Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)CSc3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.405 mmol) was reacted with N-(2-azidoethyl)-2-(phenylthio)acetamide (0.096 g, 0.405 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-(phenylthio)acetamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), δ 7.19 (m, 5H), δ 7.13 (s, 1H), δ 6.43 (s, 1H), δ 6.13 (bs, 2H), δ 4.29 (s, 2H), δ 3.68 (s, 2H), δ 3.57 (s, 2H), δ 2.56 (s, 2H), δ 2.35 (s, 2H), δ 1.52 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 187.8, 172.0, 169.1, 162.4, 156.9, 135.0, 129.5, 128.3, 126.8, 121.8, 85.00, 49.4, 39.9, 37.4, 29.4, 28.9, 28.4, 28.2, 27.6, 25.6 ppm; HRMS (ESI) calcd for C25H35N7O3S (M+) 513.2522. found 513.2522, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(phenylthio)acetamide hydrochloride (0.133 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), δ 7.30 (s, 4H), δ 7.19 (s, 1H), δ 6.58 (s, 1H), δ 4.66 (s, 2H), δ 3.76 (s, 2H), δ 3.64 (s, 2H), δ 2.84 (s, 2H), δ 2.34 (s, 2H), δ 1.73 (s, 2H), δ 1.64 (s, 2H), δ 1.26 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 170.9, 159.3, 158.9, 147.2, 135.6, 128.1, 128.9, 127.6, 126.6, 108.7, 108.6, 52.-, 39.1, 37.5, 37.2, 36.6, 36.1, 30.8, 28.1, 27.9, 27.7, 24.2, 23.7, 23.6 ppm; HRMS (ESI) calcd for C20H27N7OS (M+) 413.1998. found 413.1991.
Reaction SMILES: [CH:1]([C:3]1([C:12]([OH:14])=O)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].S(Cl)([Cl:17])=O>>[CH:1]([C:3]1([C:12]([Cl:17])=[O:14])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2]
Reactant: O=S(Cl)Cl
Reactant: C=CC1(C(=O)O)Cc2ccccc2C1
Product: C=CC1(C(=O)Cl)Cc2ccccc2C1

Procedure:
A mixture 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid (5.09 g) and thionyl chloride (25 ml) was refluxed for 10 hours. Excess thionyl chloride was distilled off under reduced pressure. The crude product was used as such for the following reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[H][H]>C(O)C.[Pd].[C]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1ncc2c(N)cccc21
Temperature: 25 °C

Procedure:
1-Methyl-4-nitro-1H-indazole (6.1 g; 35.4 mmol) and 10% Pd/carbon (500 mg) were combined in ethanol and hydrogenated in a Parr apparatus at 60 PSI hydrogen at 50° C. for 1 hour. The mixture was allowed to cool to ambient temperature, filtered through Celite, and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) δ 8.02 (s, 1H), 7.02 (t, 1H), 6.62 (d, 1H), 6.14 (d, 1H), 5.75 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>C1COCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:1]2([C:4]#[N:5])[CH2:3][CH2:2]2)=[N:18][CH:19]=1
Reactant: N#CC1CC1
Reactant: Fc1ccc(F)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
Cyclopropanecarbonitrile (815 mg) was dissolved in THF (15 ml) and the solution cooled to 0° C. before dropwise addition of 0.9 M KHMDS (14.0 ml). The reaction mixture was allowed to warm to room temperature and stirred for further 15 min. The resulting solution was then added dropwise to a solution of 2,5-difluoropyridine (1.52 g) in THF (15 ml) and the reaction mixture stirred for 1 hour. Reaction was quenched by addition of aqueous NH4Cl, stirred for 5 min and then the organics washed with NaHCO3 and brine and dried over Na2SO4. The mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO2; gradient: heptane/EtOAc) to give title compound as a white solid (880 mg). MS (ISP): 163.2 ([M+H]+)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[N:13]=[CH:14][N:8]3[C:9]=2[C:4]=1[CH2:5][CH:6]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:7]3>Br>[CH2:19]([N:15]([CH2:16][CH2:17][CH3:18])[CH:6]1[CH2:5][C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[C:10]3[N:13]=[CH:14][N:8]([C:9]=23)[CH2:7]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2c(OC)ccc3ncn(c23)C1
Agent: Br
Product: CCCN(CCC)C1Cc2c(O)ccc3ncn(c23)C1

Procedure:
5,6-Dihydro-7-methoxy-N,N-dipropyl-4H-imidazo(4,5,1-ij)quinolin-5-amine (1.0 g) was heated at 130° C. in 48% hydrobromic acid for 2 hours. The solution was cooled and was then evaporated under reduced pressure. The solid thus obtained was crystallized from methanol:ether; mp 270° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2csc(Cn3cc(N)cn3)c2)OCCO1
Product: CC(=O)c1csc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.95 min; [M+H]+=392.94.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)nc3)oc2C)cc1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 3-(4-{2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (41 mg, 0.1 mmol) and phenyl boronic acid (25 mg, 0.2 mmol) and Na2CO3 (22 mg, 0.2 mmol) in toluene (0.5 mL) and water (0.1 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (3 mg) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 45 mg of product.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH2:25]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH:25][CH3:24])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: Cl
Product: CNC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and methylamine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]([NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](N)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
(3R,5R)-3-tert-Butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester (3.25 g, 9.327 mmol) was dissolved in DCM (50 ml) and HCl 4M in dioxane (20 ml, 80 mmol) was added. The resulting colorless solution stirred at RT for 4 hours before being evaporated. The residue was dried under high vacuum overnight to give 2.89 g of (3R,5R)-3-amino-5-methyl-piperidine-1-carboxylic acid benzyl ester hydrochloride as a white foam (>95% yield).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>C(O)C.C(O)(=O)C>[Br:1][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: O=C(O)c1cccc(O)c1
Reactant: BrBr
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxybenzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40%). MS (DCI) m/z 234 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](F)[C:5]=1[CH3:14].CS(CCO)(=O)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([OH:18])[C:5]=1[CH3:14]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])ccc(O)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a stirring solution of 3-Fluoro-2-methyl-6-nitro-benzoic acid methyl ester (6 g, 28.2 mmol) and 2-(methylsulfonyl)ethanol (5.2 g, 42.2 mmol) in 47 mL of DMF is added sodium hydride (3.38 g, 84.6 mmol) at 0° C. and the reaction mixture is allowed to warm to room temperature and then stirred for 1.5 hours. The mixture is quenched with 1N HCl solution and partitioned between ethyl acetate. The organic layer is washed with brine and concentrated to dryness and the crude organics purified by flash column chromatography to give 3-Hydroxy-2-methyl-6-nitro-benzoic acid methyl ester (5.3 g) in 89% yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.22 (s, 3H), 3.99 (s, 3H), 6.38 (s, 1H), 6.87 (d, 1H), 7.99 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:7]2.[CH:52](=O)[CH3:53].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:52]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:7]2)[CH3:53]
Reactant: CC=O
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc(N)c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1cccc2c1C(=O)N(c1c[nH]c3ncc(-c4ccc(S(=O)(=O)C(C)C)cc4)nc13)C2
Reaction time: 48 h

Procedure:
7-amino-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (63 mg, 0.09133 mmol) dissolved in DCE (5 mL) and acetaldehyde (5.6 μL, 0.10 mmol) then Na(OAc)3BH (38.72 mg, 0.1827 mmol) added at RT under N2. Reaction mixture stirred for 48 h then quenched by the addition of water. DCM added and layers separated. Organic phase dried and concentrated. Residue taken up in DCM (2 mL) under N2 and treated with triethylsilane (73 μL, 0.4566 mmol) then TFA (300 μL). Reaction mixture stirred overnight then concentrated. Residue purified by hplc to give the title compound; 1H NMR (400 MHz, DMSO) δ 1.20-1.26 (9H, m), 3.50 (1H, partly obsc sep), 5.38 (2H, s), 6.64-6.68 (2H, m), 6.85 (1H, d), 7.42 (1H, d), 8.00 (2H, d), 8.44 (1H, d), 8.51 (2H, d), 9.08 (1H, s), 12.31 (1H, s) ppm; MS (ES+) 476.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([NH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
The obtained 4-(4-benzoylpiperazin-1-yl)-2-nitrobenzoic acid (0.40 g, 93%) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (20 mg, 5%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.24 g, 70%) was obtained after removing of solvents. To a solution of 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.2 g, 0.6 mmol) and benzaldehyde (0.14 ml, 1.3 mmol) added sodium triacetoxyborohydride (0.4 g, 1.8 mmol) and stirred under argon atmosphere overnight. The reaction was quenched with 10 ml water and extracted with ethyl acetate (3×20 ml), followed by drying it over anhydrous sodium sulfate. 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (0.11 g, 40%) was obtained after concentration. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.25-3.88 (m, br, 8H), 4.48 (s, 2H), 6.20 (d, J=2.3 Hz, 1H), 6.22 (dd, J=2.3, 9.1 Hz, 1H), 7.30-7.45 (m, 10H), 7.48 (d, J=9.1 Hz, 1H), 8.25 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:9]([O-:12])(=[O:11])=[O:10])[N:4]=1.[Na+:13]
Reactant: Cc1nc(CCl)cs1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(CS(=O)(=O)[O-])cs1
Yield: 101.2 %

Procedure:
4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 200° C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer is concentrated to afford 0.368 g of the desired product as a yellow solid. LC/MS ESI+ 194 (M+1, free acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: COc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(CC2=C(O)CC(CCc3ccc(OC)c(Cl)c3)(C3CCCC3)OC2=O)cc1

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methoxy-benzaldehyde using the AlCl3/reduction procedure described for Example B(13). 1H NMR (CDCl3): δ 1.45-1.85 (brm, 8H), 1.98 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44-3.02 (m, 7H), 3.88 (s, 3H), 3.94 (s, 3H), 6.73-7.85 (m, 7H). ESIMS (MH+): 471.7
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@H:8](Cl)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@@H:8]([N:19]=[N+:20]=[N-:21])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 64 h

Procedure:
The chloro ester 4a (5.5 g, 19.8 mmol) and NaN3 (5.5 g, 84.6 mmol) were dissolved 200 ml of DMF in a 75° C. oil bath and stirred at this temp. for 64 h, then worked up using method B. This gave 4.5 g (80% crude yield)of an oil, which was used directly in the next step. 1H NMR (CDCl3) δ1.28 (t, 3H), 1.41/1.46 (2s, 9H), 2.17 (m, 1H), 2.32 (m, 1H), 3.52 (m, 1H), 3.70 (dd, 1H), 4.18 (m, 3H), 4.34 (m, 1H). FAB MS; MH+ calc. for C12H21N4O4 =235.1563, found 285.1574.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[N:4]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:3]1=[O:16]
Reactant: CC(=O)CCCCCl
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCn1c(=O)c2c(ncn2CC(C)=O)n(C)c1=O

Procedure:
22.2 g (0.1 mol) of 3-methyl-7-(2-oxopropyl)-xanthine from Example 7a are stirred together with 14.8 g (0.11 mol) of 1-chloro-5-hexanone and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide at 110° C. for 1.5 hours. The mixture is then allowed to cool slowly, with further stirring, and filtered, the salt on the suction filter is rinsed thoroughly with dimethylformamide, the solution is concentrated under reduced pressure, the residue is taken up in 200 ml of methanol, 50 ml of water and 2 ml of concentrated sulfuric acid are added and the mixture is boiled under reflux for one hour. After removal of the methanol in vacuo, the residue is rendered alkaline with 33% strength sodium hydroxide solution and the mixture is extracted thoroughly by shaking with chloroform. The combined chloroform extracts are washed with a little water until neutral and dried over sodium sulfate and the solvent is distilled off in vacuo, whereupon 25.8 g of solid crude product (80.5% of theory) are obtained and are recrystallized from ethanol, with the addition of petroleum ether, at the boiling point.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.CNC.N1CC[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:15][CH2:21][CH2:20][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: C1CCNC1
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: CNC
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1

Procedure:
Following the procedures described above for the synthesis of compound 5 (scheme 1, example 1) but replacing dimethyl amine in the step 4 for pyrrolidine, title compound 139 was obtained. LRMS (M+1) 267.1 (100%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:16]([NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1)([CH3:20])[CH2:17][OH:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CO)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g) in N,N-dimethylformamide (10 mL) was added 2-amino-2-methyl-1-propanol (1.18 g) at 0° C. The mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2-(1,1-dimethyl-2-hydroxyethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.23 g) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:27](O)=[O:28])[CH2:25][Cl:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:27](=[O:28])[C@H:24]([CH2:25][Cl:26])[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a solution of 0.28 g (2 mmol) of glycine ethyl ester hydrochloride and 0.28 mL (2 mmol) of triethylamine in 10 mL of chloroform, 0.52 g (2 mmol) of N-(tert-butoxycarbonyl)-3-chloro-L-alanine in 6 mL of chloroform and 0.42 g (2 mmol) of dicyclohexylcarbodiimide were added at 0° C. The reaction mixture was stirred for 16 hours at room temperature. The resultant precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water and 3% aqueous sodium bicarbonate, then was dried over anhydrous sodium sulfate. Removal of the solvent left a crystalline residue which was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.415 g (60%) of the pure product melting at 71.5-72.0° C. The identity of the product, which has the structural formula ##STR73## was confirmed by IR and NMR analyses.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].Cl>CN(C=O)C.CS(C)=O>[CH3:18][O:17][CH2:16][CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:4][C:2]1=[O:3]
Reactant: COCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a solution of isatin (2.94 g, 20 mmol) in DMF (40 mL) at 0° C. was added 60% NaH (1.00 g, 25 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C. and 1-bromo-2-methoxyethane (2.35 mL, 25 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 10 min at 0° C., warmed to rt and stirred O/N. The reaction was then cooled to 0° C., quenched with sat. NH4Cl, ice, H2O, extracted with EtOAc (150 mL×2), dried over Na2SO4 and concentrated to give a dark orange red liquid which was redissolved in DMSO (10 mL). N2H4-xH2O (2 mL) was added dropwise over 7 min. After addition, the reaction mixture was stirred for 5 min at rt, then 2 h at 140° C. (oil temp.) before cooling to rt. Ice/H2O (20 mL) was added, followed by 6 M HCl (7 mL, 42 mmol) and the resulting mixture was stirred for 30 min at rt. Additional ice/H2O (40 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The crude product was purified by flash chromatography (gradient: EtOAc/hex 0 to 40%) to afford the title compound as an orange liquid (2.32 g, 61% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.26-7.20 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 3.82 (t, J=5.6 Hz, 2H), 3.55 (s, 2H), 3.52 (t, J=5.8 Hz, 2H), 3.22 (s, 3H); MS ESI 191.8 [M+H]+, calcd for [C11H13NO2+H]+ 192.1.