Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][C:15]([CH3:22])([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:16])[C:11](Cl)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][C:15]([CH3:16])([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:22])[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Reactant: ON=C1CSCCS1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1CSCCS1

Procedure:
Prepared as in Example 1 by reacting 8.0 g (0.053 m) of 2-oximino-1,4-dithiane, 15.2 g (0.058 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 5.42 g (0.053 m) of triethylamine in 100 ml of dioxane. The product crystallized from isopropyl ether-ethyl acetate to yield 4.3 g of a white solid, (m.p. 80°-82° C.) Recrystallization raised the melting point to 85°-86° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH2:11].[C:12](O)(=[O:16])[C:13](O)=[O:14].Cl>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[CH3:9])[NH:2][C:13](=[O:14])[C:12](=[O:16])[NH:11]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(N)c(N)cc1Cl
Agent: Cl
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 81.1 %

Procedure:
A mixture of 1,2-diamino-4-chloro-5-methylbenzene hydrochloride [J Chem Soc, 117, 784 (1920)] (1.90 g, 9.84 mmol), oxalic acid (1.24 g, 13.8 mmol) and 4M hydrochloric acid (49 ml) was heated at reflux for 4.5 hours. After cooling the solid precipitate was collected by filtration, washed well with water and dried under reduced pressure at 80° C. to afford 1,4-dihydro-6-chloro-7-methylquinoxalin-2,3-dione (1.68 g, 81%) as a dark grey solid, mp>330° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:26][NH2:27]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([NH:26][NH2:27])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of methyl 4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of the title compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([C:12](=C(C)C)[OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2].C(O)C>O.Cl>[CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]
Reactant: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)C(O)=C(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Yield: 83 %

Procedure:
12.4 g of the 3-O-ethyl-isopropylidene ascorbic acid obtained in Example 1 was dissolved in 100 ml of distilled water, to which 10 ml of 2N hydrochloric acid solution was added. The mixture was reacted at 60° C. for 2 hours and concentrated under reduced pressure to give an adhesive liquid product. Ethanol was added to the prepared liquid product, which was then concentrated to give crude crystalline 3-ethyl-ascorbic acid. The crude crystalline 3-ethyl-ascorbic acid was re-crystallized in ethylacetate/ethanol (8:2) to give 8.6 g of white crystalline 3-O-ethyl-ascorbic acid (yield: 84.3%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:20]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[C:22]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:21]=1>ClCCl.C(OCC)(=O)C>[OH:11][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][C:20]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[C:22]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:21]=1
Reactant: NCC(O)Cc1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(NCC(O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 1-amino-3-phenyl-propan-2-ol (0.51 g, 3.3 mmol) and triethylamine (0.45 mL, 3.3 mmol) in 20 mL dichloromethane was added (0.92 g, 2.6 mmol) 2-chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one. The solution was stirred for 18 h at room temperature. The solution was diluted with ethyl acetate and washed with 5% sodium bicarbonate. The organic layer was dried over magnesium sulfate and purified on 10 g silica eluting product with 0 to 5% methanol/dichloromethane to give a pale yellow solid. M+1=463.2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:21])[C@H:14]([CH:19]=[CH2:20])C(NN)=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:24](OC(C)(C)C)=O.C[CH:32]([OH:34])C>Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:21][C:32](=[O:34])[NH:24][C@H:14]2[CH:19]=[CH2:20])[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:8]=1
Reactant: CC(C)(C)ON=O
Reactant: CC(C)O
Reactant: C=C[C@H](C(=O)NN)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: C=C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
(2S)-2-[(S)-[3,5-Bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enehydrazide (14.5 g, 42.4 mmol) was dissolved in IPA (100 mL) and HCl (4N in dioxane, 20 mL). tert-Butyl nitrite (5.24 g, 50.8 mmol) in IPA (20 mL) was added via a syringe pump at 50° C. over 1 hr. The reaction mixture was stirred at 50° C. and additional hour and the volatiles were removed. The crude mixture was dissolved in ethyl acetate (150 mL), washed with aqueous Na2CO3 (100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (7 g, 21.52 mmol) as light yellow crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.90 (s, 1H), 7.82 (s, 2H), 5.91 (d, J=8.3 Hz, 1H), 5.2 (m, 3H), 4.7 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4].[Br:29]Br.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([Br:29])[CH:10]=[CH:9]2)=[O:4]
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccccc12
Reactant: BrBr
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccc(Br)cc12
Reaction time: 2 h
Yield: 69.2 %

Procedure:
The compound of example 11, step 3, (550 mg, 1.47 mmol) was dissolved in a mixture of benzene (15 ml) and chloroform (15 ml) and treated at room temperature with bromine (235 mg, 1.47 mmol) under stirring. After 2 h, DBU (224 mg, 1.47 mmol) was added and the mixture stirred for 18 h at room temperature. The solvent was removed in vacuo and the remaining residue was purified by silica gel chromatography (HEP/EA). 460 mg of the title compound were obtained.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14](I)[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12](I)[CH:11]=1)(=O)C1C=CC=CC=1.[C:30]([Cu])#[N:31].Cl.[CH3:34][N:35](C=O)C>>[C:34]([C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([C:30]#[N:31])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: COc1ccc(Oc2c(I)cc(OC(=O)c3ccccc3)cc2I)cc1C(C)C
Reactant: N#C[Cu]
Agent: Cl
Product: COc1ccc(Oc2c(C#N)cc(O)cc2C#N)cc1C(C)C
Temperature: 160 °C

Procedure:
To a stirred solution of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenyl benzoate (0.4 g, 0.76 mmol) in DMF(5.0 mL) at rt was added CuCN (0.27 g, 3.0 mmol). The reaction mixture was heated at 160° C. for 5 min under microwave irradiation, the reaction mixture was cool to room temperature and poured into 1N HCl (50 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3:7) to afford 3,5-dicyano-4-(4′-methoxy-3′-iso-propylphenoxy)phenol as a viscous (105 mg, 35%): 1H NMR (300 MD, CDCl3): δ 7.35 (s, 2 H), 6.99 (d, J=3.0 Hz, 1 H), 6.78 (d, J=8.7 Hz, 1 H), 6.99 (dd, J=3.0, 8.7 Hz, 1 H), 3.84 (s, 3 H), 3.38-3.30 (m, 1 H), 1.21 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (7:3); Rf=0.38.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])=[O:5].Cl[CH2:20][CH2:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>C1C=CC=CC=1.CN(C)C=O>[C:30]([O:29][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][CH2:20][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:4]([CH3:3])(=[O:6])=[O:5])(=[O:32])[CH3:31]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCOC(=O)CCCCCCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C

Procedure:
Sodium hydride (0.715 g., 0.0298 mole) is suspended in benzene (30 ml.) and dimethylformamide (30 ml.). Ethyl 7-(methanesulfonamido)heptanoate (6.8 g., 0.0271 mole) (Example O, Step 1) is added and the suspension heated on the steam bath for 15 minutes. After cooling to room temperature, 1-chloro-4-acetoxynonane (6.55 g., 0.0298 mole) (Example A, Step 3) is added over 15 minutes and the resulting solution heated on the steam bath for 20 hours. Then the reaction is poured into water (300 ml.) and extracted with ethyl acetate (3 × 100 ml.). The organic layer is washed with brine (2 × 50 ml.), dried over sodium sulfate then concentrated in vacuo to an oil which is purified by chromatography on silica gel. The silica gel is eluted with 3% methanol in chloroform and evaporation of the appropriate fraction affords ethyl 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoate. The yield is 6.0 g. (51%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][OH:5].CCN(CC)CC.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@H:34]([CH3:38])[C:35](Cl)=[O:36])[CH:28]=[CH:27]2>CN(C1C=CN=CC=1)C.O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@H:34]([CH3:38])[C:35]([O:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[O:36])[CH:28]=[CH:27]2
Reactant: COC(CO)OC
Reactant: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2cc([C@H](C)C(=O)OCC(OC)OC)ccc2c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
2,2-Dimethoxyethanol (8.12 g), Et3N (8.99 g), DMAP (80 mg) and toluene (71 mL) are combined and stirred at room temperature. (S)-6-Methoxy-α-methyl-2-naphthaleneacetyl chloride (18.42 g) is added in portions over a period of 8 minutes. The resulting slurry is agitated (35-40° C.) until the reaction is judged to be complete. To the reaction mixture is added water (80 mL) and the phases are separated. The toluene phase is washed with saturated sodium bicarbonate (40 mL) and water (40 mL) and concentrated. Dichloromethane (20 mL) is added and the vacuum evaporation is repeated to produce 21.20 g of 2,2-dimethoxyethyl (S)-6-methoxy-α-methyl-2-naphthaleneacetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](=N)([C:16]1C=CC=CC=1)[C:10]1C=CC=C[CH:11]=1>>[CH2:16]1[C@@H:2]([C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[NH:1][CH2:11][CH:10]=[CH:9]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCc1cccnc1
Product: C1=CC[C@@H](c2cccnc2)NC1
Reaction time: 6 h

Procedure:
3-aminomethylpyridine was added to neat benzophenoneimine (1 eq). The reaction was allowed to proceed for 6 hours at 50° C. providing Formula I as the product.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])nc2)CCN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCNC(=O)C2)cn1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added 4-(6-nitropyridin-3-yl)piperazin-2-one 141-3 (0.7 g, 3.1 mmol), Pd/C (0.2 g) and methanol (20 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flashed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give 4-(6-aminopyridin-3-yl)piperazin-2-one 141-4 as purple solid. MS m/z 193.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:8](O)=[O:9].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:8](=[O:9])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:5]([O:4][C:3]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:2]=3[Cl:1])[CH:6]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3Cl)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3Cl)c2)CC1
Yield: 80.2 %

Procedure:
Following the procedure of Example 5(c) 3-(2-chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid 1.0 g (2.55 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.54 g, 2.55 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.38 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 6.76 (1H, d), 7.22 (4H, m), 7.5 (2H, s), 7.88 (3H, m), 8.26 (1H, d), 8.38 (1H, d).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]CC)=[O:36])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)c1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(C(=O)O)cc2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([CH3:34])[C:31]([CH3:33])=[CH:32][C:6]=2[N:5]=1
Reactant: CCC(C)Cc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)Cc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylbutyl)-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:14][O:13][C@@H:12]([CH2:15][OH:16])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH2:17](OC(OC(=O)C)OCC)C>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:17][N:9]2[C@H:10]1[CH2:14][O:13][C@@H:12]([CH2:15][OH:16])[CH2:11]1
Reactant: Nc1c(Cl)ncnc1N[C@H]1CO[C@@H](CO)C1
Reactant: CCOC(OCC)OC(C)=O
Product: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of (2R-cis)-4-[(5-amino-6-chloro-4-pyrimidinyl)amino]tetrahydro-2-furanmethanol, Compound IX, (220 mg, 0.90 mmole) and diethoxymethylacetate (5 mL) in a 10 mL round bottom flask fitted with a reflux condenser was heated to 100° for 120 hours. The volatile materials were removed via rotary evaporation, and the residue was recombined with toluene (5 mL) and p-toluenesulphonic acid (5 mg). After stirring at room temperature for one hour and by flash column chromatography (10% MeOH/90% CH2Cl2) to afford 109 mg (48%) of Compound X as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][CH2:59][NH2:60]>CN(C=O)C>[CH3:56][O:57][CH2:58][CH2:59][NH:60][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-methoxy-ethylamine (35 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 8 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([F:27])[C:3]=1[C:4]#[N:5].C1(C)C=CC=CC=1.[H-].[Na+].CN([CH:40]=[O:41])C>CO>[F:27][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:9]=[C:2]([O:41][CH3:40])[C:3]=1[C:4]#[N:5]
Reactant: CN(C)C=O
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (360 mg, 0.96 mmol) was azeotroped with toluene (2×12 mL). The resulting residue was taken up in 7.5 mL of CH3OH as a suspension. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was added to a chilled (ice bath) solution of CH3OH (12.5 mL) under nitrogen portion-wise. After completion of addition, the ice bath was removed. The resulting mixture was stirred at ambient temperature for 10 minutes (concentration of CH3ONa was assumed to be 0.52 mmol/mL). A 2.25 mL portion (1.17 mmol, 1.2 equiv) of this mixture was added to the above suspension at room temperature in one portion. The resulting suspension was stirred at room temperature for 2 hours. LCMS showed no conversion. After another 1 h, 5 mL of DMF was added to the mixture, which became milky. The mixture was stirred at room temperature for another 16 hours, upon which time, it became a clear solution. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (20 mL) as a suspension, which was sonicated briefly, and then filtered. The solids collected were dried under house vacuum at room temperature for 1 hour. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (350 mg) as a foam. LC-MS (ES) m/z=386 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[S:13])[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.[Br:14][CH2:15][C:16](=O)[CH2:17][CH3:18]>C(O)C>[BrH:14].[CH2:17]([C:16]1[N:1]=[C:2]([CH2:3][CH2:4][NH2:5])[S:13][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCC(N)=S
Solvent: CCO
Product: Br
Product: CCc1csc(CCN)n1

Procedure:
2.00 g (9.50 mmol) tert.butyl N(3-amino-3-thioxopropyl)carbamate and 1.58 g (10.45 mmol) 1-bromo-2-butanone are refluxed in 40 ml of ethanol for 16 hours with stirring. The reaction mixture is evaporated down, the residue is purified by chromatography.
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8](O)=O)[CH2:3][C:4](O)=[O:5].[CH:11]([O:18]CC)([O:15][CH2:16][CH3:17])OCC.C(OC(=O)C)(=O)C.[NH3:28]>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:11]([O:15][CH2:16][CH3:17])=[O:18])=[CH:8][N:28]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(O)cc1O
Temperature: 120 °C
Yield: 60 %

Procedure:
3-Oxo-pentanedioic acid (101 g, 0.5 mmol), diethyl ester, triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120° C. for 2 h. The resulting mixture was cooled to RT and dissolved in DCM (1000 mL). After further cooling to 0° C., ammonia (30%, 80 mL) was added and the reaction mixture was allowed to warm to RT overnight. The product was extracted with water (2×1000 mL). Then the aqueous layer was acidified to pH 5 with cone HCl. The precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 5.58 (s, 1 H), 4.23 (q, J=6.8, 14.0 Hz, 2 H), 1.25 (t, J=7.2 Hz, 3 H). MS (ESI) m/z: 184.1 (M+H+).