Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[C:4]1([NH:10][C:11]2[C:19]3[CH:18]=[CH:17][C:16](=[O:20])[N:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:14]=3[S:13][C:12]=2[C:27]([O:29]CC)=[O:28])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[O:20]=[C:16]1[N:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]2[S:13][C:12]([C:27]([O-:29])=[O:28])=[C:11]([NH:10][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:19]=2[CH:18]=[CH:17]1.[NH4+:10]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Product: [NH4+]
Temperature: 60 °C

Procedure:
Lithium hydroxide monohydrate (302 mg, 7.2 mmol) was added to a suspension of the compound of Example 1 (1.49 g, 3.6 mmol) in THF (20 mL) and water (20 mL) and the mixture heated at 60° C. for 18 h. The reaction was cooled to r.t. and bulk of THF removed in vacuo. The remaining concentrate was diluted with saturated ammonium chloride(aq) (50 mL) and the solid precipitate filtered and washed with water (2×20 mL), Et2O (2×20 mL) and dried in vacuo to give the title compound as a white solid in quantitative yield. LCMS (ES+) RT 3.24 minutes, 363 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:15][CH3:16])[C:5]2[N:6]([N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=2)[CH:7]=1.[NH2:17][C:18]1[C:19]([F:25])=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].N1C=CC=CC=1.CS(C)=O>C(#N)C>[F:25][C:19]1[C:18]([NH:17][S:11]([C:9]2[N:10]=[C:5]3[C:4]([O:15][CH3:16])=[N:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=2)(=[O:13])=[O:12])=[C:23]([CH3:24])[CH:22]=[CH:21][N:20]=1
Reactant: COc1nc(Br)cn2nc(S(=O)(=O)Cl)nc12
Reactant: Cc1ccnc(F)c1N
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1nc(Br)cn2nc(S(=O)(=O)Nc3c(C)ccnc3F)nc12

Procedure:
A solution of 1.36 g (4.14 mmol) of 6-bromo-2-chlorosulfonyl-8-methoxy[1,2,4]triazolo[1,5-a]pyrazine in 15 mL of dry acetonitrile was placed in a flask equipped with a drying tube and was treated sequentially with 1.56 g (12.4 mmol) of 3-amino-2-fluoro-4-methylpyridine, 0.34 mL (4.21 mmol) of pyridine and 60 μL (0.85 mmol) of dimethyl sulfoxide at room temperature. The reaction became progressively darker and after 15 hours the volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with four portions of 1M hydrochloric acid and one portion of water and was dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the residue obtained was purified by flash column chromatography on silica gel using a 0.5 to 4 percent ethanol/dichloromethane gradient as eluent. The solid obtained was further purified by extraction with diethyl ether to obtain 373 mg (22 percent of theory) of the desired product as an off-white powder melting at 210°-211° C. (dec); Mass Spectrum, m/e 417 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:5]=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[Cl-:17].[CH3:18][N+:19](=[CH2:21])[CH3:20]>C(#N)C>[ClH:17].[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:5]=[C:6]1[CH2:10][CH2:9][CH:8]([CH2:18][N:19]([CH3:21])[CH3:20])[C:7]1=[O:11]
Reactant: [Cl-]
Reactant: C=[N+](C)C
Reactant: COc1ccc(C=C2CCCC2=O)cc1O
Solvent: CC#N
Product: COc1ccc(C=C2CCC(CN(C)C)C2=O)cc1O
Product: Cl
Yield: 93.5 %

Procedure:
0.03 mol of 2-(3-hydroxy-4-methoxybenzylidene)cyclopentanone was dissolved in mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(3-hydroxy-4-methoxybenzylidene)-5-dimethylaminomethyl cyclopentanone hydrochloride with a yield of 93.5%.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]=[C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:36]CCl>C(O)C>[ClH:36].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:18](=[CH:17][CH2:16][O:15][CH2:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (2.5 g, 5.8 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (4.3 ml) was added. The mixture was stirred vigorously at room temperature for 5 h. A 4 N hydrochloric acid solution was added until pH 1 followed by dichloromethane (400 ml). The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was evaporated twice with acetone, once with ethyl acetate, dissolved in acetone (15 ml) and left for crystallization. This afforded 1.9 g of the title compound as a solid.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17](O)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][C@H:48]([C:70]([NH2:72])=[O:71])[CH2:49][S:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl.C(Cl)CCl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH:47][C@H:48]([C:70]([NH2:72])=[O:71])[CH2:49][S:50][C:51]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-Trp-Pro-OH (76 gm) and triethylamine (18.5 ml) in methylene chloride (850 ml) at about 0° C. to about −10° C., was charged EDC (54.5 gm) and HOBT (28.5 gm). Stirred for 30 minutes and charged H-Cys(Trt)-NH2 (65 gm, obtained from Ex-12) in methylene chloride (750 ml) at same temperature. After completion of the reaction organic layer was subjected to washings with aqueous sodium bicarbonate, aqueous citric acid solution. The separated organic layer was concentrated under reduced pressure and the resultant residue was crystallized in isopropyl ether to obtain Boc-Trp-Pro-Cys(Trt)-NH2 as a white solid material.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.[CH2:52]([O:59][C:60](=[O:68])[CH2:61][C@H:62]1[CH2:64][C@@H:63]1[C:65](O)=[O:66])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:65]([C@H:63]3[CH2:64][C@@H:62]3[CH2:61][C:60]([O:59][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:68])=[O:66])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: O=C(C[C@H]1C[C@@H]1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
HATU (1450 mg, 3.81 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (1083 mg, 2.93 mmol), (1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (687 mg, 2.93 mmol) and DIEA (1.022 mL, 5.87 mmol) in DMF (14.5 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water (120 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 37→58% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate (1.60 g, 2.73 mmol, 93%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:33]6[C:28]([CH:27]=5)=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5ccccc5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 3-quinolineboronic acid (Aldrich, Buchs, Switzerland, 22 mg, 0.127 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.40 min (Method A); M+H=421 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.03-8.96 (m, 2H), 8.52 (s, 1H), 8.21-7.99 (m, 5H), 7.83-7.76 (m, 1H), 7.75-7.71 (m, 1H), 7.71-7.65 (m, 1H), 3.95 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15]([O:17]C)=O)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].O.[NH2:20][NH2:21]>C(O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15]([NH:20][NH2:21])=[O:17])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: COC(=O)c1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 97.2 %

Procedure:
A solution of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylfuran-2-yl)thiazole (5.00 g) and hydrazine hydrate (9.40 g) in ethanol (50 ml) was refluxed for 4 hours with stirring. The mixture was cooled and the resulting precipitate was collected by filtration to afford 2-(diaminomethyleneamino)-4-(5-hydrazinocarbonylfuran-2yl)thiazole (4.86 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH3:29]
Reactant: CCNCC
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: CCN(CC)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with diethylamine at 22° C. to give the title compound as a white solid. MS: 433.2 ([M+H]+).
Reaction SMILES: [Br-].[CH3:2][C:3]([CH3:15])=[CH:4][CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[CH:7]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:2][CH:3]([CH3:15])[CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([C:12]([CH3:13])=[O:14])=[CH:7]1
Reactant: CC(=O)c1ccc[n+](CC=C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C1=CN(C=CC(C)C)CCC1

Procedure:
1-(3-methyl-2-butenyl)-3-acetyl-pyridinium bromide (27.0 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 ml) over 5% palladium on carbon (5 g) was hydrogenated at room temperature and pressure until two molar equivalents of hydrogen was taken up. The catalyst was removed by filtration and the filtrate concentrated at reduced pressure. The semi-solid residue was diluted with diethyl ether (75 ml), the solid removed by filtration and the filtrate concentrated under reduced pressure to leave a pale oil which solidified on standing. Recrystallisation from ethanol/water gave the product, methyl 1-(3-methylbutenyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (4) as a pale yellow crystalline solid m.p 76-78°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Si](OC[C@@H](N1C=CC(C2C=CN=C(S(C)(=O)=O)N=2)=CC1=O)C1C=CC(Cl)=C(F)C=1)(C(C)(C)C)(C)C>>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C@H:4]3[CH2:3][CH2:2][C@H:6]([OH:1])[CH2:5]3)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Agent: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(N[C@H]3CC[C@H](O)C3)n2)cc1=O

Procedure:
1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((1S,3S)-3-hydroxycyclopentylamino)pyrimidin-4-yl)pyridin-2(1H)-one was prepared according to the general procedure of Example 2, Step A, substituting (1S,3S)-3-aminocyclopentanol for tetrahydro-2H-pyran-4-amine and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one for (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one. m/z (APCI-pos) M+1=575.2, 577.1.
Reaction SMILES: [CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@H:6]([CH2:17][OH:18])[NH:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>CS(C)=O>[CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@H:6]([CH2:17][OH:18])[N:5]1[C:26]([S:28][CH3:29])=[S:27])[CH2:2][CH3:3]
Reactant: S=C=S
Reactant: CI
Reactant: CCC[C@@H]1N[C@@H](CO)Cc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC[C@H]1c2[nH]c3ccccc3c2C[C@H](CO)N1C(=S)SC
Yield: 44.6 %

Procedure:
In the same manner as described in Example 39 by using (1RS, 3SR)-trans-1-propyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.18 g), triethylamine (0.98 g), CS2 (0.74 g), methyl iodide (1.37 g) and dimethylsulfoxide (23 ml), there is prepared the title compound (720 mg, 44%) as white powder, NMR (CDCl3, δ): 2.70 (s, 3H, CSSCH3); Mass m/e: 334 (M+), 286 (M+ --CH3SH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(#N)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][N:21]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2CNCCN2CCOCC2)n1-c1ccc(F)c(Cl)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)N(CCN1CCOCC1)Cc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-(4-[(2-morpholin-4-ylethyl)amino]methyl-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.047 mmol) was dissolved in anhydrous ACN (200 μL) followed by addition of DIPEA (40 μL, 0.2 mmol) and methanesulfonyl chloride (4.0 μL, 0.052 mmol). The reaction was stirred at 40° C. for 2 hrs. The reactions was then diluted with MeOH and purified by HPLC. The purified fractions were concentrated to dryness, redissolved in EtOH (1 mL) and 2 M of sodium hydroxide in water (0.26 mL) was added. The reaction was stirred at rt for 2 hrs, quenched with acetic acid, diluted with MeOH and purified by preparative LCMS to afford the desired product (1.4 mg). MF═C17H22ClFN6O5S; LCMS calculated for C17H23ClFN6O5S(M+H)+: m/z=477.1.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>O>[N:21]1([C:3]2[CH:4]=[CH:5][C:6]3[CH2:15][C@H:14]4[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]4[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=3[N:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: C1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(N4CCCC4)ccc3C[C@@H]21
Temperature: 210 °C
Yield: 1287.5 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (2.50 g, 8.3 mmol) and pyrrolidine hydrochloride (10 g) was heated to 210° C. to form a homogeneous molten semi-solid. After 45 minutes the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-pyrrolidino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline (Rf=0.45, 1% 32 g, 53% yield) as a brown oil.
Reaction SMILES: C([O:8]C(N1C(C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)CC2C3C(=CC=CC=3)NC=2C1)=O)C1C=CC=CC=1.[CH2:38]([O:45][C:46]([N:48]1[CH:60]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([CH:79]=NNC(N)=O)[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:65][C:66]2[N:70]=[CH:69][NH:68][CH:67]=2)=[O:62])[CH2:59][C:58]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]=2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]([N:48]1[CH:60]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([CH:79]=[O:8])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:65][C:66]2[N:70]=[CH:69][NH:68][CH:67]=2)=[O:62])[CH2:59][C:58]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]=2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1

Procedure:
The procedure described in Example 1(a) was repeated, but using 125 mg. (0.25 mmole) of N-(2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carbolin-3-ylcarbonyl)-L-histidine hydrazide. There were obtained 120 mg. of N-(2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carbolin-3-ylcarbonyl)-L-histidyl-L-leucinal semicarbazone. This product was then treated in the same way as in Example 1(b) by partition chromatography using Sephadex G-25, to give 67 mg. of the desired compound as a white powdery solid, melting at 126°-130° C.; [α]22 +21.6° (C`0.5, methanol).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](F)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])CC1.[CH3:33]NC(C1C2C=C(C3C(C)=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[CH3:1][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([CH3:33])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3C)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3C)cc12

Procedure:
Using the method of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 424 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][O:20]C(=O)C)=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH2:28].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][OH:20])=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CC(=O)OCCOc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2cc(OCCO)ccc21
Yield: 20 %

Procedure:
In accordance with general method O, 0.67 g (0.19 mmol) of acetic acid 2-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-ethyl ester, 0.26 g (0.0020 mol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (7.3 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 20%; m.p.: 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[OH:23][CH2:24][C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])[CH3:26].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][OH:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CO)on4)c3)c2cc1OC
Yield: 61 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (30 mg, 0.10 mmol) and phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (41 mg, 0.15 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (30 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 8.99 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.23-7.26 (m, 1H), 6.95-6.98 (m, 1H), 6.49 (s, 1H), 4.95 (brs, 1H), 3.98-3.99 (2×s, 6H), 3.43 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 480 (M+H)+.