Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:30](=[NH:31])[C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: N#Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 4-fluorobenzonitrile (20.00 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (22.67 g, 75.06 mmol) in a yield of 68%.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(CC)CC.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:39]([NH:13][C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=C=NCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-amine hydrobromide salt, 8, and Et3N (0.42 mL, 3 mmol) in 10 mL DCM is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[CH3:25][N:26]([CH2:34][CH2:35][CH:36]=[O:37])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>O1CCCC1>[OH:37][CH:36]([C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)[CH2:35][CH2:34][N:26]([CH3:25])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(CCC(O)c1ncccn1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To 2-(tributylstannyl)pyrimidine (690 mg, 1.87 mmol) dissolved in dry tetrahydrofuran (10 ml) cooled to −78° C. was added 2.4M n-butyl lithium in hexanes (0.8 ml, 1.87 mmol) under nitrogen. After stirring for a further 0.5 h, methyl(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester in dry tetrahydrofuran (10 ml) was added rapidly at −78° C. The reaction mixture was allowed to warm to ambient, treated with aqueous saturated ammonium chloride solution and extracted with ethyl acetate which was washed with brine and dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue eluted down a flash chromatography column using initially 10% ethyl acetate/dichloromethane, then 10% methanol/dichloromethane to give 260 mg (43%) of the subtitle compound as a viscous yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.C[OH:20]>O.[Fe]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:20])[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(-n2ccnc2)cc1

Procedure:
A mixture of 1-[4-(1H-imidazol-1-yl)phenyl]-2-nitropropene prepared above, iron powder (94.7 grams), and hydrated iron (III) chloride (1.2 grams) in 50 ml of methanol and 170 ml of water is heated to reflux and treated dropwise with 85 ml of 12N hydrochloric acid over four hours. After heating under reflux for one additional hour, the reaction mixture is cooled, and filtered. The filtrate is made basic with 40% ammonium hydroxide solution and the entire mixture is extracted thoroughly with ethyl acetate. The ethyl acetate is treated with charcoal, dried (magnesium sulfate) and concentrated on the rotary evaporator to give a dark yellow oil. This material is chromatographed on a Waters Prep 500A, using silica gel and eluting with 2% methanol in chloroform. The main fraction contains 1-[-4-(1H-imidazol-1-yl)-phenyl]-2-propanone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])(O)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>C(#N)C.O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8])=[O:20]
Reactant: Cc1cccc(O)c1N
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(O)c1NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
2-Amino-m-cresol (4.9 g, 40 mmol) was dissolved in a mixture of acetonitrile (90 mL) and water (80 mL) containing NaHCO3 (6.7 g, 80 mmol) with vigorous stirring. 3-Bromo-4-chloro-benzoyl chloride (10.1 g, 40 mmol, Step 2A) was added in several portions and the mixture was stirred at room temperature for 3 hrs. The resulting precipitates were filtered, washed with water and tert-butyl methyl ether, then dried to yield 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g). MS (M+H)+: 339.7/341.7; tR=2.36 min. (method 1)
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][C:7]([CH3:9])=[N:6][NH:5][C:4]1=[O:10].[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO.O>[CH3:9][C:7]1[CH2:8][N:3]([N:2]=[CH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:10])[NH:5][N:6]=1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=NNC(=O)N(N=Cc2cccnc2)C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 164 g of 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride in 500 ml methanol a 50% NaOH solution is added until a pH of 6 is reached. Now 486 g of a solution containing 22% 3-pyridinaldehyde in water is added maintaining a temperature below 70° C. After the addition is completed the reaction mixture is kept at 65° C. for two hours. Then the suspension is cooled to about 5° C., filtered and dried to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:25]1[CH:26]=[C:27]2[C:40](=[CH:41][CH:42]=1)[CH2:39][C@:29]1([C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]1=[O:38])[CH2:28]2.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[C:21][C:25]3[CH:26]=[C:27]4[C:40](=[CH:41][CH:42]=3)[CH2:39][C@:29]3([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]3=[O:38])[CH2:28]4)[C:17](=[O:22])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Reactant: C#CCN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1CC#Cc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 80 °C

Procedure:
A suspension of (8R)-8-(3,5-difluorophenyl)-8-methyl-9-prop-2-yn-1-yl-6,9-diazaspiro[4.5]decan-10-one from Step A (25 mg, 0.079 mmol), (R)-5-bromo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (25 mg, 0.079 mmol described in intermediate 12 tetrakis(triphenylphosphine)palladium(0) (4.5 mg, 0.0039 mmol), copper(I)iodide (3.0 mg, 0.016 mmol), and triethylamine (0.022 mL, 0.16 mmol) in degassed DMF (0.5 ml) was heated at 80° C. for 16 hour. The mixture was filtered and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The desired fractions were concentrated in vacuo to yield the title compound. MS: m/z=553 (M+1). HRMS: m/z=553.2400; calculated m/z=553.2410 for C33H31F2N4O2.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11].C(N(CC)CC)C.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[OH:11][C:5]1[CH:6]=[C:7]([NH:10][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)N2CCOCC2)cc1O
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A solution of 4-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6 mmol) and triethylamine (0.8 mL, 6 mmol) in CHCl3 (25 mL) was treated with morpholine-4-carbonyl chloride (4.2 mL, 48 mmol) and stirred at reflux for 72 h. After cooling to room temperature, the solution was washed with 5% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated to an orange solid. The crude solid was triturated with CHCl3 (10 mL) to afford the product as an off-white solid (0.25 g, 15%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OCC)=O.Cl.[CH3:31][NH:32][O:33][CH3:34]>ClCCl>[CH3:34][O:33][N:32]([CH3:31])[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:12]
Reactant: CNOC
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 106.3 %

Procedure:
To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid (27.8 g, 120.0 mmol) in dichloromethane (150 mL) at −40° C. was added a solution of 1-methylpiperidine (18.4 mL, 151.5 mmol) in dichloromethane (40 mL) over 20 min. Ethyl chloroformate (13.9 mL, 145.4 mmol) in dichloromethane (40 mL) was then added over 30 min and the reaction mixture was stirred at −40° C. for 2.5 h. A solution of N,O-dimethylhydroxylamine hydrochloride (14.2 g, 145.4 mmol) and 1-methylpiperidine (18.4 mL, 151.5 mmol) in dichloromethane (90 mL) was added over 45 min, and the reaction mixture was allowed to slowly warm to ambient temperature. It was stirred for 18 h, and then washed with water (100 mL), 1% hydrochloric acid (2×100 mL), and saturated aqueous sodium bicarbonate (100 mL). The organic layer was then dried with magnesium sulfate and concentrated in vacuo to afford the desired title compound (35.0 g, 106%) as a thick oil. 1H NMR (400 MHz, DMSO-d6): δ 6.94 (d, J=8 Hz, 1H), 4.35-4.25 (m, 1H), 3.68 (s, 3H), 3.05 (s, 3H), 1.52-1.36 (m, 2H), 1.32 (s, 9H), 1.30-1.14 (m, 4H), 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:29][CH3:30])[C:8]2[C:9]([CH2:16][NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=3)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[CH3:35].O>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:41]=[C:36]([CH:34]([N:17]([CH2:16][C:9]2[C:8]([N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:29][CH3:30])=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[N:10]=2)[C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=2)[CH3:35])[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (168 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL) stirred under ice cooling was added with sodium hydride (50% in oil, 24 mg, 1.4 mmol), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to −78° C., added with a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (250 mg, 0.78 mmol) obtained in Step 2 in N,N-dimethylformamide (0.5 mL), and the mixture was stirred for 12 hours with warming to room temperature. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (88.1 mg, 34%), as pale yellow oil.
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccccc1

Procedure:
A mixture of methyl 17β-benzoyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and methanol is heated at reflux for about 5 hours. Acidification followed by conventional workup yields title compound.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>>[NH2:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Product: C=CCCCCCCCCCN
Yield: 66 %

Procedure:
Compound XXXI was prepared as described in Scheme I from 10-undecen-1-ol, 1, by a three step procedure in an overall yield of 31%. Alkylation of phthalimide with alkanol, 1, under Mitsunobu conditions, followed by reaction with hydrazine gave 1-aminoundec-10-ene, 2, in 66% yield. The amine was derivatized with O-acetylsalicyloyl chloride and the resulting alkene, 3, was oxidized to the acid using potassium permanganate. Removal of the acetate, followed by acid precipitation provided compound XXXI in 47% yield based on amine 2. Delivery Systems
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:27]=[C:28]([CH2:30][OH:31])[N:29]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[OH:31][CH2:30][C:28]1[N:29]=[C:3]2[C:2]([N:35]3[CH2:36][CH2:37][NH:32][C:33](=[O:38])[CH2:34]3)=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[N:12][CH:13]=3)[N:4]2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c4nc(CO)cn34)cn2)CC1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCNC(=O)C4)c4nc(CO)cn34)cn2)CC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of compound 87c (90.0 mg, 0.202 mmol), piperazin-2-one (40.5 mg, 0.405 mmol) and K2CO3 (55.9 mg, 0.405 mmol) in 2.5 mL of DMF was stirred at 130° C. for 6 h under an Argon atmosphere. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with saturated NH4Cl (20 mL), water (20 mL), brine (10 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (0-7 MeOH/DCM) to give compound 88a as an off white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.34 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.23 (br. s., 1H), 4.89 (s, 2H), 4.80 (d, J=5.4 Hz, 2H), 4.55 (t, J=5.3 Hz, 2H), 3.55-3.69 (m, 10H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C25H32N8O4, 509.2 (M+H). found 509.2.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
To a stirred solution of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (290 mg, 0.979 mmol) from Step 4 of this Example in DCM (25 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (582 mg, 2.36 mmol), and the mixture was stirred at 0° C. for 2.5 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (305 mg, 100%) as a solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.84-7.94 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.30 (dd, J=4.8, 8.0 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][N:2]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Reaction time: 0.75 h
Yield: 97.2 %

Procedure:
To a solution of N-methyl-4-bromophenylsulfonamide (2.5 g, 10 mmol) in DMF (20 mL) at room temperature was added in portions NaH (264 rag, 11 mmol). The mixture was stirred for 45 minutes and then p-methoxybenzylchloride (1.49 mL, 11 mmol) was added dropwise. The mixture was stirred for 1 hour, quenched with water and the precipitate which formed was collected by filtration and dried in vacuo at 60° C. to afford 3.6 g (97%) of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][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][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:67])(=O)=O)CCCCCCCCCCCCCCC>>[I:67][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][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][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)Oc1ccon1

Procedure:
3-(3-Chloropropylsulfonylamino)-2-(3-isoxazolyloxy)-1-octadecylcarbamoyloxypropane III j2 is allowed to react and worked up by the same procedure as described in (5). m.p. 69°-71.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[C:21]([CH3:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH3:22]
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 9 h
Yield: 58 %

Procedure:
A mixture of 774.3 mg (4.05 mmoles) of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylpropylamine (prepared according to J. Org. Chem. 2004, 69, 1959-1966) and 600 mg (3.68 mmoles) of 4,6-dichloro-5-methyl-pyrimidine in 6 ml of dimethylacetamide and 1.2 ml of diisopropylethylamine is taken to 120° C. for 9 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on Alumina then on silica eluting with a gradient of 100% heptane to 100% ethyl acetate. 680 mg (Yield=58%) of expected product is obtained.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[F:9][CH:10]([F:19])[O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:1])[CH:17]=1
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(OC(F)F)cc1I
Reaction time: 16 h
Yield: 42 %

Procedure:
To a suspension of N-iodosuccinimide (1.12 g, 0.005 mol) in acetic acid (15.0 mL) was added 4-(difluoromethoxy)phenol (0.8 g, 0.005 mol) under nitrogen. Sulfuric acid (0.147 g, 0.0015 mol) was added and the resulting dark brown suspension was stirred at room temperature for 4 hours before the addition of N-iodosuccinimide (0.6 g, 0.0025 mol). The mixture was stirred for 16 hours before diluting with citric acid (1.0 M aqueous solution, 20.0 mL) and water (20.0 mL). The aqueous layer was extracted with dichloromethane (2×30.0 mL). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford a dark purple oil. This was concentrated in vacuo from toluene (3×20.0 mL) to afford a brown oil. The aqueous layer was concentrated in vacuo. Both organic and aqueous crude residues were purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 1:1, by volume) to afford the title compound as a yellow oil, 0.604 g, 42% yield.