Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:22])[CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:5]=[CH:4][CH:3]=1.O.[CH3:24][N:25]1[C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[CH2:11][CH:10]([OH:22])[CH2:9][NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]3[N:27]=[CH:26][N:25]([CH3:24])[C:29]=3[CH:30]=2)[N:7]=1
Reactant: OC(CNc1cccc(Br)n1)CN1CCc2ccccc2C1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2ccc(-c3cccc(NCC(O)CN4CCc5ccccc5C4)n3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a stirred mixture of 1-((6-bromopyridin-2-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (130 mg, 0.36 mmol) in dioxane:H2O (15 mL, 2:1) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (102 mg, 0.396 mmol), Cs2CO3 (351 mg, 1.08 mmol) and then Pd(dppf)Cl2 (10 mg). The mixture was degassed with N2 4 times and stirred at 25° C. for 16 hours. The reaction mixture was quenched with water (20 mL), extracted with EA (20 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title compound (12 mg, 8%). 1HNMR (CH3OD, 400 MHz) δ: 8.05 (s, 1H), 7.88-7.87 (m, 2H), 7.83-7.80 (m, 1H), 7.50 (t, J=8.0, 1H), 7.13-7.11 (m, 4H), 7.01-7.00 (m, 1H), 6.40 (d, J=4.0, 1H), 5.00 (s, 1H), 4.45 (br, 1H), 4.11-4.13 (m, 1H), 3.82-3.61 (m, 6H), 3.52-3.45 (m, 1H), 2.91 (s, 3H), 2.81-2.63 (m, 3H). LCMS (m/z): 414.2 [M+H]
Reaction SMILES: C([O:4][C@@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[OH:4][C@@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12]
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
A solution of (S)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (350 mg) in methanol (10 ml) was treated with 1 M hydrogen chloride in ether (5 ml). After stirring at room temperature for 12 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (30 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (S)-1-(5-hydroxyhexyl)-7-benzyl-3-methylxanthine (270 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:34]([F:37])([F:36])[F:35])[N:18]=[CH:17]4)[C:10](=[O:12])[N:11]=2)[C@@H:4]([CH2:38][OH:39])[CH2:3]1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[F:35][C:34]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:5]4[C@@H:4]([CH2:38][OH:39])[CH2:3][C@@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide was prepared from 2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one (example 258) and acetic anhydride.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([CH3:20])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]3)[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(-c2cccc3c2C(=O)C(C)C3)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Using a method similar to Example 16b), 16.25 g (0.09 mol) of (1), 14.85 g (0.1 mol) of 3,5-dimethylphenylboronic acid, 21.2 g (0.2 mol) of sodium carbonate were placed in 240 ml of o-xylene/80 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 101 mg (0.45 mmol) of palladium acetate and 472 mg (1.8 mmol) of TPP, the reaction mixture was stirred for 8 hours at 100° C. After 2, 4 and 6 hours, the same amounts of palladium acetate and triphenylphosphine were added again each time. After addition of 150 ml of water, the phases were separated, the aqueous phase was extracted 3 times with 200 ml each time of ether, the combined organic phases were washed with 200 ml of water and 200 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 20.3 g of (17) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1CCCCl.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>C(#N)C.C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH2:38][O:39][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccccc1CCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenyl)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6-fluoro-3-[1-[3-(2-methoxyphenoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.C1C(=O)N([Br:31])C(=O)C1>C1COCC1>[Br:31][C:5]1[NH:4][C:3]2[C:2](=[O:1])[N:10]3[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]3[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
The mixture of 3-(5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl)propanoic acid (203 mg, 0.64 mmole) and NBS (125.8 mg, 7.0 mmol) in THF (25 ml) was stirred at 70° C. for 2 hours. After evaporation of solvent, the residue was purified by preparative LC-MS to afford 60.2 mg (23.7%) of the desired product (60.2 mg, 23.7%) as white solid. LCMS calculated for C14H18BrN6O3 (M+H): 397.1. found: 371.1.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]1[O:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:19]1[O:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: COc1cccc2c1CCC2N
Reactant: O=C(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
A solution of 1-amino-2,3-dihydro-4-methoxy-1H-indene (0.30 g), 4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butan-1-one (0.56 g) and p-toluenesulfonic acid (catalytic amount) in toluene (50 ml) was refluxed for 2 days with Dean-stark equipment. The solvent was evaporated in vacuo and the residue was dissolved in methanol (10 ml). To the methanol solution was added NaBH4 (0.20 g) at 0° C. After being stirred for 1 hour at the same temperature, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.27 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.O.CCN(CC)CC>C1COCC1>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
In a 100 mL, 2-necked round bottom flask, to a mixture of 1-[(4-{[(tert-butoxycarbonyl) amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylic acid (5 g, 14.7 mmol, Step 7) in THF (25 mL), a solution of p-TsOH H2O (8.4 g, 44 mmol) in THF (25 mL) was added at room temperature. The resulting mixture was stirred at 70° C. for 3 h under N2 and it was cooled down to room temperature. To this solution, Et3N (6 mL, 44 mmol) was added dropwise slowly. The white precipitate was formed during the addition of Et3N and the resulting mixture was stirred at room temperature for 14 h. The suspension was filtered and the obtained solid was washed with THF (10 mL), dried at 50° C. for 5 h to give 5.9 g (97%) of the titled compound as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCCCC.[C:37]([N:52]=[C:53]=[S:54])(=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].[CH3:55][O:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][C:66]=1[O:67][CH3:68])[N:63]=[CH:62][CH:61]=[C:60]2[O:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:55][O:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][C:66]=1[O:67][CH3:68])[N:63]=[CH:62][CH:61]=[C:60]2[O:69][C:70]1[CH:71]=[CH:72][C:73]([NH:74][C:53]([NH:52][C:37](=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[S:54])=[CH:75][CH:76]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCCCCCCCCC(=O)N=C=S
Agent: CCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available tetradecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and tetradecanoyl isothiocyanate was prepared using the resultant tetradecanoyl chloride as a starting compound according to the description of the literature. Tetradecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (58 mg, yield 60%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([C:34]#[N:35])[CH:25]=4)[O:21][N:20]=3)[C:14]=2[CH3:18])[CH2:9]1)C>C(O)C>[C:34]([C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:13]3[C:14]([CH3:18])=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:17][CH2:16]4)[N:23]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:33])[CH3:32])#[N:35]
Reactant: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(CC(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
2M Sodium hydroxide (2 ml) was added to a suspension of ethyl[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate (Preparation 23; 80 mg, 0.17 mmol) in ethanol (2 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue diluted with water (5 ml). The solution was acidified with acetic acid and extracted with ethyl acetate (3×5 ml). The aqueous phase was evaporated and the residue purified by MDAP to give the title compound as a colourless solid (7 mg). 1H NMR (400 MHz, d4MeOH) δ: 1.46 (6H, d), 2.55 (3H, s), 3.19 (2H, t), 3.35 (2H, s), 3.67 (2H, t), 3.78 (2H, s), 4.53 (2H, s), 4.95 (1H, m) (part obscured by water peak), 7.20 (1H, d), 7.54 (1H, d), 7.85 (1H, d), 8.50-8.60 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[K+].[Br-].[CH:23](Cl)(Cl)Cl.CO>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:23][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2
Reactant: ClC(Cl)Cl
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc2nc(-c3ccc4c(c3)OCCO4)ncc2c1
Yield: 67 %

Procedure:
This compound was synthesized in 67% yield, according to the procedure described in example 3 for 6-amino-2-(3,4-methylendioxy-phenyl)-quinazoline. C16H13N3O2, MW: 279.30. mp 179.4-181.6° C.; 1H NMR (DMSO-d6) 9.24 (s, 1H), 7.92-7.98 (m, 2H), 7.72 (d, 1H), 7.38 (dd, 1H), 6.89-6.99 (m, 2H), 5.91 (s, 2H), 4.31 (s, 4H); IR (KBr) 1555, 1507, 1286; TLC (CHCl3/MeOH 9/1) Rf=0.65.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.C(Cl)Cl.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:14]1([S:11]([N:7]2[C:8]3[C:4](=[C:3]([CH2:20][N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:2]([OH:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNCC3)c(O)ccc21
Reaction time: 4 h
Yield: 53 %

Procedure:
tert-Butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate, (10 mg, 0.018 mmol, Intermediate 64) was dissolved in DCM/TFA 50/50 (1 mL) and left in RT for 4 hours after which time the solvent was removed at reduced pressure and the residue was purified on a preparative HPLC, Method A, to yield 5.5 mg (53%) of the target compound as a colourless oil. MS (ESI+) for C19H21N3O3S m/z 372 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:25])(=O)C.[N:26]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:25])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:39]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccc(C(F)(F)F)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: O=C1Nc2cc(C(F)(F)F)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:35][CH:36]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:49])[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:51][C:52]1[S:53][C:54]([Cl:57])=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:57][C:54]1[S:53][C:52]([NH:51][C:37](=[O:39])[CH:36]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:49])[CH2:35][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:56][CH:55]=1
Reactant: O=C(O)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Yield: 40.1 %

Procedure:
BOP coupling of 3-Cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step E; 177 mg; 0.59 mmol) and 2-amino-5-chlorothiazole hydrochloride (168 mg; 0.95 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) provided after flash chromatography (Biotage 40M, eluent: 20% ethyl acetate/hexanes) 99 mg (40%) of N-(5-Chloro-thiazol-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as an off white foam EI-HRMS m/e calcd for C21H24ClN3O2S (M+) 417.1278, found 417.1289.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][C@@H:28]1[CH2:30][O:29]1.C(N(CC)CC)C>CCO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][C@H:28]([OH:29])[CH3:30])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C[C@@H]1CO1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@@H](C)O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 19.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (200 mg, 0.545 mmol), (R)-2-methyloxirane (191 μL, 2.72 mmol), triethyl amine (8 μL, 0.054 mmol) and 2 mL of EtOH. The reaction mixture was heated at 140° C. for 30 min. in microwave. Solvents were removed in vacuum and the residue was purified by preparative HPLC to yield the title compound (46 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 1.25 (d, J=6.06 Hz, 3 H) 2.27 (s, 3 H) 3.41 (q, J=7.33 Hz, 2 H) 3.94 (m, 1 H) 4.09-4.16 (m, 2 H) 4.97 (d, J=4.04 Hz, 1 H) 7.07-7.14 (m, 2 H) 7.57 (s, 1 H) 7.85 (t, J=7.71 Hz, 1 H) 7.96-8.00 (m, 2 H) 8.09 (s, 1 H) 8.28 (d, J=1.52 Hz, 1 H) 11.94 (s, 1 H); [M+H] calc'd for C23H25N2O4S, 425.2.; found, 425.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[CH:20]=1.N1C2C(=CC=CC=2)C=N1>>[CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH2:12][C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)[NH:31][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: c1ccc2[nH]ncc2c1
Product: Fc1ccc(OCc2ccccc2)c(F)c1Cc1c[nH]c2ncc(-c3cccnc3)cc12

Procedure:
Additional compounds were prepared following steps 3 and 4 of Scheme 43a, replacing 3-benzyloxy-2,6-difluoro-benzaldehyde 526 with an appropriate aldehyde and/or pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with an appropriate azaindole (see Example 9 or Example 16) in Step 3. The following compounds were made following this procedure:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)o1
Yield: 67.6 %

Procedure:
In the same manner as in Example 259 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (84 mg, 0.59 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.71 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (140 mg, 67%) was obtained as a white solid. melting point 202° C.