Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([O:25]C(=O)C)[CH:22]=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.BrBr>>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1cccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1
Agent: BrBr
Product: Oc1cccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1

Procedure:
Prepared from acetic acid 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (Example 38) according to the procedure for Example 41. White solid: mp 110-111° C.: NMR (CDCl3); δ 8.35 (dd, J=8, 1 Hz, 1H), 7.81 (d, J=8, Hz, 1H), 7.67-7.63 (m, 2H), 7.53 (dd, J=8, 7 Hz, 1H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 7.13-7.09 (m, 2H), 7.00 (dd, J=8, 1 Hz, 1H), 6.88 (dd, J=1, 1 Hz, 1H), 6.78 (dd, J=8, 1 Hz, 1H), 4.99 (s, 1H, OH); MS (EI): [M+], 1 bromine isotope pattern, 404 (95%), 406 (100%); Anal. Calc. for C22H13BrOS: C, 65.19, H, 3.23, N, 0.00. Found: C, 64.85, H, 3.51, N, 0.43.
Reaction SMILES: C(OC([NH:8][S:9]([N:12]([CH3:50])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:49])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:26]3[C:25]3[CH:45]=[CH:46][CH:47]=[CH:48][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][S:9]([N:12]([CH3:50])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:49])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[C:26]3[C:25]3[CH:45]=[CH:46][CH:47]=[CH:48][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10]
Reactant: CN(CCN1CCC(N(C)S(=O)(=O)NC(=O)OC(C)(C)C)C1)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCC(N(C)S(N)(=O)=O)C1)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reaction time: 1 h

Procedure:
A solution of (7R)-7-[(2-{3-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]pyrrolidin-1-yl}ethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid in DCM was treated with TFA and the solution was left stirring for 1 h. All volatiles were removed in vacuo to leave the product as pale yellow foam. (ES+) m/z 610 (M+H)+.
Reaction SMILES: C1(C2C3C=CC=CC=3OC=2)C=CC=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.C[O:28][C:29]1[CH:51]=[CH:50][C:32]([C:33]([C:35]2[O:36][C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[C:39]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:34])=[CH:31][CH:30]=1>>[OH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([C:35]2[O:36][C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[C:39]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:34])=[CH:50][CH:51]=1
Reactant: COc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: c1ccc(-c2coc3ccccc23)cc1
Product: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Acylation of 3-phenylbenzofuran with p-anisoyl chloride over a four hour period as described in the procedure of Example 1 followed by demethylation of the 2-(4-methoxybenzoyl)-3-phenylbenzofuran thus formed as previously described gives 2-(4-hydroxybenzoyl)-3-phenylbenzofuran.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:18][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC(O)c1ccc(CC(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(Br)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(4-isobutylphenyl)pentanol and carbon tetrabromide in tetrahydrofuran was added triphenylphosphine and the mixture was stirred at room temperature for 1 hour. Insoluble materials were removed by filtration and the filtrate was concentrated. Hexane was added to the residue and the mixture was filtered again. Concentration of the filtrate gave crude 1-bromo-1-(4-isobutylphenyl)pentane. Sodium was added portionwise to 1,3-propanediol at 80° C. while stirring. The obtained crude 1-bromo-1-(4-isobutylphenyl)pentane was added thereto, and the mixture was stirred at 120° C. for 30 minutes. After the mixture was cooled, diluted hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>Br.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1

Procedure:
A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (600 mg, 2.7 mmol) and 4-(benzyloxy)benzohydrazide (654 mg, 2.7 mmol) in methanol (45 mL) was heated at 80° C. in a sealed tube for 3 h. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate. A solution of benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (480 mg, 1.12 mmol) in 33% HBr in acetic acid (5 mL) was stirred for 1 h. Diethyl ether was added, and the supernatant was decanted. The process was repeated, and the resulting solid was collected by filtration to yield (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine. A solution of (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine (155 mg, 0.43 mmol), 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid (110 mg, 0.43 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (99 mg, 0.52 mmol), DIPEA (0.224 mL, 1.3 mmol) and HOBt (70 mg, 0.52 mmol) in DMF (20 mL) was stirred overnight. The resulting mixture was diluted with NaHCO3 (saturated, aqueous) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide, which was in the next step used without further purification. To a solution of N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide (190 mg, 0.37 mmol) in methylene chloride (5 mL) was added 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (233 mg, 0.55 mmol) and the resulting mixture was stirred overnight, then quenched with excess sodium thiosulfate in saturated aqueous sodium bicarbonate. The mixture was then extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 6.60-8.10 (overlapping m, 14H), 5.15 (s, 2H), 4.75-4.85 (m, 2H), 3.85-4.00 (m, 2H), 2.90-3.10 (m, 2H), 1.50-1.90 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17]O)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CS([Cl:24])(=O)=O.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17][Cl:24])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](/C=C/CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](/C=C/CCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.37 g (16.35 mmol) of trans-(1E)-[4-(3-Hydroxy-propenyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 120 ml CH2Cl2 was treated at 0° C. with 1.4 ml (17.98 mmol) of methanesulfonylchloride, 1.97 ml (24.52 mmol) pyridine and 2 g (16.35 mmol) of DMAP. The reaction mixture was stirred at RT for 3 h, water (5 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.51 g (75%) of trans-(1E)-[4-(3-Chloro-propenyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, mp: 42.5-43.9° C.; MS: 387 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>CN(C)C=O.O1CCCC1.O>[N:46]1[CH:47]=[CH:48][C:43]([NH:42][C:25](=[O:27])[CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)=[CH:44][CH:45]=1
Reactant: Nc1ccncc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)Nc1ccncc1)c1nnc(C)n1-2
Temperature: -5 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
(±)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.7 g) and triethylamine (0.65 ml) are added to a mixed solvent of dimethylformamide (20 ml) and tetrahydrofuran (10 ml). The mixture is cooled to -5° C. and pivaloyl chloride (0.57 ml) is dropwise added at said temperature. Ten minutes later, a solution of 4-aminopyridine (0.43 g) in dimethylformamide (2 ml) and tetrahydrofuran (2 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away and the residue is recrystallized from isopropyl alcohol/isopropyl ether to give 1.29 g of (±)-N-(4-pyridyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine-6-acetamide, melting point 237°-239° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:21])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29])(=[O:25])=[O:24]>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]([OH:21])[CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)c1ccccc1C(=O)NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
Prepared as described in Example 1 from 1-amino-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.2 g) and 2-(methylsulphonyl)benzoic acid (0.12 g). Title compound obtained as white solid (0.090 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][O:24][CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][O:24][CH3:23])[CH:30]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1>O>[SH:1][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: COCc1nc2nc(C)cc(Cl)n2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: COCc1nc2nc(C)cc(S)n2n1
Temperature: 55 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In 350 ml of water was dissolved 24 g of sodium hydrosulfide and 34.5 g of 7-chloro-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine was added thereto, and the mixture was stirred at 55 ° C for one hour. After the reaction mixture was filtered, it was ice-cooled and adjusted to pH 1 with addition of a 2N-hydrochloric acid. The precipitates were collected by filtration, washed with water and with isopropanol, and dried to obtain 30.18 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C@@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@@H]1OB(O)c2cc(O)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3S)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.04 g, 4.16 mmol) in THF (5 mL) was treated with lithium hydroxide (0.478 g, 2.08 mmol) in water (5 mL) at 0° C. The solution was stirred at 0° C. for 1 hour then quenched with 2N HCl to pH 2 and concentrated to approximately half of the entire volume. The precipitated solid was collected by vacuum filtration, then rinsed with cold water and dried to give (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid. The filtrate was neutralized with NaHCO3 and lyophilized. The residue was suspended in water (5-10 mL) and stirred for 10 minutes. The solid was collected by vacuum filtration to give a second portion of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a yellow solid (total product; 0.49 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.30 (s, 1H), 9.08 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 5.38 (d, J=9.38 Hz, 1H), 3.00 (d, J=15.24 Hz, 1H), 2.20 (s, 3H), 2.00 (dd, J=15.24, 10.16 Hz, 1H). MS (ESI) m/z: 221 [M−1].
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:35])(=O)=O.CC([O-])(C)C.[K+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:35])[C@@H:9]([C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Temperature: 23 °C
Yield: 4 %

Procedure:
(1R)—N-benzyl-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine (0.5 g; 0.00127 mol; prepared according to experimental conditions analogous to that of example 38 using the appropriate starting compounds and reaction products) was diluted in 25 ml tetrahydrofurane. Methyl tosylate (0.24 g; 0.00127 mol) was added to the preceding at about 23° C. and then potassium tert-butylate (0.15 g; 0.00127 mol) was added quite slowly. Agitation at about 23° C. was maintained for about two hours and then the mixture was heated to around 60° C. for about 8 hours. The solvent was evaporated and the residue obtained taken up in ethyl acetate and a 10% sodium bicarbonate solution. After phase separation, the organic phase was washed with water and dried over magnesium sulfate. The solvent was then evaporated. After purification over a silica column (eluent: ethyl acetate-heptane/7-3), a light beige solid was obtained in the form of a glue (yield of 4%). Free base. Melting point: 110-112° C. MH+=407.3.
Reaction SMILES: [C:1](OCC)(=[O:23])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[CH2:1]([OH:23])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C/C=C/C(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C/C=C/CO
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)-docosa-2,4,7,10,13,16,19-heptaenoate (14) (0.12 g, 0.34 mmol) was dissolved in dry THF (3 mL) and added dropwise to a stirred suspension of LAH (0.013 g, 0.35 mmol) in dry THF (7 mL) at 0° C. The mixture was stirred at 0° C. for 45 minutes, added saturated NH4Cl (5 mL) and filtered through a short pad of celite. The celite was washed with water (10 mL) and heptane (10 mL) and the combined aqueous layer was extracted with heptane (10 mL). The combined organic layer was dried (MgSO4) and purified by flash chromatography (heptane:EtOAc 7:1). This afforded 0.070 g (66%) of the title compound 16 as colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([CH2:36]N)[CH2:35][CH2:34]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH:33]3[CH2:35][CH2:34]3)=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCC1CC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC2CC2)C1

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and cyclopropanemethylamine, afforded the crude title compound as an orange foam (114 mg); LCMS (method B): RT=3.94 min, M+H+=500. This crude material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:40]([O-])([O-])=O.[Cs+].[Cs+].IC.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:39])[N:7]([C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)[CH3:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(NC(=O)OC(C)(C)C)c12
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(N(C)C(=O)OC(C)(C)C)c12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
t-Butyl(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (45B, 86 mg, 0.159 mmol) was taken up in DMF (1.6 ml). Cs2CO3 (104 mg, 0.318 mmol) followed by iodomethane (10.93 μl, 0.175 mmol) were added. The reaction was allowed to stir at 60° C. for 2 hours. EtOAc and saturated NH4Cl were added. The products were extracted into EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give tert-butyl(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)(methyl)carbamate (46B). Reaction products were carrried forward without purification. MS: [M+H]+ m/z 555.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:26]3=[O:38])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[C:26]3=[O:38])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1CCN(c2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCN(CC(=O)O)C3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl [3-(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenyl)-2-oxoimidazolidin-1-yl]acetate obtained in Example 211 (1.28 g, 2.46 mmol) and trifluoroacetic acid (5 mL) was stirred at room temperature for 4 h. Trifluoroacetic acid was removed in vacuo and water was added to the mixture. The resulting solid was collected, washed with water, diisopropyl ether and dried under reduced pressure to give a solid (1.1 g, 96%).