Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:60]=[CH:59][C:6]([CH2:7][C:8]2[C:9]([Cl:58])=[C:10]([O:54][CH2:55][CH2:56]Cl)[C:11](Br)=[C:12]([CH:14]3[C@H:19]([O:20]CC4C=CC=CC=4)[C@@H:18]([O:28][CH2:29]C4C=CC=CC=4)[C@H:17]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:16]([CH2:44][O:45][CH2:46]C4C=CC=CC=4)[O:15]3)[CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:61]([Li])[CH2:62][CH2:63][CH3:64]>C1COCC1>[CH2:61]([O:20][C@@H:19]1[C@@H:18]([O:28][CH2:29][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:16]([CH2:44][O:45][CH2:46][C:60]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:59]=2)[O:15][CH:14]1[C:12]1[C:11]2[CH2:56][CH2:55][O:54][C:10]=2[C:9]([Cl:58])=[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:60][CH:59]=2)[CH:13]=1)[C:62]1[CH:17]=[CH:16][CH:44]=[CH:64][CH:63]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of compound 71 (1.16 g, 1.27 mmol) in THF (12.7 mL) was added dropwise n-butyllithium (2.5 M in hexane, 1.27 mL, 3.17 mmol) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 18 hours at −78° C. to 5° C. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 72 (493 mg, 48%) as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>CCOCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:16])=[CH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)ccc1-c1ncc(C=O)s1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Br)ccc1-c1ncc(C(C)O)s1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A suspension of 2-(4-bromo-2-methyl-phenyl)-thiazole-5-carbaldehyde (1.9 g, 6.7 mmol) in ether at 0° C. is treated with 3.0 M MeMgBr (5 ml, 15 mmol) in diethyl ether (50 ml). The reaction mixture is stirred for 2 hours then carefully diluted with water. Acidified with aq. sat. NH4Cl. The aqueous layer is extracted with DCM (2×100 ml). The combined organic layers are dried over magnesium sulphate, filtered and evaporated to dryness to give 1.80 g of crude product. The crude product is purified by flash chromatography on silica gel to give 1-[2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethanol (1.40 g).
Reaction SMILES: [OH:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]#[N:11])[CH2:6][CH2:5]1)[CH3:3].[Cl-].[NH4+].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C>[NH:14]1[C:10]([N:7]2[CH2:6][CH2:5][CH:4]([C@H:2]([OH:1])[CH3:3])[CH2:9][CH2:8]2)=[N:11][N:16]=[N:15]1
Reactant: C[C@@H](O)C1CCN(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)C1CCN(c2nnn[nH]2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-[(1R)-1-hydroxyethyl]-1-piperidinecarbonitrile (200 mg, 1.30 mmol) in DMF (5 mL) was treated with ammonium chloride (104 mg, 1.95 mmol) and sodium azide (126 mg, 1.95 mmol) at room temperature. The mixture was heated at 100° C. for 14 h. After allowing the mixture to cool, the solid was removed by filtration and washed with DMF. The filtrate was concentrated to give (1R)-1-[1-(1H-tetrazol-5-yl)-4-piperidinyl]ethanol, which was used without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.[NH3:15]>CO>[N:13]1[C:14]2[CH:5]([C:3]([NH2:15])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCCc2cccnc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCCc2cccnc21
Temperature: 100 °C

Procedure:
Methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (9 g.) was dissolved in methanol previously saturated with ammonia (270 ml.) and heated in a bomb at 100° C for 5 days. The solvent was removed and the residual oil triturated with hot petroleum ether (40°-60° ). The resultant solid was filtered and then recrystallised from ethylacetate giving the title compound as colourless needles mpt. 132° C (5 g.). Found: C, 67.7; H, 7.1; N, 16.0% C10H12N2O requires: C, 68.1; H, 6.9; N, 15.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23]C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[N:9]=[CH:8][NH:7][C:6]2=[O:23]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCN(C)CC1
Temperature: 95 °C
Yield: 65.4 %

Procedure:
A mixture of 6-methoxy,7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-phenoxyquinazoline (960 mg, 2.4 mmol) and 2M hydrochloric acid (20 ml) was heated at 95° C. for 2 hours and allowed to cool. The solution was basified with solid sodium hydrogen carbonate, the water removed by evaporation and the residue azeotroped with toluene. The residue was washed exhaustively with methylene chloride, the washings were combined, -insolubles removed by filtration and the solvent removed by evaporation to give 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (500 mg, 66%).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][CH:6]([CH3:39])[CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:14]=[C:15]([OH:21])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:5][CH:6]([CH3:39])[CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=3)[O:23]2)[CH:14]=[C:15]([O:21][CH2:3][CH2:2][Br:1])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])(=[O:9])=[O:10]
Reactant: BrCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
1,2-Dibromoethane (1.12 mL, 13 mmol) was added to a solution of trans-2-[3-(2-hydroxypropylsulfonyl)-4-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (331 mg, 0.65 mmol) in DMF (5 mL) containing potassium carbonate (550 mg, 3.9 mmoI). The reaction mixture was heated with stirring at 70° C. for 7 h and, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to dryness. The product was purified by flash column chromatography on silica gel using hexane-ethyl acetate (2:1, v/v) as the eluant Rf 0.42 (hexane-ethyl acetate; 1:2, v/v); NMR (CDCl3) δ 1.06 (t, CH2CH2CH3), 1.25 (d, CH2CHOHCH3), 1.90 (m, CH2CH2CH3), 3.74 (t, CH2CH2Br), 3.83 (s. OCH3 ), 3.88 (s. 2OCH3). 5.16-5.28 (m, H-2 & H-5), 6.62 (s. 2H, C5ArH), 7.28 and 7.54 (2d, 2H, C2ArH).
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[C:11]([CH:21]=[CH2:22])(O)[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:25]>C(O)(=O)C>[C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[C:11](=[CH:21][CH2:22][Br:25])[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC1(O)c2ccccc2CCc2cc(-c3ccccc3)ccc21
Reactant: Br
Solvent: CC(=O)O
Product: BrCC=C1c2ccccc2CCc2cc(-c3ccccc3)ccc21
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
A suspension of the above alcohol (1.56 g, 5.06 mmol) in acetic acid (15 mL) was stirred and treated at 15° C. with 15% solution of hydrogen bromide in acetic acid (10 mL) over 15 min. The mixture was stirred at 15° C. for 30 min and then at laboratory temperature for 1.5 h and evaporated in vacuo. The rest of acetic acid was removed by addition of 40 mL xylene and evaporation in vacuo and the residue was chromatographed in a short column of silica gel Fluka 60 (75 g, benzene). The benzene solutions were evaporated in vacuo to yield 1.58 g (87.5%) of 2-phenyl-5-(2-bromo-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Chroman-4-one (46.5 g, 314 mmol) was dissolved in pyridine (160 ml) and hydroxylamine hydrochloride (51 g, 734 mmol) was added to this solution. The solution was refluxed for 8 hours and then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was filtered, washed with diisopropylether, and dried to afford chroman-4-one oxime (22.9 g, 275 mmol, 88%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([O:30][CH3:31])[CH:29]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COc1cncc(Br)c1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cncc(OC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-bromo-5-methoxypyridine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:7]([NH:15][C:16]([N:2]([CH3:1])[CH2:3][CH:4]([CH3:6])[CH3:5])=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNCC(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C)C(=S)NC(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mmol, 4.45 mL) in 40 mL of CHCl3 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol, 4.95 mL). After stirring for 45 min, the solution was concentrated to yield the title compound as a plane yellow solid (9.22 g, 100%). 1HNMR (400 MHz, CDCl3; 2:1 mixture of rotamers) δ 7.86 (d, 2H), 7.60 (t, 1H), 7.50 (t, 2H), 3.90 (d, 2H), 3.44 (s, 3H), 3.41 (d, 2H), 3.27 (s, 3H), 2.35-2.32 (m, 1H), 2.13 (m, 1H), 1.06 (d, 6H), 0.90 (d, 6H).
Reaction SMILES: C([O:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O)C>O>[Br:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:4](=[O:3])[NH:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)NCCc1cccc(Br)c1
Solvent: O
Product: O=C1NCCc2cc(Br)ccc21

Procedure:
A suspension of N-ethoxycarbonyl-m-bromophenethylamine (6.87 g, 25.25 mmol) in polyphosphoric acid (50 mL) is heated to reflux for 5 min. When the mixture cools, H2O is added and the resulting solution extracted with EtOAc (1×300 ml). The organic phase is dried and concentrated in vacuo and the residue chromatographed (silica gel, EtOAc) to give 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[ClH:12].[Cl:1][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: OCc1ccncc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: ClCc1ccncc1
Yield: 76 %

Procedure:
A mixture of 37.0 g (0.25 mole) of 4-hydroxymethylpyridine hydrochloride and 150 ml of thionyl chloride is heated under reflux for 2 hours. After cooling, 250 ml of benzene are added to the reaction mixture, followed by filtering and washing the precipitate with benzene. There are obtained 32.0 g of 4-chloromethylpyridine hydrochloride (76% of theory); m.p. 171-172° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([Si:9]([CH3:32])([CH3:31])[O:10][C@H:11]([C:24]1[CH:25]=[N:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:8])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[C:5]([Si:9]([CH3:31])([CH3:32])[O:10][CH:11]([C:24]1[CH:25]=[N:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:12][NH:4][CH2:3][CH2:1][OH:2])([CH3:6])([CH3:7])[CH3:8]
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CNCCO)c1ccc(Cl)nc1

Procedure:
A solution of ethanolamine (1.2 mL), (R)-toluene-4-sulfonic acid 2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl ester (2.2 g) and diisopropylethylamine (1.3 mL) in DMSO (5 mL) was heated at 80° C. for 4 h. After cooling, the reaction solution was diluted into ethyl acetate, washed with water (2×), brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-3a) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:6].[C-:14]#[N:15].[K+]>CO.C(OCC)(=O)C>[C:9]1([CH3:13])[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2([C:14]#[N:15])[CH2:4][CH2:3][CH2:2][O:6]2)[CH:8]=1
Reactant: Cc1cccc(C(=O)CCCCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C2(C#N)CCCO2)c1
Temperature: 35 °C

Procedure:
To a solution of Example 91B (1.56 g, 8 mmol) in MeOH (15 mL) was carefully added KCN (0.8 g, 12.3 mmol) and the mixture was warmed at 35° C. for 48 hours. The mixture was diluted with 50 mL ethyl acetate, washed with conccentrated aqueous NaHCO3 (20 mL) and brine (10 mL). The aqueous solution was oxidized with excessive NaC100. The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound as an oil which was used directly for the next step (1.35 g, 90%). LC-MS: m/z (M+H): 161.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=3)[C:7]([CH3:17])=[C:6]2[CH3:18])=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1c(C)n(Cc2ccccc2Br)c2ccc(C(=O)O)cc12
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 38, using 1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide and the (4-(ethoxycarbonyl)phenyl)boronic acid instead of the phenylboronic acid. ESI-MS (m/z): 428 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH2:12].O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:12]
Reactant: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)cc(Br)c1N
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 109a (5.0 g, 20 mmol) in ethyl acetate (100 mL) was added SnCl2.2H2O (22.6 g, 100 mmol). The reaction was heated at reflux for 2 h. After cooled to room temperature, the reaction mixture was poured into aqueous Na2CO3 (200 mL) and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109b as a dark red liquid (4.3 g, 97%). LCMS: [M+H]+ 223. 1H NMR (500 MHz, CDCl3) δ 6.97 (d, J=2.5 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 3.67 (bs, 4H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(O)C>[CH:10]1([CH2:9][N:6]2[C:7](=[O:8])[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=3[CH3:27])=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[N:13][C:5]2=3)[CH2:12][CH2:11]1
Reactant: O=c1c(Br)nc2cccnc2n1CC1CC1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1cc(F)ccc1-c1nc2cccnc2n(CC2CC2)c1=O
Yield: 45.3 %

Procedure:
To 200 mg (0.71 mM) of 2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one and 25.3 mg (0.036 mM) of bis(triphenylphosphine) palladium(II)chloride in 1 ml of dimethylformamide were added 142.9 mg (0.93 mM) of (4-fluoro-2-methylphenyl)boronic acid, 0.1 ml of ethanol and 715 μl of a 2M aqueous solution of sodium carbonate. The reaction mixture was then refluxed for 20 h under stirring. Water and ethyle acetate were added. The organic layer was separated, washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give, after evaporation, 100 mg of 4-(cyclopropylmethyl)-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one as a white solid. (Yield: 45.3%)
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[C:36]3[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=3[CH:47]=2)=[CH:29][N:28]=1>CC(N(C)C)=O>[CH2:45]([NH:44][C:42](=[O:43])[NH:41][C:39]1[S:40][C:36]2[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:34][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:7]4[CH2:6][CH2:5][C:4]([C:3]([F:2])([F:15])[F:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]4)=[N:28][CH:29]=3)=[CH:47][C:37]=2[N:38]=1)[CH3:46]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(Cl)nc3)cc(-c3ccccn3)c2s1
Reactant: CCOC(=O)C1(C(F)(F)F)CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To the solution of ethyl 4-(trifluoromethyl)piperidine-4-carboxylate hydrochloride (0.1 g, 0.44 mmol) in DMA (5.0 mL) was added DIPEA (0.25 mL, 1.46 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 1-(5-(2-chloropyrimidin-5-yl)-7-(pyridin-2-yl)benzothiazol-2-yl)-3-ethylurea (0.12 g, 0.29 mmol). The reaction was heated up to 80° C. for 16 h and after completion (by TLC), the mixture was poured into 50 mL of ice cold water, extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain an off white solid (0.09 g, 51%). 1H NMR (DMSO-d6): δ 1.15 (t, J=7.20 Hz, 3H), 1.20 (t, J=6.80 Hz, 3H), 1.45 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 3.21 (q, J=7.20, 2H), 4.15 (q, J=6.80 Hz, 2H), 4.32 (m, 2H), 6.86 (br s, 1H), 7.44 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.47 (m, 1H), 8.80 (m, 1H), 8.92 (s, 2H) and 10.56 (br s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].Cl>O1CCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCl)C(=O)OCC
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To 458 ml of dry tetrahydrofuran (THF) was added 13.4 g of 60% sodium hydride, and 160.6 g of diethyl malonate was added dropwise with stirring under ice-cooling. After addition, stirring was continued for 15 minutes, and 57.3 g of 1-bromo-4-chlorobutane was added. The mixture was stirred for 50 hours at room temperature. The reaction solution was poured into ice-cold water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to provide 26.8 g of the objective compound as colorless oil. B.p. 127–130° C. (5 mmHg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)C(C)C.CN>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][NH:46][CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy) methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.2 mL) and DIPEA (17 μl, 0.10 mmol) was added methylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were contaminated with an impurity; the crude material was re-purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylamino) acetamide (Example 13) as a light brown solid (6 mg, 12%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.32 (3H, s), 2.39 (3H, s), 3.28 (2H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1H, m), 8.37-8.30 (3H, m), 8.59 (1H, s), 8.80 (1H, s).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Add sodium cyanoborohydride (5.57 g, 88.78 mmol) to a solution of 6-fluoroindole (10 g, 73.99 mmol) in acetic acid (100 ml). Stir at room temperature for 30 minutes. Pour the reaction mixture into 5N sodium hydroxide and extract with ethyl acetate. Wash the combined organic phases with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Concentrated under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound as a colorless oil (7.69 g, 76%).