Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (350 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl 3-mercaptopropanoate (0.12 mL, 1.1 mmol), and dioxane (10 mL). The reaction mixture was heated to 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford the title compound (328 mg, 84.5% yield) as a pale yellow solid. HCl salt made for characterization. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.45 (m, 2H), 7.36 (d, 1H), 7.22 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 3.55 (s, 3H), 3.07 (t, 2H), 2.57 (t, 2H), 2.29 (s, 3H); Mass spectrum (esi) m/z=402.2 (100)(M+H—HCl).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH:24]([N:31]([CH3:33])[CH3:32])[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOCC>[C:8]([O:29][CH2:28][CH2:27][CH2:26][C:25](=[O:30])[CH:24]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=2)[CH2:23][CH2:22][CH2:21]1)[N:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]
Reactant: CN(C)C(C(=O)CCCO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OCCCC(=O)C(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
Triethylamine and then a solution of acetyl chloride in ether were added dropwise to a solution of the product of Example 45 in ether and the mixture was heated under reflux for 90 minutes, cooled and filtered. The filtrate was diluted with water and extracted with ether. The extract was washed, dried and evaporated to give an oil which was distilled on a Buchi Kugelrohr apparatus (200°/0.5 mm) to give 5-[1-(3,4-dichlorophenyl)cyclobutyl]-5-dimethylamino-4-oxopentyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26]C5CCNCC5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O[BH-](O[C:56](=O)[CH3:57])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:13][N:9]1[CH2:57][CH2:56][CH:4]([N:23]([C:21]2[N:22]=[C:17]3[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)=[C:15]([CH3:43])[C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][N:18]3[N:20]=2)[C:24]([NH2:26])=[O:25])[CH2:5][CH2:6]1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N(C(N)=O)C3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 53 mg, 0.09 mmol) in DCM (2 mL) was added 37% aqueous formaldehyde solution (75 μL.) and 2 drops of MeOH, followed by sodium triacetoxyborohydride (160 mg, 0.75 mmol), and the solution was stirred at RT for 18 hrs. The reaction mixture was partitioned between DCM (15 ml) and aqueous 2 M Na2CO3, and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (19 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[OH:16]O.[OH-].[Na+].Cl>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:16])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(CCC2OCCO2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(CCC2OCCO2)cc1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a stirred solution of 4-(2-(1,3-dioxolan-2-yl)ethyl)benzonitrile (1.50 g, 7.34 mmol) (prepared according to the method described in Kelly, S. M., Liquid Crystals 10: 273? 287 (1991)) in MeOH (50 mL) at room temperature were added 30% H2O2 (25.70 mmol) and 6 N NaOH (7.34 mmol) solution. The mixture was warmed to 50? 60? and stirred for 2 h, and to it, 1 N HCl solution was added to adjust to pH 7? 8 at 0?. The MeOH solvent was evaporated off under reduced pressure, and the residue was extracted with CH2Cl2 (3×30 mL). The CH2Cl2 solution was washed with brine (30 mL), dried (anhydrous Na2SO4), filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19, then 1:9 (v/v)) as eluent to give 1.58 g (97%) of 4-(2-(1,3-dioxolan-2-yl)ethyl)benzamide as a solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, 2H), 7.29 (d, 2H), 6.01 (br s, 1H), 5.71 (br s, 1H), 4.89 (t, 1H), 3.99 (m, 2H), 3.88 (m, 2H), 2.80 (m, 2H), 1.99 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([C:24]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:25])=[N:20]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([C@@H:57]([O:60][Si:61]([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62])[CH2:58]Br)=[C:50]2[C:55]=1[NH:54][C:53](=[O:56])[CH:52]=[CH:51]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([C@@H:57]([O:60][Si:61]([C:64]([CH3:65])([CH3:67])[CH3:66])([CH3:63])[CH3:62])[CH2:58][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([CH2:18][N:19]4[CH:23]=[N:22][C:21]([C@:24]([CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)([OH:25])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:20]4)[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)=[C:50]2[C:55]=1[NH:54][C:53](=[O:56])[CH:52]=[CH:51]2)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1ccc(CCN2CCC(Cn3cnc(C(O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 40 %

Procedure:
The title compound was prepared from (R)-({-[(1-{2-[4-(2-aminoethyl)phenyl]ethyl}piperidin-4-yl)methyl]-1H-1,2,4-triazol-3-yl}(cyclohexyl)phenylmethanol (Preparation 13, 2.57 g, 5.12 mmol) and 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO2005/09286, 2.50 g, 5.12 mmol) using the same method as described in preparation 7 to give a white solid, in 40% yield, 2.3 g.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), pyridin-2-ylmethanamine (9.03 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). This was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyridin-2-ylmethyl)acetamide (9.9 mg, 0.019 mmol, 40.5% yield): LCMS=522.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1H, dd, J=5.40, 1.88 Hz), 8.11-8.23 (2 H, m), 7.62-7.77 (5 H, m), 7.48-7.61 (3 H, m), 7.21-7.32 (2 H, m), 5.20 (1 H, s), 4.44-4.62 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.1 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9](CC([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].CN1CCC2(C3C(=CC=CC=3)NC2)CC1>>[N:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CN1CCC2(CC1)CNc1ccccc12
Agent: [Na+]
Product: O=c1cc(N2CCOCC2)nc[nH]1

Procedure:
The product is prepared by following the procedure described in example 10d using 35.5 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) and 25 mg of 1′-methylspiro[indoline-3,4′-piperidine] in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 13.8 mg of 212-r-methylspiro[indole-3,4′-piperidin]-1(2H)-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18]([OH:20])=O)[C:10]2=[O:15])=[O:4].[C:33](N1C=CN=C1)([N:35]1C=CN=[CH:36]1)=O.CNC.O>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18]([N:35]([CH3:36])[CH3:33])=[O:20])[C:10]2=[O:15])=[O:4]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reaction time: 2 h
Yield: 102.5 %

Procedure:
A solution of 3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.0 g, 2.2 mmol) and carbonyldiimidazole (367 mg, 2.26 mmol) in tetrahydrofuran (7 mL) was stirred at room temperature for 1 h. To the mixture was added dimethylamine in tetrahydrofuran (1.3 mL, 2 N, 2.6 mmol) and the mixture was stirred for 2 h. Water (60 mL) and methylene chloride (50 mL) were then added to mixture. The aqueous layer was separated and was extracted with ethyl acetate (50 mL). The combined organic layers was washed with brine/hydrogen chloride 1N (1:1, 50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a yellow solid (1.1 g, 100% yield), which was used in the next step without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C@@H:18]2[O:9][C@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccccc1C=Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1[C@@H]1O[C@H]1c1ccccc1
Yield: 48.6 %

Procedure:
7.8 g of m-chloroperbenzoic acid (about 50% pure) are added to a solution of 6 g of methyl 2-(2-phenylethenyl)phenylacetate (E/Z=3:1) in 50 ml of methylene chloride. The reaction mixture is refluxed for 12 hours and then the precipitate is filtered off with suction and the filtrate is washed twice with saturated sodium bicarbonate solution and water. The isolated organic phase is dried over sodium sulfate and concentrated, and the residue is recrystallized from methyl tert-butyl ether. 3.1 g (48%) of methyl trans-2-(3-phenyl-2-oxiranyl)phenylacetate are obtained of melting point 118°-119° C. Chromatography of the mother liquor on silica gel (6:1 ethyl acetate/n-hexane) yields 2.8 g (44%) of methyl 2-(3-phenyl-2-oxiranyl)phenylacetate as a 1:1 cis/trans mixture.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:7])=[O:8])=[O:3]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, 2-dimethylamino-ethylamine, HOBt, TBTU and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.Br[C:25]1N2C(C(N)=NC=N2)=CC=1>>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[C:4]([CH3:25])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Reactant: Nc1ncnn2c(Br)ccc12
Product: Cc1nc(N)c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)n2n1

Procedure:
The title compound was prepared in the same manner described for the preparation of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate and substituting 7-bromo-2-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine for 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine. 1H-NMR (CD3OD): δ 7.02 (s, 1 H), 6.83 (d, 1 H), 6.62 (d, 1 H), 4.13 (s, 2 H), 3.64 (s, 2 H), 2.62 (d, 2 H), 2.33 (s, 3 H), 1.49 (s, 9 H). MS: LC/MS (+esi), m/z=330 [M+H]. RT=2.47 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][NH:3]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([N:3]1[C:2](=[O:1])[NH:7][C:6](=[O:8])[CH:5]=[N:4]1)(=[O:11])[CH3:10]
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1ncc(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
3,5-dioxo-(2H,4H)-1,2,4-triazine (48.88 g) is heated under reflux of acetic anhydride (300 ml) for 90 minutes. After cooling and concentration to dryness under vacuum, the residue is taken up in toluene (300 ml) and cooled at 0° C. for 2 hours. The white precipitate which forms is filtered off, centrifuged, and dried under vacuum at 70° C. so as to give the compound 11a (57.6 g).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][C:4]1=[O:12]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]c2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)sc2ccccc21

Procedure:
The product is produced as described in example 1 from 3 g. of NaH (80% suspension in mineral oil), 15.1 g. of benzthiazolin-2-one, 200 cc. of DMF, 23.7 g. of 8-bromo-caprylic acid methyl ester and 3 g. NaJ.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:8][C:7]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[F:31])=[O:5])C.[Li+].[OH-].CCOC(C)=O.C(O)(=O)C>C1COCC1.CO.O>[F:31][C:23]1[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:21][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:6]=1[C:4]([OH:5])=[O:3])[N:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:11]=[CH:10]2
Reactant: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To a solution of ethyl-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate (22 g, 51.2 mmol) in THF (60 mL) and MeOH (60 mL) and H2O (10 mL) is added LiOH (3 g, 125 mmol). The resulting solution is stirred at RT for 1.5 hours and the organic solvents are removed. The aqueous residue is acidified with cold 6N HCl to pH 2, and extracted with EtOAc (150 mL). The organic phase is separated, dried, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc:acetic acid (100:100:1) to afford the product (19.5 g, 95% yield). MS (m/z): 402.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:34][CH2:35][OH:36]>C(O)C.C(Cl)Cl>[OH:36][CH2:35][CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCO)CC4)cc23)cn1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid piperidin-4-ylamide (181), 150 mg, 0.43 mmol) is dissolved in 3 ml of ethanol under argon. After addition of sodium carbonate (182 mg, 1.7 mmol) and 2-bromo-ethanol (61 ul, 0.85 mmol), the reaction mixture is stirred at 80° C. for 13 h. The mixture is diluted with methylene chloride, filtrated and the filtrate is evaporated. Evaporation under reduced pressure gave 128 mg of crude product, which is further purified by Flash-chromatography (dichloro methane/methanol/25% ammonia (90:9:1). Yield: 90 mg (53%). MS (ESI): 395.2 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]([C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[Si:7]([O:6][CH2:5][C@H:4]([C:14]1[CH:19]=[N:18][C:17]([O:20][CH3:21])=[N:16][CH:15]=1)[NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reaction time: 8 h

Procedure:
A mixture of (S)-5-(1-azido-2-(tert-butyldimethylsilyloxy)ethyl)-2-methoxypyrimidine (11.7 g, 37.7 mmol) in ethyl acetate (300 mL), and 10% Pd—C (70 mg) was stirred under H2 (1 atm) overnight. The catalyst was filtered off and the filtrate was concentrated to yield a light oil. The residue was purified by silica gel chromatography (0-50% MeOH/EtOAc) to afford a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in the same way as described for Example 1 to give 2′-fluoro-5′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, DMSO) 1.76 (6H, d, J 22), 7.27 (1H, dd, J 6 and 1), 7.64-7.72 (2H, m), 7.80 (1H, s), 7.89-7.92 (3H, m), 8.04 (1H, s), 8.06 (1H, s), 9.15 (1H, d, J 7); m/z (ES+) 375 (M++H).