Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:4][CH2:5][C@@H:6]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
To a suitable reactor was added 4a (2 g, 6.18 mmol), CH2Cl2 (20 mL), DMAP (0.15 g, 1.24 mmol), and Et3N (1.37 g, 13.61 mmol) at 20-30° C. under N2. The mixture was cooled to 0-5° C., and MsCl (1.4 g, 12.36 mmol) in CH2Cl2 (3 mL) solution was added at this temperature. The mixture was warmed to 20-30° C. and stirred for 1 hr. H2O (10 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was washed with 20% NaCl aqueous solution (10 mL). The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford 5 (2.8 g) as a yellow solid in quantitative yield.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([NH2:36])=O)[CH:28]=[CH:29][CH:30]=1>O1CCCC1>[F:23][C:24]([F:42])([F:41])[C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](=[S:10])[NH2:36])[CH:28]=[CH:29][CH:30]=1
Reactant: NC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Lawesson's Reagent (4.55 g, 11.26 mmoles) is added to a colorless solution of 2-[(3-trifluoromethylphenyl)amino]-benzamide (5.22 g, 18.64 mmoles) in 100 ml of tetrahydrofuran at room temperature. The resulting mixture is stirred under nitrogen for one hour, and then heated at reflux for 2.5 hours. The solution is concentrated in vacuo, and purified by flash chromatography with a gradient of 5:1 to 3:1 hexane/ethyl acetate as eluant, to provide 3.01 g (55%) of a bright yellow solid 2-[(3-trifluoromethylphenyl)amino]-benzene thioamide, mp 106°-108° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23](=[O:30])[C:22]1=[O:31])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.ClCCl>[OH:30][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:22]1=[O:31]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol in THF (40.0 mL) was added a solution of iso-propyl magnesium chloride (7.90 mL, 15.9 mmol, 2.0 M in THF) dropwise at 0° C. over 5 min. The reaction mixture was stirred for 30 min upon which time colorless precipitate formed. After the solvent was removed under reduced pressure, the residue was dissolved in anhydrous dichloromethane (40.0 mL) and cooled to 0° C. followed by the addition of a solution of 1-pentyl-1H-pyrrolo[2,3-b]pyridine-2,3-dione (1.84 g, 8.44 mmol) in dichloromethane (10.0 mL). The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ethyl acetate and ether to afford the title compound (2.20 g, 73%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, 1H), 7.74 (dd, 1H), 7.08 (dd, 1H), 6.60 (s, 1H), 6.24 (s, 1H), 5.87 (dd, 2H), 3.78 (d, 2H), 1.77-1.67 (m, 2H), 1.33-1.28 (m, 4H), 0.85 (d, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 157.7, 148.9, 147.3, 147.2, 139.7, 131.1, 127.7, 119.3, 118.3, 107.1, 101.1, 97.8, 74.6, 40.7, 29.0, 27.0, 22.3, 14.4; MS (ES+) m/z 357 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:26])[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and azetidine hydrochloride (Aldrich, Cat. No. 414336). LCMS (M+H)+: m/z=499.2.
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CO)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccccc2)cc1

Procedure:
(-)-2-Phenoxypropanol [α]D25 = -38.95° (c. 0.9, CHCl3) was treated with tosylchloride in pyridine to give the corresponding (-)-2-phenoxypropyl tosylate of which 1.10 g. was reacted with LiPPh2 following Example 28 to give 0.87 g. of (+)-2-phenoxypropyl diphenylphosphine having [α]D25 = +27.90° (c. 3.03, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.O.N.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:17])[CH:8]=[CH:7]2
Reactant: O=c1ccc2cccc(Br)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: Clc1ccc2cccc(Br)c2n1

Procedure:
A suspension of 2.8 g (12.49 mmol) of 8-bromo-1H-quinoline-2-one in 20 ml of phosphorus oxychloride is refluxed for 90 minutes and the reaction mixture is cooled and then added dropwise to 200 ml of water. The aqueous solution is made basic with concentrated ammonia solution, the precipitate formed is filtered off and washed with water.
Reaction SMILES: [CH:1]([CH:3]([Br:6])[CH:4]=O)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1.C(O)(=O)C>C(O)C>[Br:6][C:3]1[CH:1]=[N:15][C:11]2[C:12]([CH:4]=1)=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=2
Reactant: COc1cccc(N)c1
Reactant: O=CC(Br)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)cnc2c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 20 %

Procedure:
For the synthesis of this starting compound, 1.80 g (12.3 mmol, 1.1 eq) of bromomalondialdehyde was first dissolved in 30 ml of ethanol, and 1.25 ml of m-anisidine was added. This reaction mixture is stirred over night at RT and, after the addition of acetic acid (20 ml), at 100° C. for 10 days. The solvent is subsequently removed in vacuum on a rotary evaporator, and the residual solid is partitioned between a water and an ethyl acetate phase. The aqueous phase is made alkaline with an ammonia solution, and insoluble particles were filtered off. The filtrate is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(#N)C>[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:6])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of 2,3-dimethylbenzoic acid (100 g, 666 mmol) in thionyl chloride (350 ml) was heated at 80° C. for 1 h, before cooling to room temperature and concentrating in vacuo. To the residue was added toluene (100 ml) and the solution was again concentrated in vacuo. The intermediate acid chloride was added to a mixture of 1-benzylimidazole (100 g, 632 mmol) and triethylamine (100 ml) in acetonitrile (1 l) and the reaction mixture was heated at reflux for 18 h. The reaction mixture was concentrated in vacuo and to the residue was added diethyl ether (500 ml) and ethyl acetate (50 ml). This solution was washed with water (500 ml) and saturated aqueous sodium hydrogen carbonate solution (500 ml), filtered through silica gel (100 g) and concentrated in vacuo to give the title compound (182 g).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:10]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[C:9]1=[O:31])C1C=CC=CC=1.O.[OH-].[Na+]>CS(O)(=O)=O>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:8][C:9](=[O:31])[C:10]([C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)=[C:11]2[N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1cc(-c2c(N3CCCCC3)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-c2c(N3CCCCC3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
A solution of 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-4-piperidin-1-yl-1H-quinolin-2-one (21 mg, 0.048 mmol) in 1 mL of CH3SO3H was stirred at 110° C. for 8 h, then cooled to rt. Treated with 20 mL of H2O, the mixture was neutralized to pH=7 with 2N NaOH solution and extracted with EtOAc (2×30 ml). The combined organic layers were washed with H2O (10 ml), brine (10 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-40% EtOAc/DCM) gave 4.5 mg (27%) of product as a yellow solild: 1H-NMR (CDCl3; 400 MHz) δ 10.9 (s, 1H), 7.83 (d, 1H, J=2.2 Hz), 7.45 (dd, 1H, J=8.6, 2.2 Hz), 7.18 (d, 1H, J=8.6 Hz), 6.50 (s, 1H), 3.00 (br s, 4H), 2.42 (s, 3H), 1.62-1.78 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C18H18ClN3O2, 344.1 (M+H), found 344.1.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:32][C:31]=2[C:41]2[C:42]([F:55])=[C:43]([NH:48]C(=O)OCC=C)[CH:44]=[CH:45][C:46]=2[F:47])[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[N:32][C:31]=2[C:41]2[C:42]([F:55])=[C:43]([CH:44]=[CH:45][C:46]=2[F:47])[NH2:48])[CH:27]=[CH:26][N:25]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Yield: 64 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate (5.11 g, 10.35 mmol) the title compound of Step G was obtained as a light yellow solid (2.71 g 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=5.5 Hz, 1H), 6.90-7.00 (m, 2H), 6.73 (d, J=5.5 Hz, 1H), 5.23 (s, 2H), 3.71-3.76 (m, 4H), 3.54-3.60 (m, 4H). MS (ESI): 409 [M+H]+.
Reaction SMILES: C([O:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[N:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])(=O)C1C=CC=CC=1.[BrH:24]>>[BrH:24].[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[N:15]=[C:11]1[NH:12][CH2:13][CH2:14][N:10]1[OH:9]
Reactant: O=C(ON1CCNC1=Nc1c(Cl)cccc1Cl)c1ccccc1
Agent: Br
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
A suspension of 45.3 g. of 1-benzoyloxy-2-[(2,6-dichlorophenyl)imino]-imidazolidine in 450 ml. of 48% strength hydrobromic acid is warmed to 80° for 4 hours. The resulting solution is poured onto ice and extracted with ether. The aqueous phase is evaporated in vacuo. The residue is distilled azeotropically five times with a mixture of ethanol/ethyl acetate. 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine hydrobromide is obtained by crystallization from a mixture of ethanol/ethyl acetate/ether. An analytically pure sample, m.p. 233°-234°, is obtained by recrystallization from methanol/acetonitrile.
Reaction SMILES: C[C:2]1([C:14]([O:16]C)=O)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:33]1COCC1>>[CH3:33][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:14][OH:16])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: COC(=O)C1(C)C=CC(c2ccccc2)=CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: Cc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-(1,1'-biphenyl)-4-carboxylic acid, methyl ester (1.43 g) in ER (25 ml) and THF (25 ml) was added over 5 min to LiAlH4 (420 mg) in ER (25 ml). The mixture was stirred at room temperature for 1 h and then cooled in ice. Aqueous NaOH (1 M, 2.1 ml) was added and after stirring (15 min) excess anhydrous Na2SO4 was added. The mixture was filtered and the filtrate evaporated to give a solid. Crystallisation from cyclohexanemethanol gave the title compound (1.04 g) m.p. 128°-31°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:29]1[CH2:30][CH2:31][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC(c2ccccc2)CC1

Procedure:
Using general procedure 1 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and 4-phenyl-piperidine (0.122 g, 0.76 mmol) gives the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1.[Cl-].[NH4+].[CH2:25]([OH:28])[CH2:26][OH:27]>>[N+:17]([C:16]1[C:11]([O:27][CH2:26][CH2:25][OH:28])=[N:12][CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1)([O-:19])=[O:18]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc(OCCO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
75 ml of toluene was added to 7.5 g of sodium hydride (60% in oil), and the mixture was cooled to 0° C., and 70 ml of ethylene glycol was added thereto over the course of 30 minutes. To the obtained solution was added 25.0 g (120 mmol) of 2-chloro-3,5-dinitropyridine, the temperature was raised to room temperature, and the mixture was stirred for 15 minutes. The resulting solution was added to 200 ml of a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with 200 ml of ethyl acetate. Washing the ethyl acetate extract with saturated saline, drying over anhydrous sodium sulfate, filtering and distilling under reduced pressure (bath temp. 40°-60° C., 40°-20mmHg) yielded yellow crystals, which were recrystallized from ethanol to obtain 23.2g (101 mmol) of 2-(3,5-dinitro-2-pyridyloxy)ethanol as pale yellow crystals (yield: 82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:11]=1)[C:8](=[O:25])[NH:7][CH:6]=[CH:5]2.[CH3:26][O:27][C:28]1[CH:33]=[N:32][CH:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[N:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)[N:11]=2)[C:8](=[O:25])[NH:7][CH:6]=[CH:5]3)[CH:31]=[N:32][CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Reactant: O=c1[nH]ccc2cc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c12
Solvent: CN(C)C=O
Product: COc1cncc(-c2cc3cc[nH]c(=O)c3c(Nc3ccc(N4CCOCC4)cc3)n2)n1

Procedure:
6-chloro-8-(4-morpholinophenylamino)-2,7-naphthyridin-1(2H)-one (30 mg, 0.084 mmol) was dissolved in DMF (1 mL) in a microwave vial and 2-methoxy-6-(tributylstannyl)pyrazine (40 mg, 0.1 mmol) was added followed by PdCl2dppf (6.1 mg, 0.0084 mmol) at room temperature. The vial was flushed with nitrogen and closed the cap and subjected to microwave irradiation at 135 C for 60 minutes. The reaction mixture was diluted with DMSO and purified by prep HPLC. The compound was isolated as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.96 (s, 1H), 8.33 (s, 1H), 7.68 (s, 1H), 7.67 (d, 2H, J=8.8 Hz), 7.38 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.57 (d, 1H, J=7.2 Hz), 4.0 (s, 3H), 3.69 (t, 4H, J=4.8 Hz), 3.04 (t, 4H, J=4.8 Hz); MS m/z 431.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(F)cc2)cc1

Procedure:
49.7 mg of solid beige-coloured 3-{4-[3-(4-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-fluorophenyl isocyanate.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](CO)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
A reaction flask was charged with (R)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (2.83 g, 8.5 mmol), and TBAF (11 mL, 1.0 M in THF, 11.0 mmol) in THF (10 mL) and stirred at rt for 20 h. The reaction mixture was concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give the title compound (1.72 g, 91%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 3-fluorobenzenesulfonyl chloride (124 mg, 0.639 mmol), the title compound was obtained as a solid (76 mg, 73% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: Cl
Solvent: CO
Product: COCCN1CCCc2ccc(CO[C@H]3CNCC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-methoxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-1-(2-methoxy-ethyl)-1,2,3,4-tetrahydro-quinoline as a light yellow oil; MS: 575 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][CH:24]=[CH:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=O)[C:29]2=[CH:28][CH:27]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:34]1[C:29]2[C:30](=[N:31][C:26]([CH:25]=[CH:24][O:23][CH3:22])=[CH:27][CH:28]=2)[CH2:32][O:33]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COC=Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (176 mg, 1.16 mmol) in THF (5 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.3 mL of a 1 M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(2-methoxy-vinyl)-7H-furo[3,4-b]pyridin-5-one (111 mg, 0.58 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is poured into cold 10% aqueous HCl solution (30 mL) at 0° C. The resulting mixture is stirred at 50° C. for 1 h and room temperature overnight. The solid which formed is collected by filtration and dried to give the title compound as a light brown solid (65 mg, 35%).