solvent such as dry THF, is added to dibromopyridine 77 at a temperature less than RT, preferably below about −50° C., more preferably at about −70° C. 4-Methylpiperidone is added to form the 4-hydroxy-piperidine 80 at a temperature less than RT, preferably below about −50° C., more preferably at about −70° C. The 4-hydroxy piperidine 80 is hydrated, such as with strong acid, preferably H2SO4, at a temperature above RT, preferably above 75° C., more preferably at about 100° C., to form the tetrahydro-bipyridine 81. The 2-bromo-pyridine 81 is aminated, such as with NH4OH, in the presence of Cu powder at a temperature above RT, preferably above about 75° C., more preferably at about 100° C., to form the amino-pyridine 82. Preferably the reaction is run in a sealed tube. The 1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6-ylamine is hydrogenated, such as with H2 in the presence of Pd(OH)2/C., at a temperature of about RT, to form the piperidinyl pyridine 83.
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1
Temperature: 95 °C

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 7.97 g. diallylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The reaction mixture was worked up by a method analogous to that described in Example 1 to give an oil which was not distilled but was heated under reduced pressure (95° C./0.1 mm.) for 4 hours to remove traces of volatile material. The resulting product, 1-diallylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, was obtained as an oil, nD26 1.5174. (98.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]=O)[CH:10]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=2[CH2:21][NH:26][CH2:24][CH3:25])[CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1

Procedure:
[5-(2-Formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester and ethylamine (2M in MeOH) were reacted as described in Example 8, Step 1 to provide [5(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:21][CH3:22])[CH2:4][CH2:3]1.[BH4-].[Na+].O>CO>[Si:14]([O:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]([CH2:21][CH3:22])[CH2:4][CH2:3][CH:2]2[OH:1])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCC(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 0.17 h
Yield: 105.3 %

Procedure:
4-oxo-8-t-butyldimethylsilyloxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (2.17 g) was dissolved in methanol (20 ml). To this solution was added sodium borohydride (0.26 g) at room temperature, and the mixture was stirred for 10 minutes. Water was added to the reaction mixture and the solvent was distilled off to give 8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4-tetrahydroquinoline (2.30 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 642.0 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C.N12CCCN=C1CCCCC2>[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=[CH:9][C:8]4[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=4[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccccc1C=Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Yield: 65 %

Procedure:
To a solution of 2-ethoxycarbonylbenzyltriphenylphosphonium bromide (605 mg) and 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (285 mg) in acetonitrile (5.00 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.317 ml) was added. The resulting solution was heated under reflux for 10 hours. After concentration under reduced pressure, diisopropyl ether was added to the residue. The resulting insoluble material was removed by filtration. After concentration of filtrate under reduced pressure, n-heptane was added to the residue. The resulting insoluble material removed again by filtration. After concentration of filtrate, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethenyl}benzofuran-2-yl]thiazole (280 mg) as a mixture of E and Z isomer as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCCN1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated until a solution resulted. Then there was added 32.1 g (0.25 mole) of N-propylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, and then cooled to room temperature. The mixture was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, filtered, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oily solid. The oily solid was dissolved in 25 ml of hot ethyl acetate, filtered, and allowed to crystallize first at room temperature, then at 0° C. to yield 3.20 g (30%) of product, mp 134°14 136° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+]>O>[CH2:2]([O:25][C:17]1[C:16]([CH3:22])=[N:15][N:14]([CH3:23])[C:13](=[O:24])[C:12]=1[C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH2:1][CH2:3][CH3:4]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCOc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC
Temperature: 120 °C
Reaction time: 8 h
Yield: 717.1 %

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (0.21 g), 1-butanol1 (4 ml, water (0.1 ml), and sodium hydroxide (0.20 g) were added under a nitrogen atmosphere at room temperature, and stirred at 120° C. for 8 hours. Then, to the reaction mixture was added water at room temperature, and extracted with tert-butyl methyl ether. The resulting organic layer was concentrated under reduced pressure to give 0.74 g of 5-(n-butoxy)-4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-5)-(1)-39).