Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(O)ccc21
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.400 g, 2.44 mmol), 3-fluorobenzyl bromide (0.509 g, 2.69 mmol), potassium carbonate (0.372 g, 2.69 mmol) and N,N-dimethylformamide (5 ml) was heated to 90° C. for 8 h. Water was added and the resulting precipitate was washed with diethylether and then dried under high vacuum to afford the title compound (0.580 g, 87%). MS: m/e=272.3 (M+H+).
Reaction SMILES: [N:1]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[2H]C(Cl)(Cl)Cl.CO[2H]>>[N:1]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][N:13]([CH2:14][CH2:15][C:10]2[CH:11]=[CH:12][C:4]([C:5]3[CH:4]=[CH:3][CH:2]=[C:6]([NH2:8])[N:1]=3)=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: NC1(C(=O)O)CCNCC1
Agent: NC(=O)N1CCCC1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]OC
Product: Nc1cccc(-c2ccc(CCN3CCC(N)(C(=O)O)CC3)cc2)n1
Yield: 39 %

Procedure:
Prepared as in Example 1, using 4-amino-piperidine-4-carboxylic acid pyrrolidine-amide, in 39% yield, mp 220° C. (dec.) as the hydrochloride salt.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC=O
Reactant: COC(=O)CCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCCCCCCCCNCCC(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.2 %

Procedure:
To an ice-cooled solution of tridecanal (1.0 g), methyl 3-aminopropionate hydrochloride (704 mg), and sodium acetate (414 mg) in methanol (20 ml) was added sodium cyanoborohydride (317 mg). After stirring for 45 minutes, the mixture was quenched with water (20 ml), concentrated, and extracted with ethyl acetate (40 ml). The organic phase was washed with brine, dried, and concentrated under reduced pressure. The residue was purified on silica gel, eluting with 5% methanol in chloroform to give methyl 3-tridecylaminopropionate (0.78 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-])=O.[CH2:14]([N:17]1[C:24]([NH2:25])=[C:23]([N:26]=O)[C:21](=[O:22])[N:20]([CH2:28][CH2:29][CH3:30])[C:18]1=[O:19])[CH2:15][CH3:16].C(N=C=NC(C)C)(C)C>CO>[CH2:28]([N:20]1[C:21](=[O:22])[C:23]2[NH:26][C:6]([C:5]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:4]=3[NH2:1])=[N:25][C:24]=2[N:17]([CH2:14][CH2:15][CH3:16])[C:18]1=[O:19])[CH2:29][CH3:30]
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)N=C=NC(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(CCC)c1=O
Yield: 2.1 %

Procedure:
1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine was synthesized by a modification of the method of Pfleiderer and Kempter (Ang. Int. Ed. 6:259-260, 1967). 2-nitro-4-chlorobenzoic acid (0.02 mol) was dissolved in 30 ml of methanol. 1,3-dipropyl-5-nitroso-6-aminouracil (0.01 mol) was added with stirring, followed by 0.2 mol diisopropylcarbodiimide (DICD).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCC(C)=O

Procedure:
Following a procedure similar to that described in Preparation 3, but using 15.6 g of methyl 2-hydroxyphenylacetate, 34 g of bromoacetone, 25 g of potassium carbonate and 170 ml of dimethylformamide, the title compound was obtained having an Rf=0.39 (thin layer chromatography over silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[CH:14][C:13]=1[NH:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Yield: 98 %

Procedure:
Using an analogous procedure to that described in Example 63, 3-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide. There was thus obtained the title compound in 98% yield: NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.17 (m, 4H), 3.75 (m, 4H), 4.85 (s, 2H), 7.13 (d, 1H), 7.22 (d, 1H), 7.34 (m, 2H), 7.44 (s, 1H), 7.54 (m, 2H), 7.65 (d, 1H), 7.79 (s, 1H), 7.95 (d, 1H), 8.03 (s, 1H), 9.96 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+464.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Br[CH:14]([CH3:18])[C:15](=[O:17])[CH3:16]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:14]([C:15](=[O:17])[CH3:16])[CH3:18]
Reactant: N#Cc1ccc2[nH]ccc2c1Cl
Reactant: CC(=O)C(C)Br
Product: CC(=O)C(C)n1ccc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 4-chloro-1H-indole-5-carbonitrile (see, for example, US2008139631A1) and 3-bromobutan-2-one: MS (ESI): m/z 247 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[C:23]([C:25]([CH3:37])([CH3:36])[CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])#[N:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][C:25]([C:23]#[N:24])([CH3:37])[CH3:36])[CH:28]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C#N)Cc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(CC(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 3-(2-cyano-2-methylpropyl)benzoic acid (86 mg, 420 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (160 mg, 420 μmol) in pyridine (4 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with methanol to give the title compound (108 mg, 56%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([NH:37][C:38]([C:40]1[CH:41]=[N:42][C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[C:45]([NH2:50])[CH:44]=2)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:30]([NH:37][C:38]([C:40]1[CH:41]=[N:42][C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[C:45]([NH:50][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:44]=2)=[O:39])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1
Reactant: COc1cccc(C(=O)O)c1OCc1ccccc1
Reactant: Nc1ccc2cc(C(=O)NC(c3ccccn3)c3ccccn3)cnc2c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)Nc2ccc3cc(C(=O)NC(c4ccccn4)c4ccccn4)cnc3c2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A mixture of 2-benzyloxy-3-methoxybenzoic acid (109 mg, 0.42 mmol), thionyl chloride (5 ml) and 1 drop dimethylformamide was heated under reflux for 2 hr. The thionyl chloride was removed in vacuo, with traces being removed by adding methylene chloride and concentrating the solution in vacuo. The resulting 2-benzyloxy-3-methoxybenzoyl chloride was dissolved in chloroform and the solution was added dropwise to a solution of 7-amino-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide (75 mg, 0.21 mmol), 4-(N,N-dimethylaminopyridine) (DIMAP) (3 mg, 0.02 mmol) and pyridine (0.068 ml, 0.84 mmol) in chloroform at room temperature. The resulting solution was heated under reflux for 3 hr, then cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue (960 mg) was purified by column chromatography on silica gel, eluting with 98:2 chloroform/methanol to yield the title compound as a solid (40.3 mg, 34% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].P(O)(O)([O-])=O.[Na+]>O.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:18])=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 86.4 %

Procedure:
2.3 g (15.7 mmol) of 1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde and 23 cm3 (217 mmol) of 2-methyl-2-butene were added to 120 cm3 of dioxane at a temperature of 20° C. and then a solution of 2.7 g (30 mmol) of sodium chlorite and 9.2 g (66.7 mmol) of monosodium phosphate in 100 cm3 of water was added. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of water, filtered off, rinsed with 3 times 30 cm3 of water and then dried under a hood for 16 h. 2.2 g of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were thus obtained in the form of a white powder. Mass spectrum: EI: m/z=162 M+ base peak.
Reaction SMILES: [Mg].[CH2:2](Cl)[CH:3]=[CH:4][CH3:5].ClC(C)C=C.[CH:12](=[O:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:12]([OH:18])[CH:4]([CH3:5])[CH:3]=[CH2:2]
Reactant: O=Cc1ccco1
Reactant: CC=CCCl
Agent: C=CC(C)Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)C(O)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Magnesium (36 g, 1.5 mole) and tetrahydrofuran (THF) (300 ml) were added to a reactor, and a solution of crotyl chloride or 3-chloro-1-butene (118 g, 1.8 mole) in THF (100 ml) was added dropwise at 30° to 35° C. to prepare a Grignard reagent. Thereafter, to this THF solution of the Grignard reagent was added dropwise a solution of furfural (106 g, 1.1 mole) in THF (150 ml) at 20° to 30° C. over about 1 hour, followed by stirring at room temperature for further 2 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution (about 500 ml), followed by extraction with ether. The ether extract was washed with water, dried and concentrated, and the residue obtained was distilled under reduced pressure to obtain 150 g (yield, 90%) of pure 1-(2-furyl)-2-methyl-3-buten-1-ol having a boiling point of 95°-107° C./25 mmHg.
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[O:9][CH2:8]1.O>C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]2[CH:7]=[CH:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)OCC2O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2ccoc2c1
Reaction time: 3 h

Procedure:
Sulfuric acid (0.2 ml) and 10.0 g of 3-hydroxy-6-methyl-2,3-dihydrobenzofuran were dissolved in 200 ml of benzene and heated at reflux with the azeotropic removal of water. After 3 hours, the reaction mixture was added to water (500 ml) and extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium bicarbonate, dried with sodium sulfate and the solvent evaporated to give 6-methylbenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1C=C2N(C3C=CC=CC=3Cl)CC3(CCN(C)CC3)C2=CC=1.Cl[C:56]([O:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:57].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:56]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:57])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].Br[C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C)C=O>[Cl:21][C:19]1[CH:20]=[C:15]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:16]([C:22]#[N:23])=[N:17][CH:18]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ncc(Cl)cc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A pressure vessel was charged with triethylamine (7.65 mL, 55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I) iodide (0.263 g, 1.380 mmol), palladium (0) tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol), 3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and N,N-dimethylformamide (50 ml). The vessel was flushed with argon, sealed, stirred at ambient temperature for 15 minutes, and then heated at 50° C. for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica-gel chromatography, eluting 0-50% ethyl acetate in hexane, to afford the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:15][CH2:11][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)sc2ccccc12
Solvent: c1ccccc1
Product: Cc1c(CCl)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
To an ice-cold solution of 3-methylbenzothiophene-2-methanol [Reference example 1] (480 mg, 2.69 mmol) in benzene (10 mL) was added dropwise, a solution of thionyl chloride (0.24 mL, 3.2 mmol) in benzene (3.5 mL). The mixture was stirred at room temperature for 3 hour, and concentrated under reduced pressure to give 2-chloromethyl-3-methylbenzothiophene as a yellow oil (548 mg, yield>99%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46]C(=O)C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[OH:46])[N:29]2[N:28]=1
Reactant: CC(=O)Oc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc(-c3ccccc3O)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
Into a 8-dram vial, Palladium Acetate (0.050 g, 0.022 mol) and Triphenylphosphine (0.16 g, 0.063 mmol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (17.1 mL,) was added and stirred for 10 minutes at room temperature. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.550 g, 2.25 mmol), Acetic acid 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl ester (1.18 g, 4.51 mmol), N,N-Dimethylformamide (34 mL), and 1.50 M of Sodium carbonate in Water (13.5 mL, 0.0203 mol) were added. The reaction was heated at 90° C. for 18 hours. The reaction was partitioned with water and stirred at room temperature for 2 hours. The solid was filtered and washed with water. The resulting yellow solid was dried under vacuum to give 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.53 g, 92%).
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]=1.B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH2:32]([O:31][CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][C:8]3[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)[CH2:33][CH3:34]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
In toluene (100 ml), ethanol (10 ml) and water (10 ml) were suspended methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (3.0 g), 4-propoxyethoxyphenyl borate (3.1 g) and potassium carbonate (3.8 g), and the suspension was stirred for 30 minutes under argon atmosphere. Then, to the suspension was added tetrakistriphenylphosphinepalladium (860 mg), and the mixture was heated at 100° C. for 8 hours under argon atmosphere. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give the solid, which was washed with hexane to give methyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (2.59 g) as yellow crystals.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.ClCCC1C2C(=CC=CC=2)C(C)CO1.C[C@H]1CNC[C@@H](C)N1>>[C@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: NS(=O)(=O)c1ccc(N2CCCNCC2)cc1
Reactant: OCCC1OCCc2ccccc21
Agent: CC1COC(CCCl)c2ccccc21
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure for EXAMPLE 48 and making non-critical variations (-)-2-(isochroman-1-yl)ethanol (LXXIX) and 4-(homopiperazin-1-yl)benzenesulfonamide (IV; prepared from 4-fluorobenzenesulfonamide (III) and homopiperazine (II, Aldrich) by the method of EXAMPLE 47 Step 1) give the title compound, MS (m/z) 415; [α]D -50° (c 0.9996, methylene chloride); IR (mineral oil) 1153, 1595, 1102, 1511 and 1316 cm-1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: ClCc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4ccccn4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 2-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A5 pure as a yellow solid (27 mg, 47%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.51 (m, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H), 7.60 (t, 1H), 7.36 (m, 1H), 7.13 (t, 1H), 5.40 (m, 1H), 3.65 (m, 2H), 3.07 (s, 3H), 2.72 (m, 2H), 2.45 (m, 2H), 2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 484.5 (M+H+, 100%).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]>>[Br:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: BrCCCCCBr
Reactant: CCC1C(=O)Nc2ccccc21
Product: CCC1(CCCCCBr)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.