Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.CC(C)([O-])C.[K+].[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][C:26]=1[O:33][CH:34]([F:36])[F:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(O)(C)(C)C>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[CH:27][C:26]=1[O:33][CH:34]([F:35])[F:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Reactant: FC(F)Oc1cc(CCl)ccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OC(F)F)c2)n1

Procedure:
In analogy to the method described in example A5, 3.8 g (22.7 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 2.8 g (25 mmol) of potassium tert-butoxide and 6.8 g (22.7 mmol) of 4-benzyloxy-3-(1,1-difluoromethoxy)benzyl chloride are reacted in 15 ml of tert-butanol and 15 ml of toluene and the product is worked up. After chromatography on silica gel (mobile phase: toluene/dioxane=5:1), the title compound is obtained as a viscous, colorless oil. 1H NMR spectrum (CDCl3, δ ppm): 7.5-7.3 (m, 5H), 7.19 (m, 1H), 7.12 (dd, 1H), 6.58 (t, 1H, J=80 Hz), 5.58 (tb, NH), 5.13 (s, 2H), 4.63 (d, 2H), 2.51 (s, 3H), 2.43 (s, 3H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[O:18][CH2:19][CH3:20])(=O)=O.[I-:23].[Na+].CCOC(C)=O>CS(C)=O>[CH2:19]([O:18][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[I:23])[CH:16]=[O:17])[CH3:20]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1I
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-ethoxy-4-formyl-6-nitrophenyl trifluoromethanesulfonate (4.7 g, 13.7 mmol) in DMSO (10 mL) was added sodium iodide (6.2 g, 41.1 mmol). The mixture was stirred under N2 atmosphere at 3˜10° C. overnight. EtOAc/aqueous workup. Purified by silica gel column chromatography (PE:EtOAc=50:1 to PE:EtOAc=10:1) (4.0 g, yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C@H:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:18]([CH3:20])[NH2:19])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[CH3:20][C@H:18]([NH:19][C:39]([C:35]1[O:34][CH:38]=[CH:37][CH:36]=1)=[O:40])[C@@H:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[N:8]=[CH:9]2
Reactant: O=C(Cl)c1ccco1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
(αS,βR)-β{[1-(4-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (64.3 mg, 0.19 mmol) is dissolved in 7.1 mL of dichloromethane. Triethylamine (0.062 mL, 0.45 mmol) and 2-furoylchloride (24.3 mg, 0.19 mmol) are added. After 4 h stirring at r.t. the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. The reaction mixture is filtered, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 53.7 mg (65.6%) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]([Cu])#[N:16].O>CN1CCCC1=O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:15]#[N:16])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Yield: 88.1 %

Procedure:
A solution of 3-bromo-9H-carbazole (123.4 mg, 0.50 mmol) and CuCN (49.9 mg, 0.56 mmol) in N-methyl-pyrrolidone (2 mL) was heated at 200° C. for 5 h. The cooled reaction mixture was poured into water and the precipitate was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the product as a white solid (84.7 mg, 88%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([Br:25])[CH:31]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc3c(c2)OCO3)cc(OS(=O)(=O)C(F)(F)F)n1
Product: Cc1cc(-c2ccc3c(c2)OCO3)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-benzo[1,3]dioxol-5-yl-6-methyl-pyridin-2-yl ester (example A.56) (1.1 g, 3.04 mmol) and commercially available 3-bromobenzeneboronic acid (0.611 g, 3.04 mmol) according to the general procedure IVb. Obtained as a colorless gum (0.44 g, 39%). MS (ISP) 368.0 [(M+H)+] and 370.0 [(M+2+H)+].
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc2c1CCC2O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c1CCC2Cl

Procedure:
In 6 ml. of chloroform is dissolved 5.7 g. of methyl 1-hydroxyindan-4-carboxylate and, under cooling with ice, the solution is stirred. Then, 3 ml. of thionyl chloride is added dropwise and, after the dropwise addition has been completed, the mixture is further stirred under cooling with ice for one hour. Then, the solvent and the excess thionyl chloride are distilled off under reduced pressure. The residue obtained is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The procedure gives methyl 1-chloroindan-4-carboxylate as an oily product.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccccc1OCc1ccccc1
Yield: 85.5 %

Procedure:
A mixture of benzylchloride (8.8 g), 4-(2-hydroxy phenyl)-but-3-en-2-one (11.4 g) and anhydrous potassium carbonate (11.0 g) in methyl ethyl ketone (100 ml) was stirred and heated under reflux for 5 hours. The mixture was poured into water (300 ml) and extracted with chloroform (200 ml). The chloroform extracts were washed with dilute sodium hydroxide solution and then dried over magnesium sulphate and evaporated to give 4-(2-benzyloxyphenyl)-but-3-en-2-one (15 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29](=O)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 76.8 %

Procedure:
Prepared from [2-amino-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G35) (172 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as an orange oil (198 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[H-].[Na+].CS(O[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]([N:33]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([CH:51]5[CH2:53][CH2:52]5)=[CH:47][CH:46]=4)=[C:39]([O:54][CH3:55])[CH:38]=3)[CH2:34]2)=[O:32])[CH:26]=1)(=O)=O.O>CN(C=O)C>[CH:51]1([C:48]2[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:40]3[CH:41]=[CH:42][C:37]([CH:35]4[CH2:34][N:33]([C:31]([C:27]5[CH:26]=[C:25]([CH2:24][O:16][CH2:15][C:3]6([CH2:2][OH:1])[CH2:4][O:5][CH:6]([C:9]7[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=7)[O:7][CH2:8]6)[CH:30]=[CH:29][N:28]=5)=[O:32])[CH2:36]4)=[CH:38][C:39]=3[O:54][CH3:55])=[CH:46][CH:47]=2)[CH2:53][CH2:52]1
Reactant: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Reactant: OCC1(CO)COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2CN(C(=O)c3cc(COCC4(CO)COC(c5ccccc5)OC4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-hydroxymethyl-2-phenyl-[1,3]dioxan-5-yl)methanol (0.66 g) in DMF (10 mL) was added NaH (0.12 g). The mixture was stirred at RT for 1 hr. To the mixture was added 2-{3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-ylmethyl methanesulfonate (0.7 g) prepared in Example 1 (7). The reaction mixture was stirred at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:21][CH2:20][C:6]1=2
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a stirred solution of 2-(1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol (300 mg, 0.977 mmol) and triethyl amine (0.18 mL, 1.27 mmol) in DCM (6 mL) was added ethyl chloroformate (138 mg, 1.27 mmol), and the reaction mixture stirred at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH-DCM) to yield ethyl 3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (170 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.4 (d, 2H), 7.21 (m, 4H), 7.0 (d, 1H), 5.03 (t, 1H), 4.6 (m, 2H), 4.21 (m, 4H), 3.78 (m, 2H), 3.6 (m, 1H), 2.75 (m, 1H), 2.4 (s, 3H), 1.28 (t, 3H). Separation by chiral HPLC provides enantiomers 72a and 72b.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole following the procedure set out in Example 1, substituting tetrakis triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2) Rt 3.27 [M+H]+ 478.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([O-:15])=[O:14])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C([O-])C1=Cc2ccccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
Into a solution of methyl 7-[3,4-dipropoxy]benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) in THF-methanol (5-2.5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.0 ml), and the resulting mixture was stirred at 65° C. for 24 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(3,4-dipropoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (306 mg) as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C:36]([C:32]1[CH:31]=[C:30]2[C:35](=[CH:34][CH:33]=1)[CH:27]([NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:9]3[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:1]=1)(=[O:13])=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][CH2:29]2)#[N:37]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: N#Cc1ccc2c(c1)CCC2N
Product: N#Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid [Example 1, Step F] and 1-amino-indan-5-carbonitrile (Step E), using essentially the same procedure described in Example 1, Step F, yielding a white solid. MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.C([BH3-])#N.[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=O.CC(O)=O>CN(C=O)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:37])([F:38])[F:39])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(OC(F)(F)F)c(Br)c4)CC3)OC2=O)cc1
Yield: 66.2 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (300 mg, 0.918 mmol; Example 1, Step 2), MP-cyanoborohydride (1192 mg, 2.75 mmol), 3-bromo-4-trifluoromethoxybenzaldehyde (272 mg, 1.01 mmol) and AcOH (79 μl, 1.38 mmol) was added 5 mL of DMF. The reaction mixture was filtered, the resin was washed with DMF and the solvent was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were evaporated to yield the title compound as a light yellow solid (330 mg) that was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[C:14]2[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)C#CCCC/C=C/c1ccc(Cl)cc1
Solvent: ClCCCl
Product: CC(=O)c1c2c(cc3ccc(Cl)cc13)CCC2
Temperature: 180 °C
Reaction time: 3.33 h

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added enyne 5b (0.028 g, 0.12 mmol) in DCE (2.1 mL). The reaction was irradiated with stirring at 180° C. for 200 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6b as a brown oil (0.027 g, quant.).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:43]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=5[O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:39]([O:38][C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:35])[F:37])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:43]=2)[CH:27]=[CH:26][CH:25]=1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
[8-(2-Isobutoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-[8-(2-isobutoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.263 g, 0.442 mmol) and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.190 g, 87%). MP=102-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 7.35 (m, 3H), 7.05 (t, 1H), 6.98 (d, 1H), 3.87 (d, 2H), 2.62-2.75 (br m, 9H), 1.85 (m, 1H), 0.81 (d, 6H). MS=496 (MH)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([C:16]#[N:17])=[N:5]1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][C@H:2]([OH:1])[CH3:18])[N:5]=[C:6]2[C:16]#[N:17]
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A solution of (R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (0.76 g, 2.93 mmol) in EtOH (10 ml) was added to a suspension of iron (powder) (1.310 g, 23.46 mmol) and ammonium chloride (1.569 g, 29.3 mmol) in water (10 ml). The reaction mixture was heated in a microwave reactor at 80° C. for 15 min. The reaction vial was cooled to rt and the reaction mixture was filtered through celite, rinsing with EtOH, water, EtOH again, and then EtOAc. The filtrates were combined and diluted with EtOAc. The organic layer was washed with saturated aq. NaHCO3 solution, water, then brine, then dried over MgSO4, filtered, and evaporated to dryness. (R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (470 mg) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:11]([S:18][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: SCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 59.4 %

Procedure:
35.8 g (200 millimoles) of 4,5-dichloro-2-methylpyridazin-3(2H)-one are suspended in 300 ml of isopropanol and the suspension is colled to -20° C. A solution of 24.8 g (200 millimoles) of benzyl mercaptan and 20.2 g (200 millimoles) of triethylamine in 200 ml of isopropanol is added dropwise at this temperature, after which stirring is continued for 1 hour at -10° C. and overnight at room temperature. The resulting precipitate is filtered off under suction, washed with isopropanol and water and dried under reduced pressure to give 31.7 g (60%) of a product of melting point 102°-104° C.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([OH:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(C(C)=O)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
Ethyl 5-acetylsalicylate (211 mg), 4-chloro-6,7-dimethoxyquinoline (111 mg), and 4-dimethylaminopyridine (183 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (19 mg, yield 5%).