Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[C:18]([Cl:30])[CH:19]=2)[CH3:13])(=O)=O>C1(C)C=CC=CC=1>[Cl:30][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:12]([CH3:13])[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:27]1[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=1[S:21]2
Reactant: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 21 h

Procedure:
Pyrrolidine (21.1 cc) is added to a suspension of (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (72.1 g) in toluene (166 cc). The mixture is brought to 120° C. for 21 hours, and then to 150° C. for 12 hours. After cooling, the mixture is washed with distilled water (5×250 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (19.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:17]([CH2:16][C:15]#[N:20])[C:18]#[N:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C=C/C#N
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A process according to claim 16, comprising reacting 2-(2,6-dichloro-4-trifluoromethylphenylhydrazine with fumaronitrile to afford 2-(2,6-dichloro-4-trifluoromethylphenylhydrazino)succinonitrile.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccc(F)cc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(F)cc3)c2c1
Yield: 90 %

Procedure:
This compound was prepared from 6b using 4-fluorophenylboronic acid according to method P. Orange powder; Yield: 90%; mp 240–243° C.; 1H-NMR (300 MHz, DMSO-d6) δ 7.05 (d, J=2.6 Hz, 1H), 7.07 (dd, J=8.9, 8.7 Hz, 1H), 7.32 (dd, J=9.0, 2.6 Hz, 1H), 7.44 (dd, J=8.9, 8.9 Hz, 2H), 7.63 (m, 2H), 7.86 (s, 1H), 7.95 (dd, J=8.4, 1.9 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 8.08 (dd, J=13.0, 2.0 Hz, 1H), 9.96 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 348 ([M−H]−), 350 ([M+H]+); Anal. Calcd for C21H13F2NO2: C: 72.20, H: 3.75, N: 4.01. Found: C: 69.48, H: 3.81, N: 3.68.
Reaction SMILES: ClC1SC(C[N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]2)=CC=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: NCC1CN(Cc2ccc(Cl)s2)CCO1
Product: NCC1CN(Cc2ccc(F)cc2)CCO1

Procedure:
Intermediate 21 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 4-fluorobenzyl chloride, followed by deprotection to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]CC)=O)[N:6]=[CH:5]2.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)=[O:14])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCOC(=O)c1ncc2cc(Cl)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc3cc(Cl)ccc3n2)C1
Temperature: 150 °C
Reaction time: 20 h
Yield: 24.7 %

Procedure:
To a solution of ethyl 6-chloroquinazoline-2-carboxylate (0.200 g, 0.85 mmol, 1 eq) in 0.42 mL of NMP was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.16 g, 0.86 mmol, 1 eq) and diisopropylethylamine (0.6 mL, 3.4 mmol, 4 eq). After stirring at 150° C. for 20 h, the mixture was concentrated and purified via silica gel flash chromatography to provide (S)-tert-butyl 3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate (0.08 g, 0.21 mmol, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])[S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C[O-].[Na+]>CN(C=O)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:27]([CH3:28])([C:29]([O:31][CH3:32])=[O:30])[C:8]2([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[OH:33]
Reactant: COC(=O)C(C)N(c1ccc(Cl)cc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)N(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2C1(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture containing 0.5 g of 2',5-dichloro- 2-[N-(1-methoxycarbonylethyl)-N-(tosyl)amino]benzophenone, 0.1 g of sodium methylate and 2 ml of DMF is stirred for 20 hours at room temperature under nitrogen. It is concentrated under vacuum, the residue is taken up with water and the precipitate is filtered off and washed with water. The residue is chromatographed on silica using DCM as the eluent to give 60 mg of the cis isomer and 250 mg of the trans isomer.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CS(C)=O>[CH:18]1([NH:17][C:16](=[O:1])[NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution consisting of 0.3 g (0.67 mmol) N-(2-aminoethyl) trans-1,2-diaminocyclohexane-N,N',N',N",N"pentaacetic acid in 20 ml dimethylsulfoxide was added 0.62 g (5.4 mmol) N-hydroxysuccinimide and 0.41 g (2.0 mmol) dicyclohexylcarbodiimide. This was stirred at room temperature for 24 hr. A white fluffy solid of dicyclohexyl urea formed in the reaction and was filtered. The filtrate was concentrated to a thick oil under reduced pressure. A solid precipitated from the oil upon the addition of acetonitrile. This solid was collected, washed with acetonitrile and dried under vacuum to give 0.25 g of the final product. NMR showed an average of 2 NHS esters so the yield is 58%. No further purification was attempted; mp 100°-130° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].[OH-].[K+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:2]1=[O:1])[CH3:19]
Reactant: O=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(-c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 72.6 %

Procedure:
17 g of 1,2-dihydro-2-oxo-3-phenylquinoline, 12.8 g of bromoacetic acid ethyl ester, 2.5 g of tetrabutylammonium bromide and 6.2 g of powdered potassium hydroxide are stirred in 250 ml of tetrahydrofuran at room temperature for 16 hours. The mixture is poured into 1 l of ice-water, acidified to pH 3 to 4 with dilute sulphuric acid and extracted with diethyl ether and the organic phase is dried over sodium sulphate, treated with active charcoal and concentrated. 17.1 g of the title compound are obtained as a viscous, yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1Cl
Yield: 57.8 %

Procedure:
Step AD (1): 2-(2,4-Dichlorophenyl)acetic acid (10.25 g, 50.0 mmol) was deprotonated with NaHMDS (1.0 M in THF, 100 mL, 100 mmol) and reacted with 1-chloro-3-iodopropane (5.27 mL, 50.0 mmol) using a procedure analogous to Step AC (1) to afford, after purification by silica gel column chromatography, 5-chloro-2-(2,4-dichlorophenyl)pentanoic acid (8.15 g, 28.9 mmol, 58% yield) as a colorless oil. MS (M+H)+ 280.9. 1H NMR (500 MHz, chloroform-d) δ ppm 7.47 (d, J=2.14 Hz, 1 H) 7.34-7.40 (m, 1 H) 7.28-7.33 (m, 1 H) 4.22 (t, J=7.48 Hz, 1 H) 3.57 (t, J=6.41 Hz, 2 H) 2.27 (dddd, J=13.08, 10.64, 7.55, 5.34 Hz, 1 H) 1.95-2.05 (m, 1 H) 1.82-1.92 (m, 1 H) 1.68-1.81 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a suspension of N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide (30 g, 0.11 mol) and K2CO3 (14.9 g, 0.11 mol) in DMF (300 mL) was added dropwise CH3I (15.3 g, 0.11 mol) at 0° C. under N2, and then the mixture was stirred for 1 hour at this temperature. H2O was added to the mixture and extracted with dichloromethane. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated in vacuo to give N-(4-(benzyloxy)pyridin-3-yl)-N-methylmethanesulfonamide (15 g, yield: 50%), which was used for the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 7.37˜7.39 (m, 5H), 6.94 (d, J=6.0 Hz, 1H), 5.15 (s, 2H), 3.22 (s, 3H), 2.79 (s, 3H). MS (M+H)+: 293.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[F:37])=[O:28])=[CH:22][CH:21]=2)[CH:11]=1)=[O:9])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[S:18][C:17]=23)=[CH:21][CH:22]=1)=[O:28]
Reactant: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC=O)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (680 mg, 1.20 mmol) in 10 ml of THF was added 1 ml of 2M HCl. The mixture was stirred at room temperature for 3 hours, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 550 mg, 93%.
Reaction SMILES: ClCCl.[NH2:4][C@H:5]([CH3:22])[C@:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C@@:6]([OH:13])([CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[C@H:5]([NH:4][S:31]([CH3:30])(=[O:33])=[O:32])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](NS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To dichloromethane (10 ml) was added (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.54 g). To the mixture was added, under ice-cooling, triethylamine (0.28 ml), to which was added dropwise methanesulfonyl chloride (0.15 ml), followed by stirring for 15 minutes at room temperatures. To the mixture was added water (20 ml), which was subjected to extraction with dichloromethane (30 ml). The extract was washed with water (20 ml) and dried (MgSO4). Then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel chromatography (2.9×30 cm, eluent: ethyl acetate/methanol =25/1). The object fraction was concentrated to give N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2, 4-triazol-1-yl)-2-butyl]methanesulfonamide (Compound 49, 0.52 g) as a colorless oily product. 1H-NMR(CDCl3) δ: 1.04(3H,d,J=6.6 Hz), 3.07(3H,s), 4.12-4.21(1H,m), 4.81(1H,d,J=14 Hz), 4.97(1H,d,J=14 Hz), 5.28(1H,d,J=10 Hz), 6.69-6.82(2H,m), 7.27-7.39(1H,m), 7.79(2H,s)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[F:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:13]=1[NH:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Product: Fc1ccc(C(F)(F)F)cc1Nc1nc2ccccc2o1
Reaction time: 16 h

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g., 0.1 mole) in 150 ml. of tetrahydrofuran was added dropwise to a solution of 2-fluoro-5-(trifluoromethyl)aniline in 200 ml. of refluxing tetrahydrofuran. Reflux of the reaction mixture was continued on a steam bath for 16 hours. The tetrahydrofuran solvent was then removed by distillation under vacuum. The oily residue was solidified by addition of approximately 100 ml. of water. The solid material was separated by filtration and was recrystallized from an acetone-water solvent mixture to give 2-[2-fluoro-5-(trifluoromethyl)anilino]benzoxazole having a melting point of 164°-165° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][CH2:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Br)cc1
Yield: 95.6 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (36 g, 214 mmol) in acetonitrile (400 mL) were added (S)-1-(4-bromophenyl)ethanamine (51 g, 256 mmol), K2CO3 (59 g, 428 mmol) and KI (71 g, 428 mmoL), and the mixture was refluxed overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the crude (S)-3-(1-(4-bromophenyl)ethylamino)-1-phenylpropan-1-one (68 g), which was used to the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:24]1[CH2:26][CH2:25]1)[C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:24]1[CH2:25][CH2:26]1)[C:13]([NH:15][NH2:16])=[O:14]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCCl)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl N′-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazinecarboxylate (208 mg) in methylene chloride (1 ml) under ice-cooling, and then the reaction solution was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine. The combined aqueous layers were reextracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 127 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reaction time: 16 h

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, (Example 1) 5.63 g (0.048 mol), in 100 mL of methanol saturated with gaseous ammonia is treated with 0.5 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch (psi) and 40° C. After 16 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluant to give 4.93 g of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([N:17]=O)[C:12](=[O:13])[N:11]([CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.[NH4+].[OH-]>[CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCCn1c(=O)c(N)c(N)n(Cc2ccccc2)c1=O
Yield: 45 %

Procedure:
A solution of the nitroso-uracil derivative (from Example 4) (5 mmol) in water (25 mL) and 30% NH4OH (10 mL) was heated at 85° C. and sodium dithionite (15 mmol) was added in small portions under vigorous stirring until the red color disappeared (15-30 minutes). The reaction was then cooled and the mixture extracted with ethyl acetate. The organic phase was dried with Na2SO4, evaporated under vacuum and the product purified by crystallization with ethyl acetate or ethanol. (Pale yellow solid. Yield 45%).
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][N:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:15](=[O:19])[CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNC(=O)C1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)OCc1ccccc1)C1CCN(c2ccncc2)C(=O)C1
Temperature: 90 °C
Yield: 41 %

Procedure:
Benzyl methyl(2-oxopiperidin-4-yl)carbamate (300 mg, 1.145 mmol, 1.0 eq.), 4-bromopyridine HCl (244 mg, 1.259 mmol, 1.1 eq.) and Cs2CO3 (744 mg, 2.29 mmol, 2.0 eq.) were taken up in toluene and degassed with N2. Xantphos (66 mg, 0.114 mmol, 0.1 eq.) and Pd2(dba)3 (104 mg, 0.114 mmol, 0.1 eq.) were then added and the mixture was heated for 14 hours at 90° C. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (Alox, 1% MeOH in DCM). Yield: 41% (160 mg, 0.472 mmol)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:29][OH:30])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:29][OH:30])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: COc1cccc(NC(=O)C(N)CO)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: COc1cccc(NC(=O)C(CO)Nc2nc3ccc(Cl)cc3cc2C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-hydroxy-N-(3-methoxy-phenyl)-propionamide to provide the title compound in good yield. LCMS m/z 416 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:28]1[CH:32]=[N:31][C:30]([CH3:33])=[N:29]1)[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:7].Cl.O1CCOCC1>>[OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:28]1[CH:32]=[N:31][C:30]([CH3:33])=[N:29]1)[CH2:3][CH2:4][N:5]1[C:6](=[O:7])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCNC(=O)c2ccccc2C(=O)O)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 100 °C

Procedure:
A mixture of 2-(3-hydroxy-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butylcarbamoyl)benzoic acid (2.56 g, 5.62 mmol) and hydrogen chloride in dioxane (42.2 mL, 169 mmol) was heated at 100° C. for 45 min. The reaction was cooled to rt, and then extracted with EtOAc. The combined organic layers were concentrated to get 2-(3-hydroxy-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)isoindoline-1,3-dione which was used as-is in the next step. LC-MS (M+H)+=438.2. 1H NMR (500 MHz, methanol-d4) δ 9.26 (s, 1H), 8.13-7.97 (m, 3H), 7.87-7.83 (m, 2H), 7.83-7.77 (m, 2H), 4.36 (dd, J=9.9, 3.5 Hz, 1H), 4.27 (dd, J=9.8, 6.1 Hz, 1H), 4.12 (dt, J=6.0, 2.9 Hz, 1H), 3.95-3.81 (m, 2H), 2.48 (s, 3H), 2.08-1.87 (m, 2H).