Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4](Cl)[N:3]=1.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][O:13][CH2:12]2.[OH2:19]>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([N:18]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][O:13][CH2:14]3)[C:5]([Cl:9])=[C:4]([N:18]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][O:19][CH2:12]3)[N:3]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: C1CC2COCC1N2
Reactant: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(N2C3CCC2COC3)c(Cl)c(N2C3CCC2COC3)n1
Temperature: 25 °C

Procedure:
To a solution of 2,4,5,6-tetrachloro-pyrimidine (2.0 g, 9.2 mmol) in THF (20 mL) and triethylamine (excess) was added 3-oxa-8-aza-bicyclo[3.2.1]octane (2.7 g, 18 mmol) at −78° C. The reaction slowly warmed to room temperature and a white precipitate formed. To the reaction was added water (2.0 mL) and the mixture was refluxed for three days. The reaction was cooled and water was added to precipitate a white solid. The solids were collected by filtration and washed with diethyl ether to yield the title compound (2.0 g). MS m/z=372 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)C>O.O1CCOCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 8.80 g. of 4-fluorophenylhydrazine hydrochloride in a mixture of 10.9 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The reaction mixture is stirred and heated at 90° C. for 1.5 hours, then poured into 200 ml. of water. The solid is collected and recrystallized from ethanol, giving 10.4 g. of the desired product as yellow crystals, mp. 132°-134° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[C:13]([Br:22])[C:12]=1[NH2:23])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[ClH:24]>>[ClH:24].[CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[C:13]([Br:22])[C:12]=1[NH2:23])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1
Agent: Cl
Product: CCN(Cc1cc(C(=O)O)cc(Br)c1N)C1CCCCC1

Procedure:
13 gm of N-ethyl-2-amino-3-bromo-5-carbethoxy-N-cyclohexyl-benzylamine were boiled with 100 ml of 6 N hydrochloric acid for 1 hour. Subsequently, the supernatant liquid was decanted from the oily phase which had formed at the bottom, and the solution was evaporated to dryness. The residue was recrystallized from methanol, yielding N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine hydrochloride, m.p. 227-229° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27]C(=O)C)[C@H:17]([C:31]([OH:33])=[O:32])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([C:31]([OH:33])=[O:32])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@H]1[C@H](C(=O)O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@@H](C(=O)O)[C@@H]2O
Temperature: 50 °C
Yield: 69.1 %

Procedure:
A solution of 784.4 mg (1.75 mmol) of 6, 5% aqueous KOH in MeOH (7 mL) was stirred and heated at 50° C. for 3 h. Reaction was cooled to rt, poured into H2O (50 mL), adjusted to pH 1 with 10% aqueous HCl, and extracted with EtOAc (3×, 100 mL). Combined organic extracts were washed with H2O (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×17 cm column of silica gel using EtOH/EtOAc (10:90) gave 491.5 mg (69%) of 7 as a white foam. Data for 7: TLC, T-4, Rf0.63. 1H NMR (500 MHz, CDCl3) δ 0.86 (2, 3H, H-18), 3.94 (d, 1H, J=8.3 Hz, H-17α), 5.04 (s, 2H, benzylic), 6.73 (d, 1H, J=2.2 Hz, H-4), 6.80 (dd, 1H, J=8.7, 2.2 Hz, H-2), 7.21 (d, 1H, J=8.7 Hz, H-1), 7.32-7.45 (m, 5H, Ar—H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24]Br)[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[CH2:24][N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2ccc(C(F)(F)F)n2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (632 mg, 4.65 mmol) and 2-benzyloxy-4-bromomethyl-1-nitrobenzene (1.0 g, 3.1 mmol) in DMF (8 mL) is added K2CO3 (642 mg, 4.65 mmol) and the mixture is stirred at RT for 48 h. The mixture is partitioned between EtOAc and water and the organic phase is washed with brine and dried over MgSO4. The solvent is removed under reduced pressure to give the title compound: (M+1)+=378.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])C.[H-].[Na+]>C1COCC1>[CH2:23]([O:22][C:20]([C:19]1[C:18](=[O:25])[NH:17][C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[C:4]=1[OH:5])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)Nc1scc(-c2ccccc2)c1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2c(-c3ccccc3)csc2[nH]c1=O
Reaction time: 1 h

Procedure:
2-(2-Ethoxycarbonyl-acetylamino)-4-phenyl-thiophene-3-carboxylic acid ethyl ester (5.0 g, 13.8 mmol) and sodium hydride (1.1 g, 27.7 mmol) in anhydrous THF (120 ml) were refluxed for 6 hr under nitrogen. On cooling, solvents were removed in vacuo and the residue suspended in water (100 ml). The mixture was acidified by addition of concentrated hydrochloric acid (5 ml) and stirred for 1 hr. The precipitate was filtered and dried, then recrystallised from ethanol to give 4-hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester as a pale yellow solid. Yield=2.59 g (63.3%).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].C1COCC1>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:30]=[C:25]([C:11]2[CH:10]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:39])=[O:2])[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[N:12]=2)[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 2-[2-(3,5-bis-trifluoromethyl-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pentanoic acid methyl ester (80 mg, 0.14 mmol) in NaOH (1N, 1 mL) and THF (4 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature, acidified with 10% citric acid, extracted with CH2Cl2 (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (5-30% ethyl acetate in CH2Cl2) to give the product as a white solid (60 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 2H), 8.23 (d, J=7.91 Hz, 2H), 7.96 (s, 1H), 7.72-7.85 (m, 4H), 3.89 (t, J=7.91 Hz, 1H), 2.08-2.22 (m, 1H), 1.75-1.85 (m, 1H), 1.55-1.68 (m, 1H), 0.99 (d, J=6.40 Hz, 6H). MS m/e 550.2 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:30])([C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:30])([F:13])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:23])([F:24])[F:25])=[CH:34][CH:33]=1
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCOc1ccc(Br)cc1

Procedure:
A solution of diethyl azodicarboxylate (3.5 g, 20 mmol) in dry diethyl ether (20 cm3) was added dropwise into a stirred solution of 5,5,6,6,7,7,8,8,8-nonafluorooctan-1-ol (Preparation 2A, 5.8 g, 20 mmol), 4-bromophenol (3.5 g, 20 mmol) and triphenylphosphine (5.3 g, 20 mmol) in dry diethyl ether (50 cm3) at room temperature.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)=[O:19]
Reactant: Cc1cccc(N)n1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: Cc1cccc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 33 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-6-methyl-pyridine with a yield of 33% of theory.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[CH2:8]([NH:7][C:4]1[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[NH:6][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(OCC)N(C)C
Reactant: N#Cc1c(NCc2ccccc2)n[nH]c1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(NCc2ccccc2)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a suspension of 74.3 g (348 mmol) of 5-amino-3-benzylamino-1H-pyrazole-4-carbonitrile in 1.0 liter of toluene is boiled under reflux for 2 hours with 70.1 ml (95%; 409 mmol) of N,N-dimethylformamide diethyl acetal. Cooling to RT, filtration with suction and washing with diethyl ether yield N′-(3-benzylamino-4-cyano-1H-pyrazol-5-yl)-N,N-dimethyl-formamidine; m.p. 197-200° C.; TLC: Rf=0.50 (ethyl acetate).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:30][C:31]1[C:32]([C:38]([OH:40])=O)=[N:33][C:34]([Br:37])=[CH:35][N:36]=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:38]([NH:50][NH:49][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])=[O:40])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.5 %

Procedure:
TBTU (22.09 g, 68.80 mmol) and triethylamine (4.642 g, 6.394 mL, 45.87 mmol) were added to a suspension of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10 g, 45.87 mmol) and benzohydrazide (7.494 g, 55.04 mmol) in DMF (100.0 mL) and the resulting solution stirred at ambient temperature for 48 hours and then poured into water (400 mL) with vigorous stirring. This was allowed to stir for 30 minutes, filtered and washed with water. The moist solid was dissolved in hot EtOAc, dried (MgSO4), filtered and concentrated in vacuo and the resultant solid dried under vacuum to give the desired product (11.34 g, 73% Yield). 1H NMR (400.0 MHz, DMSO) d 7.51 (2H, m), 7.61 (1H, m), 7.69 (2H, br s), 7.92 (2H, m), 8.44 (1H, s), 10.48 (1H, br s), 10.54 (1H, br s) ppm; MS (ES+) 338.01
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3ccccc3)CCN4)cc2)CC1
Yield: 32 %

Procedure:
4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as a yellow solid (32% yield). M.p. 180-181° C., LCMS: m/z=428.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.33-2.52 (m, 4H), 3.38-3.43 (m, 2H), 3.45-3.55 (m, 2H), 3.46-3.50 (m, 2H), 3.58-3.62 (m, 2H), 3.64-3.82 (m, 2H), 4.48 (s, 2H), 5.29 (s, 1H), 6.83 (s, 1H), 7.27-7.39 (m, 9H), 7.69 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]=[C:37]=[O:38])=[CH:31][CH:30]=1>CN(C=O)C.O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)NCc3ccc(F)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg) in DMF (3.5 ml) were added sequentially triethylamine (62 μl) and 1-fluoro-4-(isocyanatomethyl)benzene (58.4 μl) and the mixture was stirred at 60° C. for 17 h. The suspension was cooled to room temperature, then diluted with water and extracted twice with EtOAc. The combined organic phases were washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified was purified by flash chromatography (silica gel; gradient: EtOAc/heptane) to afford (S)-tert-butyl 2-(4-(3-(4-fluorobenzyl)ureido)phenyl)morpholine-4-carboxylate (164 mg, quant.) as a white solid. MS (ISP): 374.0 ([M+H—C4H8]+).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([C:43]1[CH:48]=CC=C[CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:12][CH2:13][C@H:14]1[O:21][C@@H:18]([S:19][CH3:20])[C@H:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:16]([O:32][CH2:33][CH:34]=[CH2:35])[C@H:15]1[OH:36])(C)(C)C.[C:49](OC(=O)C)(=[O:51])[CH3:50].N1C=CC=C[CH:57]=1>>[Si:11]([O:12][CH2:13][C@H:14]1[O:21][C@@H:18]([S:19][CH3:20])[C@H:17]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C@@H:16]([O:32][CH2:33][CH:34]=[CH2:35])[C@H:15]1[O:36][C:49](=[O:51])[CH3:50])([C:43]([CH3:44])([CH3:57])[CH3:48])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCO[C@H]1[C@@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)c2ccccc2C(C)(C)C)O[C@@H](SC)[C@@H]1OCc1ccc(OC)cc1
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: C=CCO[C@H]1[C@@H](OC(C)=O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@@H](SC)[C@@H]1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
To a solution of methyl 6-O-(t-butyldiphenylsilyl)-2-O-(4-methoxybenzyl)-3-O-allyl-1-thio-β-D-galactopyranosidee (30) (1.4 g, 2.3 mmol) in pyridine (30 mL) was added acetic anhydride (20 g, 196 mmol) in one portion. The resulting solution was left to stir at room temperature for 72 h. The reaction contents were then evaporated to dryness and there residue was dissolved in dichloromethane (200 mL). The solution was washed with potassium hydrogen sulphate solution (1 M×2×50 mL) followed by saturated sodium chloride (150 mL), dried over MgSO4 and evaporated to dryness. The crude residue was purified by chromatography using dichloromethane as the mobile phase to give Methyl 6-O-(t-butyldiphenylsilyl)-2-O-(4-methoxybenzyl)-3-O-allyl-4-O-acetyl-1-thio-β-D-galactopyranoside (31)(750 mg, 48%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>COC(OC)N(C)C>[CH3:3][N:11]([CH:16]=[C:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:12]1)[CH3:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1
Agent: COC(OC)N(C)C
Product: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Temperature: 25 °C

Procedure:
A solution of 1-(2-Methyl-5-nitro-phenyl)-piperidin-4-one [100 mg, 0.426 mmol] in N,N-Dimethylformamide dimethyl acetal (DMA.DMF) [1 ml] was heated to reflux for 12 hrs. After cooling to room temperature, reaction mixture was concentrated under vacuum. The dark brown crude product obtained was further purified by silica gel chromatography using 30-60% ethyl acetate/hexane as eluent to obtain pure desired product i.e., 3-Dimethylaminomethylene-1-(2-methyl-5-nitro-phenyl)-piperidin-4-one [4] as orange solid [Yield: 76.2 mg, 62.02%]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH3:38][O:39][CH2:40][CH2:41][C:42]1[C:47]([C:48](O)=[O:49])=[CH:46][N:45]=[C:44]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[N:43]=1.COC(=O)CC(=O)CCOC>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:48]([C:47]2[C:42]([CH2:41][CH2:40][O:39][CH3:38])=[N:43][C:44]([C:51]3[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:56]=3)=[N:45][CH:46]=2)=[O:49])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COCCC(=O)CC(=O)OC
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[CH3:19][N:20]([C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)[C:16]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([C:8]([F:9])([F:11])[F:10])[C:12]([F:14])([F:13])[F:15])[C:2]=1[CH3:1])=[O:18]
Reactant: Cc1c(C(=O)O)cnn1C(C(F)(F)F)C(F)(F)F
Reactant: CNc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N(C)c2ccnnc2)cnn1C(C(F)(F)F)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
A mixture of 300 mg 5-methyl-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyrazole-4-carboxylic acid, 127 mg N-methylpyridazin-4-amine, 710 mg O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate [HATU] and 220 mg triethylamine in 30 ml THF was stirred at 20-25° C. for about 24 h, then evaporated. The residue was taken up in 21 ml CH2Cl2, washed with 3×14 ml water, dried over Na2SO4, then evaporated. Purification by flash chromatography (CH2Cl2/MeOH) gave 130 mg of the title compound (90% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=CC=[CH:4][C:3]=1NN.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH2:31][CH2:32]O)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([C:31]3[CH:32]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: NNc1ccccc1Cl
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc(Cl)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from 2-chlorophenylhydrazine and compound C as described for compound 35. M.p. 140°-141° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:28]1.O>C(Cl)(Cl)Cl>[Br:1][C:28]1[O:27][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]=1[CH:36]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(OC(C)(C)C)c1coc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(Br)oc2ccccc12
Yield: 45.5 %

Procedure:
N-Bromosuccinimide (265 mg, 1.48 mmol) and 1,1′-Azobis(cyanocyclohexane) (20 mg, 0.06 mmol) were added to a solution of ethyl 2-(1-benzofuran-3-yl)-2-(tert-butoxy)acetate (20b) (340 mg, 1.23 mmol) in chloroform (5 mL). The reaction mixture was refluxed for 5 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/05) to provide ethyl 2-(2-bromo-1-benzofuran-3-yl)-2-(tert-butoxy)acetate (20c) (200 mg, 0.56 mmol, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)#[N:29].C(N1C2C(=CC(Cl)=CC=2)CC(NC(=O)OC(C)(C)C)C1)C1C=CC=CC=1>>[C:28]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[CH2:11][CH:12]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:13]1)#[N:29]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=S(=O)(NC1CNc2ccc(-c3ccc(F)cc3)cc2C1)c1ccccc1
Agent: CC(C)(C)OC(=O)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Product: N#Cc1cccc(CN2CC(NS(=O)(=O)c3ccccc3)Cc3cc(-c4ccc(F)cc4)ccc32)c1

Procedure:
Compound 113B was prepared from 113A and 3-cyanobenzaldehyde by procedures analogous to those described in 22A. HPLC: 96% at 6.25 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 498 [M+1]+.