Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([N:16]([CH3:17])[CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc(NCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred suspension of 2-((4-methoxyphenyl)amino)acetic acid (18) (45 g, 0.25 mol) and dimethylamine hydrochloride (40.5 g, 0.5 mol) in acetonitrile (1 L) at 0° C., was added DIPEA (174 ml, 0.99 mol) followed by HATU (99 g, 0.26 mol). The reaction mixture was stirred at RT for 1 h, and then partitioned between EtOAc (1 L) and 5% NaH2PO4 (aq.) (250 mL), the organic layer was washed with sat. NaHCO3 (aq.) (3×300 mL), and 3M HCl (aq.) (4×250 mL). The combined acidic extracts were cooled to 0° C. and solid NaOH was added to pH 14 and the aqueous phase was extracted with EtOAc (3×400 mL), the combined organics were washed with brine (500 mL) dried (MgSO4), filtered and solvents removed in vacuo to give 2-((4-methoxyphenyl)amino)-N,N-dimethylacetamide (19) (37.1 g, 71%) as a brown solid: m/z 209 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.74-6.70 (m, 2H), 6.65-6.59 (m, 2H), 5.10 (br s, 1H), 3.81 (s, 2H), 3.64 (s, 3H), 3.01 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>[Pd].C1C=CC=CC=1>[ClH:1].[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:2]=1)[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: c1ccccc1
Product: Cl
Product: Nc1ccc(C(=O)c2cccc(N)c2)cc1

Procedure:
In a closed glass vessel equipped with a thermometer and a stirrer there are charged 30.7 g (0.1 moles) of 4-chloro-3,4'-dinitro benzophenone, 1 g of palladium black catalyst and 300 ml of benzene. While the mixture being stirred, at 65°-70° C., hydrogen is introduced so that 13.3 l (0.59 moles) of hydrogen is absorbed in the mixture during about nine hours. After there are added 45 g (0.12 moles) of 15% aqueous solution of sodium hydroxide and 2 g of 90% aqueous solution of trioctyl methyl ammonium chloride (available from Tokyo-Kasei Co.), hydrogen is again introduced so that 2.35 l (0.105 moles) is absorbed during about six hours, while the mixture being stirred at 65°-70° C. The reaction mixture is filtered to remove the catalyst and organic layer is separated. The organic layer is added with magnesium sulfate for water removal and then blown with hydrochloric gas to saturation therewith. The precipitate thus formed is filtered, washed with 50 ml of benzene, and dried to obtain hydrochloric acid salt form of 3,4'-diamino benzophenone. Yield 23.4 g (82%). Recrystallization from 20% aqueous isopropanol gives yellow needle-like pure crystals of the benzophenone. M.P. is 250° C. or higher.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl (rac)-7-(4-cyanophenyl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (600 mg, 1.9 mmol) was stirred in abs. dichloromethane (450 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (1.10 g, 5.8 mmol, 3 eq.), anhydrous copper(II) acetate (1.05 g, 5.8 mmol, 3 eq.), abs. pyridine (1.25 ml, 15.5 mmol, 8 eq.) and triethylamine (0.59 g, 5.8 mmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (0.37 g, 1.9 mmol, 1 eq.), anhydrous copper(II) acetate (0.35 g, 1.9 mmol, 1 eq.) and abs. pyridine (0.63 ml, 7.73 mmol, 4 eq.) were then added, and the mixture was stirred at RT for a further 12 h. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and methanol and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (404.6 mg, 46% of theory).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:2]2.C(O)(=[O:30])C>OO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH+:9]([O-:30])[C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[CH2:2]2
Reactant: CC(=O)Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: CC(=O)O
Agent: OO
Product: CC(=O)Nc1cc(OCC2CC2)c(C(=O)[NH+]([O-])C2CN3CCC2CC3)cc1Cl
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide (2.6 g; 0.007 moles) in acetic acid (20 ml), 30% hydrogen peroxide (1.8 ml) was added and the resulting solution was stirred at 80° C. for 15 hours. The solvent was removed in vacuo, the residue was treated with water, alcalinized with sodium hydroxide aqueous solution, saturated with sodium chloride and extracted with methylene chloride. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residual yellow solid treated with diethyl ether and collected. After washing with acetonitrile and diethyl ether, N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide N-oxide was obtained as a white solid, which was dried at 50° C. to give 1.4 g; m.p. 234°-236° C. (d).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:5]=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29].S(=O)(=O)(O)[OH:32].N([O-])=O.[Na+]>CS(C)=O.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:9][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([N+:28]([O-:30])=[O:29])=[C:2]([OH:32])[N:7]=1
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(N)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of methyl 2-[4-(6-amino-5-nitro-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (56 g, 134.17 mmol) in dimethyl sulfoxide (DMSO, 400 mL) and water (320 mL), is added sulfuric acid 95-97% (80 mL) dropwise. Then the mixture is cooled to 0° C. To the above mixture a solution of sodium nitrite (18.70 g, 268.35 mmol) in water (80 mL) is added dropwise over 15 min at 0° C. The reaction mixture is stirred for 20 min at that temperature and then the cooling bath is removed and the temperature is allowed to rise to RT. To the reaction mixture is added a 0.8 M aqueous solution of buffered sodium phosphate monobasic (1200 mL, pH=6). A yellow suspension appears. This suspension is stirred at RT for 1 h. The solid is filtered, washed with water, and dried in the oven to afford the title compound as an orange solid (49.5 g, 88%). LC-ES/MS m/z 419 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1.C(N(C(C)C)CC)(C)C.[C:46](Cl)(=[O:48])[CH3:47].C(OCC)(=O)C>C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:46](=[O:48])[CH3:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one in methylene chloride (5 mL) is added diisopropylethylamine (93 mg, 0.72 mmol) followed by acetyl chloride (36 mg, 0.458 mmol) and the mixture is stirred at RT for 24 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using a gradient of 25-75% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH2:38][CH2:39]Br)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>CN(C=O)C.CCOC(C)=O>[Br:36][C:31]1[CH:30]=[CH:29][C:28]2[N:27]([CH2:37][CH2:38][CH2:39][N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[C:26]3[C:34]([C:33]=2[CH:32]=1)=[CH:35][C:23]([Br:22])=[CH:24][CH:25]=3
Reactant: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCCn1c2ccc(Br)cc2c2cc(Br)ccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Crushed KOH (0.0024 g, 0.0431 mmol) was added to 2-nitro-N-phenylbenzenesulfonamide (0.0100 g, 0.0359 mmol) in 0.2 mL DMF solution and the mixture was stirred for 30 min. 3,6-dibromo-9-(3-bromopropyl)-9H-carbazole (Example 35, 0.0240 g, 0.0538 mmol) in 0.3 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The crude reaction mixture was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0082 g white solid as impure product, purity 66.9% (impurity is starting Ns-aniline; used without additional purification), yield 35.5%.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:7][CH:6]=1.[CH3:19][Mg]Br.C(=O)([O-])O.[Na+]>C1COCC1>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (6.54 g, 24.8 mmol, Step-2) in THF (80 mL) is added dropwise 1.06M methylmagnesium bromide (46.7 mL, 49.5 mmol) at 0° C. The reaction mixture is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with EtOAc (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1) to give 4.51 g (83% yield) of the title compound as colorless oil.
Reaction SMILES: [Si:1]([C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[CH:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH:16]#[C:17][C:18]#[C:19][C:20]#[C:21][C:22]#[CH:23]>>[Si:1]([C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[CH:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Si:1]([C:8]#[C:9][C:10]#[C:11][C:12]#[C:13][C:14]#[C:15][C:16]#[C:17][C:18]#[C:19][C:20]#[C:21][C:22]#[C:23][Si:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C#CC#CC#CC#C
Agent: C#CC#CC#CC#C[Si](CC)(CC)CC
Product: CC[Si](C#CC#CC#CC#CC#CC#CC#CC#C[Si](CC)(CC)CC)(CC)CC

Procedure:
Acetylenic derivatives having the general formula H—(C≡C)m—H can be formed by the procedure disclosed in Eastmond et al., “Silylation as a Protective Method for Terminal Alkynes in Oxidative Couplings—A General Synthesis of the Parent Polyynes,” Tetrahedron, 1972, 28, 4601, incorporated herein by reference, and can be converted into dilithio salts by reacting with n-butyllithium. Synthesis of the lower polyyne series H—(C≡C)m—H (n=2, 3, 4 and 5) is known to be based upon low temperature sodamide dehydrohalogenation of α,ω-bis(chloromethyl)alkynes, ClCH2—(C≡C)m−l—CH2Cl in liquid ammonia, a technique which provided a convenient route to diacetylene but which proved increasingly troublesome for tri- and tetraacetylene. Pentaacetylene, the highest member of the series was obtained in ca. 1% yield from the precursor, ClCH2-(C≡C)4—CH2Cl. Polyynes in the series H—(C≡C)m—H (n═4, 5, 6, 7, 8, 9, 10 and 12) are known to have been prepared in solution by sequences involving Cu-catalyses oxidative couplings (Hay technique) of silyl-protected terminal alkynes, partial cleavage (desilylation) of the products by alkali, recoupling and complete desilylation. Thus using conditions established in a model coupling Et3Si—C≡C—H (I)→Et3Si—(C≡C)2—SiEt3 (II), coupling of the silyldiyne Et3Si—(C≡C)2—H (III) gives Et3S—(C≡C)4—SiEt3 (IV) which upon controlled cleavage yields a chromatographically separable mixture of Et3S—(C≡C)4—SiEt3 (IV), Et3Si—(C≡C)4—H (V) and H—(C≡C)4—H (VI). Coupling of Et3Si—(C≡C)4—H (V) in turn gives Et3Si—(C≡C)8—SiEt3 (VII) which upon cleavage yields Et3Si—(C≡C)8—H (VIII) and H—(C≡C)8—H (IX) and coupling of Et3Si—(C≡C)8—H (VIII) gives the bissilylhexadecaacetylene Et3Si—(C≡C)16—SiEt3 (X).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:18])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1Cl
Yield: 49.2 %

Procedure:
A stirred refluxing solution of 4-(4-chlorobenzoyl)-3-chlorotoluene (2.65 g, 9.99 mmol) and dibenzoylperoxide (100 mg, 0.413 mmol) in benzene (100 ml) was treated in portions with an intimate mixture of N-bromosuccinimide (2.2 g, 12. mmol) and dibenzoylperoxide (100 mg, 0.413 mmol). The mixture was refluxed 1.5 hours, cooled, and filtered. The filtrate was evaporated under vacuum, triturated with diethyl ether (100 ml), and filtered. The filtrate was evaporated under vacuum and the residue was chromatographed on silica gel (500 g) eluted with 97:3 (v/v) n-hexane-ethyl acetate using a preparative highperformance liquid chromatograph to provide 1.69 g (49%) of 4-(4-chlorobenzoyl)-3-chlorobenzyl bromide, m.p. 88°-90° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH:20]1([CH2:19][O:18][C@H:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[S:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:33][C:29]4[CH:30]=[C:31]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:23])=[CH:32]5)[CH:8]=3)=[O:12])[CH2:14]2)[CH2:22][CH2:21]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](OCC2CC2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC[C@H](OCC6CC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 447.2 (MH+); HPLC Rf: 5.341 min.; HPLC purity: 100%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]#[N:11])=[N:3]1.Cl>O.C(O)C.[Fe]>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]#[N:11])[CH:5]=1
Reactant: Cn1nc(C#N)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1nc(C#N)cc1N
Temperature: 50 °C

Procedure:
To a suspension of 1-methyl-5-nitro-1H-pyrazole-3-carbonitrile (2 g; 13.1 mmol) in a mixture of water (14 mL) and ethanol (120 mL) there are added HCl 37% (170 L) and iron filings (5.1 g; 91 mmol). The reaction mixture is heated for 5 hours at 50° C. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and ethyl acetate as eluants to yield the expected compound in the form of a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[C:19]([Cl:34])=[CH:18][N:17]=1.Cl.O1CCOCC1>COCCO>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 14 %

Procedure:
7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (160 mg, 0.84 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (280 mg, 0.84 mmol) and 4N HCl in dioxane (0.21 ml, 0.84 mmol) were dissolved in 2-methoxyethanol (4 ml) and heated to 120° C. for 5 hours. The mixture was concentrated to a brown solid. Preparative TLC (5% MeOH/CH2Cl2) gave a brown residue which was triturated with MeOH/CH2Cl2 to 2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a white solid, 58 mg. (14% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.32-8.58 (m, 1H), 8.27 (s, 1H), 7.45-7.90 (m, 5H), 7.23-7.37 (m, 1H), 7.14-7.22 (m, 1H), 3.22 (s, 3H), 2.39-2.60 (m, 5H), 1.92-2.18 (m, 4H); MS (m/e) 487 (M+1); retention time 7.65 minute; mp 175-177° C.
Reaction SMILES: [H-].[Na+].CO.[CH2:5]([C:7]1[C:8](=[S:47])[NH:9][C:10](=[O:46])[N:11]([CH:45]=1)[C@@H:12]1[O:44][C@H:33]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[C@@H:23]([O:24]C(=O)C2C=CC=CC=2)[C@H:13]1[O:14]C(=O)C1C=CC=CC=1)[CH3:6]>C(O)(=O)C>[CH2:5]([C:7]1[C:8](=[S:47])[NH:9][C:10](=[O:46])[N:11]([CH:45]=1)[C@@H:12]1[O:44][C@H:33]([CH2:34][OH:35])[C@@H:23]([OH:24])[C@H:13]1[OH:14])[CH3:6]
Reactant: CCc1cn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]c1=S
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=S
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Sodium hydride (0.1 g) (60% dispersion in mineral oil) was added to dry methanol (50 ml) under an atmosphere of nitrogen at 0° C. The product from step (i) (3.0 g) was added to the above solution and the whole was refluxed for 2 hours. After cooling to room temperature, glacial acetic acid (0.28 ml) was added and the volatiles were then removed under reduced pressure. The residue was dissolved in water (20 ml) and then extracted three times with diethyl ether (20 ml). The aqueous phase was evaporated to dryness under reduced pressure. The resulting solid was triturated with acetone and filtered to leave 5-ethyl-4-thiouridine as a yellow solid (1.39 g).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[Na+].[C:8]([OH:13])(=[O:12])[CH:9](C)C.C([O-])(=O)CO.[OH-].[Na+]>>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[C:8]([O-:13])(=[O:12])[CH3:9]
Reactant: C[C@H](O)C(=O)[O-]
Reactant: CC(C)C(=O)O
Agent: O=C([O-])CO
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(=O)[O-]
Product: CC(=O)[O-]
Temperature: 15 °C
Reaction time: 5 h

Procedure:
Into a 3 oz. Fischer-Porter glass aerosol reaction vessel was placed a magnetic stirring bar and 10 mL of an aqueous solution containing sodium L-lactate (0.500M), isobutyric acid (HPLC internal standard, 0.100M), soluble spinach glycolate oxidase (6.0 IU/mL), and soluble Aspergillus niger catalase (10,000 IU/mL) at pH 9.0 (adjusted with 50% NaOH) and at 15° C.; no buffer was added. The reaction vessel was sealed and the reaction mixture was cooled to 15° C., then the vessel was flushed with oxygen by pressurizing to 70 psig and venting to atmospheric pressure five times with stirring. The vessel was then pressurized to 70 psig of oxygen and the mixture stirred at 15° C. Aliquots (0.10 mL) were removed by syringe through a sampling port (without loss of pressure in the vessel) at regular intervals for analysis by HPLC to monitor the progress of the reaction. After 5 hours, the HPLC yields of pyruvate and acetate were 95.3% and 0.9%, respectively, and 4.5% lactate remained. The remaining activities of glycolate oxidase and catalase were 68% and 100%, respectively, of their initial values.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][CH2:12][OH:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH2:11][CH2:12][OH:13])(=[O:22])=[O:23])=[CH:17][C:16]=1[C:25]([F:28])([F:26])[F:27]
Reactant: OCCBr
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCCO)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-bromo-ethanol, and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.