Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:16][C:15]1[C:10]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1cccnc1Cl
Reactant: CC1CNCC(C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(c2ncccc2Cl)CC(C)N1
Yield: 64.4 %

Procedure:
2,6-dimethylpiperazine (291 mg, 2.55 mmol) and 2,3-dichloropyridine (377.4 mg, 2.55 mmol) were charged to a microwave vial, dissolved in DMF (0.25 mL) and added with diisopropylethylamine (1.11 mL, 6.38 mmol). The reaction mixture was irradiated at 165° C. for 30 minutes. The reaction was complete as determined by TLC. After solvent removal the crud product was purified via flush column chromatography to afford 1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine in 64.4% yield (370 mg).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[C:15]([F:22])[CH:14]=1>CCCCCC.CCOCC>[C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=1[F:22])=[O:21])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)C1CSCCN1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C1CSCCN1C(=O)Nc1ccc(Cl)cc1F
Yield: 87.7 %

Procedure:
An emulsion of 14 g of 3-carbethoxythiomorpholine in 50 ml of n-hexane was added dropwise to a solution of 14 g of 4-chloro-2-fluorophenylisocyanate in 60 ml of anhydrous ether at 15° to 28° C. with stirring. A heavy oil formed after the addition. The oil crystallized after stirring at room temperature for 15 min. The precipitate was collected by filtration to give 24.3 g of 3-carbethoxy-4-(4-chloro-2-fluorophenylaminocarbonyl)thiomorpholine, m.p. 111.5°-112.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[CH:5][CH:4]=1)=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17]>C(O)C.N1CCCCC1>[C:16]([C:15]([C:14]#[N:18])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:17]
Reactant: COC(=O)Nc1ccc(C=O)cc1
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Methyl (4-formylphenyl)carbamate (560 mg) and malononitrile (206 mg) were dissolved in 10 mL of ethanol, and one drop of piperidine was added to the resulting solution, and then the mixture was stirred at room temperature for 3 hours. IPE (10 mL) was added to the reaction mixture, and a precipitated crystal was filtrated to give 441 mg of methyl [4-(2,2-dicyanovinyl)phenyl]carbamate as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:13])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (1 g, 5.81 mmol) and urea hydrogen peroxide (1.1 g, 12.2 mmol) in DCM (30 mL) at 0° C. was added trifluoroacetic anhydride (1.6 mL, 11.6 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (660 mg, 60%) as a white solid: LCMS (ES) m/z=190 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[CH:38]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-{6-[8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.140 g, 0.242 mmol) was dissolved in dichloromethane (2 mL). 2 N HCl in diethyl ether (2 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated to give 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.1 16 g, 85.9%). MS (APCl) Calc'd for M+1: 450.3. Found: 450.1. 1H NMR δ(400 MHz, DMSO-d6) 9.12 (s, 2H), 8.34 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.76 (d, J=9.5 Hz, 1H), 5.84 (m, 1H), 4.32 (d, J=1.2 Hz, 1H), 3.57 (q, J=6.8 Hz, 2H), 3.38 (m, 4H), 3.23 (m, 4H), 2.26 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H), 1.19 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[CH:2](C1C=CC=CC=1)[C:3]([O:5]C)=[O:4].[N:13]1(C2C=CC(C#N)=CC=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[N:13]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCNCC1
Temperature: 25 °C
Yield: 183.8 %

Procedure:
Methyl 2-bromo-2-phenylacetate (0.1 mol) was added dropwise to a mixture of 4-(1-piperazinyl)benzonitrile (0.1 mol) and Na2CO3 (90.15 mol) in DMF (250 ml), stirred at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM, washed, dried, filtered and the solvent evaporated. The residue was triturated under DIPE, filtered off and dried, yielding 26.5 g of 1-piperazineacetic acid, 4-(4-cyanophenyl)-α-phenyl-, methyl ester (intermediate 5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:14]=[N:13]1)[CH2:9][C:10]#[CH:11]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Solvent: c1ccncc1
Product: Fc1ccc(-c2cn(CCC#Cc3ccccn3)nn2)cc1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (80 mg, 0.37 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 28 mg (96 μmol, 26%) of 2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a brown solid (M.P.=120-122° C.).
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.O[CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]#[N:30].N1C=CN=C1>C(Cl)Cl>[I:20][CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]#[N:30]
Reactant: N#CCOCC#CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CCOCC#CCI
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Triphenylphosphine (10.94 g, 41.7 mmol) and iodine (10.55 g, 41.6 mmol were added sequentially to a solution of (4-hydroxy-but-2-ynyloxy)-acetonitrile (4.35 g, 34.8 mmol) in CH2Cl2 (100 mL). The reaction mixture became homogeneous after 5 min at rt and imidazole (2.76 g, 40.5 mmol) was added slowly in small portions. After 1.5 h at rt, the reaction was filtered through activity I basic alumina, washing with 20% EtOAc/Hexane. The filtrate was concentrated in vacuo then purified by flash column chromatography on silica gel (hexane→10% EtOAc/hexane, gradient) to afford 7.51 g (92%) of (4-iodo-but-2-ynyloxy)-acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), morpholine-4-carbonyl chloride (26.3 mg, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr and monitored by LC/MS. The crude product was purified using preparative reverse-phase HPLC, giving the desired product morpholine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide. MS calcd. for C21H21ClN3O3 [(M+H)+] 398.1, obsd. 398.0.
Reaction SMILES: [CH2:1]([C@H:8]([N:17]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=1)[C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH:50]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:1]([C@H:8]([N:17]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=1)[C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:9](=[O:16])[N:10]1[CH2:11][CH2:12][N:13]([CH2:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
N—((S)-1-Benzyl-2-oxo-2-piperazin-1-yl-ethyl)-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (50 mg, 0.084 mmol) was dissolved in acetonitrile (1 mL) and pyridine-2-carbaldehyde (10 mg, 0.092 mmol) and sodium triacetoxyborohydride (26.7 mg, 0.126 mmol) was added. The mixture was stirred at rt for 16 h, filtered and directly purified by prep. HPLC to give 29 mg of N—[(S)-1-Benzyl-2-oxo-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=683.58.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=1.CCOCC.N.[Li]>C(O)C>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][CH2:7]1
Reactant: CN(C)CCCC1=CCc2ccccc21
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCCC1CCC2=C1CC=CC2
Reaction time: 1 h

Procedure:
A solution of 35 g. (0.174 mole) of N,N-dimethylinden-3-propylamine in a total volume of 125 ml. of ether is added to 2 liters of liquid ammonia. Over 1 hr., 44 g. (6.3 g-atoms) of lithium ribbon is added at the reflux temperature. After a total of 3 hours, the reaction mixture is blue. 550 ml. of ethanol is added over 135 min. whereupon the blue color fades. The ammonia is allowed to evaporate overnight and the residue dissolved in 1500 ml. of water and extracted twice with ether. The ether extract gives 34.5 g. (98.6%) of crude diene upon drying and solvent removal which contains ca, 10% of the corresponding aromatic compound by nmr integration.
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2>C(Cl)Cl>[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14]([NH2:1])=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2
Reactant: N
Reactant: O=C(O)c1cc(Br)c(F)c2cc[nH]c12
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)c(F)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A solution of 2 M NH3/MeOH (0.6 mL, 1.2 mmol) was added to a solution of 5-bromo-4-fluoro-1H-indole-7-carboxylic acid (20 mg, 0.078 mmol) in DCM. The reaction was stirred at room temperature overnight. The mixture was washed with water, and the organic layer was concentrated. The residue was purified by flash chromatography, giving 4 mg (20%) of the title compound.
Reaction SMILES: CN.Cl[C:4]1[C:13]([C:14]([C:16](=[CH:22][N:23]([CH3:25])C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][C:11]2[C:6](=[C:7]([F:28])[C:8]([F:27])=[C:9]([F:26])[CH:10]=2)[N:5]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]3[CH:10]=[C:9]([F:26])[C:8]([F:27])=[C:7]([F:28])[C:6]3=[N:5][C:4]=2[N:23]([CH3:25])[CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Agent: CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution, at about 5° C., of 10 g of methylamine in 50 cm3 of ethanol is added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 19.3 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 150 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 7.6 g of DBU are added to the solution obtained and the mixture is heated at about 30° C. for 1 hour. After cooling to a temperature close to 20° C., the product is drained and washed with twice 100 cm3 of ethanol and twice 100 cm3 of diisopropyl ether. 13.4 g of 3 -ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 320° C., which is used for the subsequent steps without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:30]=[CH:29][O:28][CH:27]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:30]=[CH:29][O:28][CH:27]=1)#[N:25]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1ccoc1
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
100 mg (0.22 mmol) of 4-((6-chloro-4-(furan-3-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 2.4 mL of 1,4-dioxane, and 33.6 mg (0.24 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 8.3 mg (3 mol %) of Pd(PPh3)4, 76.2 mg (0.72 mmol) of Na2CO3, and 2.4 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 80 mg (70% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=COCCCC
Reactant: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylformanilide (100 g), butyl vinyl ether (74.12 g) in 85 ml of clorobenzene under stirring at 5° C., a solution of bis-trichloromethylcarbonate (87.84 g) in 170 ml of clorobenzene is added dropwise in 2 hours. The reaction mixture is kept under stirring at room temperature overnight. The mixture is cooled at about 5° C. and the pH is corrected to about 7 by adding sodium hydroxide 15% aqueous solution (348 ml). After separation of the phases, the aqueous layer is extracted with chlorobenzene (90 ml) and the combined organic layers are washed with water (100 ml) and evaporated under reduced pressure. The obtained residue (116.9 g, containing, according to HPLC assay, 104.8 g of pure product, 88% molar yield) is used for the next step of the synthesis without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[N:25][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[N:13]([C:21]3[CH:26]=[N:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CNC(=O)O2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CN(c1ccc([N+](=O)[O-])nc1)C(=O)O2
Yield: 92.4 %

Procedure:
Following general N—C coupling procedure 1, 2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester (0.510 g, 1.887 mmol) (Reference: German Patent DE10 2005 030051A1 (28 Dec. 2006)) was combined with 5-bromo-2-nitropyridine (0.400 g, 1.971 mmol, 1.05 eq) which gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a brown solid (0.684 g, 1.743 mmol) in 92% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (br. s., 9H) 1.54-1.72 (m, 1H) 1.86-2.16 (m, 3H) 3.30 (d, J=8.03 Hz, 1H) 3.66 (br. s., 2H) 3.81 (d, J=9.03 Hz, 1H) 3.94 (d, J=7.53 Hz, 1H) 8.33 (d, J=9.03 Hz, 1H) 8.52 (br. s., 1H) 8.60 (dd, J=9.03, 3.01 Hz, 1H). MS m/z 337.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[NH2:15][C:4]1[N:3]=[C:2]([NH:21][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH3:14])[N:5]=1
Reactant: CCCCCN
Reactant: CCCCCCc1c(C)nc(N)nc1Cl
Product: CCCCCCc1c(C)nc(N)nc1NCCCCC
Yield: 87 %

Procedure:
A mixture of 4-chloro-5-hexyl-6-methylpyrimidine-2-ylamine (1.00 mg, 0.44 mmol) and amylamine (2 ml) was refluxed for 11 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (MeOH:CHCl3=1:20) to give the object compound (107 mg, 87%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Product: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)CC2)CC1
Yield: 66.6 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.066 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (23 mg, 67%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.28 (d, J=1.3 Hz, 1H), 8.05-7.99 (m, 2H), 7.58-7.53 (m, 1H), 7.46 (dd, J=11.6, 2.2 Hz, 1H), 3.55 (d, J=13.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.93-2.47 (m, 10H), 2.39 (s, 3H), 2.12 (d, J=10.8 Hz, 2H), 1.96-1.82 (m, 2H), 1.34-1.28 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 523 [C29H32ClFN4O2+H]+; HPLC>99% (AUC), tR=10.14 min.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:40])=[C:33]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[OH:28]>>[CH2:1]([O:8][NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:25][CH2:26][C@H:27]([OH:28])[C:29]3[CH:30]=[CH:31][C:32]([OH:40])=[C:33]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2ccc(C(=O)NOCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NOCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-benzyloxy-4-(4-oxo-piperidine-1-yl)-benzamide (which was obtained in Example 155) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >70° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.40 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.95 (m, 5H), 2.92 (s, 3H), 3.70-3.85 (m, 2H), 4.47 (dd, J=8.0, 4.2 Hz, 1H), 4.89 (s, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.30-7.50 (m, 5H), 7.60 (d, J=9.0 Hz, 2H); MS (ES) m/z: 555.3 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2272. Found: 555.2260.