Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>O1CCCC1.C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 462 mg 3-Methyl-indole-1-carboxylic acid tert-butyl ester in 2.5 ml anhydrous tetrahydrofuran at −78° C. under argon is added 1.2 ml of a 2M LDA solution in THF/hexane and stirred at 0° C. for 30 min to complete the deprotonation. The reaction mixture is cooled to −78° C., 0.6 ml 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane are added, and stirred at 0° C. for 60 min. The reaction is quenched by the addition of 2 ml MeOH/water (1:1), diluted into water and extracted with ethylacetate. After evaporation of the solvent and purification on silica gel, 385 mg of 3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO.Cl[Ni]Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
Alternative Procedure: To a solution of 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (100 mg, 0.29 mmol) and NiCl2 (49 mg, 0.38 mmol) in methanol (1.0 mL) was added NaBH4 (14 mg, 0.38 mmol) portion-wise at 0° C. The reaction was stirred for 5 min then quenched with NaHCO3 and diluted with ethyl acetate. The reaction mixture was filtered through a pad of Celite and the layers separated. The aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel chromatography (10% ethyl acetate/hexane) provided 5-amino-4-bromo-2-cyclopentylphenyl methyl carbonate (49 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Yield: 68.3 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) was added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution was stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane (5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-20% ethyl acetate/hexanes) to give (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide (120 mg, 68%) as a white solid.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1.[CH3:15][C:16](Cl)([CH3:18])[CH3:17].[Cl-].CN1CCCC1=[O:27]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:27][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:13])[CH2:4]1
Reactant: CC(C)(C)Cl
Reactant: CC1(C)O[C@H](CCl)C[C@H](CC(=O)O)O1
Reactant: CN1CCCC1=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Solid tetrabutylammonium acetate obtained as above (111 g, 0.368 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (d) above (35 g, 0.125 mole) in HPLC grade 1-methyl-2-pyrrolidinone (504 ml) under argon. The resulting solution was stirred at 85° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf=0.63 for the chloride starting material; Rf =0.54 for the title compound (silica gel, Ethyl acetate:Hexane, 1:1, visualization by Ce(SO4)2 spray). GC: Rt =7.20 minutes (starting material) and 8.66 minutes (title compound).) After 11 hours the reaction was completed.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH:12]1([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)C1CCCCC1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C2CCCCC2)c2ccccc21
Yield: 45 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and cyclohexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 45%. 1NMR (DMSO-d6): δ δ 0.85 (t, J=6.8 Hz, 3H), 1.24-1.83 (m, 19H), 3.74 (t, J=6.9 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.59 (d, 3H), 12.34 (br s, isomer 1: 50%, 0.5H ), 13.00 (br s, isomer 2: 50%, 0.5H), both isomer are in the same proportion. 13C NMR (DMSO-d6): δ 14.33(CH3), 22.42 (CH2), 25.48 (CH2), 26.34 (CH2), 25.83 (CH2), 27.37 (CH2), 31.29 (CH2), 39.64 (CH2), 110.52 (CH), 119.78 (C), 123.48 (CH), 131.79 (CH), 143.27 (C═N), (C═O). HRMS (ES+) calcd for C21H30N3O2 (M+H+), m/e, 356.2328; found, 356.2333.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>O1CCCC1.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCOCCCCCCBr
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynyl ether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5 g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) in tetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogen for 20 mins. Copper (I) iodide (12.5 g) was then added to give a dark red/brown mixture that was heated to 50° C. for 23 h. The reaction mixture was then cooled to room temperature and filtered through a short silica pad (100 g). The pad was washed with additional tetrahydrofuran (15.6 L) and the resulting solution then concentrated under reduced pressure to give crude product (1382 g) as a viscous oil. This was purified by chromatography (7 kg silica) eluting with 5:1 petroleum ether:ethyl acetate followed by 2:1 petroleum ether:ethyl acetate to give the title compound (932.9 g) as an oil, LC RT=5.69 min, δ (DMSO-d6) 7.79 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55 (2H, t, J 6.6 Hz), 3.49 (2H, t, J 6.6 Hz), 3.42 (2H, t, J 6.6 Hz), 2.68 (2H, t, J 6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>C1COCC1.C(Cl)(Cl)Cl>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=1)[CH2:20][CH3:21]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCNCCC
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Yield: 74.4 %

Procedure:
Thionyl chloride (50 ml, 680 mmol) was added dropwise to a solution of (4-hydroxy-3-nitrophenyl)acetic acid (25 g, 127 mmol) obtained in 1) in THF (100 ml) at room temperature, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated, and the resultant residues were dissolved in chloroform (250 ml) and added dropwise over 1 hour to a solution of dipropylamine (35 ml, 255 mmol) in chloroform (300 ml) under cooling with ice-bath. After this addition, the reaction solution was washed with water and aqueous saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residues were crystallized from ethyl acetate-hexane, whereby N,N-dipropyl-(4-hydroxy-3-nitrophenyl) acetamide (26.5 g) was obtained as crystals with a mp of 55 to 57° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].O.[NH2:6][NH2:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C(O[Na])CCC>C1COCC1.CCCCO.O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:4]2[CH:1]=[CH:2][CH2:3][N:6]2[NH2:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NN
Reactant: C=CC#N
Agent: CCCCO[Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCO
Product: COc1ccc(CN2C=CCN2N)cc1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
Acrylonitrile (7.5 g, 141 mmol) is dissolved in THF (75 mL) and cooled at 0° C. and hydrazine monohydrate (7.41 g, 148 mmol) is added at the same temperature. The reaction mixture is brought to room temperature and stirred for 2 h. p-Anisaldehyde (20.1 g, 148 mmol) is added drop wise and stirred at room temperature for 10 h. The above reaction mixture is then concentrated to result red oil. To the above oil n-BuONa in 80 mL n-BuOH is added drop wise at 0° C. and brought to room temperature. The reaction mixture is heated at 120° C. for 3.5 h. After cooling it is poured onto 300 mL of cold water and extracted with 2×200 mL of Et2O. The ether layer is collected and washed with 3×100 mL of 1N HCl. The combined acidic layer is collected and neutralized with 50% NaOH. The mixture is again extracted with 200 mL of Et2O and washed with water. It is dried (Na2SO4) and concentrated to yield 1-(4-Methoxy-benzyl)-1H-pyrazol-2-ylamine as red oil. MS m/z 204.1 (M+1). Mixture of 1-(4-methoxy-benzyl)-1H-pyrazol-2-ylamine (1 g, 5.0 mmol) and diethyl ethoxymethylenemalonate (1 mL, 5.0 mmol) is heated at 120° C. for 5 h. It is cooled and then the desired compound is isolated by silica gel column chromatography. MS m/z 374.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(#N)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[S:38]([CH3:37])(=[O:40])=[O:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.16 g, 0.34 mmol) in acetonitrile at 0° C. was added triethylamine (0.043 g, 0.42 mmol), followed by the addition of methane sulfonylchloride (0.047 g, 0.41 mmol) and stirred at room temperature for 1 h under argon atmosphere. The solvents were removed in vacuo and the residue was triturated with water and filtered. It was washed with water an, acetonitrile and dried in vacuo to afford 0.11 g of material. 1H NMR (CD3OD/400 MHz) δ 8.62 (s, 1H), 8.55 (s, 1H), 7.61 (m, 1H), 7.0 (m, 2H), 6.53 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 4.49 (s, 2H), 2.95 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR (CD3OD/400 MHz)-111.70 (m) and −116.07 (m); ES-HRMS m/z 543.0515 (M+H calcd for C21H22BrF2N4O4S requires 543.0508).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[CH3:23]>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([NH:24][CH2:22][CH3:23])=[O:38])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc(Cc4ccccc4)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 353A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.32 (d, J=6.82 Hz, 3H) 2.41-2.49 (m, 4H) 3.16-3.29 (m, 6H) 3.38 (s, 2H) 3.89 (s, 2H) 4.53-4.60 (m, 1H) 6.75-6.82 (m, 2H) 6.93 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.23 (m, 2 H) 7.24-7.29 (m, 2H) 7.71 (m, 2H) 8.17 (t, J=5.68 Hz, 1H) 10.59 (s, 1H). ESI-MS: m/z 499.4 (M+H)+. mp=198.1-205.7° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=O.[OH-].[Na+]>C(Cl)Cl.O>[Cl:36][CH2:37][C:38]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)[C:3]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 0 °C
Reaction time: 13 h
Yield: 76 %

Procedure:
To an ice-cooled solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) and triethylamine (0.3 g) in methylenechloride (10 ml) was added chloroacetyl chloride (0.24 ml) in portions. The mixture was allowed to stir for 13 hours and then evaporated to dryness to give a residue. The residue was washed with H2O, dried and dissolved in EtOH (10 ml). To the solution was added conc-HCl (1 ml) and the solution was refluxed for 6 hours. The reaction solution was evaporated to dryness to give a residue and the residue was dissolved in methylene chloride and water. The solution was made basic with 1N-NaOH and the organic layer was washed with water, dried and evaporated to dryness to give crystals Recrystallization from ethyl acetate-isopropylether gave colorless crystals (0.88 g, 76%) 1H-NMR(200 MHz, CDCl3) δ: 1.21(3H,t), 4.21(2H,q), 4.83(2H,s), 6.02(2H,s), 7.02(2H,d), 7.29- 7.49(5H,m), 7.58-7.79(3H,m), 8.00 (1H,dd).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(Cl)Cl.B(Br)(Br)[Br:32].C([O-])(O)=O.[Na+]>C(=O)=O>[Br:32][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][C@@H:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc([C@@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](Nc1nc(Nc2cccc(CBr)c2)ncc1Cl)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Into a 1-neck round-bottom flask were added {3-[(5-chloro-4-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.26 g, 0.68 mmol) and methylene chloride (5 mL). To the mixture was added a solution of boron tribromide in methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when NaHCO3 (saturated aqueous solution, 10 mL) was added. The mixture was allowed to warm up to rt and DCM was added. The aqueous layer was extracted with DCM twice. The organic layers were combined, dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product (40 mg, 30%). LCMS for C19H19BrClN4O (M+H)+: m/z=432.9, 434.9.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[OH:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:33][CH2:32][CH2:31][OH:30])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Reactant: NCCO
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino) carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.18 (d, 1H, J=1.8 Hz), 7.80 (bs, 1H), 7.60 (m, 1H), 7.34-7.16 (m, 3H), 7.10 9t, 1H, 8.4 Hz), 6.85 (bdd, 1H), 6.62 (dd, 1H, J=1.5 and 8.1 Hz), 3.70 (t, 2H, J=4.8 Hz), 3.52 (t, 2H, J=4.0 Hz); LCMS: ret. time: 14.49 min.; purity: 97%; MS (m/e): 424 (MH|).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: CONCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CONCc1nc2c(N)nc3cc(-c4cccnc4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A stream of nitrogen was bubbled through a stirring suspension of 1-{4-amino-7-bromo-2-[(methoxyamino)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (0.590 g, 1.49 mmol),3-pyridineboronic acid (0.220 g, 1.79 mmol), and potassium carbonate (0.681 g, 4.93 mmol) in ethylene glycol dimethyl ether (10 mL) and water (5 mL) in a pressure vessel for 5 minutes. Dichlorobis(triphenylphosphine)palladium(III) (0.031 g, 0.045 mmol) was added and nitrogen was bubbled through for an additional 5 minutes. The pressure vessel was capped and placed in a 110° C. oil bath for 10 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-25% 1M ammonia/methanol in dichloromethane). The resulting yellow solid was crystallized from acetonitrile and isolated by filtration to yield 167 mg of 1-{4-amino-2-[(methoxyamino)methyl]-7-(pyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 195-197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[H][H]>CO.[Pd].ClCCl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc2cc(CC(=O)O)cc(C(=O)c3ccc(S(C)(=O)=O)cc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2cc(CC(=O)O)cc(Cc3ccc(S(C)(=O)=O)cc3)c2c1
Yield: 21.4 %

Procedure:
A solution of [6-methyl-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid (example 2-28) (70 mg, 0.183 mmol) in methanol (8 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1 mL/min and a 10% palladium on carbon catalyst cartridge at 30° C. under 10 bar hydrogen pressure. After the reaction was complete (monitored by TLC, 4% methanol in dichloromethane), the solvent was evaporated in vacuo. Reverse-phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) gave [4-(4-methanesulfonyl-benzyl)-6-methyl-naphthalen-2-yl]-acetic acid (14.4 mg, 21%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 7.83 (d, J=8.4 Hz, 2 H), 7.74 (d, J=8.7 Hz, 1 H), 7.66 (s, 1H), 7.60 (s, 1 H), 7.38 (d, J=8.4 Hz, 2 H), 7.32 (d, J=8.7 Hz, 1 H), 7.22 (s, 1 H), 4.48 (s, 2 H), 3.78 (s, 2 H), 3.02 (s, 3 H), 2.46 (s, 3 H); HRMS cald. for O21H20O4S (ESI+) [(M+Na)+] 391.0974, obsd. 391.0976.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[Cl:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[C:26]([N:31]2[CH2:32][CH2:33][N:34]([C:14]([CH:13]3[CH2:12][N:11]([S:17]([CH:20]([CH3:21])[CH3:22])(=[O:18])=[O:19])[C:10](=[O:23])[N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[O:16])[CH2:35][CH2:36]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Product: CC(C)S(=O)(=O)N1CC(C(=O)N2CCN(c3ncccc3Cl)CC2)N(c2ccc(F)cc2F)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 82, step 3) was coupled with 1-(3-chloropyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 527.8 ([M+H]+)