Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([NH:1][C:2]1[C:12]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1)(=[O:23])=[O:22]
Reactant: Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Yield: 81.1 %

Procedure:
In 200 ml of pyridine was dissolved 25.5 g of 7-amino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one. To the solution being maintained at 20°-25° C. was dropwise added 12.6 g of methanesulfonyl chloride. The mixture was subjected to reaction for 12 hours at the same temperature. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate. The solution was extracted with two 500-ml portions of a 1N aqueous sodium hydroxide solution. The extracts (the aqueous layers) were combined, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 300-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from methanol to obtain 27.0 g (yield: 81.1%) of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16].BrBr.[OH-].[Na+]>>[CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC/C=C\CCCCCCCCCCO
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCC#CCCCCCCCCCCO
Temperature: 15 °C
Yield: 79.8 %

Procedure:
Cis-11-Hexadecen-1-ol (4.94 g, 20.4 mmoles, Sigma) was placed in a 25 ml 3-neck roundbottom flask equipped with a thermometer, an overhead mechanical stirrer, and a reflux condenser. The contents of the flask were cooled to 15° C. and bromine (3.28 g, 20.4 mmole) was added slowly with stirring at such a rate as to keep the reaction temperature below 30° C. After addition of the bromine, the reaction was stirred at room temperature for 10 minutes. Polyethylene glycol 300 (0.5 g, Fluka) was added followed by powdered sodium hydroxide (2.05 g, 51.25 mmoles). A large exotherm was noted which brought the reaction temperature to 150° C. The reaction was stirred vigorously with heating to maintain a temperature of 125° C. for 2.5 hours. The reaction was cooled and filtered to remove the solid sodium bromide. The filtered salts were washed with 25 ml of hexanes and the solvent removed in vacuo. The crude product was kugelrohr distilled (ca. 160° C./ 0.20 torr) to yield 11-hexadecyn-1-ol (3.88 g, 80% yield) as a clear colorless liquid.
Reaction SMILES: [CH3:1][C@@H:2]([NH:9][C:10](=[O:29])[CH2:11][CH:12]([NH:21]C(OC(C)(C)C)=O)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:1][C@@H:2]([NH:9][C:10](=[O:29])[CH2:11][CH:12]([NH2:21])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](NC(=O)CC(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)CC(N)c1ccc(F)c(F)c1)c1ccccc1
Reaction time: 0.67 h

Procedure:
3-t-Butoxycarbonylamino-3-(3,4-difluorophenyl)propionic acid (R)-α-methylbenzylamide (6.5 g, 16.1 mmol) was dissolved in 40 mL of ethyl acetate and cooled in an ice bath. The solution was treated with 50 mL of saturated HCl/ethyl acetate solution and allowed to stir for 40 minutes. Nitrogen was bubbled through the reaction solution for 45 minutes, and the mixture was then evaporated to dryness. The resulting residue was reconcentrated from methanol and ethyl ether, and filtered from ethyl ether to yield the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NC(=O)c1ccc(Br)cc1
Product: NC(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 4-bromobenzamide (203 mg, 1 mmol) according to general procedure II. Obtained as a white solid (80 mg, 16%). MS (ISP) 474.2 [(M+H)+]; mp 286° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]=[N:21][CH:20]=[CH:19]2.C1CCN2C(=NCCC2)CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[Cl:26])[CH:22]=[N:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: Clc1cc2cnccc2cc1Br
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester (273) were dissolved in 20 ml degassed DMF was added 1.3 g (7.1 mmol) 6-Fluoro-7-chloroisoquinoline (263) and 1.23 ml (8.2 mmol) DBU. After stirring for 90 min at 80° C. the solvent was evaporated. The residue was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (40% to 60% ethyl acetate in heptane) gave 1.98 g of the expected compound.
Reaction SMILES: [C:1]([C:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:4][F:5])#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:4][F:5]
Reactant: [H][H]
Reactant: CC(C#N)(CF)NC(=O)OCc1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)(CF)NC(=O)OCc1ccccc1
Yield: 98.3 %

Procedure:
Under argon, 1.2 g (5.08 mmol) of rac-benzyl (2-cyano-1-fluoropropan-2-yl)carbamate from Example 54A in 14.9 ml of 7 N ammonia in methanol were admixed with 1.55 g of Raney nickel (aqueous slurry) and hydrogenated at hydrogen pressure about 25 bar and RT for 24 hours. The reaction mixture was filtered through kieselguhr, washed with methanol and concentrated. 1.2 g of the target compound were obtained (98% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].C(O)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([C:11]1([C:24]([OH:26])=[O:25])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Agent: [K]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3,3-dibenzyl ester (3.59 g 7.9 mmol) in N,N-dimethylformamide (100 mL) cooled with a water/ice bath, is added dropwise a solution of potassium hydroxyde (0.68 g 85% 10 mmol) in water (29 mL). The mixture is further stirred with cooling for 2 h, then allowed to warm to room temperature and acidified with acetic acid (1.05 eq). After concentration under reduced pressure, the crude product is dissolved in diisopropyl oxyde, washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:15]=1[CH2:16][O:17]C(=O)C)[CH:7]=[CH:6]2.O.[OH-].[Li+]>O1CCCC1.CO>[CH3:1][N:2]([CH3:48])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:15]=1[CH2:16][OH:17])[CH:7]=[CH:6]2
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)c(=O)n(C)c4)c3CO)ccc2c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To Acetic acid 2-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzyl ester (29 mg, 0.045 mmol) in 2 ml tetrahydrofuran, 1 ml methanol, and 1 ml water was added 1M aq. lithium hydroxide solution (0.13 mL, 0.13 mmol). After stirring for 18 hours, this was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (20 mg, 0.033 mmol). MS (ESI) 607.2 (M+H)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:46]4[CH:54]=[CH:55][CH:56]=[CH:57][C:45]=4[N:44]=3)=[CH:39][CH:38]=2)=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)(C(C)(C)C)(C)C>C1COCC1>[C:48]1([N:47]2[C:46]3[CH:54]=[CH:55][CH:56]=[CH:57][C:45]=3[N:44]=[C:43]2[C:40]2[CH:39]=[CH:38][C:37]([C:30]3[CH:29]=[CH:28][C:27]([OH:26])=[C:36]4[C:31]=3[CH:32]=[CH:33][CH:34]=[N:35]4)=[CH:42][CH:41]=2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)c2cccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)c2cccnc12
Reaction time: 4 h

Procedure:
A 1M TBAF solution in THF (22.4 ml, 22.4 mmol) is added dropwise to a solution of 8-(tert-butyldimethylsilanyloxy)-5-[4-(1-phenyl-1H-benzimidazol-2-yl)phenyl]quinoline (7.9 g, 14.90 mmol) in THF (20 ml). After stirring for 4 h, the mixture is washed with 5% aqueous NH4Cl (100 ml) solution and extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on silica and crystallisation from MeOH (5.9 g, 90%).
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](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:23]([C:19]3[N:20]=[CH:21][N:22]=[C:17]([N:14]4[CH2:13][CH2:12][CH:11]([N:3]5[C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:16][CH2:15]4)[CH:18]=3)=[O:24])[CH2:35]2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1ccc2c(c1)NCC2CCCN1CCCC1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC(CCCN2CCCC2)c2ccccc21

Procedure:
140 mg (0.41 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 94.4 mg (0.41 mmol) 3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole, 138.2 mg (0.43 mmol) TBTU and 112 μL (0.8 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][CH:16]=2)[C@H:11]([NH:19]C(=O)OC(C)C)[CH2:10][C@@H:9]1[CH3:26])(=[O:7])[CH3:6].[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.O>[NH2:19][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:8]([C:5](=[O:7])[CH3:6])[C@@H:9]([CH3:26])[CH2:10]1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Temperature: 0 °C
Yield: 97 %

Procedure:
Aluminium trichloride (31.6 g, 237 mmol) was suspended in DCM (320 mL) and cooled in an ice-bath. A solution of 1-methylethyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation, see Intermediate 1) (25 g, 67.7 mmol) in DCM (100 mL) was added dropwise over approximately 45 mins and the mixture was left to stir in the ice-bath for a further 1 h. The reaction mixture was quenched by dropwise addition of NaOH (28.4 g, 711 mmol) in water (350 mL), resulting in the formation of a thick precipitate which was broken up to ensure stirring continued. A solution of potassium sodium tartrate (100 g, 354 mmol) in water (400 mL) was added and the mixture stirred overnight. The organic layer was separated and the aqueous layer was further extracted with DCM (2×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (20.71 g, 65.8 mmol, 97% yield) as a sticky brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])=[CH:4][CH:3]=1.[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:10](=[N:29]/[NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21
Product: O=C(N/N=C1\C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21)c1ccccc1
Yield: 86 %

Procedure:
The title compound was prepared as a yellow solid, using 1-(4-chlorobenzyl)-isatin and benzhydrazide according to the synthetic method D. The resulting solid was purified by crystallization in ethyl alcohol. Yield: 86%. 1H NMR (DMSO-d6): δ 5.03 (s, 2H), 7.08 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 7.39-7.47 (m, 5H), 7.60-7.74 (m, 4H), 7.94 (m, 2H), 13.84 (br s, 1H). 13C NMR (DMSO-d6): δ 42.43 (CH2), 110.97 (CH), 119.87 (C), 121.35 (CH), 123.99 (CH), 127.93 (CH), 129.15 (CH), 129.70 (CH), 129.88 (CH), 132.14 (CH), 132.45 (C), 132.78 (C), 133.44 (CH), 135.15 (C), 143.04 (C═N), 161.74 (C═O). HRMS (ES+) calcd for C22H17N3O2Cl (M+H+), m/e, 390.1018. found, 390.1004.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([Br:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:18][N:19]([CH3:27])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[Br:12][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([C:21](=[CH:20][N:19]([CH3:27])[CH3:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:6])=[C:2]([F:1])[C:10]=1[CH3:11]
Reactant: Cc1c(F)c(C(=O)O)cc(F)c1Br
Reactant: CCOC(=O)C=CN(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Br)c(C)c1F
Yield: 71.2 %

Procedure:
2,5-Difluoro-4-bromo-3-methylbenzoic acid (10.7 g, 42.4 mmol) was dissolved in toluene (160 mL). Thionyl chloride (5.00 mL, 63.9 mmol) and dimethylformamide (5.0 mL) were added, and the mixture was heated to reflux for two hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (300 mL). Ethyl 3-dimethylaminoacrylate (7.30 ml, 50.9 mmol) and triethylamine (7.60 mL, 54.5 mmol) were added, and the mixture was heated to reflux for three hours. The solvent was evaporated under reduced pressure, and dichloromethane and water were added to the residue to separate the layers. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to flash column chromatography (hexane:ethyl acetate=2:1→1:1→1:2) to give the title compound (11.35 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:17][C:18]1[C:21](=[O:22])[C:20](=[O:23])[C:19]=1[NH:24][CH2:25][CH2:26][CH2:27]Cl>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:27][CH2:26][CH2:25][NH:24][C:19]2[C:20](=[O:23])[C:21](=[O:22])[C:18]=2[NH2:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Nc1c(NCCCCl)c(=O)c1=O
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium hydride (0.16 g; 50% dispersion in oil) in dimethylformamide (20 ml) was cooled to 0° C. To this was added dropwise 3-(piperidinomethyl)phenol (0.6 g) in dimethylformamide (10 ml) and the mixture was allowed to warm to room temperature and stirred for 150 minutes. 1-Amino-2-(3-chloropropylamino)cyclobut-1-ene-3,4-dione (0.6 g) in dimethylformamide (30 ml) was added dropwise and the reaction mixture stirred for 20 hours. On examination by thin layer chromatography it was found that the reaction had not gone to completion. Sodium hydride (0.16 g; 50% dispersion in oil) was added, the reaction mixture stirred for 3 hours at room temperature, then stirred for 3 hours at 65° C. and cooled. The reaction mixture was evaporated under reduced pressure, the residue was treated with dilute sodium hydroxide and extracted into chloroform/methanol (9:1). The chloroform/methanol extracts were combined, dried oer magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound; δppm 1.45 (6H, m), 2.00 (2H, m), 2.40 (4H, m), 3.43 (2H, s), 3.65 (2H, m), 4.03 (2H, t), 6.85 (3H, m), 7.23 (1H, t), 7.50 (broad m) (spectrum consistent with an authentic sample).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C1COCC1.[C:14]1(C)[CH:19]=[CH:18]C=[CH:16][CH:15]=1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:18][CH2:19][C:14]#[C:15][CH3:16])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC#CCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
This reagent was gradually (for about one hour), dropwise added to a mixture consisting of p-dibromobenzene (150 mmol), bis(triphenylphosphine) Ni(II) dichloride (7.5 mmol) and THF (150 ml), at 0° C. or lower, followed by heating the mixture under reflux with stirring, allowing the mixture to cool down to room temperature, adding toluene (200 ml) and water (200 ml) to the reaction solution, sufficiently stirring the mixture, three times washing the organic layer with a brine (200 ml), drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure at 30° C. or lower, purifying the residue subjecting to silica gel column chromatography (eluent solvent: heptane/toluene mixture) and further distilling under reduced pressure to obtain oily 4-bromo-1-(3pentynyl)benzene (61 mmol).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].O.O.Cl[Sn]Cl>O.Cl>[ClH:15].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(C(=O)O)c1
Temperature: -3 °C
Reaction time: 2 h
Yield: 123.1 %

Procedure:
A solution of 2.11 g of NaNO2 in 40 ml of water is added over 30 minutes to a suspension, cooled to -2° C., of 5 g of 5-amino-2-chlorobenzoic acid in 50 ml of concentrated HCl. The solution is stirred for 2 hours at -3° C. and cooled to -10° C., and a solution of 23 g of SnCl2.2H2O in 20 ml of concentrated HCl and 20 ml of water is added over 30 minutes. The mixture is stirred for one and a half hours at 0° C. and filtered, and the precipitate is dried to obtain 4 g of expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH:34]([C:36]1([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38][CH2:37]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCCl>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:34][C:36]3([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:41][O:40][C:39]([CH3:42])([CH3:43])[O:38][CH2:37]3)[CH2:21]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Reactant: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)no2)cc1OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)C4)no2)cc1OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
A mixture of the product of Step E (0.084 g; 0.186 mmol) in 60% TFA/CH2Cl2 (1.5 ml) was stirred for 5 min at room temperature under N2, then diluted to 4 ml with EtOH, stirred for additional 15 min and evaporated to dryness under reduced pressure. To it, tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.05 g; 0.193 mmol) was added followed by NaBH(OAc)3 (0.13 g; 0.58 mmol) and 1,2-dichloroethane (1.5 ml). The resulting mixture was stirred for 1 h at room temperature, diluted to 15 ml with EtOAc, washed with 10% NaOH (2×5 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO2; CH2Cl2:EtOAc 8:2) to give the title compound (0.07 g; 63%) as off white foam. 1H-NMR (CDCl3) 1.38-1.61 (m, 21H); 3.21 (s, 2H); 3.82 (d, 2H, J=12 Hz); 4.05-4.24 (m, 10H); 4.98 (broad s, 1H); 6.97 (d, 1H, J=9 Hz); 7.2-7.3 (m, 1H+CDCl3); 7.66 (d, 1H, J=3 Hz); 7.78 (dd, 1H, J=3, 6 Hz); 7.96-8.02 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: BrBr
Reactant: Nc1ccc(C2CC2)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(C2CC2)cc1Br
Reaction time: 18 h

Procedure:
To a solution of 5-cyclopropyl-pyridin-2-ylamine (1.1 g, 8.19 mmol) in dry chloroform (100 mL) was added bromine (0.42 mL, 8.2 mmol) in chloroform (11 mL) at room temperature and stirred for 18 hours. An aqueous solution of sodium thiosulfate was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as light yellow oil (1.0 g, 57%).