Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7](O)C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(CS(O)(=O)=O)N=NN=4)CS[C@H]23)=O)=[CH:5][CH:6]=1.C(O)(=O)C.C(O)(=O)C.[CH2:44]([N:51](CC1C=CC=CC=1)[CH2:52][CH2:53][NH2:54])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O.CO>[CH2:44]([NH:51][CH2:52][CH2:53][NH:54][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)C1=C(CSc2nnnn2CS(=O)(=O)O)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: c1ccc(CNCCNCc2ccccc2)cc1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a stirred solution of cefonicid (5.76 g, 9.8 mmol) in water (6.3% w/w), at pH 5-6 and ambient temperature, methanol (50 ml) was added, followed by a suspension of N,N-dibenzylethylene diamine diacetate (8.6 g, 24 mmol) in methanol (50 ml). The reaction mixture was stirred for 3 h at 20°-25° C., resulting in formation of a white solid. The reaction mixture was cooled to 10°-15° C. and filtered. The white solid was washed with water (3×15 ml) and methanol (3×10 ml). The solid was dried at 30°-35° C. under vacuum. (7.63 g, 99.4% yield). The melting range of the crystals was 191°-193° C. Washed salt with water (50 ml×2) followed by methanol (120 ml) to yield a product with a melting range of 195°-198° C. Elemental Analysis (C34H38N8 O8S3) calcd: C, 52.16; H, 4.89; N, 14.31; S, 12.26. found: C, 52.06; H, 4.89; N, 14.01; S, 12.27.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:13][C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)[NH:5][CH2:4]1.IC.[C:30]([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:13][C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)=[CH:9][CH:10]=2)[N:5]([CH3:30])[CH2:4]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1)Nc1ccc2c(c1)NCC(CO)C2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CC(CO)Cc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (2E)-N-[3-(hydroxymethyl)(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide, Example 87, (75 mg, 0.20 mmol), iodomethane (0.014 mL, 0.22 mmol, Aldrich) and NaHCO3 (84 mg, 1.0 mmol) in DMF (1.0 mL, Aldrich) was stirred for 4 h at room temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (5 mL), satd NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/CH2Cl2) provided the title product as a white solid. MP 167-169° C. MS (ESI, pos. ion) m/z: 391 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)=[O:4].CCCCCC.CC[O:23]C(C)=O>CC(C)=O.S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:23])=[O:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCCO)s1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3 (1.14 g, 5.3 mmol) in acetone (15 mL) was added dropwise to a cold solution (ice bath) of CrO3 (3 g, 30 mmol) in sulfuric acid (23 mL) and water (67 mL). After the addition, the resulting solution was stirred in an ice bath for an additional 2 h and the solution was allowed to warm to room temperature overnight. TLC indicated the disappearance of the starting alcohol and the formation of one major spot at Rf=0.35 (hexane/EtOAc 2:1). The solution was extracted with 5×30 mL of ethyl ether and dried over Na2SO4. After evaporation of the solvent under reduced pressure, the resulting residue was flash chromatographed through silica gel column (3.5×15 cm) using hexane/EtOAc (2:1) as eluent. The desired fraction (TLC) was collected and the solvent was evaporated under reduced pressure to afford 570 mg of 4 as colorless oil. 1H NMR (DMSO-d6): δ 1.79-1.87 (m, 2H), 2.24-2.27 (t, J=7.2 Hz, 2H), 2.82-2.86 (t, J=7.2 Hz, 2H), 3.77 (s, 3H), 6.95-6.96 (d, J=3.6 Hz, 1H), 7.63-7.64 (d, J=3.6 Hz, 1H), 12.17 (br, 1H). HRMS calcd for C10H12O4S (M+), 228.0456; found: 228.0458.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:38]/[C:39](/[CH3:45])=[CH:40]\[C:41]([O:43][CH3:44])=[O:42]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([CH3:45])[NH:38][C:12]([CH3:14])=[C:11]1[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][CH2:20]1)=[O:15]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccccc1Cl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1ccccc1Cl

Procedure:
A mixture of o-chlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 4-(2-chlorophenyl)-2,6-dimethyl--1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 81°-83° C. (sintering). Yield (30.8%). IR(Nujol)cm-1 : 3320, 1680. NMR(CDCl3)δ: 2.26(6H,s, ##STR15## 3.56(3H,s,COOCH3), 4.12(2H,t,J=6,--COOCH2CH2 --), 4.17(1H,s, >N--CH<), 5.36(1H,s,C(4) --H), 5.63(1H,s,NH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 58 mL of o-chlorobenzoyl chloride and 24 mL of thiophene in 700 mL of carbon disulfide, cooled to 0° C. under a nitrogen atmosphere, was added 134 g of aluminum trichloride portionwise over a 20-minute period. A delayed exotherm was noted and the resulting deep red mixture was stirred for one hour at room temperature. Reaction mixture was poured into 4.0 kg of ice-water, extracted with methylene chloride and the organic layer washed three times with 1N NaOH followed by a final water wash. The organic layer was dried (MgSO4), filtered and concentrated to a dark oil. Distillation under vacuum provided 55 g of the subject compound as a light green viscous liquid, B.P. 160° C. at 1.6 mm.
Reaction SMILES: [F:1][C:2]1[C:16](=[O:17])[NH:15][C:5]2[N:6]=[C:7](S(C)(=O)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[C:18]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[C:16](=[O:17])[NH:15][C:5]2[N:6]=[C:7]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]3[CH2:32][CH2:33][N:28]([C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=4)[CH2:29][CH2:30]3)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: Cc1nc(S(C)(=O)=O)nc2[nH]c(=O)c(F)cc12
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Product: Cc1nc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc2[nH]c(=O)c(F)cc12

Procedure:
Following the same procedure as in Example H12 and starting from 6-fluoro-2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg, 1.166 mmol, U.S. Pat. No. 6,498,163) and 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (331 mg, 1.166 mmol), the title compound was made as a solid (323 mg, 0.684 mmol, 58.7%). MS: APCI: M+1: 462.1 (Exact Mass: 461.22).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
As shown in FIG. 7—step i, to a solution of 2,6-dibromopyridine (4.738 g) in dichloromethane (80 mL) was added dropwise n-butyllithium (2.5 N, 8.9 mL) at or below −65° C., followed by stirring at this temperature for 20 min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (compound 1030) (4.38 g) was added. After 15 min, the temperature was brought up to −30° C. and a saturated aqueous ammonium chloride solution (100 mL) was added. The organic and aqueous layers were separated, the aqueous layer extracted with dichloromethane (2×80 mL). The combined organics were evaporated to gave a residue which was triturated with hexane to give 6-bromo-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (compound 1031) as a white solid (7.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1F.[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:15][CH2:13][CH3:14]
Reactant: CCS
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(C(F)(F)F)ccc1Br
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.5 g of 4-bromo-3-fluorobenzotrifluoride, 0.46 ml of ethanethiol, 851 mg of potassium carbonate and 2 ml of DMF was stirred at 75° C. for 2.5 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.15 g of 4-bromo-3-ethylsulfanylbenzotrifluoride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: O=C(c1ccc(-c2cccc(OC(F)(F)F)c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Trifluoromethoxybenzene boronic acid. MS (M+H) 437.1
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][NH:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][N:17]([CH3:18])[C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1
Reactant: CNCCN(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
To a solution of 4-nitro-benzoic acid (3.0 g, 0.01795 mol) in DMF (40 mL), N,N,N′-trimethyl ethylenediamine (2.2 g, 0.02154 mol), HOBt (3.15 g, 0.02335 mol), EDC.HCl(5.16 g, 0.02692 mol) and DIPEA (4.64 g, 0.0359 mol) were added. The reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [4.5 g, 100%]; LC-MS (ESI): Calculated mass: 251.1; Observed mass: 251.9 [M+H]+ (RT: 0.21 min).
Reaction SMILES: CN(C=O)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([OH:21])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(Cl)CCl.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=1>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:18][CH:17]2[C:19]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=2)=[O:21])=[CH:14][CH:15]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C2CC2C(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.5 %

Procedure:
To a DMF (10 ml) solution of trans-2-(4-tert-butylphenyl)cyclopropanecarboxylic acid (435 mg, 1.89 mmol)) [Journal of medicinal chemistry, 2005, vol. 48, 71-90], EDC (572 mg, 3.0 mmol), DMAP (73 mg, 0.6 mmol), triethylamine (0.836 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (507 mg, 1.89 mmol) were added and the mixture was stirred for 5 hours at room temperature. Then, the reaction was quenched with saturated sodium bicarbonate aqueous solution and the whole was extracted with EtOAc/hexane (3:1), and dried over sodium sulfate. Then, filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane/EtOAc (1:2), gave title compound (75 mg, 9% yield) as white solids.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11]Br)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11][P:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:21])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)CC(CBr)CC(C)C
Product: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Temperature: 190 °C
Yield: 47.8 %

Procedure:
3-Bromomethyl-3-isobutyl-propionic acid ethyl ester (4.6 g, 18.3 mmol) is warmed in a 170° C. oil bath under Ar. Triethyl phosphite (3.6 g, 22 mmol) is added dropwise over 2 hours. When addition is complete, the oil bath temperature is raised to 190° C. for 4 hours. The reaction mixture is cooled to room temperature, and the product is purified by MPLC in EtOAc to give 2.7 g (48% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester. NMR (H1, 400 MHz, CDCl3) δ 0.8 (6H, d); δ 1.2 (5H, m); δ 1.3 (6H, m); δ 1.6 (1H, m); δ 1.7 (1H, d); δ 1.8 (1H, d); δ 2.3 (2H, m); δ 2.5 (1H, dd); δ 4.1 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=O.[C:12](OC)(OC)(OC)[CH2:13][CH2:14][CH3:15].C(O)(=O)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[CH2:26]([N:33]1[C:7](=[O:9])[C:3]2[CH:4]=[N:5][NH:6][C:2]=2[N:1]=[C:12]1[CH2:13][CH2:14][CH3:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC(OC)(OC)OC
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2[nH]ncc2c(=O)n1Cc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (1-1, 3.1 g, 20 mmol, 1 equiv), trimethyl orthobutyrate (5.9 g, 40 mmol, 2 equiv) and acetic acid (120 mg, 2 mmol, 0.1 equiv) was heated at 90° C. for 3 h. Excess trimethyl orthobutyrate was removed by distillation. The residue added to a solution of benzylamine (4.2 g, 40 mmol, 2 equiv) in ethanol (25 mL), and the resulting solution was heated at reflux for 18 h, then cooled and concentrated. The residue was triturated with EtOAc to provide 5-benzyl-6-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-2) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 11.5 (bs, 1H), 8.19 (s, 1H), 7.34 (m, 2H), 7.28 (m, 1H), 7.15 (d, J=7 Hz, 2H), 5.41 (s, 2H), 2.75 (t, J=7 Hz, 2H), 1.82 (m, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CCN=C=NCCC[N:20]([CH3:22])C.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34]CN.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH3:33][O:34][N:20]([CH3:22])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COCN
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a stirred solution of 4-methoxybenzoic acid (10.0 g, 65.70 mmol) in DCM (50 mL) were added EDCI (18.90 g, 98.60 mmol), HOBT (10.0 g, 65.70 mmol), N-methoxy methylamine (13.0 g, 131.40 mmol) and DIPEA (34.3 mL, 197.20 mmol) at RT under a nitrogen atmosphere. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (2×100 mL), brine (2×50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford crude product. The crude material was purified by flash column chromatography using 20% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford N,4-dimethoxy-N-methylbenzamide (11.0 g, 86%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[C:5]([F:12])=[CH:4][N:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:12])=[CH:4][N:3]=1
Reactant: CC(C)(O)c1cc(Br)ncc1F
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (24.7 g, 106 mmol) and methanesulfonic anhydride (55.1 g, 317 mmol) in DCM (250 ml) was added triethylamine (58.8 ml, 42.7 g, 422 mmol). The reaction mixture was stirred at rt for 20 h. Another 1 eq. (18 g) of methanesulfonic anhydride and 1.2 eq. (17 ml) of triethylamine were added and the reaction mixture was stirred an additional 20 h at rt. The reaction mixture was quenched with 1M aq. Na2CO3 sol. and diluted with DCM. The phases were separated and the aq. phase was reextracted twice with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (hexane:EtOAc 8:1) yielded the title compound as a clear colourless liquid. HPLC RtH4=1.12 min; ESIMS: 216, 218 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, 1H), 7.40 (d, 1H), 5.48-5.44 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][C:23]2[C:21](=[O:22])[N:20]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:24]=2)[CH:30]=[N:31]1
Reactant: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)n1
Temperature: 130 °C
Yield: 7.2 %

Procedure:
To the solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethyl imidocarbamate (200 mg, 0.737 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (174 mg, 0.885 mmol) in NMP (3 mL) was added K2CO3 (408 mg, 2.95 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (22 mg, 7.15% yield). LCMS: rt=2.38 min, [M+H+]=418
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(O)ccc1-c1nc2ncncc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: CCCc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-n-propyl-4'-hydroxy-phenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1)OCc1ccccc1
Yield: 95.9 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.373 g, 8.660 mmol) and benzyl (3S)-piperidin-3-ylcarbamate (MolBridge, 2.077 g, 8.865 mmol), 1-butanol (10.0 mL) was added followed by DIPEA (1.836 g, 14.20 mmol). The mixture was irradiated with microwaves at 130° C. for 1 h. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound as a yellow solid (2.96 g, 96%). LCMS calc. for C18H21N4O4 (M+H)+: m/z=357.2. found 357.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:30])=[C:23]([CH2:28]O)[C:24]([Cl:27])=[CH:25][CH:26]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CS([Cl:42])(=O)=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:30])=[C:23]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:28][Cl:42])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(CCl)c2Cl)cn1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dichlorobenzene (5.36 g) was dissolved in N,N-dimethylformamide (30 ml) under nitrogen atmosphere, triethylamine (2.4 g) and methanesulfonyl chloride (1.3 ml) were added to the mixture at 0° C., and the mixture was stirred at 0° C. for 1 hour and at ambient temperature for 18 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with ethyl acetate to give 3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyl chloride (5-1 g) as a powder.