Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH:8]=O)[CH2:7][O:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:34]#[N:35])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19](=[O:33])[CH:18]=2)[CH:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:34]#[N:35])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([C:25](=[CH:8][C:4]3([CH3:3])[CH2:5][O:6][CH2:7]3)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:19](=[O:33])[CH:18]=2)[CH:16]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC1(C=O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn(C(=CC2(C)COC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.25 h

Procedure:
64.0 mg (1.60 mmol, 60% in mineral oil) of sodium hydride and 200 mg (2.00 mmol) of 3-methyloxetane-3-carbaldehyde in 1 ml of dimethylformamide were added in succession to a solution of 300 mg (800 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 9 ml of dimethylformamide. After 15 min at room temperature, the reaction was terminated by addition of saturated aqueous ammonium chloride solution and the reaction mixture was then extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (24 g silica cartridge, flow rate 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 356 mg (96% of theory)
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH:15]([NH:17][OH:18])[CH3:16])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.[CH3:23][N:24]=[C:25]=[S:26]>>[CH3:21][C:19]([C:6]1[CH:7]=[C:8]([CH:15]([N:17]([OH:18])[C:25]([NH:24][CH3:23])=[S:26])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]=1[OH:4])([CH3:22])[CH3:20]
Reactant: CN=C=S
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Product: CNC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.500 g (0.0016 mole) of 2,6-bis (1,1-dimethylethyl) -4- [1- (hydroxyamino) ethyl ]phenol acetate is added 0.128 g (0.00175) of methyl isothiocyanate. The reaction mixture is stirred at room temperature for 18 hours and evaporated to near dryness. The residue is washed with Et2O and there is obtained 0. 300 g (55% ) white solid, m.p. 175°-175.5° C.
Reaction SMILES: [Br:1][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]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>>[Br:1][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[NH:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[CH:32][CH:31]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cc2)CC1
Yield: 56 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.644 mmol) was reacted with 4-[(4-methylpiperazin-1-yl)methyl]aniline (200 mg, 0.966 mmol) to afford the desired product (173 mg, 56%) as a yellow solid: ESI MS m/z 479 [C25H27BrN4O+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22][OH:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[OH:23][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16]1
Reactant: CCCc1cc(Cl)ncc1C(=O)NC
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Product: CCCc1cc(N2CCN(CCO)CC2)ncc1C(=O)NC
Temperature: 100 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
6-Chloro-N-methyl-4-propylnicotinamide (123 mg, 0.578 mol) was dissolved in tetrahydrofuran (2 mL), added 1-piperazineethanol (355 μL, 2.89 mol) at room temperature, and stirred at 100° C. for 18 hours. The reaction solution was purified by silica-gel column chromatography (chloroform/methanol). The title compound (177 mg (yield >99%)) was obtained as a yellow crystal.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](Cl)=[N:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17].C1CCN2C(=NCCC2)CC1.[OH-].[K+].Cl>O>[Br:10][C:8]1[C:7]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: COCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COCCOc1ncc(C(=O)O)cc1Br
Yield: 66 %

Procedure:
A mixture of 325 mg (1.3 mmol) 5-bromo-6-chloro-nicotinic acid methyl ester, 233 mg (3.24 mmol) 2-methoxyethanol and 493 mg (3.24 mmol) DBU was heated under microwave radiation for 2 min to 180° C. 0.65 mL water and 0.49 mL 5N KOH aq. was added and the mixture was heated under microwave radiation for 2 min to 160° C. The mixture was acidified with 1N HCl aq. and extracted with ethyl acetate. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 237 mg (66%) of the title compound as white solid. MS (ISP): 274 (M−H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[C@H:29]12[CH2:35][C@H:32]([CH2:33][CH2:34]1)[CH2:31][CH:30]2[NH2:36]>>[CH3:28][N:4]1[C:3]([CH2:2][NH:36][CH:30]2[CH2:31][C@H:32]3[CH2:35][CH:29]2[CH2:34][CH2:33]3)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NC1C[C@H]2CC[C@@H]1C2
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3C[C@@H]4CCC3C4)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1R,4S)-bicyclo[2.2.1]heptan-2-amine via General Procedure E to give 16 mg of 272 following reverse phase purification. MS (Q1) 473.3 (M)+
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Product: FC(F)(F)c1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Hydroxy-2,6-bis(trifluoromethyl)quinoline (1.28 g) was dissolved in phosphorus oxychloride (5.0 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform and concentrated under reduced pressure to give 4-chloro-2,6-bis(trifluoromethyl)quinoline (1.17 g).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:29][CH:28]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1ccc(Cl)cc1)C(=O)N2
Yield: 70 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4-chlorophenyl hydrazine and following the method described in Example 21,the desired compound was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:12][C:11]([OH:13])=[N:10][C:8]2=[O:9])=[CH:5][CH:6]=1.C=O.[C:22]([O-])([O-])=[O:23].[K+].[K+]>O>[C:14]1([C:7]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[NH:12][C:11](=[O:13])[N:10]([CH2:22][OH:23])[C:8]2=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reaction time: 24 h
Yield: 91 %

Procedure:
Phenytoin (5 g, 0.02 mol) was suspended in 180 ml of water; 20 ml of formaldehyde (37% solution) and 0.25 g K2CO3 were added and the mixture was stirred at 25°-30° C. for 24 hours. The white solid which formed was removed by filtration and washed repeatedly with a 3% solution of formaldehyde, then air dried for 3 to 4 hours and over P2O5 in a vacuum dessicator. Yield 91-93%, m.p. 185°-189° C. Anal. calc. for C16H14N2O3 : C, 68.07; H, 5.00; N, 9.93. Found: C, 67.97; H, 5.05; N, 9.93. The product has the formula: ##STR1539##
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].Cl>CN(C=O)C.O>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])([CH3:24])[CH3:23]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)O)cc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred mixture of 4-chloro-3-nitrocinnamic acid (500 mg, 2.2 mmol) in 5 mL of anhydrous DMF with K2CO3 (911 mg, 6.6 mmol) was added 2-isopropylbenzenethiol (372 mL, 2.2 mmol) in 1 mL of DMF dropwise. The resulting mixture was then heated at 70° C. under nitrogen atmosphere overnight. Water (25 mL) was then added and the reaction mixture was acidified to pH=4 with 3N HCl. The cloudy mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo to give the title compound as a viscous light-yellow oil, which was used for coupling with further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[NH:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(CCCC2=NCCN2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CCCC2=NCCN2)cc1)OCc1ccccc1
Yield: 76 %

Procedure:
To a solution of compound 55 (318 mg, 1.56 mmol) in DMF (1 mL) was added dropwise CbzCl (0.29 mL, 2.03 mmol) at 0° C. with stirring. The reaction mixture was stirred at room temperature for 3 h. The DMF was removed by vacuum. The residue was purified with silica gel column chromatography (EtOAc:CH3OH:TEA=3:1:0.2) to give compound 56 (400 mg, 76%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.70 (s, 1H), 7.30-7.40 (m, 5H), 7.25 (d, 2H, J=8.3 Hz), 6.98 (d, 2H, J=8.3 Hz), 5.15 (s, 2H), 3.65 (s, 4H), 2.50 (t, 2H, J=7.4 Hz), 2.43 (d, 2H, J=7.4 Hz), 1.85-1.97 (m, 2H).
Reaction SMILES: [ClH:1].ClC1C=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([NH2:15])=O)=O>O1CCOCC1>[Cl:1][C:5]1[CH:4]=[CH:22][CH:23]=[CH:24][C:6]=1[CH2:7][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]#[N:15]
Reactant: Cl
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Solvent: C1COCCO1
Product: N#Cc1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1

Procedure:
One milliliter of 35% hydrochloric acid was added to a solution of 850 mg of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide in 10 ml of 1,4-dioxane, and the mixture was heat-refluxed for 4 days. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was separated by being poured in a mixture solution of water and chloroform. The organic layer was washed with water, and was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified through column chromatography [50 ml, chloroform] to give 230 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH2:23][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-(piperazin-1-yl)pyrimidine (144.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 192 mg (95%) of methyl 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:11][CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCNCCC
Product: CCCN(CCC)C(=O)CC(C)=O
Yield: 0.6 %

Procedure:
43.4 g (43.3 mol) of ethyl acetoacetate and 33.7 g (43.3 mol) of dipropylamine were treated as described in preparation 1. The crude oil was distilled at 86°-89° C./ 0.8 mmHg, to give 44.3 g of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2ncccc2c1
Product: O=C1NC(=S)SC1=Cc1ccc2ncccc2c1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and rhodanine, the title compound was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccccc1CBr

Procedure:
o-Tolylacetic acid (40 g, 266 mmol), N-bromosuccinimide (52.147 g, 293 mmol) and benzoyl peroxide (0.174 g, catalytic) are dissolved in 300 ml of CCl4. The suspension is brought to and maintained at reflux for 12 hours. After cooling, the solid particles are separated out by filtration. and the CCl4 is evaporated off under vacuum, which allows a white solid to appear. This is sufficiently pure without recrystallization.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:5]([NH:6][C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[CH2:4][C@@H:3]1[OH:21].Cl.Cl.[F:25][C:26]([C:29]1[C:34]([CH2:35][NH2:36])=[CH:33][N:32]=[CH:31][N:30]=1)([CH3:28])[CH3:27]>O1CCOCC1>[F:25][C:26]([C:29]1[C:34]([CH2:35][NH:36][C:9]2[N:8]=[C:7]([NH:6][C@@H:5]3[CH2:4][C@H:3]([OH:21])[C:2]3([CH3:22])[CH3:1])[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=2)=[CH:33][N:32]=[CH:31][N:30]=1)([CH3:27])[CH3:28]
Reactant: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: CC(C)(F)c1ncncc1CN
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(F)c1ncncc1CNc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of (1S,3R)-2,2-Dimethyl-3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.) and (4-(2-fluoropropan-2-yl)pyrimidin-5-yl)methanamine dihydrochloride (1.3 equiv.) were combined in dioxane (0.4 M) and stirred at ambient temperature. After 1 h, the solution was heated to 75° C. After 16 h, the solution was concentrated under reduced pressure and after standard work-up the title compound (50.9% yield) was obtained. The absolute stereochemistry was determined, using the chiral intermediate, as described herein for other compounds. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.01 (s, 1H), 8.47-8.67 (m, 1H), 7.94-8.14 (m, 1H), 7.78 (br. s., 1H), 6.07 (d, J=7.81 Hz, 1H), 4.66-4.91 (m, 2H), 3.35 (br. s., 1H), 1.96-2.22 (m, 1H), 1.62-1.82 (m, 6H), 0.54-1.23 (m, 6H); MS(ESI) m/z 429.3[M+1]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=O.Cl.[CH2:26]([O:29][NH2:30])[CH:27]=[CH2:28].C(N(CC)CC)C>C1COCC1>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[C:22]([F:23])=[CH:21][C:17]=1[C:18]([NH:30][O:29][CH2:26][CH:27]=[CH2:28])=[O:20]
Reactant: C=CCON
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCONC(=O)c1cc(F)c(F)cc1N
Yield: 53.6 %

Procedure:
Carbonyldiimidazole (3.37 g, 20 mmol) was added to a suspension of 4,5-difluoroanthranilic acid (3.0 g, 17 mmol) in 80 mL of THF, and the mixture was heated to reflux for 2 hours. The solution was cooled and O-allylhydroxylamine hydrochloride (1.89 g, 17 mmol) and triethylamine (2.8 mL, 20 mmol) were added, and the mixture was heated to reflux for 17 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, and brine and dried over magnesium sulfate. The solution was concentrated and purified by column chromatography (silica gel, CHCl3/MeOH, 98:2) to give 2.08 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:32]=[C:31]([C:39]([N:41](C)[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16].[CH3:58][O:59][CH2:60]CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:19][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[N:32]=[C:31]([C:39]([NH:41][CH2:42][CH2:58][O:59][CH3:60])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:21]1)#[N:16]
Reactant: COCCN
Reactant: CN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Product: COCCNC(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared by a procedure similar to that of Example 46 using 6-[(cis-4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (20.00 mg, 0.02866 mmol) (Example 46, Step 4) and 2-methoxyethylamine (4.98 μL, 0.0573 mmol). 1H NMR (300 MHz, CD3OD) δ 9.09 (s, 1H), 8.88 (s, 1H), 8.79 (brs, 1H), 8.59 (s, 1H), 7.79 (d, 1H), 7.58 (s, 1H), 7.25 (d, 1H), 5.53 (m, 1H), 5.10 (d, 2H), 4.82 (d, 2H), 3.73 (s, 2H), 3.65-3.45 (m, 5H), 3.37 (d, 3H), 2.31 (m 2H), 2.04 (m, 2H), 1.90-1.55 (m, 4H). MS (ES): 625(M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]([CH3:36])([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21](O)=[O:22]>>[F:19][C:20]([CH3:36])([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(F)(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CN1C(=O)[C@@H](NC(=O)C(C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2RS)-2-fluoro-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:8]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 20.0 g of 4,5-dichloro-2-nitroaniline and 16.0 g of 1-ethylpiperazine in 50 ml of dimethylsulfoxide, 20.0 g of potassium carbonate was added, followed by 2 hours' stirring at 120° C. Water was added to the reaction liquid, followed by extraction with diethyl ether. The diethyl ether layer was successively washed with water and saturated brine, dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from chloroform-diethyl ether, to provide 20.3 g of the title compound.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Li])CCC.IC.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][CH3:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: [Li]CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CI
Product: CC#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Under argon condition, tert-butyl((4-ethynylbenzyl)oxy)dimethyl-silane (247 mg, 1.00 mmol) was dissolved in 5 mL of dry THF, cooled to −78° C., and n-butyl lithium (805 μL, 2.49 M solution in n-hexane, 2.00 mmol) was slowly added thereto. After stirring for 20 minutes at −78° C., iodomethane (313 μL, 5.00 mmol) was added again thereto. Thereafter, the temperature was raised to room temperature and the reaction mixture was stirred for 30 minutes at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (5 mL×4) and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out, and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 253 mg (0.971 mmol, 97%) of the desired compound.