Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([N+:23]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>CO.C1COCC1.[Pt]>[NH2:23][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])=[O:10])[C:19]2[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=2[CH:14]=1
Reactant: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc([N+](=O)[O-])cc2[nH]1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(N)cc2[nH]1
Reaction time: 4 h
Yield: 77 %

Procedure:
To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:6][N:7]=[C:8]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=[O:10])[C:4]#[CH:5].C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:3]([O:6][N:7]=[C:8]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][C:16]=1[Cl:1])[C:9]([OH:11])=[O:10])[C:4]#[CH:5]
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: ClCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C#CCON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
A solution of chlorine (3.2 g) in acetic acid (44 ml) was added dropwise to a solution of 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(10 g) in chloroform (250 ml) at 0° C. and the mixture was stirred for 30 minutes at the same temperature. The resulting solution was added to a saturated aqueous sodium bicarbonate and the mixture was adjusted to pH 7.5 with 10% aqueous sodium hydroxide. The separated aqueous layer was adjusted to pH 2.0 with conc. hydrochloric acid and extracted with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether and filtered to give 2-(2-propynyloxyimino)-2-(2-formamido-5-chlorothiazol-4-yl)acetic acid (syn isomer)(5.96 g), mp 161°-162° C. (dec.).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@H:12]2[O:13]C(=O)C2C=CC=CC=2)=[C:4]([NH2:44])[N:3]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]2[OH:13])=[C:4]([NH2:44])[N:3]=1
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Reaction time: 5 h

Procedure:
A suspension of 1a (108 mg, 0.18 mmol) in ethanol (10 ml) at room temperature is treated in one portion with 0.50 M KOH (anhydrous powder) in ethanol (180 μl). The mixture is stirred 5 h, neutralized with glacial acetic acid (6 μl), and evaporated to dryness. The resulting residue is crystallized from 1:1 acetonitrile/water to afford pure (1b) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([SH:6])=[S:5])[CH3:2].[K].[C:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+]#N)([OH:10])=[O:9].[B-](F)(F)(F)F>CC(C)=O>[Cl:17][C:16]1[C:11]([C:8]([OH:10])=[O:9])=[C:12]([S:5][C:4]([O:3][CH2:1][CH3:2])=[S:6])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=S)S
Reactant: N#[N+]c1cccc(Cl)c1C(=O)O
Agent: F[B-](F)(F)F
Agent: [K]
Solvent: CC(C)=O
Product: CCOC(=S)Sc1cccc(Cl)c1C(=O)O
Reaction time: 18 h

Procedure:
To a stirred suspension of 2.4 grams (0.014 mole) of ethylxanthic acid, potassium salt in 30 mL of acetone was added, by pipette, a stirred suspension of 2.0 grams (0.007 mole) of 2-carboxy-3-chlorobenzenediazonium tetrafluoborate in 50 mL of acetone. The flask containing the fluoborate suspension was rinsed with 20 mL of acetone, and the rinse was added to the reaction mixture. Upon completion of addition which required 7 minutes, the reaction mixture was stirred for about 18 hours. The reaction mixture was filtered to collect 2.0 grams of 6-chloro-2-[ethoxy(thiocarbonyl)thio]benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH:19]#[C:20][CH2:21]CCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.C1COCC1.[C:57]([OH:66])(=[O:65])[C@@H:58]([C@H:60]([C:62]([OH:64])=[O:63])[OH:61])[OH:59]>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C#CCCCCCC.CCOCC>[OH:61][C@H:60]([C@@H:58]([OH:59])[C:57]([OH:66])=[O:65])[C:62]([OH:64])=[O:63].[CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:19]#[C:20][CH3:21])=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Reactant: C#CCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#Cc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a two-neck round bottom flask was added (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride (3.94 g, 0.0118 mol), 1-octyne (3.48 mL, 0.0235 mol), triphenylphosphine (0.309 g, 0.00118 mol), piperidine (6.99 mL, 0.0706 mol), and THF (100 mL, 1 mol). The mixture was degassed, and Pd(PPh3)2Cl2 (0.41 g, 0.00059 mol) was added and the mixture was stirred for a few minutes under an atmosphere of nitrogen before addition of the copper(I) iodide (0.11 g, 0.00059 mol). The reaction was stirred under an atmosphere of nitrogen at 60° C. for 2 hours. More 1-octyne (12 mL, 0.081 mmol) was added in 3 portions. The reaction mixture was heated at 60° C. for a total of about 36 hours. The solvent was then removed and crude material was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was back-extracted once with EtOAc. Organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using 1 L of EtOAc followed by 1 L of 2% MeOH in EtOAc to give 3.38 g crude product as a yellow oil. The crude product was dissolved in minimum amount of MeOH, to which L-tartaric acid (1.69 g) in MeOH was added. Ether was then added dropwise until solution just turned turbid. The mixture was left to crystallize. The solid was collected by filtration, washed with ether to give 3.91 g (72.6%) (1R,3S)-1-amino-3-(4-prop-1-ynyl-phenyl)-cyclopentanecarboxylic acid methyl ester; compound with (2R,3R)-2,3-dihydroxy-succinic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(O)c(O)c1
Yield: 53 %

Procedure:
To the solution of 3,4-dihydroxybenzoic acid (1.13 g) in benzene (50 ml) were added benzyl alcohol (3.8 ml) and p-toluenesulfonic acid (139 mg), and the mixture was heated at reflux in the presence of Molecular Sieves 4A for 2 days. Further amount of benzyl alcohol (1.5 ml) was added. The mixture was then heated at reflux overnight. After cooling by standing, saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation, the residue was dissolved in ethyl acetate and extracted with 1N sodium hydroxide. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the solvent was removed by distillation. The residue was purified by column chromatography on silica gel with an eluent system of chloroform:methanol=30:1 to give 953 mg of benzyl 3,4-dihydroxybenzoate (yield, 53%).
Reaction SMILES: CS(O[C:6]#[C:7][CH3:8])(=O)=O.[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([O:27][CH2:8][C:7]#[CH:6])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Reactant: CC#COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C#CCOc1cc(-c2c(Br)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 42.8 %

Procedure:
2 propinyl methanesulfonate (0.22 g; 1.61 mmoles) is added to a mixture of 4-bromo-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-chloro-1-methyl-5-trifluoromethyl pyrrole (0.6 g; 1.47 mmoles) and potassium carbonate (0.21 g; 1.54 mmoles) in methylisobutylketone (6 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (0.65 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 85:15. 0.28 g of solid white product with a melting point of 87° C., are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][C@H:16]([CH3:19])[CH2:17][OH:18].C(N(CC)CC)C.CO>>[OH:18][CH2:17][C@H:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH3:19]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@@H](N)CO
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 88 °C
Yield: 40 %

Procedure:
A 250 mL round bottom flask was charged with 5-nitro-isochromen-1-one (40 g, 0.2 mol), (2R)-2-Aminopropan-1-ol (18 g, 0.24 mol), triethylamine (100 mL, 0.7 mol) and methanol (500 mL, 10 mol) and the reaction heated at 88° C. for 1.5 hours. The product precipitated out upon cooling the reaction and was filtered to afford the product as a yellow solid. (17.3 g, 40% yield).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.O/[N:23]=[C:24](/[C:26]1[CH:27]=[CH:28][C:29]([CH3:40])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1)\[NH2:25]>CN1C(=O)CCC1>[F:21][C:14]1([F:13])[CH2:15][CH:16]([C:18]2[O:20][N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH3:40])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH:31]=3)[N:25]=2)[CH2:17]1
Reactant: Cc1ccc(/C(N)=N/O)cc1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
CDI (1.2 g, 7.34 mmol) was added portion-wise to a stirred solution 3,3-difluorocyclobutanecarboxylic acid (1 g, 7.34 mmol) in NMP (10 mL). After 30 minutes, (Z)-tert-butyl 5-(N′-hydroxycarbamimidoyl)-2-methylphenylcarbamate (35) (1.8 g, 7.34 mmol) was added in one portion and stirred for another hour at room temperature. The solution was then heated via microwave at 120° C. for 20 minutes. The solution was partitioned with EtOAc and water. The organic phase was separated, dried over MgSO4 and purified over silica gel to afford tert-butyl (5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (36) (1.2 g, 45% yield). MS m/z 366.1 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:18]>C1C(O)=CC=CC=1C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[NH:18])=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: COc1ccc(N)c(-c2ccccc2)c1
Reactant: N#CN1CCCCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(NC(=N)N2CCCCC2)c(-c2ccccc2)c1

Procedure:
2-Amino-5-methoxybiphenyl hydrochloride (0.9 g) was heated with N-cyanopiperidine (0.45 g) in m-cresol (1 ml) at 140° C. for 8 hours to give N-(5-methoxy-2-biphenylyl)piperidine-1-carboxamidine which was crystallised from a 1:9 mixture of ethylacetate and hexane to furnish N-(5-methoxy-2-biphenylyl)piperidine-1-carboxamidine as a pale brown crystals (m.p. 155° C.).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:8]=1[CH2:27][CH3:28]>C1COCC1.CO>[CH2:27]([C:8]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:29])=[O:4])[CH3:28]
Reactant: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1

Procedure:
0.5 M Aqueous NaOH (1.0 ml) is added to a solution of [2-ethyl-1-(4-trifluoromethyl-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (48 mg, 0.13 mmol) in 1:1 THF/MeOH (1 ml). After 3 hours the reaction is concentrated in vacuo, and the residue dissolved in water. The aqueous solution is cooled in an ice-bath and acidified to pH 2 using concentrated HCl. The resulting precipitate is filtered and dried under high vacuum at 50° C. to yield the titled compound as a white powder. (MH+ 363)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: CN1CCN(c2ccc(C(=O)[O-])cc2)CC1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc(N6CCN(C)CC6)cc5)cc4)cc3)cc2)CC1

Procedure:
Compound 316 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-methylpiperazino)benzoate. [M+H]+ calcd for C37H41N6O3: 617.32; found: 617.12.
Reaction SMILES: [S:1]([N:11]([C:18]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:21])[CH2:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH-].[Na+]>C(#N)C.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:16][N:14]([CH3:15])[C:13]([CH:12]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])([OH:21])[C:19]2[C:18](=[CH:32][CH:31]=[C:30]([Cl:33])[CH:29]=2)[N:11]1[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2c3ccc(Cl)cc3C(O)(c3ccccc3Cl)C2C(=O)N(C)C)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
The compound of step B (1.0 g) is dissolved in acetonitrile (25 ml), and 109 mg of sodium hydroxide in 2 ml of water are added. The medium is heterogeneous; it is stirred violently at 45° C. for 1 hour, using a turbine and compressed air, either in the presence of 110 mg of benzyltriethylammonium chloride or without the addition of this reagent.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[S:29][C:30]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)=[CH:31][N:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:30]1[S:29][C:28]([CH2:27][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]3)[CH:24]=[CH:23][C:22]=2[C:25]#[N:26])=[N:32][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ncc(-c2ccco2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20285.7 %

Procedure:
To a solution of the peracetylate 59 (208 mg, 0.35 mmol) in MeOH (10 mL) was added NaOMe (25 wt. % in MeOH, 0.2 mL). The reaction mixture was stirred at ambient temperature for 3 h. Acetic acid was added to neutralize the reaction mixture and concentrated in vacuo. The residue was redissolved in MeOH and further purified by prep HPLC (C18) to provide the titled compound (106 mg, 71 mmol) as a white solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:25]([CH3:24])=[CH:26][CH:27]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 27.4 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylbenzylamine (41.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylphenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (18.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Temperature: 125 °C
Yield: 96 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (7.83 g, 31.3 mmol) and POCl3 (20 mL) in toluene (50 mL) was heated at 125° C. for 5 hours, to afford 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline as a solid (8.098 g, 96%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 4.36 (t, 2H), 4.01 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH:15]2[CH:13]([CH2:14]2)[CH2:12]1.[Cl-].[NH4+].N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(O)C.O.ClCCl.[Fe]>[CH2:29]([O:28][C:26](=[O:27])[NH:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH:15]3[CH:13]([CH2:14]3)[CH2:12]2)=[C:2]([F:1])[CH:7]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1ccc(N2CC3CC3C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CC3CC3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Iron metal (0.168 g, 3.15 mmol) was added in five portions over 1 h to a refluxing solution of 3-(2-fluoro-4-nitro-phenyl)-3-aza-bicyclo[3.1.0]hexane (0.233 g, 1.05 mmol) and ammonium chloride (0.566 g, 10.5 mmol) in 7.5 mL of 2:1 ethanol-H2O. The rust colored mixture was refluxed for another 30 min and then cooled and filtered to remove iron oxide. H2O was added to the filtrate and the mixture concentrated to remove ethanol. The resulting aqueous solution was extracted with three 20 mL portions of ethyl acetate and the combined organic phases washed with H2O, brine, and dried (MgSO4). Filtration and concentration gave the crude amine (0.194 g, 0.99 mmol) which was dissolved in 8.0 mL of dichloromethane. Pyridine (0.160 mL, 2.0 mmol) was added to the amine solution and after cooling to 0° C., benzyl chloroformate (0.162 mL, 1.14 mmol) was added. The mixture was stirred for 30 min at 0° C. and for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane and washed with H2O, brine and then dried (MgSO4). Concentration gave a yellow oil that was triturated with hexane to afford [4-(3-aza-bicyclo[3.1.0]hex-3-yl)-3-fluoro-phenyl]-carbamic acid benzyl ester as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(Nc2cc(C)ccc2C)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)c(Nc2ncc(C(=O)O)c(=O)[nH]2)c1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Ethyl 1,6-dihydro-2-(2,5-dimethylanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (4 g) are added to water (200 ml), and the mixture is refluxed with stirring for 2 hours. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2,5-dimethylanilino)-6-oxo-5-pyrimidinecarboxylic acid (7 g). M.p. 242°-244° C.