Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:21])=[C:7]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:33][C:34]([NH2:41])([CH3:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CCOCC>[C:1]([C:5]1[C:6]([OH:21])=[C:7]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([NH2:41])=[O:17])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]([NH2:41])([CH3:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)CCCC(=O)O)c1
Agent: CC(C)(C)CC(C)(C)N
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)CCCC(N)=O)c1

Procedure:
2.0 Parts of 5-(3-t-butyl-2-hydroxy-5-methyl-phenyl)-5-methylhexanoic acid and 2.0 parts thionyl chloride in 25 parts of toluene were stored for 2 hours at room temperature. The toluene and other volatiles were then stripped off at room temperature and 16 mb pressure. To the residue was then added 10 parts of 1,1,3,3-tetramethyl-butylamine and this mixture heated for 3 hours on a steam-bath. After diluting the reaction mixture with ether, the ether solution was washed successively with dilute hydrochloric acid, water, dilute sodium hydroxide, and water. Evaporation of the ether and crystallisation from 60°-80° C. petroleum-ether gave 5-(3-t-butyl-2-hydroxy-5-methylphenyl)-5-methyl-hexanoic acid amide of 1,1,3,3-tetramethylbutylamine m.p. 110°-2° C. with the following percentage composition by weight.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:13]S(C(C)(C)C)=O)=[CH:5][CH:4]=1>O1CCOCC1>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[NH:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)S(=O)N=C1CCCc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: N=C1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4M in 1,4-dioxane) (6.75 mL, 222.07 mmol) was added to a suspension of N-(7-bromo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-sulfinamide (Example 51 Step 1, 7.29 g, 22.2 mmol) in anhydrous 1,4-dioxane (50 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 1 h. The formed precipitate was filtered off and washed with Et2O. The solid was then dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic layer was collected and concentrated. The product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][N:25]([CH3:29])[C:26]([NH2:28])=[O:27]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:28][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C(N)=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(NC(=O)N(C)C)cc3)CC2)c(C)c1
Yield: 11.5 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (211 mg) described in Preparation Example 113 and 1,1-dimethylurea (66 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (22 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl.[N:16]([O-])=O.[Na+]>O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[N:1]=[N:16][CH:13]=[C:12]2[OH:14]
Reactant: O=N[O-]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2nncc(O)c2cc1OC
Temperature: 2 °C
Reaction time: 1 h

Procedure:
1-(2-Amino-4,5-dimethoxyphenyl)ethanone (105 g, 0.538 mol) was dissolved in concentrated HCl (2000 mL, 20 mol) at ambient temperature. The solution was then cooled to 0-4° C., and sodium nitrite (37.5 g, 0.543 mol) was added dropwise over 45 minutes as a solution in water (200 mL). The reaction mixture was stirred at 0-4° C. for one hour during which time it turned dark brown and became homogenous. The reaction mixture was then heated to 60-70° C. for four hours, and a yellow solid formed. After cooling the reaction mixture to 10° C., the solid was collected by filtration. The wet solid was suspended in 1500 mL of water, and the pH was adjusted to 12 with 4N NaOH to give a brown solution, followed by adjusting the pH to 7 with concentrated hydrochloric acid (78 mL). 6,7-Dimethoxycinnolin-4-ol precipitated as an off-white solid, which was filtered, washed with water (3×300 mL), and dried in a vacuum overnight at 50° C.
Reaction SMILES: Cl[C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[H][H]>[Ni]>[C:3]([CH:2]([C:7]([F:10])([F:9])[F:8])[F:11])([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(Cl)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Product: FC(C(F)(F)F)C(F)(F)F

Procedure:
2-Chloroheptafluoropropane (1.38 g/hr) and hydrogen (22 cc/min) were fed into the 1/4" Inconel® nickel alloy reactor filled with Inconel® nickel alloy chips (10 g). Operation at 500° C. and 250 psig for 33.3 hours gave an average of 91.3% conversion with 99.4% selectivity to CF3CHFCF3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9](=O)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[CH3:10]
Reactant: Cc1cccc(N)n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1cccc(C)n1
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 mL, 9.34 mmol) were stirred together in anhydrous methyl alcohol for 1 hour at room temperature under a nitrogen atmosphere. The mixture was then treated with sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and five drops of acetic acid and all was allowed to continue stirring for 4 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the separated aqueous phase was extracted twice with DCM. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a mobile oil which was purified by flash column chromatography, eluting with 2% MeOH/DCM, to give 2-ethylamino-6-methylpyridine (636 mg, 51%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:24][CH:23]=1)=[O:17])[CH3:15])=[O:12])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:54].[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:26][CH:27]=1)=[O:17])[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
200 mg (0.245 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-beta-alanyl-L-alaninate (Example 8A) were dissolved in 2 ml dichloromethane, and 2.45 ml 1M HCl in diethyl ether were added. After 3 hours, 1 ml of a 1N solution of hydrogen chloride in diethyl ether was added and the mixture was stirred at room temperature for a further 2 hours. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 155 mg (yield: 82% of theory) of the target compound were obtained.
Reaction SMILES: [NH:1]=[C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=1)/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH3:15])\[NH2:5].N[C:27](N)=[O:28].Cl>C(O)C.O1CCOCC1>[CH3:25][C:18]1[CH:17]=[C:16]([C:2]2[CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:13][CH2:14][CH3:15])[NH:5][C:27](=[O:28])[N:1]=2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23]
Reactant: NC(N)=O
Reactant: CCCOc1ccccc1/C(N)=C/C(=N)c1ccc([N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCCOc1ccccc1-c1cc(-c2ccc([N+](=O)[O-])c(C)c2)nc(=O)[nH]1
Temperature: 75 °C
Yield: 76.4 %

Procedure:
To a solution of (1Z)-3-imino-3-(3-methyl-4-nitrophenyl)-1-[2-(propyloxy)phenyl]prop-1-en-1-amine (2.20 g, 6.45 mmol) in ethanol (100 mL) was added urea (6.0 g, 100 mmol) and hydrochloric acid in dioxane 4.0 N (25 mL) at room temperature. The reaction mixture was heated to 75° C. for 16 h, at which time it was concentrated in vacuo, diluted with water (200 mL) and adjusted to pH 10 with sodium hydroxide 2.0 N. The product was extracted with chloroform (200 mL) then diluted with hexanes (50 mL) to precipitate the product. The solid was filtered and washed with chloroform/hexanes (1:4) to give 4-(3-methyl-4-nitrophenyl)-6-[2-(propyloxy)phenyl]pyrimidin-2(1H)-one (1.80 g, 81%). MS (EI) for C20H19N4O3: 363 (MH+).
Reaction SMILES: ClC1[CH:24]=[CH:23][C:5]2N(C)[C:7](=[O:21])[C:8]3[CH:15]=[N:14][C:13]4[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:12]=4[C:9]=3[N:10](C)[C:4]=2C=1.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCC[C:45]([OH:47])=[O:46])C(=O)C[C@H]1O>>[CH2:4]([NH:10][C:9]1[C:8]2[C:7](=[O:21])[O:46][CH:45]([OH:47])[C:15]=2[N:14]=[C:13]2[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:12]=12)[CH2:5][CH2:23][CH3:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CCn1ncc2c3c(cnc21)C(=O)N(C)c1ccc(Cl)cc1N3C
Product: CCCCNc1c2c(nc3c1cnn3CC)C(O)OC2=O

Procedure:
10-Chloro-3-ethyl-7,12-dimethyl-7,12-dihydropyrazolo-[4',3':5,6]pyrido[4,3-b][1,5]benzodiazepin-6(3H)-one, said PGE1 being present in a concentration of from about 10-6 molar to about 10-9 molar, and said member being present in a concentration of from about 0.1 mM to about 4 mM
Reaction SMILES: C([O:4][C:5]1[CH2:9][C@H:8]([C@@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14](=[O:15])[O:13][C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[O:11]2)[CH2:7][CH:6]=1)(=O)C.C[N+]1([O-])CC[O:30]CC1.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:16]([C@H:12]1[O:13][C:14](=[O:15])[C@@:10]([C@H:8]2[CH2:7][C:6](=[O:30])[C@H:5]([OH:4])[CH2:9]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:11]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(=O)OC1=CC[C@@H]([C@]2(c3ccccc3)O[C@@H](C(C)(C)C)OC2=O)C1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CC(=O)[C@H](O)C2)O1
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of 169 mg of (4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-1-cyclopentenyl acetate in 7.5 ml of acetonitrile and water (2:1), 80 mg of N-methyl morpholine-oxide and 0.2 ml of 2% aqueous osmium tetraoxide solution were successively added at 0° C. by the order stated, followed by 3 hours' stirring at the same temperature. Sodium sulfite was added to the reaction liquid and stirred for further 30 minutes. The reaction liquid was then diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on silica gel column chromatography (eluent: hexane−hexane/ethyl acetate=2/1) to provide 32 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([N:5]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([N:5]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[CH3:34])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1N(CC(C)C)S(=O)(=O)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 3-(4-(N-isobutyl-N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)phenyl)-2,2-dimethylpropanoate (15 mg, 0.030 mmol) in tetrahydrofuran (THF) (1.5 mL), at room temperature, was added a solution of lithium hydroxide (approximately 0.719 mg, 0.030 mmol—tip of spatula used) in water (1.5 mL). The reaction mixture was stirred at 20° C. for 4 hours and then stood overnight. The mixture was evaporated in vacuo, then partitioned between water (2 mL) and ethyl acetate (2×5 mL). The organic fraction was separated (hydrophilic frit) and evaporated in vacuo to give a residue. This was redissolved in THF (1 mL) and water (1 mL) and new lithium hydroxide (tip of spatula) was added. The reaction was stood for 3 days, after which time the solvents had evaporated to give a white residue. The residue was acidified (2N HCl, 3 mL) and extracted with ethyl acetate (2×5 mL). The organics were separated (hydrophilic frit) and concentrated in vacuo, then purified by MDAP (Method F) to give the required product, 2.38 mg. LCMS (M+1) 472, RT 1.37 mins.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: CN(C)CCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (59 mg, 0.099 mmol), N1,N1-dimethylethane-1,2-diamine (0.13 ml, 1.2 mmol), sodium triacetoxyborohydride (104 mg, 0.493 mmol) and AcOH (0.023 ml, 0.394 mmol) in DCE (3 ml) was stirred at rt for 12 h. The solvent was removed in vacuo. LCMS showed desired product and some imine not reduced yet. The residue was redissolved in DCE (3 ml) and treated again with sodium triacetoxyborohydride (104 mg, 0.493 mmol) and AcOH (0.023 ml, 0.394 mmol) at rt for 48 h. Solvent removed in vacuo and the residue redissolved in methylene chloride and purified by silica gel column (0-10% MeOH/CH2Cl2) to afford the title compound as a white solid (65 mg, 98% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 5.30 (dd, J=6.1, 1.6 Hz, 1H), 4.72 (d, J=1.5 Hz, 1H), 4.63 (s, 1H), 3.17-2.95 (m, 3H), 2.72 (t, J=5.9 Hz, 2H), 2.54 (d, J=12.3 Hz, 1H), 2.48-2.41 (m, 1H), 2.40 (s, 6H), 2.21-1.10 (m, 22H), 1.72 (s, 3H), 1.61 (s, 9H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[I-:12].[K+]>>[I:12][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: [I-]
Agent: [K+]
Product: O=C1OCc2ccc(I)cc21
Yield: 23 %

Procedure:
The 6-iodophthalide was prepared in 23% yield via diazotization of 6-aminophthalide and subsequent treatment of the diazonium salt with potassium iodide according to the method of Tassman (Rec. Trav. Chim. Pays-Bas, 46, 653).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: N#Cc1ccc(CN)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 10) (2.35 g, 5.97 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound (1.27 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:52])=[C:34]([N:36]2[CH2:45][C:44]3[C:39](=[N:40][C:41]([S:46]([CH3:49])(=[O:48])=[O:47])=[N:42][CH:43]=3)[N:38]([CH3:50])[C:37]2=[O:51])[CH:35]=1>O1CCCC1.ClCCl>[Cl:52][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)=[O:21])=[CH:35][C:34]=1[N:36]1[CH2:45][C:44]2[C:39](=[N:40][C:41]([S:46]([CH3:49])(=[O:47])=[O:48])=[N:42][CH:43]=2)[N:38]([CH3:50])[C:37]1=[O:51]
Reactant: O=C(O)c1ccc(-c2ccc(CN3CCOCC3)cc2)cc1
Reactant: CN1C(=O)N(c2cc(N)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
300 mg of 4′-Morpholin-4-ylmethyl-biphenyl-4-carboxylic acid in 15 ml dry tetrahydrofuran (THF) were treated dropwise with 129 mg oxalyl chloride under cooling with ice. The mixture was subsequently stirred for 20 min at room temperature (RT) before a suspension of 200 mg aniline derivative from example d in 5 ml dichloromethane was added slowly. The mixture was stirred over night and then diluted with 50 ml dichloromethane. Precipitate was filtered off and the filtrate was washed several times with conc. aqueous sodium carbonate solution. The organic phase was dried, evaporated and purified by flash chromatography on silica, using a gradient from dichloromethane to dichloromethane/methanol (60/1) to dichloromethane/methanol/concentrated ammonia (60/1/0.2).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[Cl:13])(=[O:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:33])=[CH:8][C:7]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc(CBr)cc1Cl

Procedure:
(2-chloro-4-methylphenyl)methyl acetate (453 mg, 2.280 mmol) was dissolved in Chloroform (20 mL) and AIBN (18.72 mg, 0.114 mmol) and NBS (406 mg, 2.280 mmol) were added under Ar atmosphere. The reaction was left under reflux for 5 hours. HPLC showed a new pick which we thought it was the desired product and a bit of starting material and the reaction was stopped. The mixture was allowed to reach room temperature, succinimide was filtered, and volatiles removed under vacuum. Corresponding crude was purified by using flash master chromatography Si II MERCK, 20 g Hexane-acetate (0-30%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=CC=CC=1.C1C[O:40]CC1>[C].[Pd]>[F:36][C:10]1[CH:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2](=[O:40])[CH3:7]
Reactant: C1CCOC1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Product: CC(=O)COc1ccc(-c2nc3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (4.26 g), 10% palladium-carbon (containing water (50%), 0.920 g) and THF (40 mL) was stirred at room temperature for 1 hr and min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the solution was subjected to silica gel chromatography (ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in DMF (40 mL) were added potassium carbonate (1.32 g) and bromoacetone (0.888 mL), and the mixture was stirred overnight at 60° C. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.67 g).