Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][C@@H:21]1[CH2:27][CH3:28])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([N:20]1[CH2:25][CH2:24][C@@H:23]([O:26][N:30]2[C:34](=[O:35])[C:33]3[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]2=[O:40])[CH2:22][C@@H:21]1[CH2:27][CH3:28])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC[C@H]1C[C@H](ON2C(=O)c3ccccc3C2=O)CCN1C(=O)OC(C)(C)C

Procedure:
With stirring and under nitrogen, a solution of 0.283 ml (0.001693 mol) of diethyl azodicarboxylate (93%) in 1 ml of benzene is added dropwise at 20°-30° C. to a suspension of 0.37 g (0.001613 mol) of cis-N-BOC-2-ethyl-4-hydroxypiperidine, 0.263 g (0.001613 mol) of N-hydroxyphthalimide and 0.423 g (0.001613 mol) of triphenylphosphine in 5 ml of benzene. The reaction mixture is further stirred for 15 hours at room temperature, then filtered to remove precipitated diethyl 1,2-hydrazinedicarboxylate, and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:3), to give the title compound as a colourless resin; Rf =0.66 (silica gel/ethyl acetate:hexane (2:1)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>C(#N)C>[N:11]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: N#Cc1ccccc1F
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CC#N
Product: N#Cc1ccccc1-n1ccnc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
2-Fluorobenzonitrile (0.70 g, 5.78 mmol) was dissolved in acetonitrile (1 ml), and a sodium salt of imidazole (1.34 g, 14.8 mmol) was added thereto, followed by stirring at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (the sample was eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to 100% chloroform) to give the title compound (0.96 g, 98%).
Reaction SMILES: N#N.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=1)(=[O:5])[CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1>[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]([Cl:29])=[O:16])[N:14]=1)(=[O:5])[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)c1cccc(Cc2nc(C(=O)O)co2)c1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(Cc2nc(C(=O)Cl)co2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(3-acetyl-benzyl)-oxazole-4-carboxylic acid (314 mg, 1.28 mmol) in toluene (12.8 mL) was treated with a drop of DMF followed by oxalyl chloride (0.14 mL, 1.54 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(3-acetyl-benzyl)-oxazole-4-carbonyl chloride.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:15]2[CH2:14][CH2:13]S[CH2:11][C:10]=2[S:9][C:8]=1[NH:16][C:17]([CH:19]1[C:21]([CH3:23])([CH3:22])[C:20]1([CH3:25])[CH3:24])=[O:18])=[O:6])[CH2:2][CH3:3].O[O:27][S:28]([O-:30])=O.[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[C:15]2[CH2:14][CH2:13][S:28](=[O:30])(=[O:27])[CH2:11][C:10]=2[S:9][C:8]=1[NH:16][C:17]([CH:19]1[C:20]([CH3:25])([CH3:24])[C:21]1([CH3:23])[CH3:22])=[O:18])=[O:6])[CH2:2][CH3:3]
Reactant: O=S([O-])OO
Reactant: CCCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCSC2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCS(=O)(=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 133D (0.16 g, 0.41 mmol) in 40 mL acetone was added OXONE® (1 g, 1.29 mmol) in one portion. The resulting suspension was allowed to stir at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water (2×), brine (1×), dried (MgSO4), filtered and concentrated. The crude material was chromatographed (15% ethyl acetate/hexanes) to afford the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 0.81-0.97 (m, 3H) 1.10-1.30 (m, 12H) 1.39-1.66 (m, 3H) 3.09-3.25 (m, 4H) 3.36 (t, J=6.10 Hz, 2H) 4.41 (s, 2H) 7.93 (t, J=5.49 Hz, 1H) 10.83 (s, 1H). MS (ESI+) m/z 413.1 (M+H)+. Anal. calcd. for C19H28N2O4S2: C, 55.31; H, 6.84; N, 6.79. Found: C, 55.31; H, 7.13; N, 6.54.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH3:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccn(N)c1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Yield: 23 %

Procedure:
Prepared from 2.00 g (9.29 mmol) of 1-amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide and 2.11 g (11.15 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid following the experimental procedure described in Preparation 22a. After purification by flash chromatography (0 to 10% methanol in dichloromethane), 825 mg (23% yield) of the title product were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[CH:7]2[CH2:15][CH:3]1[N:4]([CH3:16])[CH2:5][CH2:6]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>ClCCl>[C:17]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[N:2]([CH3:1])[CH:3]3[CH2:15][CH:7]([CH2:6][CH2:5][N:4]3[CH3:16])[C:8]=2[CH:13]=1)(=[O:19])[CH3:18]
Reactant: CN1CCC2CC1N(C)c1ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
A catalytic amount, (0.019 g) of N,N-dimethylaminopyridine was added to a deoxygenated solution of 5.8 g of 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol and 5.4 g of acetic anhydride in 270 ml of dichloromethane. After stirring for 15 minutes, the reaction mixture was treated with a saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (7.1 g). Column chloromatography of a 3.5 g aliquot of the oil (silica gel; elution with triethylamine-methanol-ethyl acetate) afforded 2.2 g of 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate as a solid.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:9]1[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1>>[F:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:4]1
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: Cl
Product: NC1CCC(N2CC[C@@H](F)C2)CC1
Yield: 45.9 %

Procedure:
Following General procedure I, (R)-3-fluoropyrrolidine hydrochloride (407 mg, 3.26 mmol) was reacted with tert-butyl 4-oxocyclohexylcarbamate (500 mg, 2.34 mmol) to afford the desired product (200 mg, 51%) as a colorless oil: ESI MS m/z 187 [C10H19FN2+H]+.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][C:13](O)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:5]([C@H:6]1[CH:10]([OH:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][CH2:13][OH:14])/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a condenser, a thermometer and a magnetic stirrer, 1 g (4.5 mmol) of methyl (+/−)-jasmonate was dissolved in 15 ml of tetrahydrofuran. 430 mg (11.3 mmol) of lithium aluminium hydride, LiAlH4, were added. The mixture was stirred at 50° C. for 4 hours. When the reaction was finished, 5 ml of water were added slowly. The precipitate formed was filtered off and the filtrate was acidified to pH=5 with hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered on filter paper, and then concentrated. The colourless oil obtained was purified by chromatography on silica gel (eluent: dichloromethane/methanol). The colourless oil obtained was dried under vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29]I>C1COCC1.[H-].[Na+]>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:25])([F:26])[F:27])[CH:18]=2)=[CH:14][CH:15]=1)[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.1 g, 2.64 mmol, 1 eq) was dissolved in dry THF (18 ml) and NaH, 60% (316 mg, 7.92 mmol, 3 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (1.65 ml, 2.64 mmol, 10 eq) and was stirred for 3.5 h. The excess NaH was quenched by a slow addition of water, diluted with brine (40 ml) and extracted with Et2O (3×40 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a product without further purification {2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.08 g, yield=56.1%, purity=59%). [M+H]+=430.87 1H NMR (300 MHz; CDCl3) δ/ppm 1.38-1.48 (s, 9H), 2.74-2.90 (m, 4H), 3.38-3.50 (m, 2H), 6.93-7.08 (m, 3H), 7.15-7.31 (m, 3H), 7.41 (t, J=8.43 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:15])([CH3:14])[CH3:13]>>[Cl:9][CH:10]=[C:11]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cccc(O)c1
Reactant: CC(C)(C)C=C(Cl)Cl
Product: Cc1cccc(OC(=CCl)C(C)(C)C)c1
Yield: 87.2 %

Procedure:
Analogously to Example A6(a), 0.2 mol of 3-methylphenol and 0.1 mol of 1,1-dichloro-3,3-dimethyl-1-butene are reacted to give 19.6 g of 1-chloro-3,3-dimethyl-2-(3'-methylphenoxy)-1-butene of boiling point 95°-100° C./0.7 mm Hg. The yield is 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To 3,4-dichlorophenol (13.8 g) dissolved in a 60 ml THF/60 ml DMSO mixture was added 9.5 g of t-BuOK. The temperature rose to about 40° C. and then 19.8 g of 2,5-bis(methylsulfonyl)pyridine was added. The reaction mixture was warmed to 50° C. and the temperature maintained at 50° C. for 1 hour. The reaction mixture was cooled, poured into approximately 3 volumes of water and the solid collected. The solid was dried on a porous plate and then recrystallized from CH2Cl2 /ethanol to give 23.5 g of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)pyridine as shiny white plates, m.p. 120°-121° C.
Reaction SMILES: Cl.[CH2:2]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH2:11])=[NH:10])[N:8]=1)[CH3:3].[O-]CC.[Na+].C(O[CH:19]=[CH:20][C:21]#[N:22])C>>[CH2:2]([C:4]1[S:5][CH:6]=[C:7]([C:9]2[N:11]=[C:21]([NH2:22])[CH:20]=[CH:19][N:10]=2)[N:8]=1)[CH3:3]
Reactant: CCOC=CC#N
Reactant: CCc1nc(C(=N)N)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1nc(-c2nccc(N)n2)cs1

Procedure:
This material was obtained as described in example 2, step A] from 2-ethyl-thiazole-4-carboxamidine hydrochloride (3 g) by treatment with sodium ethoxide (3.13 mL of a 5.4 M solution) and 3-ethoxyacrylonitrile (1.73 mL) to give 2-(2-ethyl-thiazol-4-yl)-pyrimidin-4-ylamine (2.56 g) as a brown solid. MS (ESI): 193.3 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[N:6]=[C:5]1Cl.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(O)C>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:21]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH2:3][CH2:2]1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3
Reactant: NCc1ccccc1Cl
Reactant: O=c1c2cc(Cl)ccc2nc(Cl)n1CCCl
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=c1c2cc(Cl)ccc2nc2n1CCN2Cc1ccccc1Cl

Procedure:
A solution of 1.0 g. of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g. of 2-chlorobenzylamine in 50 ml. of ethanol and 1.0 ml of dimethylacetamide is stirred and heated at reflux for 12 hours. The solvent is removed by evaporation in vacuo and the residue dissolved in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chloride/pentane and filtered to obtain 1-(o-chlorobenzyl)-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 173°-174° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:40]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:36]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:37])[NH2:40]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 50.1 %

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (540 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (345 mg) and WSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24 hr, and the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object product (270 mg).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[CH3:10][C:9]1[C:2]2[NH:1][CH:12]([C:13]([Cl:16])([Cl:15])[Cl:14])[O:5][CH2:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cc1cccc(CO)c1N
Product: Cc1cccc2c1NC(C(Cl)(Cl)Cl)OC2
Reaction time: 0.5 h

Procedure:
2-Amino-3-methylbenzyl alcohol (1.7 g.) and anhydrous chloral (2.4 ml.) were mixed for 10 minutes with external ice-cooling, and the mixture was left to stand for 1/2 hour. The mixture was then chromatographed on silica, and elution with diethyl ether/petroleum ether (b.p. 60°-80° C.), 7:3 by volume, gave 1,2-dihydro-8-methyl-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, which was crystallised from aqueous ethanol, m.p. 69°-70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:5]3[C:10]=2[C:9]([NH2:11])=[N:8][CH:7]=[N:6]3)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(COc2cccc(B(O)O)c2)cc(OC)c1
Reactant: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(COc2cccc(-c3cc(CCCCN4CCCC4)n4ncnc(N)c34)c2)cc(OC)c1
Temperature: 80 °C
Yield: 27.5 %

Procedure:
To a stirred solution of 5-bromo-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (70 mg, 0.21 mmol), 3-(3,5-dimethoxybenzyloxy)phenyl boronic acid (179 mg, 0.62 mmol), and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.021 mmol) in degassed DME (1.5 mL) was added aqueous Na2CO3 solution (2 M, 310 μL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic phase was washed dried (Na2SO4) and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 20% to 70% acetonitrile followed by preparative TLC eluting with 9:1 ethyl acetate/methanol (with 1% concentrated ammonium hydroxide) to obtain 29 mg (28%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1 H), 7.36 (t, 1 H), 7.07-7.04 (m, 1 H), 7.03-6.96 (m, 2 H), 6.60 (d, 2 H), 6.55 (s, 1 H), 6.43 (t, 1 H), 5.07 (s, 2 H), 3.73 (s, s H), 2.88 (t, 2 h), 2.56-2.48 (m, 6 H), 1.78-1.65 (m, 6 H), 1.60-1.49 (m, 2 H); ES-MS m/z 502.2 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:19]1[O:22][CH:20]1[CH3:21]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:19][CH:20]([OH:22])[CH3:21])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CO1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na]
Solvent: CCO
Product: CC(O)CSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
4.8 (20 mmoles) of 5-benzyl-benzimidazoline-2-thione and 0.46 g sodium dissolved in ethyl alcohol and 2 ml of 1,2-propylenoxide are refluxed for 5 hours. The reaction mixture is evaporated and 50 ml of benzene and 20 ml of 1N sodium hydroxide solution are added. The aqueous phase is extracted twice with 10 ml of benzene, the combined benzene phases are evaporated and the residue is crystallized from nitromethane. The title product thus obtained melts at a temperature of 115° C.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:16]Br>O>[Br:16][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole, and 0.13 g (0.001 mole) of aluminum chloride and 200 g of dichloromethane, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 5° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 2 hours. After completion of the reaction, 50 g of water was added, and phase separation was effected, whereby a 4-bromothioanisole-containing organic layer was obtained. The dichloromethane was distilled off from the organic layer obtained, whereby 203.1 g of crude 4-bromothioanisolve was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.1% as determined by gas chromatography.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C1CCCNc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
A 3.32 g portion of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one and 4.31 ml of triethylamine were dissolved in 33 ml of dichloromethane and, with stirring on an ice bath, 4.59 g of p-nitrobenzoyl chloride was added to the resulting solution. The reaction solution was stirred at room temperature for additional 60 minutes. The reaction solution was then mixed with a saturated sodium bicarbonate aqueous solution and subjected to phase separation. The dichloromethane layer was separated and washed with a 1N hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution once for each. The thus washed layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 5.68 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][O:13][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CC1
Product: Brc1ccc(OCC2CC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopropylmethanol by the method of Example 10 (b).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:28]C)[CH2:24][CH2:25][CH2:26]Cl)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[N:7]([CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:21])[C:6]=2[N:18]=1
Reactant: CCN(CC)CCCCl
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN(C)C)c1ccccc1N(C)C2=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 70 ml of dimethyl formamide and 1.9 gm of 50% sodium hydride in mineral oil was stirred at 30°-50° C. in a nitrogen atmosphere for 30 minutes. Then, a solution of 6.1 gm of 3-diethylamino-propyl chloride in 30 ml of dimethyl formamide was added dropwise, and the mixture was heated on an oil bath at 120° C. for 3 hours and then evaporated in vacuo. The residue was mixed with an aqueous potassium carbonate solution, and the mixture was extracted with ether. The ethereal phase was dried with sodium sulfate and evaporated, and the residue was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 76% of theory of the compound named in the heading, which had a melting point of 130°-131° C.