Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[K+].S(=O)(=O)(O)O>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
4.0 g of ethyl p-[(E)-2-(4,4-dimethyl-6-chromanyl)-propenyl]benzoate were dissolved in 80 ml of ethanol and the solution obtained was treated with a solution of 5.6 g of potassium hydroxide in 20 ml of water and 20 ml of ethanol. After stirring at 50° C. for 3 hours, the mixture was cooled, poured into ice/water, acidified with 2N sulphuric acid and extracted repeatedly with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated. After recrystallization of the residue from methylene chloride/hexane, there was obtained 3.4 g of p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)propenyl]benzoic acid in the form of colorless crystals of melting point 196°-197° C.
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([C:13](=[O:15])[NH2:14])[C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]1=[O:24])C1C=CC=CC=1>CO.[Pd]>[C:20]([O:19][C:17]([NH:16][C@H:11]1[C@H:12]([C:13](=[O:15])[NH2:14])[N:9]([OH:8])[C:10]1=[O:24])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
In 200 ml of methanol is suspended 3.69 g (11 mmole) of trans-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyl-2-azetidinone, and 350 mg of 10% palladium-charcoal is added to the suspension, followed by stirring under a hydrogen atmosphere at room temperature for 30 minutes. The catalyst is filtered off, and the filtrate is concentrated to dryness under reduced pressure to give 2.7 g of trans-3-(tert-butoxycarbonylamino)-4-carbamoyl-1-hydroxy-2-azetidinone as a yellowish foamy product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=O)[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCCc1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-butyryl-4-(2-methylphenylamino)-8-(3-methylthiopropoxy)quinoline (0.33 g, 0.8 mmol) was dissolved in methylene chloride (15 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 0.18 g (53%) of the title compound.
Reaction SMILES: C1(C2[C:13]3=[CH:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[C:10](=[O:20])[NH:9][N:8]=2)C=CC=CC=1.N1C2C=CC=C(C(OC)=O)C=2C=C1.[F:34][C:35]([F:43])([C:39]([F:42])([F:41])[F:40])[C:36](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].O.NN>ClC(Cl)C.CO.Cl>[F:34][C:35]([F:43])([C:36]1[C:13]2=[CH:14][NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=32)[C:10](=[O:20])[NH:9][N:8]=1)[C:39]([F:42])([F:41])[F:40]
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Reactant: O=C1NN=C(c2ccccc2)c2c[nH]c3cccc1c23
Agent: COC(=O)c1cccc2[nH]ccc12
Agent: Cl
Agent: NN
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=C1NN=C(C(F)(F)C(F)(F)F)c2c[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 28, a solution of methyl indole-4-carboxylate (351 mg, 2.01 mmol) in dichloroethane (7 mL) was treated with pentafluoropropionyl chloride (2.51 mmol) and aluminum chloride (575 mg). The intermediate ketone (50 mg, 0.16 mmol) in MeOH (2 mL) and conc. HCl (0.02 mL) was treated, as described, with hydrazine hydrate (0.1 mL). The reaction was quenched at 0° C. with 1 M NaOAc and the aqueous layer was adjusted to pH=8 with 1 M NaOH. The product was isolated by extraction with CH2Cl2, and recrystallized (CH2Cl2/MeOH/hexanes) to give 1,5-dihydro-3-pentafluoroethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 15 mg (28%) as a yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 7.16 (app br t, 1H), 7.54 (m, 2H), 7.65 (m, 1H), 10.87 (s, 1H), 12.15 (s, 1H). HRMS (FAB, Mna+) Calcd for C11H10N3Ona: 352.0674. Found: 352.0668.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:3]=1
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 58 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 2-methoxy-phenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (75 mg, 58%). 1H NMR (500 MHz, CDCl3) δ 7.49 (br s, 1H), 7.41 (br s, 1H), 7.37-7.28 (m, 3H), 7.23 (d, J=7.5 Hz, 1H), 7.04-6.94 (m, 3H), 4.83 (m, 1H), 3.80 (s, 3H), 3.29 (m, 1H), 2.97-2.70 (m, 5H), 2.10 (m, 1H), 1.91-1.82 (m, 1H), 1.74-1.65 (m, 1H), 1.62-1.53 (m, 1H), 1.46-1.37 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 156.4, 153.4, 139.4, 137.6, 130.9, 130.2, 128.8, 128.6, 124.8, 120.8, 119.9, 117.3, 111.2, 72.0, 55.6, 55.4, 47.4, 46.5, 25.4, 24.5, 19.5 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.52 min; (M+1) 353.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Br:18][C:17]1[CH:16]=[N:15][N:14]2[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C:19]([N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[O:21])[CH:11]=[N:12][C:13]=12
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: c1csc(C2CCNCC2)c1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2cccs2)CC1
Yield: 97.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.10 g, 0.29 mmol) obtained in Example 22, step 3 and 4-(thiophen-2-yl)piperidine hydrochloride (0.07 g, 0.35 mmol), the title compound (0.14 g, 99%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of o-anisidine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][S:15][C:13]2[O:14][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[N:11][N:12]=2)[CH2:20][CH2:19]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: ClCC1CC1
Product: c1cc2c(cc1-c1nnc(SCC3CC3)o1)CCO2
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and (chloromethyl)cyclopropane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[C:13](Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl>C(Cl)Cl.CO.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C#N)cc1F
Yield: 102.8 %

Procedure:
4-Cyano-2-fluorobenzoic acid (ABCR, 16 g; 96.90 mmol) was suspended in 300 mL of DCM. Oxalyl chloride (9 mL; 106.59 mmol) was added, followed by DMF (0.5 mL). After 3 hours at RT the yellow solution was evaporated under reduced pressure and the resulting yellow oil was taken up in anhydrous THF (150 mL) and added dropwise to a 4° C. solution of methanol (50 mL) and triethylamine (25.80 mL; 193.79 mmol; 2 eq.). An HCl solution (0.1 N, 200 mL) was added and the product was extracted with EtOAc (3×100 mL). The combined organic phases were washed with a semi-saturated NaHCO3 solution (200 mL), water (200 mL) and dried over MgSO4. Evaporation under reduced pressure gave the title compound as a light yellow solid (17.84 g, quantitative). HPLC (Method A) Rt 2.81 min (Purity: 93.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:21][CH2:20][CH2:19][O:18]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: OCCO
Reactant: CCCCCCC(=O)c1cc(OC)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC1(c2cc(OC)cc(OC)c2)OCCO1
Yield: 90.4 %

Procedure:
1-(3,5-Dimethoxyphenyl)heptan-1-one (200 mg, 0.80 mmol), ethylene glycol (173 mg, 2.80 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated sodium bicarbonate solution (2×25 mL) then brine (1×25 mL). The organic phase was dried (Na2SO4) and evaporated to give 2-(3,5-dimethoxyphenyl)-2-hexyl-1,3-dioxolane (41) as a light yellow oil (213 mg, 90%). 1H NMR (CDCl3, 300 MHz): δ 0.94, t (6.5 Hz), CH3; 1.31, m, methylene envelope; 1.89, m, CH2; 3.79-3.83, m, 2×OMe, OCH2; 4.04, m, OCH2; 6.46, m, H4′; 6.63, m, H2′,6′. ESI (+ve) MS: m/z 295 (M+H, 62%).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[C:9]#[N:10])(=O)C.S(OOS([O-])(=O)=O)([O-])(=O)=[O:17].[NH4+].[NH4+].S(=O)(=O)(O)O>C(O)(=O)C>[OH:17][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCCOc1ccc(C(C)=O)cc1C#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCOc1ccc(O)cc1C#N
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-acetyl-2-n-propoxybenzonitrile (20.3 g, 0.10 mol) was dissolved in glacial acetic acid (100 ml), followed by addition of ammonium persulfate (60 g, 0.26 mol). After sulphuric acid solution (H2SO4 10 ml/H2O 14 ml) was slowly added dropwise under ice-water bath, the reaction temperature was raised to 45° C. for 3 h. The reaction mixture was poured into ice water to generate precipitates, stirred for 0.5 h, filtered, and dried to give the title compound (13.0 g, yield: 73%). 1H NMR (CDCl3) δ: 8.00 (1H, d), 7.04 (1H, dd), 6.90 (1H, d), 4.05 (2H, t), 1.78 (2H, m), 1.01 (3H, t).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[NH:22]([C:50]([O:52][CH2:53][CH:54]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])[C@H:23]([C:47](O)=[O:48])[CH2:24][C:25](=[O:46])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[C@@H:5]([N:7]([CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:47](=[O:48])[C@@H:23]([NH:22][C:50](=[O:51])[O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:24][C:25](=[O:46])[NH:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:6])[CH3:21]
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-2) 12.9 g (45 mmol) and Fmoc-Asn(Trt)-OH 35.1 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 21.4 g, (yield 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:37])[CH2:33][N:34]=[C:35]=[O:36])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:37])[CH2:33][NH:34][C:35]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:36])[CH3:30]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)CN=C=O
Product: CCOC(=O)CNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 87.3 %

Procedure:
In a manner similar to the method described in Example C3, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (80 mg, 0.189 mmol) was reacted with isocyanato-acetic acid ethyl ester (122 mg, 0.945 mmol) to give rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid ethyl ester (91.2 mg, 87%). HRMS (ES+) m/z Calcd for C27H29Cl2F2N3O3+H [(M+H)+]: 552.1627; Found: 552.1629.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])#[N:2].FC(F)(F)C(O)=[O:30]>C(Cl)Cl>[C:1]([CH2:3][NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:30])[NH2:2]
Reactant: O=C(O)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NCC#N)c2nc(C3CC3)cnc21
Solvent: ClCCl
Product: NC(=O)CNC(=O)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyanomethyl-amide (0.19 g, 0.50 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (10 mL) and H2O (2 mL) and Et3N (2 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was triturated with EtOH to afford 0.093 g (77%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid carbamoylmethyl-amide as a light yellow solid. MS: (M+H)+=260; mp=215.0-220.0.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[C:7]([N+:13]([O-])=O)[CH:8]=2)[N:3]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1COCC1.[H][H]>[C].[Pd].CO>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[N:3]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2](=[O:1])[C:11](=[O:12])[NH:10]2
Reactant: [H][H]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(-n3ccnc3)cc21
Yield: 85.6 %

Procedure:
A mixture of 1.30 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 80 ml of THF, 20 ml of methanol and 600 mg of 10% palladium-carbon was stirred in a hydrogen gas atmosphere for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.02 g (86%) of ethyl 2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)-l,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)[CH2:2][CH3:3].[CH3:18][CH:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:21][CH:19]([CH3:20])[CH3:18])[C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: CCCNc1nc(Cl)c2ccn(C(C)C)c2n1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCCNc1nc(NC(C)C)c2ccn(C(C)C)c2n1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To 2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIV, 3.0 g, 12 mmol) in n-butanol (10 mL) was added propan-2-amine (1.05 g, 18 mmol) and potassium carbonate (2.5 g, 18 mmol). The resulting mixture was stirred in an autoclave equipped with a stirrer at 140° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution and dried over anhydrous Na2SO4. After the solvents were removed in vacuo, the residue was purified by flash column chromatography (PE/EtOAc=5/1 to 3/1) to yield 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXV, 1.2 g, 36%) as a yellow solid. LCMS: (ESI) m/z=276 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][CH3:12]>C(O)C>[NH2:2][C:3]1[S:4][C:5]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:7]=1
Reactant: CCCCS
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: CCO
Product: CCCCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-amino-5-bromothiazole hydrobromide (13.0 g, 0.05 mol, available from Acros Organics) and 1-butanethiol (4.5 g, 0.05 mol) in ethanol (50 ml) was heated under reflux on a steam-bath for 30 h. The mixture was then allowed to stand at room temperature for 18 h before being distilled under reduced pressure. Water (25 ml) was added to the residue followed by the cautious addition of 0.88 ammonia (25 ml). The mixture was stirred at room temperature for 4 h, then the resulting beige solid was filtered off, washed with water and dried to give 2-amino-5-butylthiothiazole, (Yield 6.0 g (63%)).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][C:6]=1Br>[Zn]>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][CH:6]=1
Reactant: Cc1c(C#N)sc(Br)c1Br
Agent: [Zn]
Product: Cc1c(Br)csc1C#N

Procedure:
reacting 4,5-dibromo-2-cyano-3-methylthiophene with zinc dust to provide the required 4-bromo-2-cyano-3-methylthiophene starting material;
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[C:4]([O:9][CH3:10])=[CH:5][C:6](=[O:8])[CH:7]=1.[Si](O[N:20]=[CH:21][CH:22]=[CH:23][CH3:24])(C(C)(C)C)(C)C>ClC1C=CC=CC=1>[CH3:10][O:9][C:4]1[C:3](=[O:11])[C:2]2[N:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:7]=2[C:6](=[O:8])[CH:5]=1
Reactant: COC1=CC(=O)C=C(Br)C1=O
Reactant: CC=CC=NO[Si](C)(C)C(C)(C)C
Solvent: Clc1ccccc1
Product: COC1=CC(=O)c2c(C)ccnc2C1=O
Yield: 46.9 %

Procedure:
In a 50 mL round bottom flask 2-bromo-6-methoxy-1,4-benzoquinone (282 mg, 1.3 mmol) was dissolved in dry chlorobenzene (28 mL) along with 1-(tert-butyldimethylsilyloxy)-1-aza-1,3-pentadiene (130 mg, 0.65 mmol). The solution was stirred and heated to reflux for 4 days under N2. The dark reaction was allowed to cool and was added to a silica gel column (2.5×9 cm). The column was eluted with EtOAc/hexane (5:1) then EtOAc and finally ethanol. The solvent was removed, benzene was added, and the resulting mixture was heated and filtered to remove insoluble impurities. Evaporation of the filtrate gave 62 mg, 47% of the crude product. 1H NMR (CDCl3) δ2.76 (s, 3H), 3.93 (s, 3H), 6.20 (s, 1H), 7.52 (d, J=8 Hz, 8.30 (d, J=8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([SH:36])[CH:33]=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:4]1[CH:3]=[C:2]([S:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: Cc1cccc(S)c1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4cccc(C)c4)cc3F)cc2)COC(C)(C)OC1
Yield: 108 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (158 mg) of Reference Example 10, 3-methylbenzenethiol (48 mg), diisopropylethylamine (90 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.1 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (10.4 mg) in 1,4-dioxane (2 mL) was heated under reflux for 13 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (187 mg) as a colorless oil.