Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[NH:8][CH2:7][CH2:6][C:5]2=1.CCN(CC)CC.[NH:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32]>C1COCC1>[C:44]([O:43][C:41]([NH:29][CH2:30][C:31]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)=[O:32])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CNC(=O)OC(C)(C)C)C3c1cccc(O)c1
Reaction time: 2 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and Boc-Gly-OSu (1.2 equiv). After 2 h, the solvent was removed to give a residue, which was purified via prep-HPLC to give 3-{2-[N-(tert-butoxycarbonyl)-glycyl]-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)}phenol 11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12].CO[CH:15]1[CH2:19][CH:18](OC)[CH2:17]O1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: NCCCc1ccc(F)cc1F
Reactant: COC1COC(OC)C1
Product: Fc1ccc(CCCn2cccc2)c(F)c1

Procedure:
17.1 g (0.10 mol) of 3-(2,4-difluorophenyl)propylamine are heated at 260° C. for 2 hours in an autoclave with 13.2 g (0.10 mol) of 2,4-dimethoxytetrahydrofuran. The reaction mixture is cooled and then purified by vacuum distillation. 10.6 g (48% of theory) of a colourless oil which boils at 80° C. and 0.2 mbar or 146°-147° C. and 15 mbar are obtained.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][OH:19])[N:14]=[CH:15]2)=[CH:10][N:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]([OH:2])=[O:19])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1cc2cnc(Cl)cc2cn1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cnc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
Potassium permanganate (280 mg, 1.8 mmol) was added in small portions to a slurry of (7-chloro-2,6-naphthyridin-3-yl)methanol (105 mg, 0.54 mmol) in water (2 mL). The mixture was stirred for 30 minutes at room temperature, and was then diluted with sodium hydroxide (1.0 M solution in water, 5 mL) and filtered over Celite. The filtrate was acidified to a pH of ˜3 via addition of citric acid, and the resulting precipitate was collected by vacuum filtration and washed with water (2×5 mL) to afford the title compound as a white solid (55 mg, 50%). 1H NMR (400 MHz, DMSO) δ 13.40 (s, 1H), 9.54 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 8.36 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:8]([C:3]4[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: Cc1nccnc1C(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2nccnc2C)C3)cc1
Reaction time: 8 h

Procedure:
3-Methylpyrazine-2-carboxylic acid (0.0501 g, 0.000363 mol) in dry N,N-Dimethylformamide (1.80 mL, 0.0232 mol) was added 1-Hydroxybenzotriazole (0.0580 g, 0.000429 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0765 g, 0.000399 mol) then followed by N,N-Diisopropylethylamine (0.1150 mL, 0.0006602 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.1021 g, 0.0002670 mol). The reaction mixture was stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.73-8.60 (m, 2H), 8.55 (s, 1H), 8.17 (dd, J=43.9, 8.8, 2H), 7.47 (dd, J=25.7, 8.8, 2H), 6.22-6.10 (m, 1H), 4.79 (s, 1H), 4.37 (s, 1H), 3.90 (t, J=5.3, 1H), 3.78-3.66 (m, 4H), 3.56-3.37 (m, 6H), 3.21-3.03 (m, 2H), 2.81 (s, 1H), 2.68 (s, 1H), 2.53 (s, 2H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.CO.[CH2:21](N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([O:7][CH3:21])=[O:6]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(OC)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.9 %

Procedure:
3-Bromo-2,6-dimethoxybenzoic acid (5.0 g, 19.2 mmol) and thionyl chloride (10 ml) were heated to reflux for 2 h. The mixture was then concentrated in vacuo and diluted with CH2Cl2 (20 ml) and added to a solution of MeOH (614 mg, 38.4 mmol) and triethylamine (3.88 g, 38.4 mmol) in CH2Cl2 (100 ml) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 64 h. The organics were washed with 10% HCl (50 ml), brine (50 ml) and dried (MgSO4) and purified by chromatography (0-50% EtOAC in heptane) to leave a white solid (4.17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCc1cccs1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 16 mL of (16 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 5.42 g (100% of yield) of 4-(6-fluoro-1-thiophen-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][OH:9])=[NH:7])#[N:2].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=O>ClCCl>[Cl:20][CH2:21][C:22]1[O:9][N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:7]=1
Reactant: N#Cc1cccc(C(=N)NO)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(-c2noc(CCl)n2)c1

Procedure:
3-cyano-N-hydroxy-benzamidine (1.0 g, 6.2 mmol), triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl chloride (0.74 ml, 9.3 mmol) in dichloromethane (12 ml). Purification was performed by decolorizing with silica gel. 1H NMR (CDCl3), d (ppm): 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 62.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (200 mg, 0.380 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (185 mg, 0.58 mmol) in sodium carbonate (121 mg, 1.14 mmol), Pd(PPh3)2Cl2 (26.6 mg, 0.038 mmol), toluene/ethanol/water (20/7/3 mL). This afforded 153 mg (62.4% yield) after purification by column (Silica gel 6/120) using 3% methanol in chloroform as eluent. MS: m/z=645.7 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[N:16]1([C:22]2[N:23]=[C:24]3[NH:32][C@H:31]([C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:32]1[C:24]2=[N:23][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:27][C:26](=[O:28])[N:25]2[CH2:29][CH2:30][C@H:31]1[C:33]([F:34])([F:35])[F:36]
Reactant: Clc1ccccc1CBr
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccccc1Cl
Reaction time: 16 h

Procedure:
214 mg of caesium carbonate and 74 mg of 1-(bromomethyl)-2-chlorobenzene are added to a solution of 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 2 ml of dimethylformamide. After 16 hours at a temperature in the region of 20° C., the reaction medium is run into water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC/MS (Method C). After evaporation of the acetonitrile and lyophilization, 94 mg of (8S)-9-(2-chloro-benzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].[CH2:17]=O>>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:17][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[C:3]=1[OH:9]
Reactant: Oc1ccc(Br)cc1Br
Reactant: OCCNCCO
Reactant: C=O
Product: OCCN(CCO)Cc1cc(Br)cc(Br)c1O

Procedure:
252 g of 2,4-dibromophenol and 105 g of diethanolamine were charged to a 1 liter round-bottomed flask fitted with an agitator. The temperature of the clear viscous liquid was adjusted to 40 Deg. C. and 100 g of formalin (30% formaldehyde in water stabilised with methanol) was added dropwise over 1 hour while maintaining the temperature at 40-45 Deg C. The temperature was then raised to 100-110 Deg. C. and maintained at that temperature for 4 hours. Vacuum was then applied to distil off excess formaldehyde, methanol and water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([NH:30][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccc3)nc21
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido-[2,3-d]pyrimidin-7-one of Example 37, 0.50 g (4.70 mmol) of benzylamine and 0.5 mL of dimethylformamide was heated with stirring in a 120° C. oil bath. After 5 minutes, solution was complete. After 5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure, and the residue was triturated with a solution of 1 mL of acetone and 2 mL of petroleum ether. The tacky solid was filtered and recrystallized from ethyl acetate/petroleum ether to give 0.092 g of pure product; mp 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][C:12]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.3 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 3,4,5,6-tetrahydrophthalic anhydride (6 g) were dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture was allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract was washed with a saturated sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[I:14]I>FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([I:14])[CH:13]=1)[O:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(=O)c1cc(I)c2c(c1)CCCO2

Procedure:
In accordance with this scheme a 6-bromochroman compound of Formula 2 (see Reaction Scheme 1) is reacted with by tributyl(1-ethoxyvinyl)tin in the presence dichlorobis(triphenylphosphine)palladium(II) under an inert gas (argon) atmosphere in an aprotic neutral solvent, such as tetrahydrofuran (THF), to provide a 6-acetylchroman derivative of Formula 25. The 6-acetylchroman derivative of Formula 25 is then reacted with iodine and silver(I)trifluoromethanesulfonate (AgOTf) to give a 6-acetyl-8-iodochroman derivative of Formula 26. The compound of Formula 26 is reacted with with trimethylsilyl acetylene in triethyl amine under argon atmosphere in the presence of copper(I)iodide and dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2) to give the 6-acetyl-8-trimethylsilanyl-ethynyl-chroman derivative of Formula 27. The latter reaction is analogous to the conversion of the 8-iodo-substituted chroman compounds of Formula 4 to the 8-trimethylsilanyl-ethynyl-chroman derivatives of Formula 5, as shown in Reaction Scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 70%), 1H NMR (300 MHz, CDCl3): δ 3.63-3.73 (m, 7H), 4.08-4.15 (m, 4H), 6.68 (d, J=8.7 Hz, 2H), 7.20-7.31 (m, 1H), 7.42-7.53 (m, 2H), 7.65-7.80 (m, 2H), 8.21 (d, J=3.6 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (2.00 g, 12.04 mmol) and methyl 4-aminobenzoate (1.94 g, 12.83 mmol) in DMSO (40 mL) was cooled in an ice-bath and potassium tert-butoxide (2.96 g, 26.38 mmol) was added over 15 min. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with ice; the solid product was recovered by filtration, washed with water and dried under vacuum to afford 2.4 g (68%) of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate. To a solution of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate (0.2 g, 0.67 mmol) in ethanol (4 mL) was added palladium on carbon (10 wt. %, 0.06 g) and hydrazine hydrate (0.13 g, 2.60 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent evaporated. The residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated under reduced pressure to afford a crude oil. To a solution of the oil in trimethyl orthoformate (10 mL) was added formic acid (0.31 g, 7.7 mmol, 3 eq) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was dried (Na2SO4) and evaporated to afford a crude solid. Purification by flash column chromatography (silica, CHCl3/MeOH 98:2) afforded 0.12 g (63%) of methyl 4-(5-cyano-1H-benzimidazol-1-yl)benzoate. MS [M+H] 277.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2COCCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1,4-Dioxan-2-yl)methanol (380 mg, 3.22 mmol) in tetrahydrofuran (30 ml) was treated with sodium hydride (60%) (245 mg, 6.13 mmol) at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg, 3.06 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and another portion of sodium hydride (60%) (245 mg, 6.13 mmol) was added. The reaction mixture was stirred overnight and quenched with ice water (3 ml). The cloudy mixture was filtered and the filtrate was concentrated. The residue was triturated with methanol to give the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(N(CC)CC)C>O1CCOCC1>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: ON=Cc1ccccc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a solution of benzaldehyde (2.0 g, 19 mmol) in 1,4-dioxane (6.0 ml) was added hydroxylamine hydrochloride (1.3 g, 19 mmol) and triethylamine (2.6 ml, 19 mmol). The mixture was sonicated for 0.5 h and stirred at room temperature for 116 h and at 35° C. for 24 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water, dried (MgSO4), filtered and evaporated in vacuo affording 1.9 g (84%) of benzaldehyde oxime as an oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])=[O:12])[CH2:14][CH2:15]2)[N:23]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2ncnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (315 mg, 1.10 mmol, 1.10 equiv) in acetonitrile (5 ml) at room temperature, 2,4-dichloro-1,3,5-triazine (150 mg, 1.00 mmol, 1.00 equiv) and diisopropylethylamine (DIEA, 0.875 ml, 5.00 mmol, 5.00 equiv) were added. The reaction mixture was stirred for 3 h at room temperature. Without workup or purification, the reaction was carried forward to the next step. MS (ES+): m/e 401.8 [M+H]+
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:26])[C:23]([N:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:16]([CH3:18])[CH3:17])[C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:24]
Reactant: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)n1

Procedure:
A mixture of 2-(2-diisopropylaminoethylamino)-4,6-dimethyl pyrimidine (17.0 g. 0.068 mole) and sodium hydride (50% in mineral oil) (4.19 g., 0.86 mole) in 175 ml. of dry toluene is stirred under nitrogen at 85°-95° C. for one half hour and then heated under reflux for one half hour. Dimethylcarbamoyl chloride (8.6 g., 0.08 mole) is added and heating under reflux is continued for twenty-four hours. The reaction is cooled and ethanol (10 ml) and sodium hydroxide (75 ml., 3.3N) are added. The aqueous layer is extracted with methylene chloride and the extracts are dried over sodium sulfate and concentrated to an oil. The oil is distilled at 0.5 mm of Hg and the product boiling at 155°-158° C. is collected.