Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:5].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[S:40](Cl)(=[O:42])=[O:41])([O-:29])=[O:28]>ClCCl.C(OCC)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:2]([NH:1][S:40]([C:31]2[CH:32]=[CH:33][C:34]([C:36]([F:38])([F:39])[F:37])=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:41])=[O:42])=[C:3]([CH:16]=1)[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:5]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccccc1CNC(=O)c1cc(Br)ccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 45.5 %

Procedure:
2-Amino-5-bromo-N-(2-methoxy-benzyl)-benzamide (9 g, 28 mmol) was suspended in anhydrous dichloromethane (300 ml) and cooled in ice bath. Pyridine (20 ml) was added with stirring, followed by addition of 2-nitro-4-trifluoromethyl-benzene sulfonyl chloride (15 g, 52 mmol). The reaction mixture was allowed to stir at room temperature for 2 days. The mixture was filtered to remove a solid precipitate and the filtrate was evaporated to dryness. Aqueous HCl (2N, 300 ml) was added, and the resulting solution was extracted with dichloromethane (500 ml). The organic layer was concentrated and the resulting residue was dissolved in ethyl acetate. Addition of hexanes to this solution produced a solid precipitate. This solid was dissolved in ethyl acetate and passed through a short column of silica using an eluent of dichloromethane and ethyl acetate to provide the desired product (7.5 g, 46% yield). M/Z of [M−H]−=587.1 1H NMR (DMSO) δ=3.8 (s, 3H), 4.35 (sd, 2H), 6.85 (1H), 6.95 (1H), 7.1 (1H), 7.2 (1H), 7.4 (1H), 7.65 (1H), 8 (1H), 8.15 (1H), 8.25 (1H), 8.55 (1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=3[CH3:28])[C:7]([CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:11][CH:10]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(N)cc1
Reaction time: 18 h
Yield: 48.9 %

Procedure:
3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]propanoic acid ethyl ester (36 mg, 0.09 mmol) was dissolved in 1 mL methanol. 1 N NaOH (0.18 mL, 0.18 mmol.) was added. After 18 hrs, the reaction was concentrated in vacuo and diluted with water. The pH was adjusted to 1 with 1 M HCl and extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and dried under high vacuum to yield 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoic acid (16 mg, 50%, light orange powder).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]I)=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1.[CH3:40][NH:41][CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:41]([CH3:40])[CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48])=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CN(CCOCCOCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
230 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}phenyl)azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 280 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C37H48F2N2O10 (718) MS (ESI): M+
Reaction SMILES: [C:1]1([C:7]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:15]3[C@@H:11]([CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)[C@@:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])(O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38]>C(O)(=O)C>[ClH:38].[C:32]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C@H:11]3[C@@H:15]2[CH2:14][NH:13][CH2:12]3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccccc1C1=CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@@H]12
Temperature: 25 °C

Procedure:
A solution of 8.56 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindol-4-ol in 53 cm3 of acetic acid and 30 cm3 of 12N hydrochloric acid is heated at 95° C. for 45 minutes, and then cooled to room temperature and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallised from 20 cm3 of acetonitrile. 5.2 g of (3aS,7aR)-4,4-diphenyl-7-(2-methoxyphenyl)-2,3,3a, 4,5,7a-hexahydroisoindole hydrochloride are obtained in the form of white crystals which melt at a temperature above 300° C., and the product is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2cccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1conc1-c1ccc(OCc2cccnc2)cc1
Reaction time: 3 h
Yield: 6.7 %

Procedure:
{3-[4-(Pyridin-3-ylmethoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (from previous reaction) was dissolved in dioxane (18 mL) and treated with conc. HCl (3.6 mL). After stirring for 3 h, the reaction mixture combined with satd aqueous NaHCO3 (20 mL). The organic layer was separated and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave an oily white solid from which 3-[4-(pyridin-3-ylmethoxy)-phenyl]-isoxazol-4-ylamine (6.5 mg, 6.7%) was isolated as a white solid by chromatography (5% CH3OH in CH2Cl2). HRMS: 268.108 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccnc(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(O)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 2-hydroxyisonicotinic acid (1.4 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 40 mmol) at 0° C., the mixture was stirred overnight. The solvent was evaporated in vacuo and water was added. The mixture was extracted with ethyl acetate (100 mL×3), the organic phase was dried sodium sulfate and evaporated in vacuo to give methyl 2-hydroxyisonicotinate (1.2 g, 78%). LRMS (M+H+) m/z: calcd 153.04. found 153.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(C=O)n2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(c2cccc(CO)n2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a ice-cold solution of 6-(2-methyl-[1,3]dioxolan-2-yl)-pyridine-2-carbaldehyde (713 mg, 3.69 mmol) in MeOH (10.0 mL) was added NaBH4 (180 mg, 4.57 mmol in four equal portions). The reaction mixture was then stirred for 1 h at rt. Water was added and the mixture was extracted with EA followed twice with EA-MeOH 9:1. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.46 min; [M+H]+=196.49.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O[CH:23](N(C)C)[N:24]([CH3:26])[CH3:25])(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15](=[CH:23][N:24]([CH3:26])[CH3:25])[C:16](=[O:17])[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)CCCC2=O
Solvent: Cc1ccccc1
Product: CN(C)C=C1CCc2sc(C(=O)OC(C)(C)C)cc2C1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
4-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid tert-butyl ester (8.75 g, 34.68 mmol) was suspended in dry toluene (40 mL) and Bredereck's reagent (6.65 g, 38.14 mmol) was added. The resulting suspension was heated at reflux for 2 hours, during which time all starting material dissolved, allowed to cool to room temperature and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (50% EtOAc in hexanes on 1 L silica, loaded as a solution in dichloromethane) to afford the title compound as a brown solid (6.21 g, 58% yield). MS (ES+) 308. δH (CDCl3) 1.5-1.6 (9H, s), 2.9-3.0 (2H, m), 3.0-3.1 (2H, m), 3.1 (6H, s), 7.6 (1H, s), 8.0 (1H, s).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH2:19][CH2:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(F)C(O)C=CC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCCCC(F)C(O)CCC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Yield: 94 %

Procedure:
To 1.1 g of platinium in 50 ml of ethyl acetate was added a solution of 11 g (0.028 mol) of [3aR-[3a alpha,4alpha(1E,3R*,4S*),5beta,6a alpha]]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxy-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-one in 110 ml of ethyl acetate. The mixture was then hydrogenated until the theoretical uptake of hydrogen was complete and then filtered through a bed of Celite. The solvent was then removed under reduced pressure and the residue chromatographed over 250 g of silica gel (toluene --α 30% by volume ethyl acetate/70% by volume toluene) to afford 10.7 g of [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6a alpha)]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)hexahydro-2H-cyclopenta[b]furan-2-one (94% yield) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:42][C@H:41]([CH2:43][CH2:44][NH2:45])[CH2:40][O:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:42][C@@H:41]([CH2:40][OH:39])[CH2:43][CH2:44][NH:45][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33])[NH:17]1)=[O:36]
Reactant: CC1(C)OC[C@@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 78.2 %

Procedure:
In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.37 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.159 g, 1.1 mmol), HATU (0.25 g, 0.66 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 81%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[F:13][C:2]([F:1])([F:12])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=1)[OH:4]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To a stirred solution of 2,2,2,4′-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBH4 (0.98 g, 26.5 mmol) at 0° C. After stirring at 25° C. for 2 h, the reaction mixture was quenched by adding 1N HCl (100 mL) and then extracted with ethyl ether. The ether extract was washed with brine, dried with MgSO4, and concentrated to give 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (11.32 g) which was used in next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[S:21]1[C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:30]([C:27]2[CH:28]=[CH:29][C:24]3[N:23]=[CH:22][S:21][C:25]=3[CH:26]=2)=[O:31])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc2ncsc2c1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2ncsc2c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 1,3-benzothiazole-6-carboxylic acid (0.056 g). Title compound obtained as white solid (0.066 g).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH3:12])[N:9]=1.[N+:13]([C:16]1[CH:20]=[N:19][NH:18][N:17]=1)([O-:15])=[O:14].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:12][O:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:18]2[N:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:20]=[N:19]2)[O:6][CH:7]=1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: COCc1coc(CCl)n1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1coc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(chloromethyl)-4-(methoxymethyl)oxazole (1.38 g, 8.55 mmol) in DMF (24.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (10.16 g of a 9.6% solution in DMF, 8.55 mmol) in DMF (24.0 mL) pre-treated for 30 min with DIPEA (2.93 mL, 17.10 mmol) and the reaction mixture was stirred overnight at 50° C. Water (200 mL), followed by EA (200 mL) was added. The layers were separated and the org. layer was washed with water (3×70 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a yellow oil: TLC: rf (4:6 hept-EA)=0.38. LC-MS-conditions 07: tR=0.63 min.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8](OC=C)(=O)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][CH:8]=[CH2:9]
Reactant: C=COC(C)=O
Reactant: CC(C)(C)CCO
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: C1=CCCC=CCC1
Product: C=COCCC(C)(C)C
Temperature: 25 °C

Procedure:
Add chloro(1,5-cyclooctadiene)iridium(I) dimer (0.39 g, 0.59 mmol) to 3,3-dimethylbutan-1-ol (3.00 g, 29.35 mmol), vinyl acetate (10.11 g, 117.42 mmol) and sodium carbonate (1.87 g, 17.61 mmol) in benzene (10 mL) at room temperature. Boil under nitrogen 12 hours. Cool to room temperature and filter. Distill the filtrate and collect fraction boiling ˜125° C.-130° C. Flush through a silica gel pad with hexanes and concentrate to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:21].[C:22](Cl)(Cl)=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:21][C:22](=[O:23])[N:9]2[C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of (R)-6-chloro-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine (0.9 g, 2.91 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 20 min, a solution of phosgene in THF (2.6 mL of a 20% solution of phosgene in toluene, 4.94 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min. The solvent was then removed in vacuo, and the residue was taken in ethyl acetate/saturated aqueous NaHCO3. The layers were separated, and the aqueous layer extracted with ethyl acetate three times. The combined organic extracts were put together, dried (anhydrous Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 6/1 to 4/1 methylene chloride/ethyl acetate) to give 0.78 g (80% yield) of the desired product as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 7.13-7.06 (m, 1H), 6.90-6.82 (m, 1H), 6.75-6.72 (m, 1H), 5.92-5.82 (m, 1H), 4.80-4.73 (m, 1H), 4.50-4.42 (m, 1H), 3.20-3.05 (m, 1H), 2.42-2.30 (m, 1H); MS (EI) m/z 336.3 (MH)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.CC([O-])=O.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (21.60 g, 65 mmol) in acetic acid (130 mL) containing anhydrous NaOAc (6.045 g, 74 mmol), was slowly added iodine monochloride (19.65 mL, 3.75M in HOAc). The reaction mixture was stirred at rt overnight. The suspension was diluted with water, the yellow crystalline filtrated, washed with water and dried in vacuum overnight to give 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.1 g, 100%) as yellow crystalline solid. MS (ISP) 458.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>>[CH:22]1([O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: OC1C=CCCC1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OC1C=CCCC1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and cyclohex-2-en-1-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [C:1]1([CH2:17][C:18]([OH:20])=[O:19])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[CH2:21]([OH:27])[CH2:22][O:23][CH2:24][CH2:25]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:17][C:18]([O:20][CH2:25][CH2:24][O:23][CH2:22][CH2:21][OH:27])=[O:19])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2ccc3cccc4ccc1c2c34
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(Cc1ccc2ccc3cccc4ccc1c2c34)OCCOCCO
Temperature: 130 °C
Yield: 83.5 %

Procedure:
1-Pyreneacetic acid (1 g, 3.85 mmol), diethylene glycol (10 ml, 91.0 mmol) and p-toluenesulfonic acid (100 mg, 0.58 mmol) were mixed and heated to 130° C. for 16 h with stirring under N2. After the reaction was completed (confirmed by TLC), the reaction mixture was cooled to 20° C. and poured into 50 ml ice-water drop-wise. The aqueous reaction mixture was extracted with EtOAc (3×100 ml) and the combined organic solutions were washed with 5% aqueous KOH (2×50 ml), H2O (2×50 ml) and brine (1×50 ml), and were subsequently dried over anhydrous MgSO4. The crude product was purified by column chromatography (silica gel, EtOAc/hexanes: 1/1) to yield 1.12 g (83.59%) 15 as a light green oil. Purity: 99+% (HPLC). TLC: Rf=0.17 (EtOAc/hexanes: 1/1). 1H NMR (250 MHz, CDCl3, 20° C.): δ 8.26-7.94 (m, 9H), 4.38 (s, 2H), 4.27 (m, 2H), 3.63 (m, 2H), 3.53 (m, 2H), 3.39 (m, 2H), 2.82 (s broad, 1H). 13C NMR (125 MHz, CDCl3, 20° C.): δ 171.5, 131.3, 130.8, 130.7, 129.4, 128.3, 127.9, 127.4, 127.3, 126.0, 125.3, 125.1, 125.0, 124.8, 124.7, 123.2, 72.2, 68.9, 64.1, 61.6, 39.4.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Ic1ccccn1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccccn2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-iodopyridine. The title compound was obtained in 88% yield as an orange oil. MS (m/e): 483.3 (MH+, 100%).