Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:16][O:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[CH:16][O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC=C1CCC(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
3-(4-Methoxyphenyl)cyclopentanone (8.51 g) and methoxymethyltriphenylphosphonium chloride (16.9 g) were dissolved in tetrahydrofuran (200 ml). After gradually adding potassium tert-butoxide (6.70 g) while maintaining an internal temperature of 10° C. or below, the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into water, and extraction with ethyl acetate was followed by washing with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to produce a brown oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 4.73 g of 1-methoxy-4-(3-methoxymethylenecyclopentyl) benzene (48.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2C)=[O:12])N)=[CH:4][CH:3]=1.Cl.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])C.[CH3:33]COC(C)=O.CCO.[NH4+].[OH-]>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH2:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([CH3:33])[CH2:17][CH2:18]1)=[O:12])[CH:24]=[C:25]2[CH2:26][CH2:27][NH:28][CH3:29]
Reactant: CC1CCCCN1C(=O)CN(N)c1ccc(Cl)cc1
Reactant: CCOC(CCCNC)OCC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CNCCc1cn(CC(=O)N2CCC(C)CC2)c2ccc(Cl)cc12
Temperature: 60 °C

Procedure:
2-[N-(4-Chloro-phenyl)-hydrazino]-1-(methyl-piperidin-1-yl)-ethanone (0.75 g, 2.66 mmol) was dissolved in ethyl acetate (3 mL) and 4M hydrochloride in dioxane (0.7 mL) was added. The mixture was concentrated under reduced pressure to a glassy oil/foam. This was dissolved in a mixture of ethanol (4 mL) and water (2 mL) and heated to 60° C. The 4,4-diethoxy-N-methylbutan-1-amine (0.47 g, 2.68 mmol) was added and then heated to 7{tilde over (0)}80° C. 28% aqueous HCl (0.35 mL, 2.66 mmol) was added and the reaction heated at 80° C. for 1 h. More 4,4-diethoxy-N-methylbutan-1-amine (0.2 g, 1.14 mmol) and 28% aqueous HCl (0.3 mL, 2.30 mmol) was added and heated for a further 3 h. Further 4,4-diethoxy-N-methylbutan-1-amine (0.3 g, 1.71 mmol) was added and heated for a further 6 h. The reaction was concentrated under reduced pressure to give a dark brown oil. The oil was subjected to column chromatography (silica gel, eluent: EtOAc:EtOH:NH4OH 7:3:1) to give a brown oil (0.29 g). Further purification of the brown oil by column chromatography (silica gel, eluent: EtOAc:EtOH:NH4OH 7:3:1) gave pure product (179 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:19][CH:7]1[C:6]2[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[CH2:8]1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reaction time: 8 h

Procedure:
103 G. of 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one, 500 ml. of benzene and 38.4 g. of finely pulverized calcium chloride are saturated with hydrochloric acid gas at 15° and stirred overnight. The residue is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 10 -chlor-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin, having a melting point of 63°-64°.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>ClCCCl>[Br:18][C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C=C(c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClCCCl
Product: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Into a reactor were introduced 8.81 g (39.6 mmol) of the 1,1-diphenyl-3-methylbutene and 35 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 6.33 g (39.6 mmol) of bromine was gradually added dropwise thereto. This mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and ethyl acetate to obtain 8.64 g (72%) of the target compound as white crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O1CCOCCOCCOCCOCCOCC1.Cl[CH:24]([C:26]1[O:27][C:28]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:29]([CH3:31])[N:30]=1)[CH3:25]>C(#N)C>[N:1]([CH:24]([C:26]1[O:27][C:28]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:29]([CH3:31])[N:30]=1)[CH3:25])=[N+:2]=[N-:3]
Reactant: Cc1nc(C(C)Cl)oc1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(C(C)N=[N+]=[N-])oc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Sodium azide (635 mg, 9.760 mmol) and a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane was added to a solution of 2-(1-chloroethyl)-5-(4-chlorophenyl)-4-methyloxazole (250 mg, 0.976 mmol) in acetonitrile (10 ml) and reluxed at 80° C. for 3 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 0-5% EtOAc/DCM provided the title compound (254 mg, clear oil). HRMS(C) tR=1.52 min; MS m/z 262.0621
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[CH:54]=[CH:53][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([C:38](=O)[C:39]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[N:48]=[CH:47][CH:46]=[CH:45]4)=[O:40])=[CH:30]2)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:54]=[CH:53][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([C:38](=[S:10])[C:39]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[N:48]=[CH:47][CH:46]=[CH:45]4)=[O:40])=[CH:30]2)=[CH:26][CH:25]=1
Reactant: O=C(Nc1ccc2ncccc2c1)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ncccc2c1)C(=S)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 75 °C

Procedure:
3.68 g (9.1 mMol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide are added, under nitrogen, to a suspension of 4.00 g (9.1 mMol) of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinolin-6-ylacetamide in 200 ml of toluene, after which the mixture is heated at 75° C. for 3 h. The residue which has formed is filtered off in the hot from the reaction solution and subsequently washed with 100 ml of methylene chloride. The filtrate is concentrated in vacuo and the residue is chromatographed on flash silica gel (eluent: methylene chloride/methanol 99:1). The product fractions are filtered on flash silica gel (eluent: n-heptane/ethyl acetate 1:1) after the solvent has been removed once more.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:9]([OH:11])=[O:10])=[O:4].[S:28]1[CH:32]=[C:31](C=O)[N:30]=[CH:29]1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:22]1([CH2:21][C@H:2]([NH:1][CH2:35][C:32]2[S:28][CH:29]=[N:30][CH:31]=2)[C:3]([NH:5][C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH:14]=2)[C:9]([OH:11])=[O:10])=[O:4])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cscn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(=O)O)cc(-c2ccncc2)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cc(NC(=O)[C@H](Cc2ccccc2)NCc2cncs2)cc(-c2ccncc2)c1
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a solution of (S)-3-(2-amino-3-phenylpropanamido)-5-(pyridin-4-yl)benzoic acid (45.1) (181 mg, 0.50 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (56 mg, 0.50 mmol). The mixture was stirred for 1 h, sodium triacetoxyborohydride (212 mg, 1.00 mmol) was then added and the mixture stirred for an additional 1 hour at room temperature. The reaction mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (S)-3-(3-phenyl-2-(thiazol-5-ylmethylamino)propanamido)-5-(pyridin-4-yl)benzoic acid (45.2) as a white solid (82 mg, 36% yield). LCMS ESI (pos.) m/e: 459.0 (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.13 (d, J=1.96 Hz, 1H), 8.93 (d, J=6.85 Hz, 2H), 8.35 (d, J=1.22 Hz, 1H), 8.32-8.34 (m, 2H), 8.31 (t, J=1.83 Hz, 1H), 8.18-8.23 (m, 1H), 7.82 (d, J=1.96 Hz, 1H), 7.23-7.37 (m, 5H), 4.48-4.58 (m, 2H), 4.35 (dd, J=9.29, 5.87 Hz, 1H), 3.41-3.51 (m, 1H), 3.24-3.30 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:3]1=[O:12]
Reactant: Brc1ccccn1
Reactant: Cn1c(=O)[nH]c2nc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccccn2)c2nc(Cl)ccc21
Temperature: 30 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one were dissolved in 160 ml of hot dimethylformamide and after cooling the solution to 30° C., 4.64 g of a 50% sodium hydride-oil suspension were slowly added thereto. The mixture was stirred at 30° C. for 2 hours and then 80 ml or 129.6 g of 2-bromo-pyridin and 1.2 g of cuprous chloride were added thereto. The mixture was refluxed for 4 hours and was then cooled and evaporated to dryness. The residue was taken up in ammonium hydroxide solution and the mixture was extracted with chloroform. The organic phase was dried and evaporated to dryness and the residue was taken up in petroleum ether. The mixture was filtered and the product was crystallized from 95% ethanol to obtain 6.5 g of 1-methyl-3-(2-pyridyl)-5-chloro-1,3-dihydroimidazo-(4,5-b)-pyridin-2-one in the form of white crystals melting at 192°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:13]=[C:12]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH2:23]([NH:26][CH2:27][C:28]#[CH:29])[C:24]#[CH:25].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:15]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:11])[N:26]([CH2:27][C:28]#[CH:29])[CH2:23][C:24]#[CH:25]
Reactant: O=C(O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: C#CCNCC#C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCN(CC#C)C(=O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 0.20 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)valeric acid and 0.05 g of dipropargylamine dissolved in 10 ml of chloroform was added 0.11 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(N,N-dipropargylcarbamoyl)butyloxy)benzene (92% yield), nD25.0 1.5481.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[CH:14]([OH:17])([CH3:16])[CH3:15].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:13])[NH:5][CH:6]=[N:7]2)=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.1 %

Procedure:
5,7-Difluoroquinazolin-4(3H)one (2.73 g, 15 mmol) in dimethylformamide (20 ml) was reacted with isopropanol (1.26 ml, 16.4 mmol) and sodium hydride (1.8 g, 45 mmol) at 0° C. under argon. The mixture was stirred at ambient temperature for 14 hours, acidified with acetic acid and concentrated. The residue was washed with water and dried to yield 7-fluoro-5-isopropoxyquinazolin-4(3H)-one (3.17 g, 95% yield) as a beige solid:
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.[CH2:17](N)[CH2:18][CH2:19][CH3:20]>CCCCO>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCCc1ncnc(Cl)c1N
Reaction time: 16 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in n-BuOH was treated with Et3N (1.2 mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed under reduced pressure. The residue was dissolved in EtOAc, the organic layer washed with water and then dried (MgSO4). Filtration and removal of solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid. Rf=0.5 in 1:1 EtOAc:hexane. 1H NMR (CDCl3) δ 8.07 (s, 1H), 4.88 (br s, 1H), 3.49 (m, 2H), 3.35 (br s, 2H), 1.6 (m, 2H), 1.44 (m, 2), 0.95 (t, 3H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[C:5]=1[F:13].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22]O)[CH:16]=1.Cl.C[O:27][C:28]([C:30]1([NH2:39])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29]>>[F:13][C:5]1[C:6]([O:12][CH2:22][CH2:21][C:17]2[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=2)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:39][C:30]1([C:28]([OH:29])=[O:27])[CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38]1)=[O:14]
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COC(=O)c1ccc(OC)c(O)c1F
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(F)c1OCCc1cccc(C)c1

Procedure:
2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was etherified with 2-m-tolyl-ethanol in analogy to step 1 of example 1, the obtained ester hydrolyzed in analogy to example 2, the obtained carboxylic acid reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 3 of example 1, and the methyl ester hydrolyzed in analogy to example 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([OH:30])=O)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30])[NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)Nc2ccccc2)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1:1 mixture of the R and S isomers of N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLEs 60 and 62, 45 mg, 0.10 mmol) and aniline hydrochloride (28 mg, 0.22 mmol) in pyridine (2 mL) cooled in an ice-bath, POCl3 (0.040 mL, 0.44 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to the titled compound as a powder (12 mg). MS 519.1 and 521.1 (M+H, Cl pattern).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1.Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>CN1CCCC1=O>[Cl:17][C:13]1[N:12]=[C:11]([NH:28][C@H:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH3:27])[CH:16]=[N:15][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(F)cn1
Temperature: 180 °C
Yield: 58465.3 %

Procedure:
N,N′-Diisopropylethylamine (2.50 mL, 14.35 mmol) was added dropwise to a solution of 2,6-dichloropyrazine (525 mg, 3.52 mmol) and (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 750 mg, 3.52 mmol) in 1-methylpyrrolidin-2-one (4 mL) and the resulting mixture was stirred and heated for 6 hours at 180° C. in a microwave oven. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 hexanes/ethyl acetate) to give the title compound (520 g, 57%) as a brown oil.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16].O>C(OC(=O)C)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C2CCC2)c([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g, 20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL) 0° C. was added dropwise fuming HNO3 (5 mL, 97%). The resulting mixture was stirred at 30° C. in an oil bath. After 2 h, 30 mL of water was carefully added and the mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with aqueous saturated NaHCO3 (note: gas evolution), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:25) as eluent to furnish 3.00 g (64%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].CC(C)=[O:12]>C(Cl)Cl>[C:3]([OH:12])(=[O:4])[C:2]([CH3:1])=[CH2:8].[CH2:3]([CH:5]1[CH2:6][CH2:7][O:9]1)[CH3:2]
Reactant: Cc1cc(O)ccc1O
Reactant: CC(C)=O
Solvent: ClCCl
Product: C=C(C)C(=O)O
Product: CCC1CCO1

Procedure:
The following morning, the white precipitate was filtered from the mix, leaving a dark red-brown solution. Methyl hydroquinone was added to the solution at ˜1000 ppm and the acetone was stripped. The resulting thin brown liquid was then dissolved in 100 mL methylene chloride and washed five times with 200 mL of a 5% sodium chloride solution. This was followed by two water washes of 300 mL each. The resulting pH was 9. Another 1000 ppm of methyl hydroquinone was added to the solution and the methylene chloride was then stripped. The resulting dark liquid was then dissolved in ethyl acetate and the solution was run through silica gel (5 tbsp) in a glass Buchner funnel. The solvent was stripped from the clear orange solution resulting in a clear brown product. To remove residual solvent, air was then bubbled through the product overnight. The structure of this dark-brown liquid was confirmed by NMR and determined to be ˜93 mole % pure.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8](CO)[CH2:9][N:10]1[C:19]([C:20]#[N:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:29][CH3:30])[CH:16]=2)[C:11]1=[O:31]>O.C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:29][CH3:30])[CH:16]=3)[C:11](=[O:31])[N:10]([CH2:9][CH:8]=[O:7])[C:19]=2[C:20]#[N:21])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(=O)n(CC(O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(CC=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 8 h

Procedure:
A solution of sodium periodate (368 mg, 1.72 mmol) in water (7 mL) was added to a solution of diol 106 (0.96 mmol) in THF (15 mL) at 0° C. After 7 h an additional 1.8 equivalents of NaIO4 were added. The reaction mixture was stirred overnight then partitioned between EtOAc and NaHCO3. The aqueous phase was extracted with EtOAc and the combined extracts dried (MgSO4). Concentration gave the desired product 107.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][C:17](Br)=[CH:16][CH:15]=2.[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Nc1ncnc2c1ncn2Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 36.9 %

Procedure:
To a solution of Example 1 (0.1 g, 0.22 mmoles) in methanol (10 ml), palladium on carbon (10 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 3 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale yellow solid (0.030 g, 37% yield).: MP: 173-175° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.10(d, J=12.5 Hz, 1H), 8.05(d, J=8.0 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.48-7.41(m, 6H), 7.22(s,2H), 5.34(s, 2H). Mass: 370.05(M++1).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:13])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34])([O-:23])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 6.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-nitro-3-(trifluoromethyl)aniline (2.39 g, 11.6 mmol) in 19 mL of pyridine. The crude product was recrystallized from ethyl ether to yield 0.25 g of the title compound, mp 167°-169° C.