Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Reaction time: 2 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (3.0g., 0.012 mol) and 1,1'-carbonyldiimidazole (2.0 g., 0.012 mol) in tetrahydrofuran (180 ml) and dimethylformamide (3.5 ml) is refluxed under nitrogen for 5 hours. The solution is cooled in an ice-bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice-bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off and washed with tetrahydrofuran. The precipitate is treated with hot 0.5 mol aqueous sodium bicarbonate solution, filtered, washed with water, washed with acetone and sucked dry to give the product (2.0 g.), mp 334° C. (dec).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[C:7]([C:8]3[N:9]=[CH:10][S:11][C:12]=3[C:13]3[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Clc1ncccc1-c1ncsc1-c1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc(CNc2ncccc2-c2ncsc2-c2cccnc2Cl)cc1
Temperature: 130 °C
Yield: 24.1 %

Procedure:
A mixture of 4,5-di-(2-chloropyridin-3-yl)thiazole (0.047 g), 4-methoxybenzylamine (0.021 g), and diisopropylethylaamine (0.025 g) in xylene was heated in a sealed tube at 130° C. for 4 days. The solvent was evaporated, and the residue was fractionated by chromatography to give 4-[2-(4-methoxybenzylamino)pyridin-3-yl]-5-(2-chloropyridin-3-yl)thiazole (0.015 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:4][CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:2]2[CH2:7][CH2:6][C:5]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8]3)[CH2:4][CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine)hydrochloride (65 mg, 293 μmol) and p-toluenesulfonyl chloride (61.9 mg, 325 μmol) were combined in CH2Cl2 and treated with triethylamine (2 drops). The mixture was stirred at ambient temperature for 1 hour, then poured onto a silica gel column and eluted with 35% hexane in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo to provide the title compound which was crystallized from ether, filtered and dried in vacuo overnight at ambient temperature: (m.p. 168°-170°).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cl
Product: COC(=O)c1ccc(N)nc1
Yield: 97 %

Procedure:
A solution of 6-aminonicotinic acid (3.0 g, 19 mmol) in HCl/MeOH (2M, 100 mL) was heated at reflux overnight. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with aqueous Na2CO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness to give 6-aminonicotinic acid methyl ester as a white solid (2.8 g, 97%), which was directly used in the next step without further purification. 1H NMR (300 MHz, d-DMSO) δ 8.48 (d, J=1.5 Hz, 1 H), 7.79 (dd, J=1.8, 6.6 Hz, 1H), 6.81 (brs, 2H), 6.42 (d, J=6.6 Hz, 1H), 3.73 (s, 3H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[C:13]1([CH2:12][O:19][C:20]2[CH:21]=[C:22]([CH:23]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)SC1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of rhodanine-3-acetic acid (1 g, 5.20 mmol, 1 eq), 3,4-dibenzyloxybenzaldehyde (2.04 g, 6.25 mmol, 1.2 eq), and sodium acetate (1.3 g, 15.6 mmol, 3 eq) in acetic acid (30 ml) was heated to reflux, and stirred overnight. As the reaction mixture cooled to room temperature the product precipitated and it was filtered and washed with acetic acid, then petroleum ether. The gummy solid was dissolved in ethyl acetate (20 mL) and extracted into saturated aqueous sodium bicarbonate (2×30 mL). The basic extracts were combined, washed with ethyl acetate, and acidified to pH 1 with concentrated HCl. The aqueous solution was extracted with ethyl acetate (2×10 mL), and the organic extracts combined, dried over sodium sulfate and evaporated in vacuo. Recrystallization from ethyl acetate and petroleum ether gave the product which was suspended in water and freeze-dried overnight in vacuo to give the product as a fluffy yellow powder (2.1 g, 81%). mp 235–238° C.: 1H NMR (d6 DMSO) δ 7.79 (s, 1H, C═C—H), 5.25 (s, 2H, CH2Ph), 5.23 (s, 2H, CH2Ph), 4.73 (s, 2H, CH2CO2H). Anal. Found: C, 63.53; H, 4.31; N, 2.85; S, 13.05. Calcd for C26H21NO5S2: C, 63.39; H, 4.21; N, 2.84; S, 12.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([I:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1.0 gram (0.0036 mole--1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole in 10 mL of concentrated sulfuric acid (% wt/vol. triazole to solvent--10%) was added in small portions 0.972 gram (0.0043 mole--1.2 equiv.) of N-iodosuccinimide. Upon completion of the addition the reaction mixture was stirred at ambient temperature and in absence of light for 30 minutes. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was then quenched with 50 mL of water, and the resulting mixture was extracted with two 25 mL portions of ethyl acetate. The extracts were combined and washed with one 15 mL portion of an aqueous 10% sodium bisulfite solution followed by one 15 mL portion of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.2 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (83.2% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1
Product: CCCCOC(=Cn1ncnn1)c1ccc(Cl)cc1

Procedure:
Analogously to Example 7a,b, after reacting 1-(4-chlorophenyl)-2-tetrazol-2-yl-ethanone with n-butyl bromide there was obtained 2-[2-(4-chloro-phenyl)-2-butoxy-vinyl]-2H-tetrazole as a colourless oil. [M+H]+ =279.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1.[N+]([O-])([O-])=O.[NH4+].O.[CH3:30]COC(C)=O>CC#N>[CH2:1]([O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[NH:10][C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1)[CH3:30]
Reactant: CCOC(C)=O
Reactant: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc2c(n1)C(C)(C)NC2=O
Yield: 72 %

Procedure:
To solution of 2-methoxy-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (0.33 g, 1.0 mmol) in CH3CN (5 mL) was added eerie ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.15 g, 72%) as a solid. MS: 207.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(OCc3ccc(Cl)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of ethyl 7-hydroxyquinoline-3-carboxylate (Intermediate 1, 50 mg, 0.23 mmol) in DMF (1.15 mL) was added Cs2CO3 (150 mg, 0.46 mmol) and 4-chlorobenzyl chloride (41 mg, 0.25 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was loaded directly onto a column and purification (FCC, SiO2, EtOAc/hexanes, 0-20%) afforded the title compound as a white solid (50 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.45-7.35 (m, 4H), 7.34-7.29 (m, 1H), 5.20 (s, 2H), 4.45 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=342.3.
Reaction SMILES: [CH:1]1([CH:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][CH:6]=O)[CH2:3][CH2:2]1.[O:15]([C:22]1[CH:23]=[C:24]([CH2:28][C:29]#[N:30])[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>CO>[CH:1]1([CH:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][CH:6]=[C:28]([C:29]#[N:30])[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Reactant: O=CCC(c1ccc(Cl)cc1)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=CCC(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccccc2)c1
Yield: 67.9 %

Procedure:
A mixture of 1.5 grams (0.007 mole) of 3-cyclopropyl-3-(4-chlorophenyl)propionaldehyde and 1.5 grams (0.007 mole) of 3-phenoxyphenylacetonitrile in 50 ml of methanol was stirred, and 0.7 ml of 25% sodium methoxide in methanol was added quickly. Upon completion of addition, the reaction mixture was stirred at ambient temperature for four hours. The reaction mixture was then concentrated, and the residue was taken up in 100 ml of diethyl ether. The ether solution was washed with two 100 ml portions of water. The ether layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to centrifugally accelerated, radial thin layer chromatography. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-cyano-4-(3-phenoxyphenyl)-3-butene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:40])[C:30](=[O:31])[NH:29][C:6]2=[N:7][CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:21](C5CCCCO5)[CH:20]=[N:19][N:18]=4)=[CH:13][C:12]=3[CH3:28])[N:10]=[C:5]2[N:4]1[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O.C(O)C>[CH3:2][C:3]1([CH3:40])[C:30](=[O:31])[NH:29][C:6]2=[N:7][CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[NH:21][CH:20]=[N:19][N:18]=4)=[CH:13][C:12]=3[CH3:28])[N:10]=[C:5]2[N:4]1[CH2:32][CH2:33][CH:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Temperature: 80 °C
Yield: 48 %

Procedure:
6 N Hydrochloric acid in water was added to a stirred mixture of 3,3-dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one in ethanol at 80° C. The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 70 min. The resulting mixture was filtered and purified using reverse-phase preparatory HPLC (10-65% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and the acetonitrile removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and diethyl ether and dried under high vacuum at 50° C. to give the desired product in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (br. s., 1H), 8.44 (br. s., 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=7.81 Hz, 1H), 3.78 (dd, J=2.93, 11.13 Hz, 2H), 3.52-3.64 (m, 2H), 3.23 (t, J=10.93 Hz, 2H), 2.48 (s, 3H), 1.51-1.66 (m, 5H), 1.49 (s, 6H), 1.11-1.26 (m, 2H); MS (ESI) m/z 448.3 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C([BH3-])#N.[Na+]>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:24])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]4[CH:33]=[CH:32][C:29]5[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=5[N:35]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 8 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 99), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 8% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH3:38])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-iodopropane (107 μL). The reaction mixture is allowed to stir at room temperature for 4 h. Additional 1-iodopropane (107 μL) is added and the mixture is heated to 60° C. for 2 h. The mixture is allowed to cool to room temperature and stand for 18 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 335 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.89 min; Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)CCO2
Yield: 92.4 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (150 mg), methanol (6 ml) and THF (6 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1ccccc1Cl
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: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Yield: 92.9 %

Procedure:
853 mg of 2-chlorophenylboronic acid, 30 cm3 of water, 964 mg of sodium carbonate and 252 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 60 μm3 of dioxane. The reaction medium is then refluxed for 18 hours and filtered through a sinter funnel packed with Celite, and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 70 cm3 of ethyl acetate and the organic phase is washed with 2×30 cm3 of distilled water and then with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1 g of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][NH:20][CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1.C(#N)C.FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>O>[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][N:20]([CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CNC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Reaction time: 15 h
Yield: 59.9 %

Procedure:
To a mixture of 2-(3-(4-(7-cyclopropylimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile trihydrochloride (100 mg; 0.233 mmol) and acetonitrile (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (108 mg; 0.466 mmol) and TEA (118 mg; 1.17 mmol). The mixture was stirred in a sealed vial for 15 hours. Water (40 mL) was added and the mixture was extracted into methylene chloride (3×30 mL). The combined extracts were dried (sodium sulfate and magnesium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with methylene chloride/6% ammonium hydroxide in methanol (98:2-96:4 gradient) to give the desired product as a white foam (56 mg). MS (apci) m/z=402.1 (M+H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)CBr>CN.CO>[Br:8][C:9]1[CH:16]=[C:15]([CH:14]=[CH:11][CH:10]=1)[CH2:7][CH2:6][NH2:3]
Reactant: BrCc1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Product: NCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.2 %

Procedure:
Triethylamine (19.2 g; 100.5 mmol) was dissolved in 40% solution of methylamine in methanol (150 ml). While the resultant solution was stirred in an ice bath, a solution of 3-bromobenzylbromide (25.1 g; 100.5 mmol) in methanol (40 ml) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 15 hours at room temperature. Methanol and excess methylamine were evaporated under reduced pressure, and the residue was taken up in a mixture of ether and 2N hydrochloric acid (100 ml-100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 12.7 g of the target compound as a yellow-orange oily substance (yield: 63.2%).