Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccccc4)CC3)s2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (70 mg, 0.22 mmol) in methylene chloride (5 mL) is added 1-phenylpiperazine (30 mg, 0.22 mmol), piperidinomethyl polystyrene (75 mg, 0.262 mmol) and the mixture is stirred overnight at room temperature under a nitrogen atmosphere. After the reaction is completed (determined by TLC) it is filtered and the filtrate concentrated. The residue is purified by chromatography on a 5 g silica gel cartridge (eluting with ethyl acetate-50% heptane then 100% ethyl acetate) affording the corresponding sulfonamide as a solid (95% yield). LC/MS: RT 3.79 min; m/e 444 (M+H); 1H NMR (δ, ppm): 11.83 (1H, s), 7.65 (1H, d); 7.38 (1H, s); 7.28 (1H, d), 7.21 (2H, m), 6.94 (2H, d), 6.81 (1H, t), 3.26 (4H, br d), 3.12 (4H, br d), 2.38 (2H, q), 2.32 (3H, s), 1.09 (3H, t).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[Cl:36]>>[Cl:36][C:28]1[CH:29]=[C:30]([C:31]#[N:32])[CH:33]=[C:34]([CH3:35])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Cc1cc(C#N)cc(Cl)c1N
Product: CCc1cc2c(C(=O)Nc3c(C)cc(C#N)cc3Cl)cnc(OC)c2o1
Yield: 42.6 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 4-amino-3-chloro-5-methylbenzonitrile (195 mg). Purification by column chromatography on silica eluting with 2% methanol in dichloromethane gave the title compound (92 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1.Cl>N1C=CC=CC=1>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][O:1][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:36])[O:7]1
Reactant: O=C1CCC(=O)O1
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 50 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (50 mg, 0.12 mmol) obtained in step B of Example 1-14 was dissolved in pyridine (3 ml). Thereafter, succinic anhydride (14 mg, 0.14 mmol) was added to the solution, and the obtained mixture was then stirred at 50° C. for 6 hours. Thereafter, succinic anhydride (24 mg, 0.25 mmol) was further added to the reaction solution, and the obtained mixture was then stirred at 50° C. for 15 hours. Thereafter, 1 N hydrochloric acid was added to the reaction mixture, and precipitated powders were collected by filtration. The obtained filtrate was washed with water. The resultant was subjected to air-drying, and was then dried under reduced pressure, so as to obtain 3-{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethoxycarbonyl}propionic acid (46 mg, 74%) in the form of white powders.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.[C-:18]#[N:19].[Na+].[I-].[Na+]>CN(C)C=O>[N:11]1([C:13](=[O:15])[C:14]2[N:5]([CH2:4][CH2:3][CH2:2][C:18]#[N:19])[CH:6]=[N:7][C:8]=2[N:9]([CH3:17])[C:10]1=[O:16])[CH3:12]
Reactant: [C-]#N
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCC#N)n(C)c1=O
Yield: 88 %

Procedure:
57.9 g. of 7-(3-chloro-propan-1-yl)-theophylline, 12.29 g. of sodium cyanide, 2.0 g. of sodium iodide and 400 cm3 of dimethylformamide are stirred at 90° C. for 3 hours. 49.1 g. (88% yield) of γ-(theophylline-7-yl)-butyronitrile are obtained. M.p.: 146°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:14].[O:16]=[C:17]1[NH:21][C:20](=[S:22])[CH2:19][S:18]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH:14]=[C:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]=2[Cl:13])[C:4](=[C:19]2[S:18][C:17](=[O:16])[NH:21][C:20]2=[S:22])[NH:5]1
Reactant: O=C1NC(=S)CS1
Reactant: N=C1NC(=N)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N=C1NC(=C2SC(=O)NC2=S)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 25 °C

Procedure:
To a mixture of 14.1 parts of 4,5,6,7-tetrachloro-1,3-diiminoisoindoline, 6.7 parts of 2-oxo-4-thioxothiazolidine and 10.0 parts of freshly prepared, ground anhydrous sodium acetate, there was added 157 parts of glacial acetic acid. The resulting slurry was heated at reflux under a continuous flow of nitrogen for approximately one hour. The reaction solution was cooled to room temperature, sealed under an atmosphere of nitrogen and set aside for about sixty hours. The solid which separated on standing was collected by filtration at room temperature, washed five times, each with 21.0 parts glacial acetic acid and then a total of eight times, each with 20.0 parts distilled water. The water-wet pulp was stirred with 90.0 parts of 28 percent aqueous ammonia, filtered to remove any insolubles and the product reprecipitated by adjusting the pH of the solution to 6.0 by the addition of 99.2 parts of 6N hydrochloric acid solution. The solid was collected by filtration, washed with 3000 parts of water and air dried at 60° C. to obtain 1-imino-4,5,6,7-tetrachloro-3-(2-oxo-4-thioxo-5-thiazolidinylidene)isoindoline as a brown powder which did not melt up to 340° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:10]=[CH:11][CH:12]=1)=[O:7].CN>CN(C)C=O.O>[NH2:13][N:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: O=C(c1cccs1)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: Nn1cccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
To a solution of 2-[2-(2-thienylcarbonyl)-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)dione (15.43 g) in 50 ml of dimethylformamide was added 50 ml of 40% methylamine. The reaction mixture was stirred for 1.5 hours at room temperature, diluted with water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residual oil was recrystallized from ethyl ether/hexane to afford the product (5.96 g), m.p. 81°-82° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11]CC)=O)(=[O:3])[NH2:2].[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCO>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH:16]=[CH:15][CH:14]=1)[C:1]([NH2:2])=[O:3]
Reactant: CCOC(=O)COc1cccc(C(N)=O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: NC(=O)c1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
To a stirred mixture of ethyl 2-(3-carbamoylphenoxy)acetate (150 mg, 0.673 mmol) in EtOH (1 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (138.6 mg, 0.673 mmol). The mixture was stirred at 120° C. for 0.5 hour under mediated heating. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired title product (64 mg, Yield 25%). 1H NMR (400 MHz, MeOD) δ 7.53 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.39 (dd, J1=J2=7.9 Hz, 1H), 7.12-7.00 (m, 5H), 4.60 (s, 2H), 4.04-4.01 (m, 1H), 3.74-3.65 (m, 2H), 3.47-3.39 (m, 2H), 2.95-2.87 (m, 2H), 2.85-2.77 (m, 2H), 2.58 (d, J=6.0 Hz, 2H). LCMS (m/z): 384.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:20](Cl)(=[O:22])[CH3:21]>C(#N)C>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][N:15]([C:20](=[O:22])[CH3:21])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1cccc(Nc2ncnc3[nH]ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)n1ccc2c(Nc3cccc(C)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.2 %

Procedure:
To (3-methyl-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (0.75 g, 3.4 mmol) dissolved in hot acetonitrile (30 ml) was added sodium hydride (0.16 g, 4.0 mmol, 60% dispersion in mineral oil). After stirring at ambient temperature for 0.75 hours, acetyl chloride (0.48 ml, 6.7 mmol) was added and stirring continued for 48 hours. The reaction mixture was concentrated in vacuo, triturated in hot ethyl acetate, and filtered. The filtrate was concentrated in vacuo to give an orange solid residue. The solid was purified by flash chromatography on silica gel (13 g,40 mm mesh) using 1:3 ethyl acetate/hexanes to afford 1-(4-m-tolylamino-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone as a yellow solid (0.21 g). TS-MS: 309 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N2CCCC2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (1.66 g, 8.0 mmol), pyrrolidine (0.66 mL, 8 mmol) and sodium carbonate (1.54 g, 14.0 mmol) in methanol (8 mL) was stirred for 1 h at 20° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was subsequently washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude title compound (0.78 g, 40%) as light yellow solid. MS ISP (m/e): 242.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Br)ccc1Sc1ccccc1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 121c (437 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (129 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 6.43 (d, J=6.99 Hz, 1H) 7.20 (d, J=8.46 Hz, 1H) 7.34 (s, 5H) 7.69 (dd, J=8.82, 2.21 Hz, 1H) 7.81 (m, 2H) 8.47 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H); MS (ESI+) m/z 422 (M+H−TFA)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=[O:4].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([O:26][CH3:29])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=[O:4]
Reactant: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
To a solution of T21.4 (1530 mg, 4269 μmol) in DMF (40 mL), was added sodium hydride (60% in oil) (213 μL, 8538 μmol). The mixture was stirred at room temperature for 10 minutes and then methyl iodide (530 μL, 8538 μmol) was added in one portion and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was, extracted with EtOAc. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give the product as a residue which was purified by chromatography to give the product as an oil (0.75 g, 47%). MS ESI m/e: 373.2 (M+18)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH2:19][OH:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1>O1CCCC1.CC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: OCc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C
Reaction time: 10 h
Yield: 85.2 %

Procedure:
[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H -benzoimidazole-5-yl]-methanol 10e (0.96 g, 2.58 mmol) is dissolved in tetrahydrofuran/acetone (1:1, 15 mL), and MnO2 (2.24 g, 25.8 mmol) is added. The reaction mixture is stirred at 50° C. for 10 hours under N2. The reaction mixture is filtered through silica gel and eluted with methylene chloride/methanol (10:1, 1 L). The filtrate is concentrated under reduced pressure to a small volume and then filtered through an Acrodisc syringe filter to remove small amounts of MnO2 that passed through the silica gel. The filtrate is concentrated under reduced pressure and the residue is purified by flash column chromatography (eluting with 20:1 methylene chloride:methanol) to yield 0.81 g (85%) of the pure desired product as a bright yellow solid. MS ESI (+) m/z 368, 370 (M+, Br pattern) detected.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14])=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1CCO)COC2=O
Temperature: 105 °C

Procedure:
A mixture of 5-bromo-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (0.460 g, 1.78 mmol), tributyl(vinyl)tin (0.676 g, 2.13 mmol), LiCl (0.224 g, 5.33 mmol) and Pd (PPh3)4 (0.10 g, 0.087 mmol) in toluene (50 mL) was heated at 100-110° C. under N2 overnight after which TLC indicated that the reaction had gone to completion. Next, EtOAc (100 mL) was poured into the solution and it was washed with brine, then water, then dried over Na2SO4, filtered and concentrated to dryness. The residue was then absorbed onto silica gel and separated over silica column to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[F:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[F:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1cc(C)ccc1F
Yield: 79.6 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (400 mg, 1.31 mmol) obtained in Example 22, step 1 and 2-fluoro-5-methylaniline (0.18 mL, 1.57 mmol), the title compound (410 mg, 91%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[S:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[N:9]=[CH:10]1
Reactant: O=[N+]([O-])c1ccc2scnc2c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitrobenzo[d]thiazole (150 mg) was dissolved in THF (20 mL) at 0° C. and AcOH (1 mL) was added followed by Zinc dust (1.65 g). Mixture was stirred at RT for 1 h and was filtered on silica pad (rinsed with EtOAc). Solvent was evaporated, residue was diluted with NaHCO3 and extracted with EtOAc. Organic phases was dried, filtered and evaporated to give benzo[d]thiazol-5-amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(F)c1
Reactant: Ic1ccc(I)cc1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)cc1F

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 7) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 470.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C@H:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:11]1[C:10]2([CH2:13][C@@H:14]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[NH:8][CH2:9]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CNc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NC[C@@H]2CC3(CC3)CN2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl6-(((5-chloropyridin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate Intermediate 60, 600 mg, 1.77 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (4 ml) was added. After 1 hour at 0° C. and 3 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum. The crude was purified by silica gel column chromatography (CHCl3/MeOH=8/2). (S)—N-(5-azaspiro[2.4]heptan-6-ylmethyl)-5-chloropyridin-2-amine was obtained as light yellow oil (400 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[Na+].[I-].[CH3:18][CH2:19][SH:20].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:20][CH2:19][CH3:18])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: CCS
Reactant: FC(F)(F)COc1ccc(CCl)cc1Br
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSCc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a solution of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM (200 mL) was added TEA (1 g, 9.89 mmol), NaI (898 mg, 5.99 mmol) and EtSH (613 mg, 9.89 mmol). The mixture was stirred at 30° C. for 4 hrs. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA=1:0˜3:1) to give the title compound (2.1 g, 96.8%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J=2.0 Hz, 1 H), 7.24 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.42 (q, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).
Reaction SMILES: CCN(CC)CC.[C:8]1([CH:14]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][NH:28][CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18].[BH3-]C#N.[Na+]>CCO>[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][N:28]([CH2:14][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 3 h

Procedure:
Et3N (6.27 mL), PhCHO (4.92 mL) were added successively to the EtOH (81 mL) solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester, hydrochloride (9.47 g) at room temperature and stirred for 3 h under a nitrogen atmosphere. Then NaBH3CN (2.97 g) was added to the reaction mixture and stirred for 19 h. The mixture was filtered through a pad of Celite and diluted with CH2Cl2 and washed with 50% K2CO3 aq. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (1/0˜9/1) and CHCl3-MeOH (19/1˜9/1). The titled compound was obtained as pale yellow crystals (4.16 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:29])=[O:28]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:27]([OH:29])=[O:28])[CH:36]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1cccc(B(O)O)c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: COCCOC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1951 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (10 ml) were added 3-carboxymethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).