Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(O)(=[O:3])=[O:2].[K].[Cl:15]S(O)(=O)=O>>[Cl:15][S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:2]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Agent: [K]
Product: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-Chlorosulfonylbenzoic acid is prepared by procedures described in (J. Chem. Soc., Vol. 121, 2022-26, 1922). A 250 mL flask equipped with condenser, CaCl2 drying tube and magnetic stirrer is charged with 35.1 g (0.146 mol) of potassium 4-sulfobenzoic acid and 50 mL of chlorosulfonic acid. The flask is placed in an oil bath and warmed to 100° C. After 1 hour at temperature, the reaction mixture is homogeneous. The reaction mixture is cooled and poured onto 300 g of crushed ice. The white precipitate is collected by filtration and washed 3 times with 100 mL portions of cold water. After air drying the solid is placed in a vacuum oven at 65° C. to yield 26.7 g of 4-chlorosulfonyl benzoic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.I[CH3:23]>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:23])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethlylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22]([CH2:23][CH2:24][C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.58 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.87 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:36][CH2:35][CH:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([N:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]3=[O:1])[CH2:16][CH2:15]2)[CH:18]=1)=[O:25]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: OCC1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1c2ccccc2CC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.25 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH:14]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[N:26][O:27][CH3:28])[CH2:21][CH2:20]3)=O)=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+:41]>C(O)(=O)C>[CH3:28][O:27][N:26]=[C:22]1[C:23]2[C:19](=[CH:18][C:17]([C:15]3[NH:41][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:36])=[CH:11][CH:10]=4)=[CH:13][C:14]=3[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CON=C1CCc2cc(C(=O)C(CC(=O)c3ccc(OCCN(C)C)cc3)c3ccncc3)ccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CON=C1CCc2cc(-c3[nH]c(-c4ccc(OCCN(C)C)cc4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A solution of the product of Step 4 (0.45 g, 1 mmol) and ammonium acetate (0.77 g, 10 mmol) in glacial acetic acid (15 ml) was heated under reflux for 3 hours. After cooling to room temperature the reaction mixture was concentrated in vacuo and saturated sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo to afford the title compound (0.47 g, 100%); MS(ES+) m/e 467 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH:5]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([C:8]2[N:13]=[C:12]([C:14](=[NH:15])[O:1][CH2:2][CH3:3])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: CC[O-]
Reactant: N#Cc1cncc(C2CC2)n1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.9 %

Procedure:
Sodium ethoxide (140 mg, 2.06 mmol) was added to a solution of 6-cyclopropylpyrazine-2-carbonitrile (150 mg, 1.03 mmol) in ethanol (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (250 mg). MS (ES+) (M+H) 192.1012
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=O)[CH:4]=1)[NH2:2].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[NH2:15][C:14]1[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: NNc1cc[nH]c(=O)c1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Yield: 33 %

Procedure:
Following the procedure for Example 282A Step 1, 4-hydrazinylpyridin-2(1H)-one was heated at 80° C. overnight with 4,4-dimethyl-3-oxopentanenitrile. The reaction mixture was concentrated, triturated with DCM, and purified using silica gel chromatography eluting with a MeOH/DCM gradient (2-10%) to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H-one (307 mg, 33% yield). 1H NMR (300 MHz, DMSO d6) δ 1.18 (s, 9H), 5.43 (s, 1H), 5.47 (s, 2H), 6.55 (s, 1H), 6.66 (m, 1H), 7.37 (d, 1H), 11.40 (s, 1H); LC-MS (ESI) m/z 233 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][N:35]([CH3:39])[CH2:36][C:37]#[CH:38]>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.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][N:35]([CH3:39])[CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), 1-dimethylamino-2-propyne (0.070 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 4% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, toluene, methanol-ether and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.06 g of the title compound as a tan solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]([CH3:9])[NH:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:3]2[C@@H:4]([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C@@H:2]2[CH3:1])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C[C@H]1CC(=O)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
trans-2,6-Dimethylpiperidin-4-one (93; 5.2 g, 39 mmol) was dissolved in CH2Cl2 (100 mL) and triethylamine (22 mL, 155 mmol) was added. The solution was stirred and treated with 4-chlorobenzenesulfonyl chloride (9.2 g, 43 mmol). The mixture was stirred for 24 hr and then partitioned between water (300 mL) and CH2Cl2 (300 mL). The organic layer was washed with 0.2 N citric acid, water, brine, dried over Na2SO4, filtered and the solvent evaporated. The residue (6.7 g) was purified by flash chromatography, eluting with EtOAc-hexane (1:3) mixture to yield 3.6 g (35%, 2 steps) of product 94.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:38]([O:45][C:46]1[C:51]([CH2:52][NH:53][CH2:54][CH2:55][OH:56])=[C:50]([CH3:57])[CH:49]=[C:48]([CH3:58])[N:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]1[C:51]([CH2:52][N:53]([CH2:54][CH2:55][OH:56])[C:4](=[O:6])[C:3]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[Cl:1])=[C:50]([CH3:57])[CH:49]=[C:48]([CH3:58])[N:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(F)c(C(=O)O)c1Cl
Reactant: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C(=O)N(CCO)Cc2c(C)cc(C)nc2OCc2ccccc2)c1Cl
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
To a solution of 2-chloro-6-fluoro-3-methoxy-benzoic acid (1.00 g, 4.89 mmol) in anhydrous DMF (30 mL) were added HATU (2.30 g, 5.85 mmol) and TEA (1.36 mL, 9.76 mmol). The reaction mixture was stirred for 5 minutes, then 2-[(2-benzyloxy-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-ethanol (Cpd KK, 1.47 g, 5.12 mmol) was added as a solid in one portion. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with brine (2×200 mL), dried over sodium sulfate, and concentrated under vacuum to give N-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-2-chloro-6-fluoro-N-(2-hydroxyethyl)-3-methoxybenzamide (124a, 2.31 g, 100%) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6](=[O:18])[C:5]2([CH3:20])[CH3:19].[CH:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[CH:27][CH:26]=1)([CH3:23])[CH3:22]>>[CH2:14]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:33](=[O:34])[CH2:32][CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH:21]([CH3:22])[CH3:23])=[CH:26][CH:27]=3)=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:5]([CH3:19])([CH3:20])[C:6]1=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)Oc1ccc(CCC(=O)Cl)cc1
Reactant: CCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Product: CCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccc(OC(C)C)cc3)c([N+](=O)[O-])cc21

Procedure:
N-(1-Butyl-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-(4-isopropoxy-phenyl)-propionamide is prepared from A4 (500 mg) and 3-(4-isopropoxy-phenyl)-propionyl chloride (1.01 g; 5.5 mmol) as described in Example 1a. The crude material is purified by flash chromatography eluting with light petroleum/EtOAc (6:1) to give the compound (791 mg).
Reaction SMILES: BrC1C=CC([C@@H]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])C)=CC=1.[CH3:27][Mg]Br>C1COCC1>[OH:25][C:23]([CH3:24])([CH3:27])[CH2:22][C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:26])[NH:10][CH2:15][CH2:14]1
Reactant: C[Mg]Br
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl -1,3-oxazinan-2-one (12 g, 28.8 mmol) in anhydrous THF (100 mL) was added dropwise methylmagnesium bromide (48 mL, 144 mmol) at −78° C. under nitrogen. The mixture was stirred at rt for 1 h. The reaction mixture was quenched with aqueous NH4Cl solution (50 mL) in ice water bath. The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford (S)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)[CH2:20][CH2:21]1
Reactant: N#CCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Yield: 68 %

Procedure:
A mixture of 15 parts of 4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo [4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile and 400 15 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybis-propane, yielding 10 parts (68%) of N-[1-(2-aminoethyl)-4-piperidinyl]-3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine; mp. 174.5° C. (50). In a similar manner there were also prepared:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[C:7]([O:11]C(=O)C)[C:6]=2[CH:15]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[C:7](=[O:11])[C:6]=2[CH:15]=1
Reactant: CC(=O)Oc1c(C)oc2ccc(Br)cc12
Agent: Cl
Solvent: CO
Product: CC1Oc2ccc(Br)cc2C1=O
Temperature: 75 °C
Yield: 91.9 %

Procedure:
A suspension of acetic acid 5-bromo-2-methyl-benzofuran-3-yl ester (18.9 g, 70.4 mmol) in methanol (232 mL) and a 1 M aqueous HCl solution (44 mL) is heated under reflux (75° C.) for 7 h. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is diluted with water and extracted three times with diethyl ether. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a yellow oil (14.7 g, 64.7 mmol, 92%). MS (ES+): 227 (M(C9H779BrO2)+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCCC1
Yield: 70.1 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with pyrrolidine (0.45 ml, 5.4 mmol) to give the title compound (189 mg, 70%) as a solid, except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 1-5% methanol in DCM); NMR Spectrum 1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum 500.
Reaction SMILES: [CH2:1]([C:3]1([C:13](=[O:17])[C:14](O)=[O:15])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([C:3]1([C:13](=[O:17])[C:14]([Cl:27])=[O:15])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC1=CC(CC)(C(=O)C(=O)O)CC(CC)=C1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC1=CC(CC)(C(=O)C(=O)Cl)CC(CC)=C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a 3 L volume four-necked flask, 2-(1,3,5-triethylphenyl)-2-oxoacetic acid (8-b) (214.8 g), toluene (anhydrous) (740 ml), and dimethylformamide (anhydrous) (22.8 ml) were added under a nitrogen atmosphere. After the temperature was raised to about 50° C., thionyl chloride (131 g) was added. The resulting mixture was stirred at 50° C. for 2 hours, and concentrated under reduced pressure to give 204.5 g of 2-(1,3,5-triethylphenyl)-2-oxoacetyl chloride (6-b).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br.C(N(CC)CC)C>ClCCl.BrN1C(=O)CCC1=O>[C:1]([N:9]1[CH2:15][CH2:14][CH:13]([Br:21])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN(C(=O)c2ccccc2)c2ccccc21
Reactant: BrBr
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Temperature: 25 °C

Procedure:
1-Benzoyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.6 (54.2 g, 205 mmol), N-bromosuccinimide (3.6 g, 20.4 mmol) and bromine (11.1 ml, 214.7 mmol) were dissolved in dichloromethane (1.0 liter). Triethylamine (30 ml, 215 mmol) was added dropwise over 30 minutes then the reaction mixture was heated at reflux for 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added and the reaction mixture was heated at reflux for a further 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added again and the reaction mixture was heated at reflux for a further 4 h. On cooling to room temperature, the reaction solution was washed with 5% aqueous sodium metabisulfate solution (150 ml) and the aqueous phase was diluted with water (600 ml). The organic phase was separated, washed with saturated Na—HCO3 (aq), dried over sodium sulphate and filtered. The filtrate was diluted with EtOAc (100 ml), filtered through a silica pad (eluant; CH2Cl2) and reduced in vacuo to yield the title compound (73.6 g) which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[Cl:25][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)c(Cl)c1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dichlorophenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 4-(3,4-dichlorophenyl)-2-(N,N-diethylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 157°-158° C.