Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CCOc1cc2ncc(Cl)nc2cc1OCC
Product: CCOc1cc2ncc(NCc3ccccc3)nc2cc1OCC
Yield: 87.6 %

Procedure:
To 0.3 g (1.19 mmol) of 2-chloro-6,7-diethoxyquinoxaline is added 2 mL of benzylamine. This mixture is heated under nitrogen overnight to 120° C. The resulting mixture is partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic layer is concentrated, and the residue chromatographed (30:1 CH2Cl2; EtOH) to provide 0.337 g of the product as a yellow solid in 87.6% yield (m.p. 136° C.). Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.54; N, 12.99. Found: C, 70.54; H, 6.66; N, 12.80.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:3]([NH2:5])=[O:4].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[NH2:5][C:3](=[O:4])[C@@H:2]([NH:1][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
(S)-2-Amino-3-(6-bromopyridin-3-yl)propanamide (1 g), (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.939 g) and triethylamine (2.86 mL) in DMF (3 mL) were stirred under nitrogen at 0° C. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosorinan-2,4,6-trioxide (3.13 g) was added and stirring at 0° C. was continued for 1 h. The reaction mixture was allowed to reach RT then it was diluted with ethyl acetate, washed with water and brine sequentially, dried over magnesium sulfate, filtered and concentrated in vacuo to give the sub-title compound (1.740 g).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:23][C:22]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][CH3:19])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: COc1cccc(C)c1N
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2OC)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-methoxy-6-methyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 8.71 (br, 1H), 7.71 (br, 1H), 7.35-6.80 (5H), 6.39 (br, 1H), 3.92 (br, 2H), 3.83 (br, 3H), 3.74 (br, 3H), 2.94 (t, 2H) and 2.14 (br, 3H); MS (ESI) (M+H)+ 364.
Reaction SMILES: IC.[F:3][C:4]1[C:12]([F:13])=[C:11](O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:15](=O)([O-])[O-].[Li+].[Li+].CN(C)[CH:23]=[O:24]>O>[F:3][C:4]1[C:12]([F:13])=[C:11]([O:24][CH3:23])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)c(F)c1F
Agent: [Li+]
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(F)c1F
Temperature: 40 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
Iodomethane (10.7 mL, 172.5 mmol) was added into a mixture of 2,3-difluoro-4-hydroxybenzoic acid (10.0 g, 57.5 mmol), lithium carbonate (12.7 g, 172.5 mmol) and N,N-dimethylformamide (100 mL). The mixture was stirred at 40° C. for 12 h, and then poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (10.2 g, 88% yield, m.p. 66–68° C.); MS m/e 203 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8]([Si:12]([CH3:32])([CH3:31])[O:13][Si:14]([CH:24]([CH2:27][CH:28]1[CH2:30][O:29]1)CC)([CH3:23])[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:11])([CH3:10])[CH3:9].[CH2:33]([OH:35])[CH3:34]>>[O:15]([Si:14]([O:13][Si:12]([C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:32])[CH3:31])([CH3:23])[CH2:24][CH2:27][CH2:28][O:29][CH2:30][CH:33]([OH:35])[CH2:34][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:17])[CH3:18]
Reactant: CCO
Reactant: NCCOCCO
Reactant: CCC(CC1CO1)[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[Si](C)(CCCOCC(O)CNCCOCCO)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
2-(2-Amino-ethoxy)-ethanol (2.50 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,5-Di(tert-butyl)-3-(oxiranylmethylpropyl)-1,1,3,5,5-Pentamethyltrisiloxane (2.0 g) mixed with ethanol (10 mL) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Reaction progress was monitored by NMR spectroscopy. Upon reaction completion, the ethanol was removed by rotary evaporation, and the mixture was distilled under vacuum to remove impurities and excess raw material.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.Cl.[F:35][C:36]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][CH2:39][N:38]5[CH2:32][CH2:31][C:36]([F:41])([F:35])[CH2:37]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: FC1(F)CCNC1
Reactant: ClCCBr
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCC(F)(F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and 3,3-difluoropyrrolidine hydrochloride following General Procedure G.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]([NH2:20])=[O:19].Cl.C(O)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:20][C:18](=[O:19])[N:17]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: O=C1CCCCC1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1nc(-c2ccc(F)cc2)c2c([nH]1)CCCC2
Yield: 61.8 %

Procedure:
A mixture of 2-(4-fluorobenzoyl)cyclohexanone (14 g), urea (7.6 g), conc. hydrochloric acid (8 ml) and ethanol (40 ml) is refluxed for 8 hours. After cooling, the reaction mixture is diluted with water and washed with methylene chloride. The aqueous layer is made alkaline with potassium carbonate, and the precipitated crystal is separated by filtration and recrystallized from N,N-dimethylformamide-ethanol to give the desired compound (9.6 g), m.p. 248°-253° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]([O-])([O-])=O.[K+].[K+].CN[C@H:14]1[C@H:19]([NH:20]C)[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN1C(=O)CCC1.[Cu]I.CCOC(C)=O>[CH3:6][C:14]1[CH:15]=[C:16]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:17]=[CH:18][C:19]=1[NH2:20]
Reactant: O=C([O-])[O-]
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(-n2cccn2)ccc1N
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of intermediate 82 (200 mg, 0.7 mmol), 1H-pyrazole (95 mg, 2 eq), CuI (133 mg, 1 eq), K2CO3 (290 mg, 2.1 eq) and (1R,2R)-diaminomethylcyclohexane (100 mg, 1 eq) in anh. NMP (1 mL), under N2, was heated at 150° C. for 6 hr. It was cooled down to r.t. and poured into water. EtOAc was added and the phases were separated. The aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The residue was purified by flash-chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound as a white solid (85.6 mg, 70%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11]>C1C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH:11][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(Br)c1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
84 g of diketene were added over 20 minutes to a mixture of 172 g of m-bromo-aniline and 600 ml of benzene and the mixture was stirred for 5 hours at 20° C. The mixture was filtered and the precipitate was washed with benzene and isopropyl ether. The filtrate was vacuum filtered and evaporated to dryness to obtain 189 g of m-bromo-acetylacetanilide melting at 110° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:23])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10]>CS(C)=O.O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:23])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Reaction time: 0.67 h
Yield: 26.8 %

Procedure:
Trimethylsulfoxonium iodide (14.15 g, 63 mmol) is suspended in dry DMSO (126 mL) and Sodium hydride (60% in mineral oil, 2.52 g, 63 mmol) is added. The mixture is stirred for 40 minutes and then a solution of 4-methoxycinnamic acid ethyl ester (5 g, 24.2 mmol) in dry DMSO (64 mL) is added and the mixture stirred for 3 hours at room temperature. The mixture is diluted with water and extracted with ethyl acetate, the organic phase is dried by passing through a phase seperator and the solvent is removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (yield 1.43 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[O:6]1[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.CN(C)[CH:16]=[O:17]>ClCCl.C(OCC)(=O)C>[Cl:3][C:10]1=[C:9]([CH:16]=[O:17])[CH2:8][CH2:7][O:6][CH2:12][CH2:11]1
Reactant: O=C1CCCOCC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC1=C(Cl)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (3.45 mL) was added dropwise to a cooled (0° C.) solution of EXAMPLE 314A (4.2 g) in N,N-dimethylformamide (12 mL) and dichloromethane (30 mL). The mixture was then stirred at room temperature overnight before it was diluted with ethyl acetate (300 mL) and washed with aqueous sodium acetate, water (3×), brine and dried over Na2SO4. After filtration and concentration, the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH:18]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:19]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:20][CH2:21][C:22](=O)[OH:23].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:18]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:19]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:20][CH2:21][C:22]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:23]
Reactant: CCCC[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The resulting H-Nle-OBzl.HCl was dissolved in methylene chloride (30 mL) and the resulting reaction solution was maintained at 0° C. To the reaction solution, Z-Glu-OBzl (N-α-carbobenzoxy-L-glutamic acid α-benzyl ester, 0.70 g, 1.90 mM), triethylamine (0.29 mL, 1.1 eq., 2.10 mM), HOBt.H2O (1-hydroxybenzotriazole hydrate, 0.32 g, 1.1 eq., 2.10 mM), and WSC.HCl (0.41 g, 1.1 eq., 2.10 mM) was added. The temperature of the reaction solution was gradually raised and stirred at room temperature overnight (16 hours). Then, the reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was added to the resulting residue, and the organic phase was then washed once with water (30 mL), twice with a 5% aqueous solution of citric acid (30 mL), once with a saturated common salt solution (30 mL), twice with a 5% aqueous solution of sodium hydrogen carbonate (30 mL) and once with a saturated common salt solution (30 mL). Then, the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed through filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate and n-hexane, the crystals thus obtained were collected through filtration and dried under reduced pressure to give crystals of Z-Glu(Nle-OBzl)-OBzl (0.91 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:35]>C1COCC1.C(OCC)C>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)c3ccccc23)cc1

Procedure:
1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL) and treated with a 1N solution of HCl in diethyl ether (30 mL) for twelve hours. The product was collected as a pale pink solid. Yield 0.2 g (60%). mp 181° C. (dec); 1H NMR (DMSO-d6) δ 2.80 (s, 3 H), 3.1 (br, 4 H), 3.3 (br, 4 H), 7.00 (q, J=8.06 Hz, 2 H), 7.27 (ab, J=8.30 Hz, 2 H), 7.4–7.5 (m, 2 H), 7.53 (ab, J=8.30 Hz, 2 H), 7.99 (d, J=8.06 Hz, 1 H), 8.07 (d, J=7.57 Hz, 1 H), 9.2 (br, 2 H); MS (ESI+) for C21 H23 N3 O2 S Found m/z 381.1499 M+. Calc. 381.1611.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4](=[O:13])[CH2:3]1.[OH-].[CH2:15]([N+:22](C)(C)C)[C:16]1C=CC=C[CH:17]=1.C(#N)C=C.Cl>O.N1C=CC=CC=1>[C:15]([CH2:16][CH2:17][N:5]1[C:4](=[O:13])[CH2:3][CH:2]([CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6]1)#[N:22]
Reactant: CC1CC(=O)NCc2ccccc21
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C=CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC1CC(=O)N(CCC#N)Cc2ccccc21
Temperature: 80 °C

Procedure:
To a mixture of 6 g. (0.034 moles) of 5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one and 4 drops of Triton B (benzyltrimethylammonium hydroxide) in 10 ml. of pyridine, are added dropwise 2 g. (0.038 moles) of acrylonitrile dissolved in 2.5 ml. of pyridine. The reaction mixture is heated to 80° C. for 2 hours and then poured into iced water. It is acidified with hydrochloric acid to pH 4 and extracted with chloroform. The organic phase is washed neutral with water and then dried over anhydrous sodium sulfate. It is filtered and the solvent is evaporated off in vacuo. 8 g. (almost theoretical yield) of syrupy 2-(2-cyanoethyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH3:20][CH:21]([CH3:27])[C:22](=O)[CH2:23][C:24]#[N:25]>Cl.C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:24]([NH2:25])=[CH:23][C:22]([CH:21]([CH3:27])[CH3:20])=[N:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=N[O-]
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2ccc3[nH]ncc3c2)n1
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 1H-indazol-5-ylamine (8.0 g, 60.1 mmol) in concentrated HCl (20 mL, 240 mmol) was added an aqueous solution (50 mL) of NaNO2 (4.2 g, 60.1 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (27 g, 120 mmol) in conc HCl (30 mL) was then added at 0° C. The reaction was stirred for an additional 2 h at RT. A solution of 4-methyl-3-oxo-pentanenitrile (8.0 g, 1.1 eq) in ethanol (50 mL) was added and the resultant mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and was purified by silica gel chromatography to provide 2-(1H-indazol-5-yl)-5-isopropyl-2H-pyrazol-3-ylamine (8.5 g, 59% yield, two steps). 1H NMR (300 MHz, DMSO-d6) 8.09 (s, 1H), 7.82 (s, 1H), 7.57 (d, J=6.6 Hz, 1H), 7.51 (d, J=6.6 Hz, 1H), 5.31 (s, 1H), 5.12 (s, 2H), 2.74 (m, 1H), 1.15 (d, J=5.1 Hz, 6H); MS (ESI) m/z: 242.3 (M+H+).
Reaction SMILES: Br[CH:2]([CH2:26][CH2:27][Cl:28])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]([NH2:32])=[S:31].C(O)C>O>[NH2:32][C:30]1[S:31][C:2]([CH2:26][CH2:27][Cl:28])=[C:3]([C:5]2[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:7][CH:6]=2)[N:29]=1
Reactant: N#Cc1ccc(OCCCCCOc2ccc(C(=O)C(Br)CCCl)cc2)cc1
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(OCCCCCOc2ccc(-c3nc(N)sc3CCCl)cc2)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
16.9 g (36.3 mmol) of 4-{5-[4-(2-bromo-4-chlorobutyryl)phenoxy]pentyloxy}-benzonitrile compound (9) of Preparative Example 1-4 and 5.53 g (72.6 mmol) of thiourea were added to 100 ml of ethanol, and the mixture was refluxed at 80□ for 12 hrs. The reaction solution was cooled to room temperature, added with purified water for recrystallization, and filtered under reduced pressure to obtain 3.3 g (yield: 21%) of a title compound (16).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15](I)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C[Si]([C:28]#[CH:29])(C)C.C(N(CC)CC)C>CN(C)C=O.[Cu]I.[Pd].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>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:28]#[CH:29])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(I)cc3c12
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2[nH]c3cnc(C(=O)OC(C)C)c(COC)c3c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g of 6-iodo-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 30 ml of dimethylformamide in succession with 1.53 ml of trimethylsilylacetylene, 15 ml of triethylamine, 50 mg of copper (I) iodide and 100 mg of tetrakis (triphenylphosphine)-palladium (O) and heated for 3 hours under argon to 60° C. solution temperature. After removal of the solvent the residue is taken up in ethyl acetate and in succession is washed with saturated sodium bicarbonate and common salt solution. The organic phase was dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=12:1. The correspondingly combined fractions are stirred for 1 hour in 50 ml of methylene chloride with 4 ml of tetrabutylammonium fluoride at room temperature. The solution is washed with water, dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 830 mg of 6-ethinyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 191°- 193° C. (ethyl acetate/hexane) is obtained by the corresponding combination of the fractions.
Reaction SMILES: C[O:2][C:3](=[O:18])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)\[CH2:8][CH3:9].[OH-].[Na+]>CO>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10](/[C:7](/[CH2:8][CH3:9])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:18])=[O:2])=[CH:15][CH:14]=1
Reactant: CC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid methyl ester (8 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the reaction was worked up in the usual way and the acid crystallized from 2-propanol-hexane to give 5.4 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid, mp 135.5°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: COCc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)OC
Reaction time: 1 h

Procedure:
A sample of methyl 4-chloro-α-methoxy-o-toluate (10 g.) is added in small portions at 15°-20° to a solution of potassium nitrate (4.9 g.) in concentrated sulfuric acid. When the addition is complete, the mixture is stirred for 1 hour at 10°-15°, the poured onto ice and the precipitated solid (12.8 g.) collected by filtration. A sample of the damp product is recrystallized from 90% ethanol. After recrystallization, the solid mp is 77°-81°.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]([F:37])([F:36])[O:23][C:24]1[CH:25]=[C:26]([CH:33]=[CH:34][CH:35]=1)[O:27][CH2:28][CH2:29][C:30](O)=O.CCN=C=NCCCN(C)C.[CH2:49]([OH:51])C>O>[NH2:8][C:7]1[N:6]([CH3:9])[C:5](=[O:10])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3](=[O:20])[C:2]=1[NH:1][C:49](=[O:51])[CH2:30][CH2:29][CH2:28][O:27][C:26]1[CH:33]=[CH:34][CH:35]=[C:24]([O:23][C:22]([F:37])([F:36])[F:21])[CH:25]=1
Reactant: O=C(O)CCOc1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Solvent: O
Product: COc1ccc(Cn2c(=O)c(NC(=O)CCCOc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (100 mg, 0.362 mmol, Intermediate 59) in ethanol (3 mL) was added 3-(3-(trifluoromethoxy)phenoxy)propanoic acid (96 mg, 0.364 mmol) and EDCI (105 mg, 0.546 mmol). The reaction was stirred at room temperature for 3 h. Then the mixture was diluted with water and the precipitate was collected by filtration and rinsed with water. The solids were then dissolved in ethyl acetate. This organic solution was dried over sodium sulfate and concentrated to give N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(3-(trifluoromethoxy)phenoxy)butanamide (150 mg, 79.3%) as a yellow solid. LCMS retention time 1.422 min; LCMS MH+ 523.