Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@:9]([O:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[K+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[C:1]1([CH2:7][CH2:8][C@:9]([O:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)([CH2:13][CH2:14][CH3:15])[CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[C@](CCO)(CCc1ccccc1)OCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCC[C@](CC=O)(CCc1ccccc1)OCOc1ccc(-c2ccccc2)cc1

Procedure:
To a mixture of crude (R)-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanol (XI, EXAMPLE 8, 91.1 wt %, 15.40 g, 34.68 mmol) in methylene chloride (47 ml) at 0° is added a solution of potassium bromide (0.4057 g, 3.409 mmol, 0.098 equiv) and sodium bicarbonate (1.557 g, 18.53 mmol, 0.53 equiv) in water (20.5 ml) followed by 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, free radical (0.3060 g, 1.776 mmol, 0.051 equiv.). Aqueous sodium hypochlorite (13.4 wt %/vol, 26.6 ml, 47.88 mmol, 1.38 equiv) is then added by syringe pump over 1 hr while maintaining 1-5°. A solution of sodium thiosulfate pentahydrate (0.5182 g, 2.088 mmol, 0.0602 equiv) in water (14 ml) is then added. The phases are separated at 0° and the aqueous phase is washed with 2×50 ml methylene chloride. The organic phases are immediately filtered through magnesol (50.25 g) and rinsed through with methylene chloride (400 ml). The extracts are concentrated to an oil (30 g) and hexane (500 ml) is added. The mixture is concentrated to 250 g net weight and hexane (100 ml) added. The mixture is concentrated to 186 g net weight and pentane (300 ml) added. The resultant slurry is cooled to −50° and the desired product collected by vacuum filtration, washed with −50° pentane (100 ml) and dried to give a solid, analytically pure to give the title compound, mp=47.0-48.5°; TLC Rf=0.41 (ethyl acetate/hexane, 10/90); HPLC rt=10.95 min; NMR (CDCl3) 9.79, 7.53, 7.40, 7.26, 7.20-7.08, 5.40, 2.67, 2.65-2.56, 1.99, 1.76, 1.38, 0.93 δ; CMR (CDCl3) 201.83, 156.90, 141.69, 140.68, 134.82, 128.72, 128.47, 128.29, 128.24, 126.77, 125.99, 116.03, 87.19, 80.36, 50.14, 39.21, 39.14, 29.74, 16.86, 14.45 δ; MS (CI, NH3) m/z (relative intensity) 420 (3.5), 220 (100); [α]25D=14 (C=1.0, methylene chloride).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]2[CH2:16][CH2:17][C@@H:12]1[CH:13]([C:21](O)=[O:22])[CH:14]2[C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:22][CH2:21][CH:13]1[CH:14]([CH2:18][OH:19])[C@H:15]2[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C@@H:12]1[CH2:17][CH2:16]2
Reactant: O=C(O)C1C(C(=O)O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1[C@@H]2CC[C@H]1C(CO)C2CO
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of (1R,4S)-7-(benzyloxycarbonyl)-7-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (L) (2.33 g, 7.30 mmol) in THF (50 mL) was added N-methylmorpholine (2.00 mL, 18.25 mmol). The mixture was cooled to −25° C. before adding methyl chloroformate (1.41 mL, 18.25 mmol) dropwise. The mixture was stirred at −25° C. for 20 minutes and the solid was removed by filtration. The solution was carefully added to a solution of NaBH4 (1.65 g, 43.80 mmol) in water (100 mL) at 0° C. The mixture was stirred for 1 hour at room temperature. The acetone was removed under vacuum and the aqueous phase was extracted with EtOAc (×3). The combined organic phases were washed with 1 M NaOH, dried over MgSO4 and concentrated under vacuum to give (1R,4S)-benzyl 2,3-bis(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LI) as a colorless oil (1.85 g, 6.35 mmol, 87% yield). 1H NMR (CDCl3) δ ppm 1.40 (brs, 1H), 1.54 (brs, 1H), 1.63 (brs, 2H), 1.81 (brs, 1H), 1.98 (brs, 1H), 3.50-3.56 (m, 1H), 3.58-3.67 (m, 2H), 3.69-3.78 (m, 1H), 4.10 (brs, 2H), 5.09 (brs, 2H), 7.34 (brs, 5H); ESIMS found for C16H21NO4 m/z 292 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:14][N:15](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:9][CH2:8][C:6]1[C:5]([O:10][CH3:11])=[CH:4][C:3]([O:12][CH3:13])=[C:2]([CH:7]=1)[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: COc1cc(OC)c(CO)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COc1cc(OC)c(CO)cc1C#N
Temperature: 90 °C
Yield: 51 %

Procedure:
To a solution of (5-bromo-2,4-dimethoxy-phenyl)-methanol (2.75 g, 11.13 mmol) in dimethylformamide (15 mL) at room temperature was added zinc cyanide (784 mg, 6.678 mmol). The reaction mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (772 mg, 0.668 mmol) was added. The reaction mixture was heated at 90° C. for 12 h. After the reaction mixture was cooled to room temperature, it was diluted with diethyl ether (100 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40-50% ethyl acetate in hexanes yielded 5-hydroxymethyl-2,4-dimethoxy-benzonitrile as a white solid (1.089 g, 51%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.65 g, 0.0019 mol), 3-methylsulfonylphenylboronic acid (0.35 g, 0.0018 mol), sodium carbonate (0.314 g, 0.0029 mol), DMF (25 mL) and water (6 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.069 g, 0.00099 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to yield the desired product [400 mg, 80%]. LC-MS (ESI): Calculated mass: 403.1; Observed mass: 404.0 [M+H]+ (RT: 1.36 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH:16]1[CH2:18][O:17]1)[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21].CCO>>[OH:17][C@H:16]([CH2:18][NH:21][CH3:20])[C@@H:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC(CC1CCOCC1)C1CO1
Reactant: CN
Solvent: CCO
Product: CNC[C@@H](O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with [1-oxiranyl-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid tert-butyl ester (150 mg, 0.55 mmol) dissolved in MeNH2/EtOH solution and stirred overnight at 30-40° C. Then the mixture was concentrated and used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:20]([CH2:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:21])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[CH2:22][N:20]([C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)NCC(=O)O)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosylsarcosylglycine and L-phenylalanyl-L-methionine benzyl ester are reacted according to the procedure detailed in Example 12, there is obtained N-t-butoxycarbonyl-L-tyrosylsarcosylglycyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[C-]#N.[Na+].[Na+].[I-].[CH3:36][N:37](C=O)C>O>[O:27]=[C:4]1[N:3]([CH2:28][CH2:29][CH3:30])[C:2]([C:36]#[N:37])=[N:10][C:9]2[N:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)[NH:6][C:5]1=2
Reactant: CN(C)C=O
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (4.0 g, 9.16 mmol), NaCN (0.67 g, 13.74 mmol), NaI (2.0 g, 9.16 mmol) and DMF (30 ml) were stirred for 48 hrs at 60° C. Reaction mixture was cooled to 20-25° C. and water was added and solid filtered off. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (2.6 g, 67%) as an off white solid.
Reaction SMILES: [NH2:1]C12CC3CC(CC(C)(C3)C1)C2.N[C:14]1([CH3:24])[CH:21]2[CH2:22][CH:17]3[CH2:18][CH:19](C[CH:15]1C3)[CH2:20]2>>[CH3:15][CH:14]([C@@H:21]1[CH2:22][CH2:17][C@H:18]([NH2:1])[CH2:19][CH2:20]1)[CH3:24]
Reactant: CC12CC3CC(C1)CC(N)(C3)C2
Reactant: CC1(N)C2CC3CC(C2)CC1C3
Product: CC(C)[C@H]1CC[C@@H](N)CC1

Procedure:
From SYNCHEM OHG, Felsberg-Altenburg, D-34587, Germany: 1-amino-3-methyladamantane; 2-amino-2-methyladamantane.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[C:7]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br)#[N:8]>CN(C=O)C>[OH:3][CH2:2][CH2:1][O:4][CH2:12][C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[C:7]#[N:8]
Reactant: OCCO
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(COCCO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A solution of ethylene glycol (7.5 g) in DMF (50 ml) under nitrogen at 0° C. was treated portionwise with sodium hydride (1.35 g) and stirred for 0.5 h. 3-Cyanobenzylbromide (4.74 g) was then added and the solution was allowed to warm to room temperature and stirred for 4 h. The solution was then concentrated in vacuo to remove the DMF. The residue was taken up in EtOAc, washed with phosphate buffer (pH=6.5) and water, dried (MgSO4) and concentrated in vacuo. The residue was then purified by chromatography (Biotage, 2×90 g) eluting with 40-60° C. petroleum ether-EtOAc (1:1) to give the title compound (2.62 g). LCMS RT=2.07 min.
Reaction SMILES: [CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C>[CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:22])(=[O:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cn1ncc2c(c1=O)S(=O)CCNC2Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1ncc2c(c1=O)S(=O)(=O)CCNC2Cc1ccccc1
Yield: 55 %

Procedure:
A mixture of 0.60 g (1.98 mmol) of 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone-1-oxide, 1.92 ml of glacial acetic acid and 1.2 ml of 30% aqueous hydrogen peroxide are left to stand for a day. The precipitated crystals are filtered, washed acid free with water and dried in an exsiccator. In this way 0.35 g (55%) of the title compound are obtained with a melting point of 288-290° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([N:11](S(C)(=O)=O)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[Cl:20].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[Cl:20]
Reactant: COC(=O)c1c(Cl)cc(N(S(C)(=O)=O)S(C)(=O)=O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1c(Cl)cc(NS(C)(=O)=O)cc1Cl

Procedure:
The mixture of 100 mg of 2,6-dichloro-4-[bis(methanesulfonyl)amino]benzoic acid methylester, 3 ml of an aqueous solution of 1N sodium hydroxide and 10 ml of ethanol was stirred. After the solvent was removed, the obtained substance was treated by an ordinary method using ethyl acetate as an extractant to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1([CH:27]([CH3:29])[CH3:28])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:30]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:30])([CH:27]([CH3:29])[CH3:28])[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C1(CCO)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (60 mg, crude) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (29 mg, 0.75 mmol) was added to the mixture in portions at rt. The mixture was stirred overnight at rt. The mixture was quenched with water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give two isomers.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9](Cl)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([N:25]3[CH2:26][CH2:27][N:22]([CH:20]=[O:21])[CH2:23][CH2:24]3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=CN1CCNCC1
Reactant: Nc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: Nc1ncnc2c(N3CCS(=O)CC3)nc(N3CCN(C=O)CC3)nc12

Procedure:
This compound was prepared analogous to Example 181 from 8-amino-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 270°-272° C., decomp.) and N-formyl-piperazine at 130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]([OH:13])=O)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:39]1([CH2:45][C:46]2[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=2)[O:49][CH2:50][CH2:51][CH2:52][NH2:53])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[N:39]1([CH2:45][C:46]2[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=2)[O:49][CH2:50][CH2:51][CH2:52][NH:53][C:11](=[O:13])[CH2:10][S:9][CH2:8][CH2:7][NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CCOC(=O)NCCSCC(=O)O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
There was dissolved 2.5 g (0.012 mol) of 2-[2-(ethoxycarbonylamino)ethylthio]acetic acid in 60 ml of dichloromethane and added 1. 8 5 g (0. 0 12 mol) of HOBt and 2.5 g (0.012 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.0 g (0.012 mol) of 3-[3-(piperidinomethyl)phenoxy]propylamine and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: methanol =5 : 1) to give 4.23 g of the titled compound as oily matter.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)[C:4]=2[O:3]1.[NH:26]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32])N>C(O)C>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:26]([C:28]5[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=5)[C:31]#[N:32])[N:21]=[CH:20][CH:19]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: N#Cc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Solvent: CCO
Product: N#Cc1cccc(-n2nccc2-c2nn(-c3cccc4c3OC(F)(F)O4)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 3-hydrazino-benzonitrile in ethanol as solvent according to the method described for example 91. MS: M=420.2 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]([C:25]2[N:26]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[N:27]=[C:28]3[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]3)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[C:11]([F:41])[CH:10]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:26]2[C:25]([N:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16](=[O:17])[NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:42])=[O:5])=[CH:10][C:11]=3[F:41])=[C:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[N:27]2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 10.9 %

Procedure:
3-(4-{3-[2-(4-Chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-3-fluoro-phenyl)-propionic acid tert-butyl ester (20 mg, 34 μmol) was dissolved in a 4 M solution of HCl in dioxane (190 μl) under an argon atmosphere. The solution was stirred for 14 h at ambient temperature, poured onto ice water/1 N aqueous NaOH solution 1/1 and extracted two times with TBME. The aqueous layer was acidified with 1 N HCl and extracted two times with iPrOAc. The extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, CH2Cl2/MeOH) to give the title compound (2 mg, 3.7 μmol; 12%) as yellow foam. MS: m/e=535.3 [M+H+].
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH2:7]([O:6][C:4](=[O:5])[C@H:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][CH:11]=1)[NH2:2])[CH3:8]
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](N)Cc1c[nH]c2cc(Cl)cc(Cl)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dichloro-3-indolyl)propanoate (1.10 g, 3.65 mmol) in acetic acid (200 mL) and add activated zinc dust (1.25 g, 19.2 mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo to give a white oil. Take the white oil up in ethyl acetate (200 mL) and treat with saturated sodium hydrogen carbonate (500 mL). Filter the resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (1.02 g, 98%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[N:6][C:7]=1[Cl:8].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:11][CH2:12][C:4]2=[N:3][C:2]=1[C:28]1[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)nc3)c(Cl)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (Intermediate EB) (150 mg, 0.371 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (97 mg, 0.445 mmol) and potassium carbonate (154 mg, 1.112 mmol) were combined in a microwave vial. Dioxane (2 ml) was added and the flask was sealed and deoxygenated by evacuation/N2 purge (×3). Pd(Ph3P)4 (42.8 mg, 0.037 mmol) was added, the mixture was de-oxygenated by evacuation/N2 purge (×3) and heated at 150° C. for 3 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a brown residue. The residue was purified by chromatography on silica eluting with 20-100% EtOAc in iso-hexane followed by 10% MeOH in DCM to afford ethyl 7-(3-chloro-2-(6-methylpyridin-3-yl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate: