Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC)=[CH:6][C:5]=1[NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C.C(OC1C=CC(OCC)=CC=1N)C.C(Cl)(=O)CCCCCCCCCCCCCCC.B(Br)(Br)Br>C(Cl)(Cl)Cl.O>[C:14]([NH:13][C:5]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=1[OH:3])(=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(OCC)ccc1OCC
Agent: BrB(Br)Br
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CCOc1ccc(OCC)c(N)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.3 %

Procedure:
83.8 g (0.2 mol) of 1,4-diethoxy-2-hexadecanoylaminobenzene prepared from 2,5-diethoxyaniline and hexadecanoyl chloride was dissolved in 500 ml of chloroform and to the solution was added dropwise 100 g of boron tribromide at a temperature range between 5° C. and 10° C. After stirring at room temperature for 6 hours, 50 g of ice and 100 ml of water were added to the mixture and chloroform was distilled off under a reduced pressure. To the residue was added 100 ml of methanol, the resulting precipitate was collected by filtration to obtain 78 g of 2-hexadecanoylaminohydroquinone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C.O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 26.0 mmol) in DMF (100 ml), cooled to 0° C. was added sodium hydride (3.12 g, 78 mmol). The mixture was stirred until bubbling had ceased, then 1-chloro-3-iodopropane (8.23 ml, 78 mmol) was added. The reaction was kept in an ice bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with a 1:1 mixture of brine and water (3×), then brine (1×). The organic phase was dried, filtered and concentrated then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol, 74.7% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][C@@H:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[CH3:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:30]1=[O:44]>CCO.ClC(Cl)C>[OH:26][C@H:25]([CH2:24][N:11]1[C:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=2[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[N:12]1)[CH2:27][N:41]1[CH2:40][CH2:39][CH:38]([N:31]2[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:29]([CH3:28])[C:30]2=[O:44])[CH2:43][CH2:42]1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cn1c(=O)n(C2CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC2)c2ccccc21
Yield: 63.4 %

Procedure:
A solution of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (134 mg, 0.334 mmol) and 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg, 0.476 mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated to 80° C. for 18 h. The mixture was then concentrated and the residue purified by column chromatography (silica, 0-50% acetone/CH2Cl2) to give the title compound (134 mg, 86%). TLC (20% acetone/CH2Cl2) Rf=0.3. MS (electrospray): calculated for C30H36F3N6O4S, [M+H]+633.24. m/z found, 633.3. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.66 (A and B of AA′BB′, Jab=8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H ), 7.08 (m, 2H), 6.98 (dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55(A and B of AB, Jab=14.5 Hz, 2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15 (m, 1H), 4.23 (dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H), 3.08 (m, 2H), 2.96 (m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23 (d, J=11.6 Hz, 1H, 1.81 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:21])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:21])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Product: CC(=O)Nc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
200 mg of 2-acetylamino-6-chloro-4-phenylquinoline were introduced in portions into 4 ml of 100% strength HNO3 at 0° C. and stirred at 0° C. to 5° C. for 30 min, and the reaction mixture was poured into ice-water. Neutralization with 2N NaOH was followed by extraction with ethyl acetate and removal of the solvent by distillation. The solid residue was boiled several times with diisopropyl ether, and the solvent of the filtrate was evaporated until the substance separated out as crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[S:10][C:11]([NH:23]C(=O)OC(C)(C)C)=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[N:13]=1>C(Cl)Cl.O>[Br:8][C:9]1[S:10][C:11]([NH2:23])=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[N:13]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Br)sc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(Br)sc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (4.0 mL) was added to a solution of tert-butyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (360 mg, 0.86 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture was stirred for 1.5 hours at room temperature and then evaporated to dryness. The residue was taken up into DCM and washed with sodium hydrogen carbonate (sat. aq.), water and brine, and concentrated under vacuum to give 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine as an orange residue. LCMS (ESI) m+H=321.3. NMR (400 MHz, DMSO-d6): δ 7.36 (d, 1H); 7.34-7.32 (m, 1H); 7.10 (d, 1H); 3.83 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH2:32](Br)[C:33]#[CH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:33]#[CH:32])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: C#CCBr
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 116.7 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.0 g), propargyl bromide (0.84 g) and potassium carbonate (1.17 g) in N,N-dimethylformamide (300 ml) was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a syrup of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine (3.80 g).
Reaction SMILES: [C:1]1(=[O:8])O[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:9]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]#[N:9].[OH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:9]
Reactant: N
Reactant: O=C1CCCCCO1
Product: C=CCCCC#N
Product: N#CCCCCCO
Yield: 22 %
Yield: 24 %

Procedure:
The reaction of epsilon-caprolactone with ammonia in the gas phase over alumina gives 22% of hex-1-ene-6-nitrile and 24% of epsilon-hydroxycapronitrile.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(C(C)C)C(C)C)C1C=CC=CC=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:1]([NH:8][C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
Heptan-1-amine (1 g, 8.679 mmol) was dissolved in dry THF under N2 and polymer supported N-benzyl-N,N-diisopropylamine (4.955 g, 26.038 mmol) was added. The mixture was stirred for 30 min and cooled to 0° C. and phenylacetyl chloride (1.610 g, 10.415 mmol) was added. The solution was stirred overnight at room temperature. The excess of phenylacetyl chloride was removed by filtering the mixture through an NH2 cartridge. The solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.886 g of N-heptyl-2-phenylacetamide (yield 43.7%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=[O:19])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:17]#[N:18])[CH:9]=1)([CH3:7])[CH3:6].[Cl:22][C:23]1[C:24]([F:35])=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[Cl:22][C:23]1[C:24]([F:35])=[C:25]([CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1)[CH2:26][C:3]([OH:19])([C:2]([F:1])([F:20])[F:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:17]#[N:18])[CH:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(C#N)cc2c1OCC2
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1CBr
Product: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cc(C#N)cc2c1OCC2

Procedure:
The title compound was prepared from 7-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)-2,3-dihydrobenzofuran-5-carbonitrile and 3-chloro-2-fluoro-5-trifluoromethylbenzyl bromide using the procedure described in Example 5.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:9]2[C:10]([CH3:17])=[N:11][C:12]3[C:7]([C:8]=2[O:26][CH:27]([F:29])[F:28])=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-4-difluoromethoxy-8-fluoro-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.18 g), methanol (3.5 mL), water (2.0 mL), tetrahydrofuran (3.5 mL) and lithium hydroxide solution (0.036 g) was stirred at room temperature for 30 minutes. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid, extracted with ethyl acetate and the combined extracts dried over sodium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC, using a gradient over 30 minutes of acetonitrile in water, gave title compound as a yellow solid, 0.088 g.
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][NH:6][C:7]=1[CH3:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:8][C:7]1[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3](=[O:12])[C:2]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5a, 12.05 g, 51.9 mmol), 3-(trifluoromethyl)phenylboronic acid (13.6 g, 71.6 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.60 g, 4.92 mmol) in acetonitrile (100 mL) is added 2 M aqueous K2CO3 solution (47 mL, 94 mmol). After stirring for 6 h at 75° C., the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in dichloromethane and extracted several times with water. The combined aqueous layer is acidified with 4 N aqueous HCl. The formed precipitate is filtered off, washed with 50 mL hexanes/ethyl acetate (4:1) and dried. Yield: 13.5 g (88% of theory); ESI mass spectrum: [M+H]+=298; Retention time HPLC: 0.80 min (Z003—001).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:23][N+:24]([O-])=O)[CH2:10][P:11]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[NH2:24][CH2:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][P:11]([CH:16]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])(=[O:15])[O:12][CH2:13][CH3:14]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(OC)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC

Procedure:
A solution of 6.6 g of ethyl 2-(4-methoxyphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methoxyphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.5 ppm (CDCl3).
Reaction SMILES: OCC[N:4]1[C:8](=[O:9])[CH:7]([CH3:10])[S:6][CH:5]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:10][CH:7]1[S:6][CH:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:4][C:8]1=[O:9]
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1SC(c2cccnc2)NC1=O
Reaction time: 5 h
Yield: 20.3 %

Procedure:
3-(2-Hydroxyethyl)-5-methyl-2-(3-pyridyl)- thiazolidin-4-one (18.75 g, 78.7 mmol) was dissolved in methylene chloride (200 ml). Pyridine (9.55 ml, 118 mmol) was added and further, thionyl chloride (20 ml, 274 mmol) was added dropwise over 2 hours at 0 to 5° C. This reaction mixture was kept between those temperatures for 5 hours. The resulting mixture was washed with aqueous NaHCO3 and aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel and upon recrystallization from hexane-ether, gave 2,5-cis-3-(2-chloroethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (7.11 g) and 2,5-2-chloroethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4one (3.11 g), (51% yield).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(Nc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To an acetic acid (3.2 mL) and dimethyl sulfoxide (54 mL) solution of (4-((E)-2-nitro-vinyl)-phenyl)-phenyl-amine (3.2 g, 13.4 mmol) described in Manufacturing Example 69-1-2 was added sodium borohydride (811 mg, 21.4 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (2.01 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(Cl)Cl.O>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: NC1CCC1
Reactant: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Solvent: O
Solvent: ClCCl
Solvent: CCCCO
Product: Fc1c[nH]c2nc(Cl)nc(NC3CCC3)c12
Yield: 93.5 %

Procedure:
A solution of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.24 mmol), cyclobutylamine (0.041 mL, 0.48 mmol) and TEA (0.070 mL, 0.50 mmol) in nBuOH (2 mL) was stirred at 70 C for 5 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with 1N HCl, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-cyclobutyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (54 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:33]([C:24]4[CH:25]=[CH:26][C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[O:34])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc5ccccc5n4)cc3C2=O)C(=O)N1
Yield: 86.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and quinoline-2-carbonyl chloride (0.57 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was isolated by filtration and dried in vacuo to give quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 76% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.08 min (96.58%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.93-2.16 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.74 (d, J=6.4 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.66-7.82 (m, 1H, Ar), 7.82-7.99 (m, 4H, Ar), 8.03-8.25 (m, 3H, Ar), 8.59 (d, J=8.1 Hz, 1H, Ar), 9.75 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.55, 48.99, 118.74, 122.24, 123.55, 128.15, 128.89, 129.15, 129.84, 130.60, 131.59, 133.67, 137.94, 146.05, 147.44, 149.89, 164.48, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C24H18N4O5: C, 65.15; H, 4.10; N, 12.68. Found: C, 65.05; H, 4.05; N, 12.58.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:3]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>CCO>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C@H:13]([OH:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)C(=O)c1nccs1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@H](O)c1nccs1
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A cooled solution (0° C.) of (S)-tert-butyl 3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)propan-2-ylcarbamate (4.220 g, 10 mmol) in EtOH (60 mL) was added dropwise via cannula to a cooled solution (−78° C.) of lithium tri-tert-butoxyaluminum hydride 1M in THF (21 ml, 21 mmol) in EtOH (40 mL). After stirring for 2 hours, the reaction mixture was quenched with 1N HCl and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 solution, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude residue was crystallized from hot EtOH/water and the solid was collected yielding tert-butyl (1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate (3.250 g, 77% yield) as a white solid.
Reaction SMILES: [C:1]([CH:5]([CH:7](C(OC)=O)O)[OH:6])([O:3][CH3:4])=[O:2].C(OC)(=O)C=O.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[O:6]1[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:7][N:30]=[CH:29]1
Reactant: COC(=O)C(O)C(O)C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: COC(=O)C=O
Product: COC(=O)c1cnco1

Procedure:
For B.4274, dimethyl tartrate was oxidised11 to methyl glyoxylate which reacted 12 with tosylmethyl isocyanide to give methyl oxazole-5-carboxylate.13This was reduced by lithium aluminium hydride by the method of Fallab14 to the alcohol.15
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[Cl:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH:13]1[CH2:15][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(Cl)c1
Reactant: OB(O)C1CC1
Product: COC(=O)c1ccc(C2CC2)c(Cl)c1

Procedure:
The title compound was prepared from methyl 4-bromo-3-chlorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.73-0.77 (2H, m), 1.07-1.12 (2H, m), 2.24-2.30 (1H, m), 3.90 (3H, s), 6.93 (1H, d, J=8.0 Hz), 7.80 (1H, dd, J=1.6 Hz, 8.0 Hz), 8.01 (1H, d, J=1.6 Hz).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][C:3]=1[CH3:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][C:3]=1[CH3:12]
Reactant: Cc1nc2c(Cl)nccn2c1Br
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: Cc1nc2c(NCc3ccc(S(N)(=O)=O)cc3)nccn2c1Br
Temperature: 108 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of 3-bromo-8-chloro-2-methyl-imidazo[1,2-a]pyrazine (0.77 g, 3.12 mmol) in iBuOH (10 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (1.04 g, 4.69 mmol) and DIPEA (1.63 ml, 9.36 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-2-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulphonamide as a white solid (0.37 g, 30%)