Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylene chloride (700 μL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (35 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (40.4 mg, 64%) as a pink solid: mp 200-202° C.; EI-HRMS m/e calcd for C18H21FN2O3S2 (M+) 396.0978, found 396.0976.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccnc(C#C[Si](C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 2-chloro-4-methoxypyrimidine (2.60 g, 17.99 mmol), ethynyltrimethylsilane (3.05 mL, 21.58 mmol), tetrahydrofuran (24 mL) and triethylamine (12.53 mL, 89.90 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then copper(I) iodide (0.14 g, 0.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.72 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath at 90° C. After 16 hours, the mixture was filtered and the solvent was removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated, washed with 4% aqueous sodium hydrogencarbonate solution, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (9:1 hexane/ethyl acetate) gave the title compound (2.85 g, 77%) as an oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([OH:19])[CH:13]2[OH:20])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si:23]([C:26]#N)([CH3:25])[CH3:24].C1N2C[CH2:35][N:30](CC2)C1>O>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15]([C:35]#[N:30])([O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]([O:19][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]2[O:20][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC2(CC(=O)N2OCc2ccccc2)C(O)C1O
Reactant: C1CN2CCN1CC2
Reactant: C[Si](C)(C)C#N
Solvent: O
Product: C[Si](C)(C)OC1C(O[Si](C)(C)C)C2(C=CC1(C#N)O[Si](C)(C)C)CC(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 638.1 %

Procedure:
To a mixture of rac-(4R,5S,6S)-1-benzyloxy-5,6-dihydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (2) (44 mg, 0.152 mmol) and trimethylsilyl cyanide (186 μl, 1.368 mmol) at room temperature (cooled with water bath) was slowly added DABCO (2 mg, 0.015 mmol). The mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:1) to give rac-(4R,5S,6S,7S)-1-benzyloxy-7-cyano-5,6,7-tris(trimethylsilyloxy)-1-azaspiro[3.5]nona-8-ene-2-one (8) as a yellow solid (51 mg, 62%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(=O)c1cc(N)c(F)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Acetyl chloride (3.12 g, 40 mmol) was added to a 0° C. solution of ethyl 2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9 g, 40 mmol) and Et3N (8.1 g, 80 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure to give ethyl 2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate (10.7 g, 100% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J=6.0 Hz, 1 H), 7.37 (brs, 1 H), 6.95 (d, J=8.7 Hz, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 2.50 (s, 3H), 2.10 (s, 3 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13].CO>>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Solvent: CO
Product: Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 130 °C

Procedure:
2-chloro-4-iodo-5-(trifluoromethyl)pyridine was dissolved in 7 M Ammonia/Methanol. It was heated in a Biotage Initiator microwave synthesizer at 130° C. for 1 h. A mixture of the 2- and 4-substituted products was obtained. The solvent was removed and the residue was purified by silica gel chromatography (DCM/MeOH) gradient. The pure title compound was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2C=O)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].COP([C:27](=[N+]=[N-])[C:28](=O)C)(=O)OC.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:11][C:12]([C:27]#[CH:28])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=Cc1ccccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (1.82 g, 6.0 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (2.3 g, 12.1 mmol) in methanol (30 mL), was added potassium carbonate (4.18 g, 30.3 mmol), and stirred for 1 h at rt. The reaction mixture was concentrated and the residue was purified by FC (PE/EtOAc 20:1) to afford the title compound as a colorless oil.
Reaction SMILES: O[N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[H][H].CC1NC(=[O:19])CCC1>[Pd]>[NH2:2][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:9])=[O:19]
Reactant: [H][H]
Reactant: CC1CCCC(=O)N1
Reactant: CC1CCCC(=O)N1O
Agent: [Pd]
Product: CC(N)CCCC(=O)O

Procedure:
5-Aminohexanoic Acid was prepared by combining 0.5 g 2-methylcyclopentanone and 9.5 ml 2 N NaOH in sufficient ethanol to give a homogeneous solution. The mixture was cooled to 0° C., 0.9 g of benzene sulfohydroxamic acid (C6H5SO2NHOH) was added, and the mixture stored overnight in the refrigerator. Thereafter the mixture was concentrated in vacuo and extracted with ether. The post-extraction residue is brought to between pH 5-6 with 2 N HCl extracted with chloroform to give an oil bp. 70°-80° C. (4 mm), 7-8% yield. This product N-hydroxy-6-methyl-2-piperidone, is reduced with hydrogen over 10% palladium-charcoal to a lactam, 6-methyl-2-piperidone (mp. 79°-80° C.). The lactam is hydrolyzed with aqueous Ba(OH)2 to yield 5-amino-hexanoic acid. ##STR7##
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C@@:17]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]2=3)[C:14]([OH:16])=[O:15])[N:6]=1.[C:36](O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH3:36][O:15][C:14](=[O:16])[C@@H:13]([O:12][C:7]1[N:6]=[C:5]([CH3:4])[CH:10]=[C:9]([CH3:11])[N:8]=1)[C@@:17]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](Oc1nc(C)cc(C)n1)[C@@]1(c2ccccc2)NCC(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Sodium methylate (10.14 g, 186 mmol) is added at 0° C. to a solution of (±)-(1S*, 9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (5.0 g, 12 mmol, Example 49) in methanol (250 ml). The solution is stirred at rt for 3 h, poured into a solution of citric acid (12.6 g, mono hydrate) in water (600 ml) and extracted three times with EA. The organic phase is washed with brine, dried over MgSO4 and evaporated to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid methyl ester (5.04 g) as a white foam. LC-MS1: tR=0.94 min, [M+1]+=447.07.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](O)[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:34])=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([Cl:34])[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1nc(O)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Temperature: 120 °C

Procedure:
To a suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (10.0 g) in phosphoryl chloride (25.7 mL) was added N,N-dimethylaniline (2.6 mL) and the mixture was heated at 120° C. for 6 hours. After cooling to room temperature the mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogencarbonate aqueous solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with diisopropylether to afford 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (8.0 g)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:26]3[C:25]([F:24])=[CH:30][C:29]([F:31])=[CH:28][N:27]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ncc(F)cc3F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 3,5-difluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: O.[Na].[CH2:3]([N:10]1[CH2:16][C:15]2(Cl)[C:17]([O:20][CH3:21])([O:18][CH3:19])[C:12](Cl)([C:13](Cl)=[C:14]2Cl)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C)(C)C>O1CCOCC1>[CH2:3]([N:10]1[CH2:16][CH:15]2[C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:12]([CH:13]=[CH:14]2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC1(OC)C2(Cl)CN(Cc3ccccc3)CC1(Cl)C(Cl)=C2Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: O
Product: COC1(OC)C2C=CC1CN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a 3 L 3NRB equipped with a thermometer, addition funnel and water condenser was added dioxane (1000 mL) then sodium (44.7 g, 1.94 mol). Upon heating under reflux (T ˜100° C.), the sodium became a dispersed immiscible liquid. While maintaining this gentle reflux, a solution of 3-benzyl-1,5,6,7-tetrachloro-8,8-dimethoxy-3-aza-bicyclo[3.2.1]oct-6-ene (52.5 g, 0.132 mol), t-butanol (160 mL, 1.67 mol) and dioxane (150 mL) was added dropwise via the addition funnel over 30 min and heat continued overnight. Upon cooling to 70° C., the residual unreacted sodium was quenched with MeOH (150 mL) then water (1 L). The dioxane and MeOH were then removed in vacuo. The product was extracted from the aqueous layer with EtOAc (3×300 mL), washed with saturated aqueous NaCl solution (1×300 mL), dried over Na2SO4, filtered and concentrated to yield a dark brown oil (29.2 g, 85%). (TLC 40% EtOAc/hexanes Rf 0.35); 1H NMR (400 MHz, CDCl3) δ 7.28–7.20 (5H), 6.01 (t, J=1.6 Hz, 2H), 3.65 (s, 2H), 3.23 (s, 3H), 3.17 (s, 3H), 2.63 (s, 2H), 2.57 (AB d, J=10.1 Hz, 2H), 2.44 (AB d, J=10.1 Hz, 2H); GCMS m/z 259 (M)+; APCI MS m/z 260.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>CS(C)=O.O.O1CCCC1>[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:31])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Agent: CS(=O)(=O)O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
Combine (±)-6-[2-methyl-4-(3-phenyl-piperidinylmethyl)-phenoxy]-nicotinonitrile (compound of example 365, step 2) (0.878 g, 2.29 mmol) and potassium carbonate (0.159 g, 1.15 mmol) in dimethylsulfoxide (11.0 mL,). Treat the mixture with 30% hydrogen peroxide solution (aq) (0.77 mL, 6.79 mmol), and stir at ambient temperature. After 4 h, dilute the reaction mixture with water (25 mL) and extract with ethyl acetate (3×30 mL). Wash combined ethyl acetate extracts with brine, dry over anhydrous magnesium sulfate, filter, and concentrate. Crude product is pure by 1H NMR and reverse-phase HPLC. Dissolve product in tetrahydrofuran (12 mL) and treat with methanesulfonic acid (0.148 mL, 2.28 mmol). White precipitate forms and turns oily within 3 minutes. Dissolve residue in tetrahydrofuran and concentrate. Product purity is 82% by reverse-phase HPLC. Purify residue by reverse-phase HPLC. Concentrate fractions containing pure product, recrystallize from methanol:diethyl ether (2:5, 16 mL), and isolate product by vacuum filtration to provide 0.0941 g (10%) of the title compound as white/tan crystals: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.62 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.57-7.54 (m, 1H), 7.48 (dd, 1H, J=1.5, 7.8 Hz), 7.43-7.38 (m, 2H), 7.37-7.30 (m, 3H), 7.23 (d, 1H, J=8.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 4.45-4.36 (m, 2H), 3.63 (t, 2H, J=14.6 Hz), 3.22 (t, 1H, J=12.2 Hz), 3.17-3.07 (m, 2H), 2.23 (s, 3H), 2.20-2.13 (m, 1H), 2.12-2.92 (m, 2H), 1.86 (dq, 1H, J=3.9, 12.2 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][OH:9])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:19][C:20](OC1C=CC([N+]([O-])=O)=CC=1)=[O:21].[F:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1.[ClH:46].CCOCC>C(Cl)Cl>[ClH:19].[ClH:46].[F:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:20]([O:9][CH2:8][CH:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCOC(CO)C1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCOC(COC(=O)N2CCN(Cc3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
(4-Methyl-morpholin-2-yl)-methanol (1.05 g, 8.0 mmol) and DIPEA (2.79 ml, 16.0 mmol were dissolved in DCM (80 mL) and the reaction mixture was cooled to 0° C. and p-nitrophenyl chloroformate (3.23 g, 16.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was divided into 4 batches and concentrated in vacuo. One portion was dissolved in DMF (20 mL) and 1-(4-fluoro-benzyl)-piperazine (0.39 g, 2 mmol) added and the resulting reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was taken up in DCM (30 mL). The organic layer was washed with 1.0M Na2CO3 solution (3×30 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in DCM, residue dry loaded). The solvents were removed in vacuo and the residue was dissolved in DCM (50 mL), filtered and 2M HCl in Et2O (2 mL, 4 mmol) added. The solvent was removed in vacuo and the residue was dried in a vacuum oven overnight to give the (4-methylmorpholin-2-yl)methyl 4-(4-fluorobenzyl)piperazine-1-carboxylate dihydrochloride salt (0.375 g, 44%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 140 °C
Yield: 69 %

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), 3-methoxybenzaldehyde (0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 20 hours. The mixture was diluted with EtOAc (300 mL), washed with water (3×75 mL), then brine (75 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel (40 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide the title compound (69%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.82-7.70 (m, 2H), 7.43 (t, J=7.98 Hz, 1H), 7.13 (dd, J=8.19, 2.46 Hz, 1H), 6.76 (d, J=2.19 Hz, 1H), 6.55 (d, J=2.19 Hz, 1H), 3.92-3.82 (m, 9H); MS (APCI) m/z 313 [C17H16N2O4+H]+.
Reaction SMILES: I[C:2]1[C:3]([CH2:8][N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])[C:10](=[O:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:10]([N:9]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH2:8]1)(=[O:12])[CH3:11]
Reactant: C=Cc1ccccc1N(Cc1ncccc1I)C(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2ncccc2C=Cc2ccccc21
Yield: 55 %

Procedure:
Compound 51D (3.1 mg, 55%) was prepared from 51C (8.5 mg, 0.0225 mmol) by a route analogous to that used for the preparation of 1D. HPLC Rt=1.503 min; LCMS Found: (M+H)+=251.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH:12]=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(O)cc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OS(C)(=O)=O)cc2o1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(6-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (116 mg, 0.407 mmol) and Et3N (0.20 mL) in CH2Cl2 (5.0 mL) at 0° C. is added methanesulfonic chloride (70 mg, 0.610 mmol). The resulting mixture is stirred for 30 min and quenched with MeOH (1.0 mL). The mixture is purified on column chromatography (25% EtOAc/Hex) to afford the title compound (185 mg, 93%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)C(O)=O.CC[N:14]([CH2:17]C)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:26])=CC=1.CCOCC>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:14][C:17](=[O:26])[O:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2o1
Temperature: 70 °C
Yield: 37.2 %

Procedure:
Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) is dissolved in THF (28 mL) and Et3N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) is added. This is heated at 70° C. overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 472 mg crude intermediate. Trituration with ether yields 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCNCCCSc1nnnn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CCCSc1nnnn1C)C(=O)C1CCCCC1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
1-Methyl-5-[3-(N-ethylamino)propylthio]-1,2,3,4-tetrazole (1 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring cyclohexanecarboxylic acid chloride (0.9 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-[3-(N-ethyl-N-cyclohexylcarbonylamino)propylthio]-1,2,3,4-tetrazole (0.9 g), colorless liquid, nD23.5 =1.5267.