Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[O:7][C:8]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C.[Cl-].[Na+].O>CS(C)=O>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:8]=2[O:7][CH:6]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1oc2cc(OC)ccc2c1C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1coc2cc(OC)ccc12
Temperature: 170 °C
Reaction time: 2 h

Procedure:
6-Methoxy-benzofuran-2,3-dicarboxylic acid diethyl ester (24) (27 g, 92 mmol) is dissolved in 200 ml of a DMSO and the mixture is heated to 170° C. Then sodium chloride (10.7 g, 184 mmol) and water (3.3 ml) are added and the mixture is stirred for 2 h at 160° C. (temperature of reaction mixture). Then the mixture is allowed to cool down and evaporated at high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave an brown solid, which is further purified by Flash-chromatography (silica gel, ethyl acetate/hexanes 3:7).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:25][N:24]=[N:23][N:14]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyanomethyl)phenyl]butanamide (17.5 g.), sodium azide (17.3 g.) and ammonium chloride (14.1 g.) was heated in dimethylformamide (250 ml.) at 130°-135° C. (oil bath) under a nitrogen atmosphere for 20 hours. Enough water was then added to the hot reaction mixture to dissolve all suspended salts and the mixture was allowed to cool to room temperature. Additional water was then added to produce a white precipitate which was filtered, washed with water and dried under vacuum. The white solid 2,2,3,3,4,4,4-heptafluoro-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]butanamide product (8.7 g., 44%, mp 176°-179° C.) was analytically pure as isolated. A sample recrystallized from acetone (minimum amount)/diethyl ether melted at 176°-178° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[CH3:16][Bi:17](Br)[CH3:18]>C1COCC1>[CH3:16][Bi:17]([CH3:18])[C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH3:7])=[O:5]
Reactant: C[Bi](C)Br
Reactant: COC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)[Bi](C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
A 2.86 g quantity (28 mmole) of methyl isobutyrate was dissolved in 25 ml of THF, and the mixture was chilled to −78° C. under argon atmosphere. To the mixture was slowly added dropwise 14.0 ml (28 mmole) of lithium diisopropylamide (Aldrich Corp., 2.0M heptane.THF.ethylbenzene solution) over a period of 10 minutes. The reaction mixture was gradually heated (one hour) and thereto was added dropwise a solution of 8.9 g of dimethylbismuthanyl bromide prepared in Preparation Example 2 in 25 ml of THF between −40° C. and −30° C. The reaction mixture was further stirred until reached to 0° C. (one hour). After the solids were filtrated with quartz wool and THF was removed in a vacuum, the reaction mixture was distilled in a vacuum, giving 4.45 g (yield 46.7%) of a yellow oily product. b.p. 59° C./2.0 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:16][C:17]([O:19][Na])=[O:18]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH2:16][C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=C(CI)O[Na]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCC(=O)O)C1
Reaction time: 0.25 h

Procedure:
Anhydrous DMF (5 mL) was added slowly to a stirred mixture of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (350 mg, 2.0 mmol) and NaH (121 mg of a 60% dispersion in mineral oil, 3.0 mmol) at 0° C. After 15 min, ICH2CO2Na (630 mg, 3.0 mmol) was added, then stirring was continued at 20° C. for 65 h. The solvent was removed in vacuo, then the residue was partitioned between H2O (15 mL) and EtOAc (10 mL). The organic phase was extracted with saturated aqueous Na2CO3 (2×10 mL), then the combined aqueous extracts were acidified to pH 2 with 2 M HCl, before being extracted with EtOAc (2×50 mL). The EtOAc extracts were washed with brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 1:1) furnished the title compound. δH (CDCl3): 1.45 (s, 9H), 3.90-4.00 (m, 2H), 4.10-4.19 (m, 4H), 4.36-4.42 (m, 1H), 10.10-10.30 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16](N)=[O:17].C1(O)C=CC=CC=1>>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:11]=2)[C:12](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: NC(N)=O
Solvent: Oc1ccccc1
Product: O=c1[nH]c(=O)c2cc3ccccc3cc2[nH]1
Temperature: 185 °C

Procedure:
A mixture of 3-amino-2-naphthoic acid (8-1,1.2 g, 6.6 mmol, 1 equiv), urea (2.0 g, 33 mmol, 5.0 equiv) and phenol (7.0 g, 74 mmol, 11 equiv) was heated at 160° C. for 0.5 h an 185° C. for an additional 1.5 h. The reaction was cooled and triturated with methanol (50 mL). The solid precipitate was filtered, washed with methanol, and dried to yield benzo[g]quinazoline-2,4(1H,3H)-dione (1-2) as an orange solid. LRMS m/z (M+H) 213.1 found, 213.1 required.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[OH:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: OCCc1ccccc1O
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccccc1CCO
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 10 g of 2-(2-hydroxyphenyl)-ethanol in 200 ml of acetone there are added 35.3 g of Cs2CO3 and then a solution of 6.5 ml of methyl iodide in 40 ml of acetone. The reaction mixture is stirred for 50 minutes at room temperature, is filtered and is concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane/diethyl ether=97:3), yielding the title compound: Rf (dichloromethane/diethyl ether=97:3)=0.34; HPLC Rt =9.31 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCC1)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 71.3 %

Procedure:
Following General Procedure R, the title compound (345 mg, 71%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (410 mg, 0.765 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (293 mg, 1.53 mmol) and DMAP (cat.) in DMF (5 ml).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Yield: 82.6 %

Procedure:
1,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.88 g, 83%) was prepared as a light yellow solid from 2-bromo-5-hydroxypyridine (0.50 g, 2.87 mmol), N-Boc-4-piperidinemethanol (0.64 g, 2.87 mmol) and Ph3P (0.77 g, 2.87 mmol) in THF (15 mL) followed by diisopropyl azodicarboxylate (0.62 g, 94%, 2.87 mmol) in THF (5 mL) in a manner similar to Example 1, Step 2. The material was purified by chromatography on a silica gel column eluted with 5 to 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.36 (d, 1H, J=8.8 Hz), 7.15-7.05 (m, 1H), 4.25-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.80-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.85-1.75 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 393/395 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 98%).
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([NH:41]N)[N:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[N:36]=[CH:37][N:38]=[C:39]([N:41]4[C:13](=[O:15])[C:12]([N:18]5[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]5)=[CH:11][NH:9]4)[CH:40]=3)[CH2:31][CH2:30]2)[CH2:26][CH2:27][CH2:28]1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCN(C5CCC5)CC4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 236 mg (1.0 mmol) of the compound from Example 6A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 3 d. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 219 mg (56% of theory)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]1[O:18][N:17]=[C:16]([CH3:19])[N:15]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>ClCCl>[CH3:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:11]2[C:2]([O:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:3]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[C:4]1=[O:13]
Reactant: Cc1noc(-c2c(O)c3nccnc3n(C)c2=O)n1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(-c2c(OC(=O)C(C)C)c3nccnc3n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-hydroxy-5-methyl-7-(3-methyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[2,3-b]pyrazin-6-one (Example 7.4) (0.044 g) and pyridine (0.018 ml) in dichloromethane (1 ml) was added dropwise isobutyryl chloride (0.022 ml). The reaction mixture was stirred at ambient temperature for 4 hours and then stored at ambient temperature for 16 hours. The reaction mixture was diluted with more dichloromethane and the mixture was washed successively with aqueous sodium hydrogen carbonate (saturated), aqueous ammonium chloride (saturated) and brine. The organic fraction was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. B6 of Table 6 as a pale yellow solid (0.020 g).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[CH2:24][CH2:25][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CC(C)N
Product: CC(C)NCCC(=O)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 101, but starting from 4-anilino-5-bromo-2-[4-(3-chloropropionamido)anilino]pyrimidine (Method 37) and isopropylamine, the product was obtained. MS (MH+): 469, 471; HPLC (RT): 3.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]#[CH:18]>ClCCl>[CH2:18]([S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCSc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (5 mmol) and triethylamine (5 mmol) was stirred together in dichloromethane (40 ml) for 5 min before propargyl bromide (6 mmol) was added. The mixture was stirred at room temperature for 1 h before the solvent was evaporated. The residue was triturated with water (20 ml), and the solid recrystallized from methanol; yield 87%, m.p. 66° C. 1H NMR (CDCl3): δ2.16 (HC≡, t, J 2 Hz), 3.88 (CH2, d, J 2 Hz), 8.80 (H-4, H-6). IR (KBr): 3300 Cm-1 (HC≡).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:31])[C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3)CC2)c(C)c1

Procedure:
Using 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 516 and methyl iodide (9 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (23 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([I:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: I[C@H]1C[C@H](OCc2ccccc2)C1
Yield: 86 %

Procedure:
A solution of cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.25 g, 4.8 mmol) and sodium iodide (2.16 g, 14.4 mmol) in dry acetone (20 ml) was refluxed under nitrogen for 3.5 days. The mixture was cooled and diluted with diethyl ether (150 ml). The suspension was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel, eluting with ethyl acetate to give trans-3-benzyloxy-1-iodocyclobutane (1.19 g, 86%) as an orange oil; 1H NMR (250 MHz, CDCl3) δ2.54-2.65 (2H, m), 2.94-3.04 (2H, m), 3.85-4.06 (2H, m), 4.40 (2H, s), 7.26-7.38 (5H1 m).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:17])C(=O)C1.S(=O)(O)[O-].[Na+]>ClCCl>[Br:17][C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)(C)n1cccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To an ice cooled solution (0° C. to 10° C.) of 1-(tert-butyl)pyrazole (1.75 kg, 14.09 mol) in dichloromethane (12.9 kg) was added NBS (2.63 kg, 14.79 mol) portionwise. The solution was stirred at 0° C. until the content of 1-(tert-butyl)pyrazole<30% (GC), then warmed to RT and stirred until the sample taken shows <1.0% by GC. On receipt of a pass result, 10% sodium bisulfite aqueous was added to the reaction mixture until KI-starch did not turn to blue. The organic phase was then washed with 5% NaCl solution and brine in sequence, then evaporated to give the title compound as a brown liquid (2.67 kg, 93.4% yield; GC purity 99.1% a/a).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].Cl>C(=O)(O)[O-]>[C:11]([C:2]1[N:3]=[C:4]2[C:8]([NH:7][CH:6]=[N:5]2)=[C:9]([NH2:10])[N:1]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: Cl
Agent: O=C([O-])O
Product: C=CC(=O)c1nc(N)c2[nH]cnc2n1
Reaction time: 1 h

Procedure:
Adenine (0.27 g, 0.002 mole) was dissolved in 7 ml of bicarbonate buffer (pH 8), cooled to 0°-4° C., and acrylic acid chloride (1.1 g, 0.01 mole) was added with intense stirring for 1 hour. The solution was acidified with 1 M HCl until pH 6 was obtained, the solvent was evaporated in vacuum and the formed white precipitate was recrystallized from dimethyl sulfoxide. The yield of the AAD was 70%. The IR spectra displayed no absorption bands at 1650 cm-1 (bending vibrations of NH2 groups); however, absorption bands appeared at 1680 (amide-1), 1540 (amide-II), and 1290 (amide-III). These data confirm that a compound of AAD having the above formula was prepared.
Reaction SMILES: O=C1NCCN1C1C=CC([C:13]23[CH2:32][CH:17]4[CH2:18][C:19]([NH:21][CH2:22][C:23]([N:25]5[CH2:29][CH2:28][CH2:27][C@H:26]5[C:30]#[N:31])=[O:24])([CH2:20]2)[CH:15]([CH2:16]4)[CH2:14]3)=CC=1.[Si](Cl)(C)(C)C.[CH3:38][OH:39]>>[O:39]=[C:38]1[CH2:17][CH2:18][CH2:19][N:21]1[C:13]12[CH2:32][CH:17]3[CH2:18][C:19]([NH:21][CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[C:30]#[N:31])=[O:24])([CH2:20]1)[CH:15]([CH2:16]3)[CH2:14]2
Reactant: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Reactant: CO
Agent: C[Si](C)(C)Cl
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Reaction time: 0.5 h

Procedure:
To a stirred solution of the compound obtained from example 19 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. was added TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain the hydrochloride salt of (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as off-white solid (38 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=1[NH2:25])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:12][CH2:13][CH2:14][C:15]1[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[N:25]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(NC(=O)CCCN(C)C(=O)OCc2ccccc2)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc2[nH]c(CCCN(C)C(=O)OCc3ccccc3)nc12
Temperature: 150 °C

Procedure:
To a mixture of crude [3-(2-amino-3-methoxy-phenylcarbamoyl)-propyl]methyl-carbamic acid benzyl ester acid in 7 mL toluene were added a few drops of DMF and 523 mg of TsOH and the reaction mixture was heated at 150° C. for 2.5 h in the microwave. Sat. aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC EtOAc/MeOH (10:1) yielded 0.74 g of the desired compound as brown foam.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].O.Cl.[CH3:26]O>O1CCCC1>[CH3:26][C:11]1[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)[C:4]([Cl:3])=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: CO
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2CC(C)=NO2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=NOC(c2c(Cl)c(C(=O)O)cc(C)c2S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
69.4 g (174 mmol) of 10% strength sodium hydroxide solution were added to a solution of 38.4 g (116 mmol) of methyl 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoate in 400 ml of methanol and 400 ml of tetrahydrofuran. The mixture was stirred for 12 hours at room temperature, the solvent volume was reduced to half, and the mixture was poured into 1 1 of water. The pH was brought to 1 using 10% strength hydrochloric acid, and the precipitate which formed was filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCNCCc1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCN1C(=O)c2ccccc2C1=O)CCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a mixture of N-[3-[2-(4-chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 6.65 mmol) and potassium carbonate (1.8 g, 13 mmol) in CH3CN (50 ml) was added ethyl iodide (1.6 ml, 20 mmol). The mixture was stirred at 70° C. for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2% methanol/chloroform) to afford N-[3-[[2-(4-chlorophenyl)ethyl](ethyl)amino]propyl]phthalimide (1.41 g, 57%): MS(ES+) m/e 371 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.71 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 3.71 (t, J=7.3 Hz, 2H), 2.66 (m, 4H), 2.57 (m, 4H), 1.83 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).