Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Br:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Br:25])=[C:15]([Br:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(Br)c(Br)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(Br)c(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:13])[NH:10][CH2:11]Cl)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:9]([NH:10][CH2:11][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:15]=1[Cl:14])=[O:13]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: O=C(NCCl)Oc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1Cl)OCNC(=O)Oc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A solution of 220.1 g (1 mole) of N-chloromethylcarbamic acid 3-chlorophenyl ester in 1 liter of anhydrous ethyl acetate was added dropwise at 0° to 10° C to a mixture of 221 g (1 mole) of 2,4-dichlorophenoxyacetic acid and 111.3 g (1.1 moles) of triethylamine in 2 liters of ethyl acetate. The mixture was stirred for a further 15 hours at 20° C and was cooled to 5° C, and the triethylammonium chloride which had precipitated was filtered off. The filtrate was washed neutral with water and was concentrated in vacuo by distilling off the solvent. The solid residue was recrystallised from ether. 290 g (71.8% of theory) of 2-(2,4-dichlorophenoxy)-acetic acid 3-chlorophenoxycarbonylaminomethyl ester were obtained in the form of white crystals of melting point 110° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][OH:18])[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1.[CH3:19][O:20][C:21](=[O:33])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27](O)=[C:26]([O:31][CH3:32])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:33])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([O:16][CH2:15][C:13]2[CH:12]=[C:11]([CH2:17][OH:18])[CH:10]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:14]=2)=[C:26]([O:31][CH3:32])[CH:25]=1
Reactant: OCc1cc(CO)cc(OCCCCCCCl)c1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(OCc2cc(CO)cc(OCCCCCCCl)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 47.5 %

Procedure:
2.7 g (10 mmol) [3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]phenyl] methanol (Example 6) were added to a solution of 2.6 g (12.5 mmol) (E)-4-hydroxy-3-methoxycinnamic acid methyl ester (Example 1) and 3.38 g (12.5 mmol) triphenylphosphine in 40 ml tetrahydrofuran. The colourless solution was cooled to 0° C. and then 5.2 ml (12.5 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise over a period of 2 hours. The mixture was allowed to react for 2 hours at 0° C. and then for 15 hours at room temperature. The reaction mixture was poured into an ice cold 1 M solution of HCl. The aqueous phase was extracted three times with a mixture of tert-butyl-methylether/ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated in vacuum. Purification of the residue by column chromatography on silica gel using hexane:ethyl acetate (1:1) as eluent yielded 2.2 g (48%) of (E)-3-[4-[3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]benzyloxy]-3-methoxyphenyl]acrylic acid methyl ester as an oily product that solidified on standing.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:4]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[OH:22][C@@H:23]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:24]([NH:26][C@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:18]1([CH2:17][N:4]2[C@H:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:32](=[O:33])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:26][C:24](=[O:25])[C@@H:23]([OH:22])[CH2:35][CH:36]([CH3:37])[CH3:38])[C:3]2=[O:21])[CH2:19][CH2:20]1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Reactant: COc1ccc([C@@H]2C=CC[C@H](N)C(=O)N2CC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc([C@@H]2C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)C(=O)N2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(cyclopylmethyl)-7-(4-methoxyphenyl)-1,3,4,7-tetrahydro-2H-azepin-2-one (11e) (35 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b) (30 mg), HOBt-hydrate (41 mg), EDAC.HCl (35 mg) and N-methyl morpholine (25 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (60 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 0.40 (m, 2H), 0.58 (m, 2H), 0.74 (m, 1H), 0.87 (d, 6H), 1.26 (m, 1H), 1.53, (m, 2H), 1.59 (m, 1H), 1.67 (m, 2H), 2.00 (m, 2H), 3.20 (m, 2H), 3.66 (s, 1H), 3.89 (m, 1H), 4.28 (m, 1H), 4.96 (m, 1H), 5.32 (m, 1H), 6.13 (bd, 1H), 6.48 (m, 1H), 6.85-6.94 (m, 4H). MS APCI, m/z=514 (M+1). LC/MS 2.47 min., Method A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O>O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([O:11][C:12]3[C:13]([F:20])=[CH:14][C:15]([O:18][CH3:19])=[CH:16][C:17]=3[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Solvent: O
Product: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 125 °C

Procedure:
5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (28.5 g, 84 mmol) and polyphosphoric acid (205 g, 2089 mmol) were combined and heated at 125° C. for two hours. The solution was diluted with water (1 L) and filtered. The solids were washed well with 2N NaOH, then with water. The solids were then dried under vacuum to afford 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as an off white solid. MS m/z=323.0 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]([C:9]([NH:11][OH:12])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([N:11]([C:9](=[O:10])[C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[NH2:1])[OH:12])=[O:23])([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)NO
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](Cc1c[nH]cn1)C(=O)N(O)C(=O)c1ccccc1C(=O)O
Reaction time: 4 h
Yield: 44.9 %

Procedure:
D-Histidine hydroxamic acid (1.9 g, 11.2 mMol) was dissolved in dimethylformamide (75 ml) and water (100 ml). Phthalic anhydride (1.65 g, 11.2 mMol) was added, the solution stirred 4 hours, evaporated to an oil which was crystallized from water/ethanol, and crystallized again from water to yield 1.6 g, m.p. 175° (dec.) of N-(2-carboxybenzoyl)-D-histidine hydroxamic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-(4-pyridyl)propanol (22.05 g, 0.16 mol) in 100 mL of dry chloroform (CHCl3) at 0° C. was added dropwise a CHCl3 solution of thionylchloride (SOCl2, 17.5 mL, 0.24 mol). The reaction was allowed to warm to room temperature, stirred for 1 hour, and then brought to reflux for 1 hour. After cooling the reaction to room temperature, it was stripped of all solvent under reduced pressure and the residue was partitioned between CH2Cl2 and water that had been made basic with concentrated NH4OH. The aqueous phase was washed 2× with CH2Cl2 and the combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 24 g of crude product. This material was vacuum distilled at 68°-71° C. (0.3 mm) to give 24 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:41][N:40]=2)=[CH:35][CH:34]=1.[O:54]1[C@@H:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C@@H:55]1[CH3:56]>O1CCCC1>[CH2:45]([C:42]1[CH:43]=[N:44][C:39]([C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:56][C@H:55]3[C@H:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[O:54]3)=[CH:38][CH:37]=2)=[N:40][CH:41]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC[C@@H]1O[C@H]1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
1.31 g (5 mmol) of triphenyl phosphine and 0.79 g (5 mmol) of diethyl azodicarboxylate are combined in 10 ml of tetrahydrofuran at 0° C. After 20 minutes, 1.49 g (5 mmol) of 2-(4-hydroxyphenyl)-5-n-nonylpyrimidine and 0.72 g (5 mmol) of (2S,3S)-2,3-epoxyoctane, each in 8 ml of tetrahydrofuran, are added. After 24 hours, the mixture is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (200 g) using CH2Cl2. After recrystallization from hexane, 0.79 g of colorless crystals is obtained; (α) D25 : -15.3° (c=5,CHCl3)
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>O1CCCC1>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[CH:2][O:3][CH3:4]
Reactant: O=Cc1ccccc1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.7 %

Procedure:
To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (10 g, 28 mmol) in tetrahydrofuran (46 mL) cooled at −15° C. was added potassium tert-butoxide (3.7 g, 31 mmol) as a solid in one portion. After 5 minutes, 2-chlorobenzaldehyde (2.0 g, 14 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for two hours. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL), tetrahydrofuran evaporated in vacuo, and the resulting residue was diluted with diethyl ether (100 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 80 g, ISCO, 0-10% ethyl acetate in heptane) to afford the title compound as a colorless oil (2.4 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:15]=[CH:14][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[N:17]=3)=[O:34])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cccc(NC(=O)Nc3csc(C4CC4)n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(C2CC2)n1

Procedure:
In a manner similar to that described in Example 2,2-cyclopropylthiazole-4-carbonylazide (133.0 mg, 0.686 mmol) and tert-butyl 4-[2-(6-amino-pyridin-2-yloxy)-ethyl]-piperidine-1-carboxylate (220.0 mg, 0.686 mmol) were heated in toluene (20 mL) to give the BOC-protected product as a yellow oil. In a similar manner to Example 274, tert-butyl 4-(2-{6-[3-(2-cyclopropyl-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylate (7.6 mg, 0.016 mmol) was heated in CH2Cl2 (10 mL) in the presence of TFA (2 mL) to give the product as yellow oil. MS m/z: 388.3 (M+H). Calc'd. for C19H26N5O2S-388.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: CCO
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Temperature: 62.5 °C
Yield: 88.1 %

Procedure:
To a solution of methyl 4-amino-2-methoxybenzoate (501 mg, 2.77 mmol) in ethanol (8 ml) was added acetic anhydride (0.42 ml, 4.44 mmol, 1.6 eq) and the clear solution heated at 60-65° C. for 2 h. After cooling to room temperature the solvent was removed by rotary evaporator and the residue treated with water (10 ml) and saturated sodium bicarbonate solution (10 ml) before extracting with ethyl acetate (20 ml, 2×10 ml). The combined ethyl acetate extract was washed with water, then brine, dried (MgSO4) and evaporated to give methyl 4-acetamido-2-methoxybenzoate (545 mg, 88%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C@H:20]([C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)[CH3:21])=[N:24][CH:25]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)cc1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 285 mg (0.69 mmol) dissolved in toluene (5 mL) were added 0.22 mL (2.07 mmol) of 1-chloroethyl chloroformate and 0.35 mL (2.07 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 152 mg (68%) of the title compound as a light yellow oil. ES-MS m/e: 321.1 (M+H+).
Reaction SMILES: [C:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-tert-butyl diethanolamine (16.4 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a non-isolable amount of product within a mixture of oligomeric diethanolamines.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>CC#N>[F:8][C:9]([F:19])([F:20])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of pivaloyl chloride (2.1 mL, 17 mmol) in MeCN (10 mL) was added dropwise over 10 min to a solution of 4-trifluoromethoxy-benzylamine (2.6 mL, 17 mmol) and TEA (4.0 mL, 29 mmol) in MeCN (20 mL) at 0° C. The mixture was stirred for 30 min, filtered and concentrated. The residue was treated with water and filtration gave the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6](CCCl)[N:7]=2)[CH:3]=1.Br[C:15]1[CH:16]=[C:17]([C:34]([NH2:36])=[O:35])[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=[CH:24][C:25]=3[C:26]=2[N:27]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:22]2[CH:23]=[CH:24][C:25]3[C:26]4[N:27]=[C:15]([C:2]5[CH:3]=[C:4]6[C:8](=[CH:9][CH:10]=5)[N:7]([CH2:21][CH2:22][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[N:6]=[CH:5]6)[CH:16]=[C:17]([C:34]([NH2:36])=[O:35])[C:18]=4[NH:19][C:20]=3[CH:21]=2)[CH2:29][CH2:30]1
Reactant: ClCCn1cc2cc(Br)ccc2n1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Product: NC(=O)c1cc(-c2ccc3c(cnn3CCN3CCOCC3)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12

Procedure:
This was similarly prepared from 5-bromo-2-(2-chloroethyl)-2H-indazole and 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide. MS (ESI) m/z 526.24 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.20 (1H, s), 8.50-8.61 (3H, m), 8.34 (1H, s), 8.26 (1H, d, J=9.15 Hz), 8.09 (1H, d, J=8.85 Hz), 7.80 (1H, br. s.), 7.73 (1H, d, J=9.16 Hz), 7.22 (1H, s), 7.01 (1H, d, J=8.55 Hz), 4.59 (2H, t, J=6.26 Hz), 3.77-3.87 (4H, m), 3.56-3.61 (4H, m), 3.20-3.27 (4H, m), 2.91 (2H, t, J=6.41 Hz), 2.42-2.48 (4H, m).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=[O:14].[Cl-].[Na+]>C(O)(=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C1OCc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCc2ccccc2C(=O)O)cc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In this example, 348.9 g of sodium salt of methyl p-hydroxybenzoate, 402.4 g of phthalide and 200 g of sodium chloride are mixed with one another and stirred at 150° C. for 6 hours. After completion of the reaction, the mixture is cooled until the temperature is brought back to room temperature, 4 l of aqueous 10% acetic acid solution is added thereto and the mixture is allowed to stand at room temperature overnight. After stirring the mixture at room temperature for 3 hours, deposited crystals are separated by filtration, and 6 l of water is added thereto. After stirring the mixture at room temperature for 30 minutes, the deposited crystals are separated by filtration. After the addition of 3 l of toluene to the crystals, the mixture is stirred at room temperature for one hour. The crystals are separated by filtration and dried over heating under reduced pressure to yield 393.9 g of 2-(4-methoxycarbonylphenoxy) methyl benzoic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][NH2:20])=[C:15]([CH3:23])[CH:14]=1)[CH3:9].Cl[C:25]1[C:30]([Cl:31])=[C:29]([CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>C1(C)C=CC=CC=1>[Cl:31][C:30]1[C:25]([NH:20][CH2:19][CH2:18][O:17][C:16]2[CH:21]=[CH:22][C:13]([CH2:12][CH2:11][O:10][CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:23])=[N:26][C:27]([CH3:33])=[N:28][C:29]=1[CH3:32]
Reactant: Cc1nc(C)c(Cl)c(Cl)n1
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCc1ccc(OCCNc2nc(C)nc(C)c2Cl)c(C)c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to 1.8 g of 4,5-dichloro-2,6-dimethylpyrimidine dissolved in 50 ml of toluene. The mixture was heated under reflux, whilst stirring, for 5 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was then removed by distillation under reduced pressure, and the oily product obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and etyl acetate) to isolate the product. The crystals obtained were recrystallized from hexane, to give 2.0 g of the title compound as colorless granular crystals melting at 61°-63° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](B(O)O)[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[C:19]([OH:25])=[CH:20][CH:21]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CCSc1ccc(Br)c(C(F)(F)F)c1
Product: CCSc1ccc(-c2cc(Cl)ccc2O)c(C(F)(F)F)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.26 g
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][C:29](=O)[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:25][O:26][N:27]=2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:16][C:15]1[CH:14]=[CH:13][C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:25][O:26][N:27]=2)=[CH:11][C:10]=1[C:8]#[N:9]
Reactant: N#Cc1cc(-n2c(-c3nonc3NC(=O)c3ccncc3)noc2=O)ccc1F
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1cc(-n2c(-c3nonc3NCc3ccncc3)noc2=O)ccc1F
Reaction time: 3 h

Procedure:
A solution of N-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}isonicotinamide trifluoroacetate (37 mg, 72 μmol) in pyridine (1.5 mL) at 0° C. was treated with phosphorus pentachloride (45 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with ethanol (2.5 mL), treated with sodium cyanoborohydride (14 mg, 0.22 mmol), and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the intermediate 2-fluoro-5-[5-oxo-3-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-4(5H)-yl]benzonitrile trifluoroacetate. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (8 mg, 24%). LCMS for C16H13FN7O2 (M+H)+: m/z=354.0.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Reactant: Cc1cc(CN)ccc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2C(=O)c3ccnc(Cl)c3C2C)ccc1OCC(F)(F)F
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (137 mg, brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (200 mg, 0.79 mmol, Amine-34) in a similar manner to Intermediate-2.