Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C@H:26]([OH:28])[CH3:27])[CH:24]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([CH2:25][C@H:26]([OH:28])[CH3:27])[CH:24]=4)[N:18]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2cccn3nc(I)nc23)cc1
Reactant: C[C@@H](O)Cn1cc(N)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(-c2cccn3nc(Nc4cnn(C[C@@H](C)O)c4)nc23)cc1
Temperature: 170 °C
Yield: 76 %

Procedure:
A suspension of 2-iodo-8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (53.6 mg, 0.153 mmol, 1 equiv), (R)-1-(4-amino-1H-pyrazol-1-yl)propan-2-ol (27 mg, 0.19 mmol, 1.2 equiv), sodium tert-butoxide (43.1 mg, 0.448 mmol, 2.94 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.2 mg, 0.0263 mmol, 0.172 equiv) and tris(dibenzylideneacetone)dipalladium (0) (10.5 mg, 0.0115 mmol, 0.0751 equiv) in dioxane (2 mL) was heated at 170° C. in the microwave for 15 min. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (5 mL) and ethyl acetate (5 mL). The organic was separated, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (5% methanol in dichloromethane) afforded product as a white solid (42.4 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.32 (s, 1 H, NH), 8.64 (dd, J=6.6, 0.9 Hz, 1 H), 8.13 (dd, J=8.8 Hz, 2 H), 7.81 (s, 1 H), 7.74 (dd, J=7.5, 0.9 Hz, 1 H), 7.47 (s, 1 H), 7.08 (d, J=8.9 Hz, 2 H), 7.03 (t, J=7.0 Hz, 1 H), 4.92 (d, J=4.7 Hz, 1 H, OH), 3.96 (m, 3 H), 3.83 (s, 3 H), 1.04 (d, J=5.8 Hz, 3 H).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[C:14]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=[CH:16][C:17]([C:20]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH:1]=[CH:2][CH:3]=[C:4]3[CH2:13]2)=[O:21])=[CH:18][CH:19]=1
Reactant: c1ccc2c(c1)NCc1cccn1-2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a mixture of 0.5 g of 4,5-dihydropyrrolo[1,2-a]quinoxaline and 0.96 g of 4-biphenylcarbonyl chloride in 50 ml of methylene chloride under argon is added 7.0 ml of triethylamine followed by stirring at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with water, 2N HCl, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 0.87 g of the desired product as a solid. M+H 351.2; M+Na 373.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C@H:16]3[C@@:25]45[CH2:35][CH2:36][C@:22]6([CH2:23][C@@H:24]4[C@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[O:28][CH2:27][O:26]5)[C@@:17]43[CH2:18][CH2:19][N:20]([CH2:38][CH:39]3C[CH2:40]3)[C@@H:21]6[CH2:37][C:12]([C:13]=24)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CC[C@@]23C4C5C[C@@H]1[C@]12CC[C@]2(OCO[C@@](C(C)(C)C)(C)[C@H]2C1)[C@@H]3OC=4C(O)=CC=5)C=C>>[CH2:38]([N:20]1[CH2:19][CH2:18][C@@:17]23[C:13]4[C:12]5[CH2:37][C@@H:21]1[C@:22]12[CH2:36][CH2:35][C@:25]2([O:26][CH2:27][O:28][C@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[C@H:24]2[CH2:23]1)[C@@H:16]3[O:15][C:14]=4[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][CH:11]=5)[CH:39]=[CH2:40]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Agent: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@]24CC[C@]3(C[C@@H]2[C@@](C)(C(C)(C)C)OCO4)[C@H]1C5
Product: C=CCN1CC[C@]23c4c5ccc(OCc6ccccc6)c4O[C@H]2[C@@]24CC[C@]3(C[C@@H]2[C@@](C)(C(C)(C)C)OCO4)[C@H]1C5
Yield: 98 %

Procedure:
The title compound 19 was synthesized similar to the procedure described in Example 5 for preparing compound 7 using compound 17 rather than 3. After column chromatography, 590 mg (98% yield) of compound 19 was isolated in a purity of 97.7% as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:23]=2)[CH2:21][CH2:20]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:29](=[O:30])[CH2:28][C:27]2[C:22]([CH:19]3[CH2:20][CH2:21]3)=[N:23][C:24]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=3)=[N:25][CH:26]=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 84A] ) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[4-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:29](=[O:31])[NH2:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:32].CCOCC>C(OCC)(=O)C>[ClH:32].[NH2:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:29](=[O:31])[NH2:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 0.33 h

Procedure:
To 0.44 g of benzyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (7, n = 2, X1 = L-valyl) at 22° C there is added 5 ml of a saturated solution of hydrogen chloride in ethyl acetate. After 20 minutes, 40 ml of ether is added and the precipitated salt is collected by centrifugation and carefully dried in vacuo to give benzyl L-valyl-D-isoglutaminate hydrochloride (10, n = 2, X1 = L-valyl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>>[CH:31]([N:25]1[CH2:26][CH2:27][C@H:28]([OH:30])[CH2:29][C@@H:24]1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C=O)c(OCc2ccccc2)c1
Yield: 68.2 %

Procedure:
Using the procedure of Example 14, Part A, 1.81 g (4.42 mmole) of cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol, 206 mg (4.48 mmole) of formic acid and 1.04 g (5.04 mmole) of dicyclohexylcarbodiimide gives 1.32 g (70%) of the corresponding formamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:24]([C:30]1[CH:36]=[CH:35][C:33]([OH:34])=[CH:32][C:31]=1[OH:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl>C1(C)C(C)=CC=CC=1>[OH:34][C:33]1[CH:32]=[C:31]([OH:37])[C:30]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][C:35]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CCCCCCc1ccc(O)cc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Temperature: 80 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 21.4 g (80 mmol) of 2-chloro-4,6-diphenyl-s-triazine, and 100 mL of xylene (mixture of isomers). To the beige suspension are added 11.3 g (85 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 80° C. for 45 minutes. 18.8 g (96 mmol) of 4-hexylresorcinol are then added in five portions over 40 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 24 hours. After cooling to room temperature, the contents of the flask are poured into 100 mL of 12% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The title compound is obtained as a crude orange product (29.2 g) and melts at 209°-213° C. It can be used without further purification.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])([OH:6])=O.[C:15]1([C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]O1)=[O:16]>C(OCC)(=O)C>[CH:20]1[C:19]2[C:18]3[C:9](=[O:10])[C:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=4[C:4]=3[O:6][C:15](=[O:16])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1OCc2ccccc21
Reactant: O=Cc1ccccc1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Temperature: 65 °C
Yield: 85.5 %

Procedure:
Sodium methoxide (40 mL of a 4 M methanolic solution) was added to a solution of 2-carboxybenzaldehyde 1d (1.000 g, 7.455 mmol) and phthalide 2d (1.119 g, 7.455 mmol) in ethyl acetate (20 mL). The solution was heated at 65° C. for 18 h, concentrated, and acidified with coned HCl. The resulting mixture was diluted with benzene (125 mL), TsOH (100 mg) was added, and the solution was heated for 7 h at reflux in a flask affixed with a Dean-Stark trap. The solution was cooled to room temperature, concentrated, diluted with CHCl3 (150 mL), and washed with sat NaHCO3 (3×50 mL) and sat NaCl (50 mL). The organic layer was dried over sodium sulfate and concentrated to provide indenobenzopyran 4d as an orange solid (1.583 g, 86%): mp 258-259° C. (published mp 257° C.). 1H NMR (CDCl3) δ 8.40 (d, J=8.56 Hz, 1H), 8.32 (d, J=7.93 Hz, 1H), 7.84-7.79 (m, 1H), 7.61-7.39 (m, 5H). Additional details regarding the synthesis of compound 8 are found in Pailer et al., Monatsh Chem., 92:1037-47 (1961), the synthetic disclosure of which is incorporated herein by reference.
Reaction SMILES: C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[C:22]1([C:28]2[N:29]=[CH:30][N:31]([C:33]3[C:38]([C:39]([OH:41])=O)=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[NH2:43][CH:44]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH:45]([OH:49])[C:46]([NH2:48])=[O:47].C([O-])(O)=O.[Na+]>ClCCl.CCN(CC)CC>[NH2:48][C:46](=[O:47])[CH:45]([OH:49])[CH:44]([NH:43][C:39]([C:38]1[C:33]([N:31]2[CH:32]=[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:29]=[CH:30]2)=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:41])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)c1cccnc1-n1cnc(-c2ccccc2)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cnc(-c2ccccc2)c1
Temperature: 2 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
0.75 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 0.51 g of hydroxylbenzotriazole (HOBt) and 0.55 ml of triethylamine (Et3N) were successively added to a solution of 1.0 g of 2-(4-phenyl-1H-imidazol-1-yl)pyridine-3-carboxylic acid (3.77 mmol) in 50 ml of dichloromethane at 0-4° C., and the mixture was stirred at 0-4° C. for 1 hour. 0.9 g of 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (3.9 mmol) and 0.55 ml of Et3N were then added and, after about 5 minutes, a pH of 8-9 was adjusted by adding 0.5 ml of Et3N. The mixture was stirred at 0-4° C. for 1 hour and then at room temperature overnight. 50 ml of saturated NaHCO3 solution were then added to the mixture, and the organic phase was separated off. Drying and evaporating the solvent resulted in 620 mg of a reddish oil, which was reacted further immediately without further purification.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:7](=[O:15])[CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][C:11]=1O.C(Cl)(=O)C([Cl:19])=O>>[Cl:19][C:11]1[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7](=[O:15])[C:6]=1[CH:2]1[CH2:3][CH2:4][CH2:5][S:1]1
Reactant: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Reactant: O=C(Cl)C(=O)Cl
Product: CC1(C)CC(=O)C(C2CCCS2)=C(Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3 parts of 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one was added to 9.9 parts of oxalic chloride, the mixture was stirred at room temperature for 1.5 hours and concentrated at a temperature below 50° C. The residue was dissolved in 40 parts by volume of benzene and 1.0 part of pyrolidine was added thereto. After stirring at room temperature for 1 hour, the mixture was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, in the order listed, and then dried. Benzene was distilled off and the residue was passed through a column containing silica gel using a solvent mixture of chloroform and benzene (2:1) as a spreading agent to obtain 1.1 parts of 3-chloro-2-(2-tetrahydrothienyl)-5,5-dimethyl-2-cyclohexen-1-one as a brown colored oily product.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:20]([Cl:26])=[CH:21][N:22]=[CH:23][C:24]=3[Cl:25])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccc1
Yield: 65 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.10 g) obtained in Example 9 and benzylamine to give Compound 25 (0.08 g, 65%) as a white solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1>O>[CH2:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][CH2:41][N:32]1[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1)c1ccncc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Isonicotinoyl chloride hydrochloride (390 mg, 2.19 mmol, commercially available product) and triethylamine (449 μl, 3.24 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-[2-amino-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline (315 mg, 1.08 mmol), obtained as described in Referential Example 21-2. The resulting mixture was warmed to room temperature and stirred for half an hour. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=2/1). Thus, N-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0621) (418 mg, 97.6%) was yielded as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15]([OH:16])=[CH:14][C:13]([F:17])=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])=O)[CH2:3][CH2:2]1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:1]1([C:4]2[O:16][C:15]3[C:7](=[C:8]([C:9]([O:11][CH3:19])=[O:10])[CH:12]=[C:13]([F:17])[CH:14]=3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])c1cc(F)cc(O)c1NC(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc2oc(C3CC3)nc12
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 2-(cyclopropanecarboxamido)-5-fluoro-3-hydroxybenzoate from Step D (180 mg, 0.71 mmol), p-toluenesulfonic acid monohydrate (202 mg, 1.07 mmol) and toluene (5 mL) was heated at reflux under nitrogen for 3 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, washed with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by Combi-flash chromatography (silica gel, 60:40 hexanes/ethyl acetate) to afford methyl 2-cyclopropyl-6-fluorobenzoxazole-4-carboxylate (115 mg, 69%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, J=10.2, 2.4 Hz, 1H), 7.34 (dd, J=7.5, 2.4 Hz, 1H), 4.02 (s, 3H), 2.39-2.29 (m, 1H), 1.35-1.29 (m, 2H), 1.26-1.17 (m, 2H); 19F NMR (282 MHz, CDCl3) δ −116.29; MS (ESI+) m/z 236 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ncsc1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ncsc1CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-(4-Methyl-5-thiazolyl)ethanol (25.71 g) was dissolved in tetrahydrofuran (200 ml), followed by the addition of 60% sodium hydride (7.185 g) under ice-cooling. The resulting mixture was stirred at room temperature for 1 hr. Thereafter, the it was ice-cooled again, followed by the addition of benzyl bromide (21.4 ml) and tetrabutylammonium bromide (665 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (39.059 g, yield; 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
A solution of 3,4,5-trimethoxyaniline (500 mg, 2.8 mmol) in pyridine (5 mL) was treated with 4-methoxybenzenesulfonyl chloride (564 mg, 2.8 mmol) in THF (5 mL), stirred at room temperature for 18 hours, concentrated, redissolved in THF (1 mL), treated with water with stirring, and filtered to provide 820 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:13][C:14]([NH:16][CH3:17])=O)=[CH:6][NH:7]2.B>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][NH:16][CH3:17])=[CH:6][NH:7]2
Reactant: CNC(=O)CC(c1ccncc1)c1c[nH]c2cccc(OC)c12
Agent: B
Product: CNCCC(c1ccncc1)c1c[nH]c2cccc(OC)c12

Procedure:
3-(4-methoxy-1H-indol-3-yl)-N-methyl-3-pyridin-4-yl-propionamide was reduced with borane using the procedure described in step 3 of Example 1 to afford [3-(4-methoxy-1H-indol-3-yl)-3-pyridin-4-yl-propyl]-methyl-amine, (M+H=296).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc2ccccc2n1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccc2ccccc2n1)NO
Reaction time: 48 h
Yield: 76 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (90 mg, 0.24 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 48 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4) to furnish IV as a colourless oil (66.43 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1Br.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:13]
Reactant: COC(=O)c1cc(C#N)ccc1Br
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 50.8 %

Procedure:
A mixture of 2-bromo-5-cyano-benzoic acid methyl ester (which may be prepared as described for Intermediate 2; 17.4 g, 72.6 mmol), 2-nitrophenylboronic acid (available from Aldrich Chemical Company, Inc.; 13.2 g, 79.9 mmol), Pd(dppf)Cl2 (available from Aldrich Chemical Company, Inc.; 7 g, 8.7 mmol) and K2CO3 (29.9 g, 218 mmol) in a mixture of water (26.5 mL) and dioxane (530 mL) was heated at reflux for 3.5 h. The reaction mixture was cooled and evaporated to dryness. The residue was co-evaporated with toluene, and then purified by silica gel chromatography, using 20-33% ethyl acetate/petroleum ether as eluent, to give 4-cyano-2′-nitro-biphenyl-2-carboxylic acid methyl ester (10.4 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J=1.7 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.71-7.57 (m, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.30-7.22 (m, 1H), 3.71 (s, 3H).