Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]1[CH:34]=[C:33]([CH2:35][CH2:36]OS(C)(=O)=O)[CH:32]=[N:31]1>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:36][CH2:35][C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: Cn1cc(CCOS(C)(=O)=O)cn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1cc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cn1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
To a solution of 1.00 gm (3.422 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 50 mL acetonitrile were added 1.04 gm (7.53 mMol) potassium carbonate followed by 1.26 gm (6.16 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane and the reaction mixture was heated to reflux for 18 hours. To the reaction mixture were then added 0.021 gm (0.171 mMol) 4-dimethylaminopyridine and reflux was continued for 36 additional hours. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and water. The aqueous phase was extracted well with dichloromethane. All of the organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 2.5% methanol in dichloromethane containing 0.5 % ammonium hydroxide. Fractions shown to contain product were concentrated under reduced pressure to give 0.610 gm (44%) of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[C:27]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:27]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:1][CH3:2])[CH3:40]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCc1cccc2c(CCO)c[nH]c12
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)CC1(c2ccccc2)OCCc2c1[nH]c1c(CC)cccc21

Procedure:
Following the procedure of example 22.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and ethyl benzoylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 10.05 (br, 1H), 7.42 (d, 1H), 7.28 (m, 5H), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H), 3.43 (d, 1H), 3.22 (d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI (−) MS m/e=362 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:9]2)=[CH:4][CH:3]=1.CO[C:37](=O)[C:38]1[CH:43]=[C:42]([S:44]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:46])=[O:45])[C:41]([Cl:52])=[CH:40][C:39]=1[O:53][CH2:54][CH3:55].C[Al](C)C>>[Cl:52][C:41]1[C:42]([S:44]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:43][C:38]([C:37]2[NH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)=[C:39]([O:53][CH2:54][CH3:55])[CH:40]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C(=O)OC
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: C[Al](C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)benzoic acid methyl ester (prepared in an analogous manner as described in example 43) in the presence of trimethylaluminum to give the title compound. HR-MS (ES, m/z) calculated for C29H33N3O3SCl3 [(M+H)+] 608.1303, observed 608.1300.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]3[CH2:21][CH2:22][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].I[N:24]1C(=O)[CH2:27][CH2:26][C:25]1=O.C(N)CC>C(O)(=O)C>[CH2:25]([NH:24][CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]4[CH2:21][CH2:22][C@H:12]4[C:11]=23)=[N:4][CH:1]=1)[CH2:26][CH3:27]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: CC(=O)O
Solvent: CCCN
Product: CCCNCc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.9 %

Procedure:
A solution of 3.10 g (0.00992 mol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.35 g (0.0149 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 24 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark residue was dissolved in 60 ml of THF, treated with 7.1 ml (0.0863 mol) of propylamine and stirred at room temperature for 6 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the dark product was chromatographed over silica gel which dichloromethane/methanol 49:1 as the eluent. There was obtained 0.29 g (8%) of (S)-1-(5-propylaminomethyl-oxazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as yellowish crystals; m.p. 145-147°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=1)=[O:4].[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([CH2:22][N:29]([CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=2)[OH:4])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COCc1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: COCc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2-bromo-1-[3-(methoxymethyl)-4-(phenylmethoxy)phenyl]ethanone (2.0 g), dibenzylamine (1.2 g) and DEA (0.8 g) in THF (30 ml) was allowed to stand at room temperature for 18 h, filtered and evaporated. The residual oil was dissolved in ethanol (20 ml) and treated portionwise with sodium borohydride (0.23 g), under nitrogen. The mixture was stirred at room temperature for 1 h, treated with methanol (20 ml), and evaporated. The residue was purified by FCC eluting with CX-ER (3:1) to give the title compound as an off-white solid (2.3 g), m.p. 52°-57°, t.l.c. (CX-ER 1:1) Rf 0.5
Reaction SMILES: O=C1C2(CCN(C(OC(C)(C)C)=O)CC2)[C:9]2[C:4](=[CH:5][C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:7][CH:8]=2)[NH:3]1.BrC1C=C[C:36]2[C:41](C)([CH3:42])[O:40][C:39](=[O:44])NC=2C=1>>[CH3:36][C:41]1([CH3:42])[O:40][C:39](=[O:44])[NH:3][C:4]2[CH:5]=[C:6]([B:23]3[O:24][C:25]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:29])[O:27]3)[CH:7]=[CH:8][C:9]1=2
Reactant: CC1(C)OC(=O)Nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: CC1(C)OC(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc21

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 (60 mg), 77 mg of 4,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2 (4H)-one 7.39 was obtained. LCMS [M+H]+: 304.19.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:31])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reaction time: 3 h

Procedure:
A solution of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (6.63 g, 17.0 mmol) in 90 mL of CHCl3 was treated with MPCBA (6.29 g, 25.5 mmol, 70%). After 3 h, HPLC and LC/MS indicated complete conversion to the intermediate 5-N-oxide. The reaction mixture was then treated with concentrated ammonium hydroxide solution (30 mL, 30%). The biphasic reaction mixture was stirred vigorously while p-toluenesulfonyl chloride (3.40 g, 17.9 mmol) was added. After 45 min, LC/MS indicated complete conversion to the 4-amine. The reaction mixture was diluted with 30 mL of water and 45 mL of CHCl3 and separated. The organic portion was washed with 10% Na2CO3 solution (50 mL) and water (50 mL). The combined aqueous portions were then back-extracted with CHCl3 (25 mL). The combined organic portions were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a tan solid. The solid was purified by chromatography (SiO2, 96:4 CHCl3:MeOH) to give 5.90 g of 7-benzyloxy-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as a light tan solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3ccnc3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[N:48]O)[NH2:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:48]=[C:21]([C:20]3[CH:19]=[C:18]([C:16]4[CH:17]=[C:8]([C:2]([CH3:1])([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:3])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:26]=[CH:25][CH:24]=3)[O:23][N:47]=2)=[CH:42][CH:41]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3nc(-c4ccc(F)cc4)no3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of acid from step 2 in DMF (0.05M) was added CDI (2 eq) and 4-fluoro-N′-hydroxybenzenecarboximidamide (2 eq). The reaction mixture was stirred at rt for 15 min and 18 h at 120° C. The reaction mixture cooled to rt, diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 20:80) to afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[K+].[H-].[Na+].Cl[C:14]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>S1(CCCC1C([O-])=O)(=O)=O.C(O)(=O)C>[C:24]1([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[N:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Reactant: O=C([O-])CCCCCO
Agent: O=C([O-])C1CCCS1(=O)=O
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCCOc1nc(-c2ccccc2)c2ccccc2n1
Yield: 11.6 %

Procedure:
To a suspension of 1.74 g of potassium 6-hydroxyhexanoate (prepared from e-caprolactone) in 35 cc of sulfolaneat 60° C. was added 0.64 g of sodium hydride (55 % w/w dispersion in mineral oil). The mixture was stirred for 30 minutes to 140° C. until effervescence had stopped. 3 g of 2-chloro-4-phenyl-quinazoline were then added and the resultant mixture was heated for further 2 hours to 140° C. The mixture was poured into 500 cc of water, neutralized with acetic acid and extracted with dichloromethane (3#300 cc). The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel (50-200 mm; eluent: 95:5 diethyl ether/methanol), then washed with n-hexane and filtered to give 0.4 g (10%) of 6-(4-phenyl-2-quinazolinyloxy)hexanoic acid as a whitish solid. (m.p.=112°-114° C.)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: COC(C)(C)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 2-Hydroxymethyl-1,3-propanediol (9.0 g, 61.6 mmol), 2,2-dimethoxypropane (11.7 ml, 95.2 mmol) 4-toluenesulphonic acid monohydrate (0.49 g, 2.58 mmol) and tetrahydrofuran (450 ml) was stirred at 20° C. for 1 hour. Triethylamine (5 ml) was then added and the solvent removed under reduced pressure. Chromatography on silica gel (eluted with chloroform ethanol, 10.1) afforded the title compound (9.62 g, 78%) as a colourless oil. 1R: υmax (film) 3431, 2993, 2943, 2874, 1482, 1456, 1373 cm-1. 1H NMR: δH [(CD3)2SO] 1.30(6H, s, 2×CH3), 1.69(1H,m,CH), 3.38(2H,dd, J=5.2, 6.6 Hz, CH2OH), 3.61(2H,dd, J=11.8, 7.1 Hz, 2×H(ax)), 3.82 (2H, dd, J=11.8, 4.4 Hz, 2×H(eq)), 4.53(1H, t, J=5.2 Hz, D2O exchangable, OH). Found: C, 56.73; H, 9.80%. C7H14O3.0.01H2O requires: C, 56.80; H, 9.69%.
Reaction SMILES: [F-].[Cs+].[CH3:3][O:4][C:5](=[S:27])[NH:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[C:15]([F:26])[CH:14]=2)[CH:12]=1>C(O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5](=[S:27])[NH:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=[C:8]([C:12]#[N:11])[C:7]#[N:6])[CH2:21][CH2:20]3)=[C:15]([F:26])[CH:14]=2)[CH:12]=1
Reactant: COC(=S)NCc1cn(-c2ccc(N3CCC(=O)CC3)c(F)c2)nn1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=S)NCc1cn(-c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of malononitrilc (22 mg, 0.33 mmol) and CsF (42 mg, 0.28 mmol) in ethanol (5 ml) was added {1-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}-thiocarbamic acid O-methyl ester (100 mg, 0.28 mmol), obtained in Example 82. The reaction mixture was allowed to stir at room temperature for 2 h and then diluted with ethyl acetate (100 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:1), the title compound was obtained as white solid (45 mg, 40%). Mp. 198° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14].Cl[C:19]1[C:20]2[S:36][C:35]([NH2:37])=[N:34][C:21]=2[N:22]=[C:23]([S:25][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[N:24]=1.O>CN1C(=O)CCC1>[NH2:37][C:35]1[S:36][C:20]2[C:19]([NH:10][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])=[N:24][C:23]([S:25][C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[N:22][C:21]=2[N:34]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CC(CO)Nc1nc(S[C@@H](C)c2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 55.1 %

Procedure:
DIPEA (400 mg, 3 mmol) and D -leucinol (400 mg, 3.4 mmol) were added to 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (300 mg, 0.9 mmol) in NMP (6 mL) and the mixture was heated to 120° C. for 24 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by flash column chromatography (EtOAc) to give the title compound (200 mg, 54% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH:15]P(OCC)(OCC)=O)[C@H:8]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:7]=1)=[O:5])[CH3:2].CCO.S(=O)(=O)(O)O.[OH-].[NH4+]>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH2:15])[C@H:8]([O:24][CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@@H](N=[N+]=[N-])C1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 300 mg of 26 and 1.25 mL EtOH in a 5.0 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply was added 0.31 mL of 96% sulfuric acid. The black solution was stirred for 18 h at RT and 8 h at 80° C. The black reaction mixture was cooled to RT treated with 8.0 μL of a mixture of 65 mL ammonium hydroxide 25% and 435 mL of brine, and extracted with 9.0 mL of EtOAc. The separated organic phase was washed with 10 mL of water and the water phase was back-extracted with 9.0 mL of EtOAc. The combined organic phases were dried (Na2SO4, 20 g), filtered and evaporated at 40° C./140-10 mbar to afford 175 mg crude product as a dark brown oil. The crude product was purified by SiO2 column chromatography eluting with EtOAc containing 1% v/v of 25% aqueous ammonium hydroxide. The combined fractions were evaporated at 40° C./140-10 mbar to afford 97 mg of 28 as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].CS(C)=O.[S-:24][C:25]#[N:26].[K+]>O>[S-:24][C:25]#[N:26].[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Agent: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOc1ccc(C(C)=O)c(O)c1CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 10.65 g. of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl bromide in 60 ml. of dry dimethylsulfoxide were added 6.5 q. of potassium thiocyanate. The solution was stirred overnight at room temperature and then was poured into water. The solution was extracted twice with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The resulting oil was vacuum distilled to provide the title compound in 95% yield as a yellow viscous oil, b.p. about 205° C. at 0.45 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32](=[O:33])[C:31]3[CH:30]=[C:29]([Cl:28])[CH:37]=[C:36]([Cl:38])[CH:35]=3)=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.15 g) is dissolved in dichloromethane (10 ml) and thereto is added triethylamine (0.31 ml). To the mixture is added dropwise a solution of 3,5-dichlorobenzoyl chloride (0.14 g) in dichloromethane (2.0 ml) under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room temperature for 1 hour. To the mixture are added triethylamine (0.31 ml) and 3,5-dichlorobenzoyl chloride (0.14 ml). The mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:5→1:4), and recrystallized from ethyl acetate/n-hexane to give 6-fluoro-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.12 g) and 6-fluoro-1-{4-[bis-(3,5-dichlorobenzoyl)amino]benzoyl}-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:40]=[CH:39][C:25]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH:36]([F:38])[F:37])[CH:30]=3)=[O:27])=[C:24]([O:41][CH3:42])[CH:23]=2)[N:17]=1>[OH-].[K+].N>[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:40]=[CH:39][C:25]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH:36]([F:38])[F:37])[CH:30]=4)=[O:27])=[C:24]([O:41][CH3:42])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Agent: N
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Yield: 26.3 %

Procedure:
The solution of 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide (0.070 g, 0.11 mmol) in 20% aq. KOH (10 mL) and aq. NH3 (2 mL) was stirred for 24 h at RT. Excess of solvent was removed under vacuum and filtered off to afford 0.015 g of desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:7][CH:6]=1.[CH:20](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=[CH:20]2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCOC(OCC)OCC
Product: COC(=O)Cc1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of [4-(3-amino-pyridin-4-ylamino)-phenyl]-acetic acid methyl ester (0.356 g, 1.39 mmol) and triethyl orthoformate (9.2 mL, 55.4 mmol, 40 equiv) is stirred and refluxed for 2 h. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound as a beige solid: ES-MS: 268.1 [M+H]+; single peak at tR=2.03 min (System 1).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[N+](C1C=CC(CC#N)=C2C=1NN=C2)([O-])=O>>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([CH2:4][C:3]#[N:2])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(C=CN(C)C)ccc1[N+](=O)[O-]
Agent: N#CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Product: COc1cc(CC#N)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
19.8 g of N,N-dimethyl-N-[2-(3-methoxy-4nitrophenyl)ethenyl]amine and 30.0 g of hydroxylamineorthosulfonic acid are reacted as described in connection with preparing 2-(7-nitro-1H-indazol-4-yl)acetonitrile, thus obtaining 17.0 g of (3-methoxy-4-nitrophenyl)acetonitrile, mp 85°-86.5° C.