Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:24]=1[CH:25]=O>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(C2CCN(C)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(C2CCN(C)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 49 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (125 mg, 0.427 mmol) and 2-Methoxy-4-(1-methyl-piperidin-4-yl)-benzaldehyde (109.5 mg, 0.469 mmol) were reacted to produce 106 mg (49%) of the title compound. mp: 232-235° C., 1H NMR (300 MHz, CDCl3): 10.67 (s, 1H), 8.33 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.42 (m, 1H), 6.38 (m, 1H), 6.35 (m, 1H), 5.48 (d, J=8 Hz, 1H), 5.18 (t, J=8 Hz, 1H), 5.05 (s, 1H), 4.06 (s, 3H), 3.19 (s, 1H), 3.03 (d, J=10 Hz, 2H), 2.91 (m, 2H), 2.57 (m, 1H), 2.37 (s, 3H), 2.34 (s, 1H), 2.10 (m, 2H), 1.89 (m, 4H), 1.76 (d, J=8 Hz, 1H), 1.27 (s, 2H). MS: 507 (M+H), HPLC: 1.86 min (G method)
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[C:20]([F:28])=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([F:28])=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1cccc(Cl)c1F
Product: Oc1ccc2ncn(-c3cccc(Cl)c3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3-chloro-2-fluorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=263.9 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 6.73 (d, J=8.7 Hz, 1H), 7.39 (td, J1=8.2 Hz, J2=1.5 Hz, 1H), 7.68 (m, 2H), 8.00 (d, J=8.7 Hz, 1H), 8.36 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O>O1CCCC1>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Fc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A solution of 2-mercapto-5-fluoro-benzimidazole (2.24 g, 13.3 mmol) in tetrahydrofuran (10 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.852 g, 21.3 mmol) and tetrahydrofuran (5 ml). The mixture is stirred at room temperature for 2 hours. A solution of 5-nitro-2-furaldehyde (1.88 g, 13.3 mmol) in tetrahydrofuran (15 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 2 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate and washed with water (2×60 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (40 g) eluted with dichloromethane to yield 700 mg of 5-(5-fluoro-1H-benzoimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as an orange powder. Yield=20%. Analytical LC/MS (method B): retention time=3.08 min., m/z=263.05 (positive ion mode).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:2][CH2:3][Cl:4])[N:10]=[CH:9]2
Reactant: ClCCBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: ClCCn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
1-Bromo-2-chloroethane (2.9 mL, 35 mmol) was added to a suspension of 5-bromo-1H-indazole (4.302 g, 21.95 mmol) and Cs2CO3 (28.56 g, 87.81 mmol) in DMSO (50 mL) under N2. The resulting suspension was stirred at 25° C. for 6 h. H2O (50 mL) was added, and the resulting suspension was cooled in an ice bath. The suspension was filtered, and the solid was dried under reduced pressure to afford a pink powder. Flash chromatography on silica gel (19:1 to 5:2 hexanes/EtOAc) gave the title compound (3.094 g, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.00 (br s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.50 (dd, J=9.0, 1.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 4.68 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:7][CH:8]=1
Reactant: OC/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Yield: 92 %

Procedure:
(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol was treated with active manganese dioxide in the same manner as in Reference example 22 to obtain the title compound in a yield of 92%.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4](F)[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F-].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[OH:25]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[O:25][C:4]1[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7](=[C:2]([F:1])[C:3]=1[O:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[Cl:17])[C:8]#[N:9]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: [F-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(F)c(Oc2cc(Cl)ccc2Cl)c(Oc2cc(Cl)ccc2Cl)c(F)c1C#N
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a separable flask of glass provided with a stirrer, a thermometer, a water separation tube, and a cooling tube and having an inner volume of 300 ml, 242.5 gr of acetone and 19.1 gr (0.0955 mol) of tetrafluorophthalonitrile were placed, to dissolve tetrafluorophthalonitrile in acetone homogeneously. Next, the resultant solution and 134 gr (0.2306 mol) of potassium fluoride were added together and the resultant reaction slurry was retained at −5° C. To this reaction slurry, 34.1 gr (0.2092 mol) of 2,5-dichlorophenol dissolved uniformly in 30.5 gr of acetone was added dropwise over a period of one hour. The reaction proceeding during the dropwise addition was continued with the reaction product cooled from the exterior so as to keep the interior temperature thereof in the range of −5° C. to 0° C. After the dropwise addition was completed, the reaction mixture was retained for additional two hours. After the reaction was completed, the contents of the flask were cooled to 20° C. and filtered to separate the solid component.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][C@:11]([CH3:16])([OH:15])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:16])([OH:15])[CH2:10]1
Reactant: C[C@]1(O)CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@]1(O)CCC[C@@H](N)C1
Yield: 62.3 %

Procedure:
A solution of (1S,3R)-3-(dibenzylamino)-1-methylcyclohexanol (5.0 g, 16.16 mmol) in ethanol (150 mL) was treated with palladium hydroxide on carbon and stirred under a balloon filled with hydrogen gas overnight. Upon completion of the reaction as indicated by LCMS the reaction mixture was filtered through a pad of celite and the filtrate concentrated to yield (1R,3R)-3-amino-1-methylcyclohexanol (1.3 g, 62%) as a thick yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.87 (br. s., 1H), 1.64-1.74 (m, 1H), 1.47-1.59 (m, 2H), 1.21-1.40 (m, 4H), 1.11-1.20 (m, 1H), 1.02 (s, 3H); MS (ESI) m/z 130.2 [M+1]+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[NH:14][C:4]1[C:5]2[C:9]3[CH2:10][N:11]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:13][C:8]=3[NH:7][C:6]=2[N:1]=[CH:2][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(Nc2ccc3c(c2)CCCC3)c2c3c([nH]c2n1)CCNC3
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)CCCC5)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
(6,7,8,9-Tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-(5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (75 mg, 0.24 mmol), acetic anhydride (25 μL, 0.24 mmol), and triethylamine (98 μL, 0.71 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 59 (22 mg, 26% yield) as a tan powder. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:8]([Si:11]([CH3:13])([CH3:12])[O:4][CH2:3][C:2]([CH3:5])([OH:6])[CH3:1])([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 83.6 %

Procedure:
2-Methylpropane-1,2-diol (1.08 g, 12.0 mmol, 1.0 equiv) in DCM (40 mL) under argon was cooled to 0° C. TEA (2.50 mL, 18.0 mmol, 1.5 equiv), DMAP (75.0 mg, 0.600 mmol, 0.05 equiv), and TBSCl (2.00 g, 13.2 mmol, 1.1 equiv) were added sequentially, and the reaction was allowed to warm up to ambient temperature overnight. Complete conversion of reactant to product was confirmed by TLC eluted with EtOAc and visualized with KMnO4. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc 2×, and the combined organics were dried with Na2SO4, filtered, and concentrated to provide 1-(tertbutyldimethylsilyloxy)-2-methylpropan-2-ol (2.05 g, 84%) as a light brown oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([O:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 951.1 %

Procedure:
A solution of 80 g of 3-chlorophenyl-carboxylic acid chloride in 100 ml of anhydrous benzene was added dropwise with stirring at 10° C. to a mixture of 5.87 g of 4-chlorophenol, 46.1 g of triethylamine and 250 ml of anhydrous benzene and the mixture was stirred overnight at room temperature. The mixture was vacuum filtered and the filtrate was evaporated to dryness to obtain 122 g of raw product which was crystallized from 200 ml of a 2-8 ethyl ether-petroleum ether (b.p.=60°-80° C.) mixture to obtain 116 g of 4-chlorophenyl 3-chlorobenzoate melting at 72° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[C:19]([S:21]([CH3:23])=O)[N:18]=[C:17]([NH2:24])[N:16]=2)=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.S[CH2:26][CH:27](C)[C:28]([OH:30])=[O:29]>>[NH2:24][C:17]1[N:18]=[C:19]([S:21][CH2:23][CH:27]([CH3:26])[C:28]([OH:30])=[O:29])[CH:20]=[C:15]([C:3]2[C:2]([Cl:1])=[CH:14][C:6]3[CH2:7][O:8][CH2:9][C:10]4[C:5]=3[C:4]=2[CH:13]=[CH:12][CH:11]=4)[N:16]=1
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Reactant: CC(CS)C(=O)O
Product: CC(CSc1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1)C(=O)O
Yield: 99.9 %

Procedure:
Partially purified 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (99.9 mg) obtained in Step 5 of Example 314 was reacted with 3-mercapto-2-methylpropionic acid (133.0 mg) instead of mercaptoacetic acid using the same operation as the production method described in Step 6 of Example 314, and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionic acid (115.4 mg) was obtained. Then, the obtained 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionic acid (58 mg) was reacted with ammonium chloride (37.9 mg) using the same operation as the production method described in Step 6 of Example 314, and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-2-methyl-propionamide (compound 321) (41.4 mg) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
6.70 g (0.17 mol) of sodium hydride are added in portions to a solution of 55.71 g (0.17 mol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate from Example 12A in 34 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 1 hour. The reaction solution is then cooled to 0° C., 42.98 g (0.20 mol) of 4-(2-bromoethyl)benzonitrile from Example 8A in 21 ml of DMF are added, and the mixture is stirred at this temperature for 30 min. The mixture is subsequently stirred at room temperature overnight. Water is added dropwise to the reaction mixture, which is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 3:1; 3 kg of silica gel). 36 g (0.078 mol, 46% yield) of a colorless solid are obtained.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)[CH:19]=1.C(N(CC)CC)C>CC(N(C)C)=O>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]3)[CH:24]=2)[CH:19]=1
Reactant: CC(C)I
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Iodopropane (0.029 ml) was added in one portion to 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.100 g) and triethylamine (0.05 8 ml) in DMA (3 ml) and the resulting solution was stirred for 30 minutes. A further portion of 2-iodopropane (0.029 ml) was added, the temperature was increased to 50° C. and the reaction mixture was stirred for a further 90 minutes. A third portion of 2-iodopropane (0.029 ml) was added, and then triethylamine (0.058 ml) was added and the reaction heated at 50° C. for a further hour. The reaction mixture was then evaporated to dryness and redissolved in DMSO (3.6 ml) and the crude product was purified by preparative X bridge HPLC (C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length using decreasingly polar mixtures of water containing 1% ammonia and MeCN as eluents). There was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.065 g); Mass Spectrum: M+H+ 403.17; RT 2.49 min; NMR Spectrum: (DMSOd6) 8.53 (1H, d), 8.44 (1H, d), 8.32 (1H, s), 7.90 (1H, s), 7.82-7.86 (1H, m), 7.77-7.81 (1H, m), 7.62 (2H, s), 7.41-7.49 (2H, m), 4.05-4.16 (1H, m), 2.91 (2H, d), 2.77 (1H, quintet), 2.29 (2H, t), 2.02-2.11 (2H, m), 1.94 (2H, qd), 1.01 (6H, d).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>C(#N)C>[N:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4.6 g of sulfuryl chloride in acetonitrile was treated dropwise with 996 mg of morpholine at ambient temperature under an atmosphere of nitrogen. After complete addition, the mixture was refluxed for 16 h, cooled to room temperature, and concentrated in vacuo to yield the title product as a red oil. TLC: Rf=0.65 CH2Cl2. (1 H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.[BrH:11]>O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][Br:11]
Reactant: OCCc1cccc(I)c1
Reactant: Br
Solvent: O
Product: BrCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-iodophenethyl alcohol (see Preparation 26) (1.2 g) and 48% aqueous hydrobromic acid (20 ml) was stirred at room temperature for 8 hours, poured into water and extracted into methylene chloride. The organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated to give the title compound as a pale brown oil (1.1 g, 73%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][PH:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[N:3]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:38])=[C:31]2[C:35]=1[C:34](=[O:36])[N:33]([CH3:37])[CH2:32]2.C(O)(C(F)(F)F)=O>>[Br:38][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][PH:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=3)[N:3]=2)=[C:35]2[C:31]=1[CH2:32][N:33]([CH3:37])[C:34]2=[O:36]
Reactant: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1
Yield: 96.6 %

Procedure:
A solution of ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)methylphosphinate (230 mg, 584 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (169 mg, 701 mmol) in TFE (2.0 mL) was charged with TFA (200 mg, 1.75 mmol) and the reaction mixture irradiated in a microwave reactor at 105° C. for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent to afford the title compound, 337.5 mg (96.6% yield). 1H NMR (CDCl3, 400 MHz): δ=1.33 (t, J=6.95 Hz, 3 H), 1.45 (d, J=13.64 Hz, 3 H), 3.22 (s, 1 H), 3.24 (s, 3 H), 3.26 (s, 1 H), 4.03-4.15 (m, 2 H), 4.34 (s, 2 H), 7.36-7.41 (m, 2 H), 7.50 (d, J=8.08 Hz, 4 H), 7.54 (d, J=8.84 Hz, 1 H), 8.20 (s, 1 H), 8.30 (d, J=9.35 Hz, 1 H). MS (ES+): m/z 600.0844 [MH+] (TOF, polar).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9]>ClC1C=CC=CC=1>[CH3:14][S:11]([N:10]([CH2:8][CH3:9])[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])(=[O:13])=[O:12]
Reactant: CCNS(C)(=O)=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Clc1ccccc1
Product: CCN(S(C)(=O)=O)S(=O)(=O)N=C=O
Temperature: 150 °C
Yield: 81.3 %

Procedure:
225 g (1.60 moles) of chlorosulfonyl-isocyanate are added to a solution of 170 g (1.38 moles) of methanesulfonic acid ethylamide in 700 ml of chlorobenzene, and the whole is heated for 5 hours at a bath temperature of 150°C while passing nitrogen through the reaction vessel. Subsequently, 256 g (81 %) of methanesulfonyl-ethylamino-sulfonylisocyanate having a boiling point of 99° - 106°C/1 torr are isolated by distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[ClH:15]>C(O)C.[Pd]>[ClH:15].[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 5-(3-nitrophenyl)tetrazole (22 g, 0.12 mol) in ethanol (500 ml) was added 10% palladium on carbon (1.5 g, 7% (w/w)) in hydrochloric acid (23 ml of a 5M solution). The mixture was hydrogenated at 40 psi for 10 min, then the catalyst filtered off and washed with water. The solvents were evaporated in vacuo and the brown solid azeotroped with toluene (4×100 ml). The resulting solid was triturated with hot ethanol to give 5-(3-aminophenyl)tetrazole hydrochloride (16.3 g, 71%) as a beige powder. mp 203°-205° C. 1H NMR (360 MHz, D2O) δ 7.63 (1H, d, J=9 Hz), 7.75 (1H, t, J=8 Hz), 8.00 (2H, m).
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]=[C:8]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:7]([C:21]([O:23]CC)=[O:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1.[OH-].[Na+].Cl>C(O)C>[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]=[C:8]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:7]([C:21]([OH:23])=[O:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)c(Cn3cncn3)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 46 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (3.0 g), 2N sodium hydroxide (15.6 ml) and ethanol (50 ml) was stirred under reflux for 8 hours. The reaction mixture was ice-cooled, adjusted to pH 5 with 2N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethanol, the insoluble materials were filtered off, and the filtrate was concentrated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/methanol (4/1, v/v) gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid (1.3 g, 46%) which was then recrystallized from dichloromethane-ethanol. Colorless prisms. mp. 270°-271° C. (decomposition).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)C[C@H]1CCCOC1
Yield: 86 %

Procedure:
Hydrogenation of tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (146 mg, 0.51 mmol) was carried out in MeOH (10 mL), 10% Pd/C (25 mg) under 40 psi of H2 for 2 h. After filtration 114 mg of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was obtained, yield 86%. MS ESI+ve m/z 259 (M+H).