Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][C:28]5([CH3:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1.[Cl:35][CH2:36]Cl.C=O.[BH4-].[Na+]>CO>[ClH:35].[ClH:1].[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][C:28]5([CH3:34])[CH2:33][CH2:32][N:31]([CH3:36])[CH2:30][CH2:29]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:4][CH2:5]1
Reactant: ClCCl
Reactant: CC1(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCNCC1
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CN1CCC(C)(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To 2-{5-bromo-2-[2-(4-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide dihydrochloric acid (0.200 g, 0.34 mmol) dissolved in 3:1 MeOH:dichloromethane (8 mL) is added 37.4% aqueous formaldehyde (0.076 mL, 1.02 mmol). After 1 hour, the reaction mixture is cooled in an ice bath and sodium borohydride is added in portions over two minutes. The reaction proceeds for 1 hour in an ice bath and 1 hour at room temperature. By TLC an intermediate is present and an additional equivalent of sodium borohydride is added at 0° C. After 30 minutes the entire reaction mixture is loaded onto a silica gel column and chromatographed, eluting with 3-7% (2 M NH3 in MeOH) in dichloromethane to give 116 mg, 64% yield, of the methylated product. It is converted to the titled compound by treating with concentrated HCl solution and isolated as a yellow solid. ES+(m/z) 528 (79Br) and 530 (81Br) [M(free base)+H].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH3:2].[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)cc2cn[nH]c12
Yield: 99.3 %

Procedure:
To a solution of ethyl 7-ethoxy-1H-indazole-5-carboxylate (400 mg, 1.71 mmol) was added 1 M LiOH (3.4 mL). The mixture was heated at reflux overnight. The reaction was concentrated to dryness and the solids were triturated with 1 N HCl. The solids were washed with water and air dried to afford the title compound as an off-white solid (350 mg, 99%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.[N+:24]([O-])([OH:26])=[O:25].N([O-])=O.[Na+]>O>[N+:24]([C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:26])=[O:25]
Reactant: O=C(O)c1cccc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 0.75 h

Procedure:
A mixture of 2.2 g (0.007 mole) of 2-bromo-3-phenyl-7-benzofurancarboxylic acid and 50 ml of acetic acid is heated on a steam bath for 45 minutes to facilitate dissolution. To this mixture is added 2 ml of nitric acid, then 0.96 g (0.0139 mole) of sodium nitrite while stirring the mixture rapidly at about 80°-90° C. After stirring for about 45 minutes the mixture is poured into water. The solid is separated by filtration and recrystallized from ethanol to provide 2-nitro-3-phenyl-7-benzofurancarboxylic acid, m.p. 271°-272° C.
Reaction SMILES: [Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:12]2[O:24][C@@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@@H:13]2[O:14]C(=O)C)[CH:3]1[NH:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:12]2[O:24][C@@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@@H:13]2[OH:14])[CH:3]1[NH:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)OC[C@@H]1O[C@H](N2c3cccc(Cl)c3N(Cl)C2NC(C)C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(C)NC1N(Cl)c2c(Cl)cccc2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O

Procedure:
3,4-Dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (2.06 g, 4.10 mmol), sodium carbonate (0.60 g, 5.66 mmol), water (12 mL), methanol (10 mL), and ethanol (24 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Product: CCOC(=O)CCc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
In a manner directly analogous to that described in Example 6, ethyl 4-aminohydrocinnamate is alkylated with 14-(trimethylsilyl)tetradecyl bromide to form ethyl 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 9, ethyl 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamate is hydrolyzed to 4-[14-(trimethylsilyl)tetradecylamino]hydrocinnamic acid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@@H:6](O)[CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].C(N(S(F)(F)[F:22])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]([C@@H:3]1[CH2:7][C@H:6]([F:22])[CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: -30 °C

Procedure:
(2S,4R)-tert-Butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloromethane with stirring under argon atmosphere. The mixture was cooled to −30° C. followed by addition of diethylaminosulfur trifluoride (56.7 g, 0.3516 mol). After stirred for 45 minutes, the reaction mixture was warmed up to −5° C. Then the mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution to pH >7 at such a rate that the reaction temperature was kept below 20° C. Then ice water and 500 mL of dichloromethane were added. The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in which the concentration temperature was kept below 38° C. to obtain the title compound (2S,4S)-tent-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate 13e (50 g, yield 100%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1([C:27](=O)[CH2:28][CH2:29][C:30](=O)[CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:31][C:30]1[N:1]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][CH:29]=1
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)n1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 31.3 %

Procedure:
25 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 10 ml of toluene. To the mixture were added 20 mg of 1-phenyl-1,4-pentandione and 0.2 mg of p-toluenesulfonate (hydrate), followed by heating under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(Cl)=O.[F:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])=[O:13].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:19])(=[O:14])=[O:13]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)F)c1
Reactant: NCc1ccccn1
Agent: O=C(Cl)c1cccc(Cl)c1
Product: O=C(NCc1ccccn1)c1cccc(S(=O)(=O)F)c1

Procedure:
Following the procedure of Example 6, Part A, supra., but replacing the 3-chlorobenzoyl chloride as used therein with 6.68 gms. (0.03 mole) of 3-fluorosulfonylbenzoyl chloride and reducing the proportion of 2-aminomethylpyridine as used therein to 3.24 gms. (0.03 mole) there is obtained 3-fluorosulfonyl-N-(2-pyridylmethyl)benzamide in the form of a tan colored solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:30]OS(C)(=O)=O)=[CH:21][CH:20]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[O:16][CH:14]([CH2:13][N:12]([CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CS(=O)(=O)OCCN(CCCc1ccc(C#N)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(CCCc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2
Temperature: 57.5 °C
Reaction time: 72 h

Procedure:
A mixture of 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (2.35 g, 0.01 mol; see WO 01/28992), methanesulfonic acid 2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl ester (3.7 g, 0.01 mol; see Preparation A above) and anhydrous K2CO3 (2.1 g, 0.015 mol) in dry acetonitrile (70 mL) was stirred under nitrogen atmosphere at 55-60° C. for 3 days. After filtration and concentration, the crude product was purified by column chromatography (silica gel: 60-120 mesh, eluent: petroleum ether-ethyl acetate, 50:50). Yield: 3.25 g (66%).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([OH:22])[C:16]([NH2:21])([CH2:19][OH:20])[CH2:17][OH:18]>CO>[OH:22][CH2:15][C:16]([NH:21][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:21][C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][OH:22])=[O:13])=[CH:11][CH:10]=1)([CH2:19][OH:20])[CH2:17][OH:18]
Reactant: NC(CO)(CO)CO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: CO
Product: O=C(NC(CO)(CO)CO)c1ccc(C(=O)NC(CO)(CO)CO)cc1

Procedure:
In a 1-liter, three-neck, round-bottom flask equipped with a thermometer, stirrer and condenser were placed 194 g (1.0 mole) of dimethyl terephthalate, 242 g (2.0 mole) tris(hydroxymethyl) aminomethane and 1 liter of methanol. The mixture was refluxed for 8 hours and then allowed to cool. The title compound crystallized and was removed by filtration and dried. The melting point was 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=O)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)=[CH:28][CH:27]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(CNc3ccc(N4CCOCC4)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-formyl-1H-indole-6-carboxylic acid methyl ester (500 mg, 2.46 mmol), 4-morpholinoaniline (482.3 mg, 2.71 mmol) and dibutyltin dichloride (76 mg, 0.25 mmol) in THF was added phenylsilane (334 μl, 2.71 mmol). The mixture was stirred at room temperature overnight under nitrogen, THF was evaporated off the mixture and the residue was purified by flash chromatography (hexane/EtOAc, 20/80) to afford the title compound 123 (881 mg, 98%). 1H-NMR (DMSO) δ: 8.00 (d, J=1.0 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H); 7.58 (dd, J=8.4, 1.6 Hz, 1H); 7.52 (d, J=2.0 Hz, 1H); 6.70 (d, J=9.0 Hz, 2H); 6.59 (d, J=9.0 Hz, 2H); 5.48 (t, J=5.8 Hz, 1H); 4.31 (d, J=5.7 Hz, 2H); 3.83 (s, 3H); 3.68 (t, J=4.7 Hz, 4H); 2.86 (t, J=4.7 Hz, 4H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: C1COCCN1
Product: c1ccc2c(c1)nc(N1CCOCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with morpholine, according to a procedure that is similar to that followed in example 3, there is obtained 4-(4-morpholinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=142.8° C. (onset); IR (KBr): 3016, 2962, 1517 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,s), 7.8÷7.5 (3H,m), 7.5÷7.2 (2H,m), 4.4 (4H,t), 3.9 (4H,t); UV (EtOH): λmax =230, 248, 292, 304, 330 nm. Elementary analysis for C14H13N4O (m.w. 254.29): calcd. C 66.13, H 5.55, N 22.03%; found C 65.43, H 5.47, N 22.25%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=2[Br:19])[C:3]1=[O:20].[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH:33]=O)=[CH:31][N:30]=[CH:29]2)=[CH:25][C:24]=1[F:37])#[N:22].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:19][C:9]1[CH:10]=[CH:11][C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=1[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:33][C:32]2[N:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([C:21]#[N:22])=[C:24]([F:37])[CH:25]=3)[CH:29]=[N:30][CH:31]=2)[C:3]1=[O:20]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(N)C2=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(NCc3cncn3Cc3ccc(C#N)c(F)c3)C2=O)c1
Reaction time: 0.5 h

Procedure:
3-Amino-1-(2-bromo-5-methanesulfonyloxybenzyl)-2-oxopyrrolidine, as described above in Step E, (640 mg, 1.12 mmol), 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Example 1, Step G, (333 mg, 1.45 mmol) were stirred in MeOH (8 mL) and the solution was acidified to pH≈5 to 6, as judged by wetted pH indicator paper, with acetic acid. Stirring was continued for 30 min, then NaCNBH3 (118 mg, 1.88 mmol) was added. Stirring was continued for 18 hours, then the reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The aqueous layer was extracted further with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 5% MeOH, to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])C(O)=O)=[CH:4][C:3]=1[O:13][CH3:14].C(=O)=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Agent: O=C=O
Solvent: O
Product: COc1cc(C=O)ccc1O
Reaction time: 0.5 h

Procedure:
10 g of 4-hydroxy-3-methoxyphenylglycolic acid (molecular weight 198) are dissolved in 100 g of water, and 82 g of an aqueous 20% FeCl3 -solution are added over a period of 20 to 30 minutes at 75° to 80° C., thus initiating a vigorous evolution of carbon dioxide which abates after another 30 minutes. The reaction takes place at a pH-value of from 2 to 0.8. Most of the 4-hydroxy-3-methoxy benzaldehyde formed completely crystallises out of the acid oxidation solution on cooling. The 4-hydroxy-3-methoxybenzaldehyde can be completely extracted from the oxidation solution with benzene or toluene. The extract is washed with a little water, after which the solvent is distilled off until the 4-hydroxy-3-methoxybenzaldehyde can be precipitated from the mother liquor in crystalline form with cyclohexane or with light petrol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([C:30](=[O:32])[CH3:31])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:14]([N:27]1[CH2:26][CH2:25][N:24]([C:23]2[CH:22]=[CH:21][C:20]([C:30](=[O:32])[CH3:31])=[CH:19][C:18]=2[F:17])[CH2:29][CH2:28]1)=[O:16]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)N1CCN(c2ccc(C(C)=O)cc2F)CC1

Procedure:
Following procedure D, the title compound is prepared by reaction of methyl 4-nitrophthalate [90072-77-8] with 1-(3fluoro-4-piperazin-1-yl-phenyl)-ethanone (m.p. 189-191° C., MS (ISP): 429.4 M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](Br)=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1cc(Br)c(F)cc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)c(F)cc1N
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate (4.00 g, 13.88 mmol), xantphos (0.402 g, 0.694 mmol)9), tris(dibenzylideneacetone)dipalladium (0.318 g, 0.347 mmol), 1,4-Dioxane (13.9 ml), and DIPEA (4.83 ml, 27.8 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to RT and benzyl mercaptan (1.724 ml, 14.58 mmol) was added and the reaction was continued heating at 80° C. for an additional 90 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford (E)-ethyl 3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (2.75 g, 8.30 mmol, 59.8% yield). m/z (ESI) 332.1 (M+H)+.
Reaction SMILES: CC1C=C(C=CC=1)O[C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=2)[CH:7]=1.NC1C=CC=C(N)N=1.[Cl:31]C1C=C(Cl)N=CN=1>C(O)CCC>[Cl:31][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Agent: Nc1cccc(N)n1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 100 °C
Yield: 36 %

Procedure:
Synthesis of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](OCc2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
(2S,4S)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyester (CAS Reg. No. 227935-38-8)(300 mg, 1.0 mmol) and 60% sodium hydride mineral oil dispersion (61 mg, 1.1 mmol) were dissolved in anhydrous dimethylformamide (9 ml) at 0° C. under a nitrogen atmosphere. After 10 mins stirring 4-chlorobenzylbromide (265 mg, 1.2 mmol) in CH2Cl2 (1 ml) was added drop wise and the reaction mixture stirred to room temperature for 1 hour. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (25 ml), washed with water (2×25 ml), dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified using flash chromatography eluting with a solvent gradient 4:1 heptane:ethyl acetate, yielding the title compound (170 mg, 40% yield) as an oil.