Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:34](N)[CH2:35][NH2:36]>C(O)C>[NH:6]1[CH2:34][CH2:35][N:36]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C4=NCCN4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a solution of N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (200 mg) in ethanol (4 ml) was added ethylenediamine (0.09 ml). The resulting mixture was stirred at room temperature overnight, was then concentrated and was mixed with an aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate/tetrahydrofuran, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated, and the residue was recrystallized from ethyl acetate/methanol to obtain N-[4-(2-imidazolin-2-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 92) (60 mg) as colorless crystals.
Reaction SMILES: Cl[C:2](=[CH:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].CN(C=O)C.[SH:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>O>[OH:8][CH:7]1[N:19]2[C:15](=[N:16][C:17]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=32)[S:14][CH:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)=CO
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1Sc2nc3cc(C(=O)O)ccc3n2C1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Methyl 2-chloro-3-hydroxypropenoate (114 g) was added to DMF (460 ml) solution of 2-mercaptobenzoimidazole-5-carboxylic acid (135 g), and the mixture was stirred overnight at 60° C. After cooling to room temperature, water (3 L) was gradually added to the reaction solution and stirred. The thus precipitated crystals were collected by filtration to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,7-dicarboxylate (168 g). Next, the thus obtained crude crystals were suspended in 1,4-dioxane (1.5 L), and the suspension was mixed with 4 M HCl 1,4-dioxane solution (500 ml) and stirred at room temperature for 60 hours. The resulting precipitate was collected by filtration and washed with 1,4-dioxane to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,6-dicarboxylate hydrochloride (189 g). The thus obtained crude crystals were slowly added to concentrated sulfuric acid (750 ml) which was heated at 60° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the thus precipitated crystals were collected by filtration to obtain the title compound (152 g).
Reaction SMILES: [OH:1][CH:2]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][O:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.CNN.C(OCC)C>ClCCl>[NH2:5][O:4][CH2:3][CH:2]([OH:1])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(O)CON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C(O)CON
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of 2-(2-hydroxy-3,3-dimethyl-butoxy)-isoindole-1,3-dione (1.47 g, 5.60 mmol) in dichloromethane (20 mL) cooled to 0° C. was added methylhydrazine (0.31 mL, 5.90 mmol). The white suspension was allowed to stir for 16 hours at room temperature. Diethyl ether (50 mL) was added and the solids were removed by filtration. The filtrate was concentrated, diluted with diethyl ether and the solids were removed by filtration. This procedure was repeated twice more and the final filtrate was concentrated to provide the desired product as a yellow liquid (0.643 g, 86%). 1H NMR (400 MHz, CDCl3) δ 4.87 (br s, 2H), 3.85 (q, 1H), 3.58 (q, 2H), 0.93 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O.[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[N:15]=[C:16]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[C:17]3[S:22][C:21]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[CH:20][C:18]=3[N:19]=1)[CH:6]=[CH:5]2
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cc(F)ccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 51.1 %

Procedure:
A solution of 5-fluoroindole (0.148 g) in DMF (6 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 3 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The solid separated was filtered, and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 120 (0.252 g, 51%) as a off white solid. MS m/e 495 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, 2H) 2.08 (t, 3H) 2.18 (s, 6H) 2.95 (d, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.75 (d, 1H) 7.0-7.10 (m, 1H) 7.37 (s, 1H) 7.6-7.7 (m, 1H) 8.33 (d, 1H) 8.5-8.6 (d, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][CH:52]1[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[N:53]1[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[C:62]([O:61][C:59]([N:53]1[CH:52]([CH2:51][N:37]2[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]2)[CH2:56][O:55][C:54]1([CH3:57])[CH3:58])=[O:60])([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1C(CO)COC1(C)C
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC2COC(C)(C)N2C(=O)OC(C)(C)C)c1C(=O)OCC
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a stirred solution of triphenylphosphine (5.84 g, 22.25 mmol) in THF (20 mL) was added DIAD (4.50 g 22.25 mmol) dropwise at 0° C. and the resulting solution was stirred for 15 min. Intermediate 104C (3.0 g, 8.90 mmol) in THF (20 mL) was added slowly at 0° C. and stirred at room temperature for 45 min. Intermediate tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.470 g, 10.68 mmol) in THF (20 mL) was added at 0° C. and resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the crude compound was purified by silica gel chromatography (40 g REDISEP® column, eluting with 10-13% ethyl acetate in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 351A (3.5 g, 58.5%) as a pale yellow oil. MS(ES): m/z=552 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.53-4.18 (m, 6H), 3.96-3.82 (m, 2H), 1.50-1.21 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18](F)[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].[OH-].[K+]>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:17]=[C:18]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[C:19]([N+:23]([O-:25])=[O:24])=[C:20]([F:22])[CH:21]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O
Temperature: 70 °C

Procedure:
To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (5.0 g, 12.1 mmol, example 24f) and 2,2,2-trifluoroethanol (24.49 g, 242 mmol) was added pulverized KOH (0.694 g, 12.1 mmol) and the reaction mixture was heated at 70° C. for 3 h. The reaction mixture was evaporated and after addition of ice-water the product was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from Et2O-hexane as light yellow crystals: TLC (toluene-EtOAc 3:1) Rf=0.17; HPLC RtA=2.28 min; ESIMS [M+H-isobutylene]+=429; 1H NMR (600 MHz, DMSO-d6): δ 7.13 (s, 1H), 7.10 (d, 1H), 6.76 (d, 1H), 5.10 (s, 1H), 5.01 (m, 2H), 3.37 (m, 1H), 3.19 (dd, 1H), 2.92 (dd, 1H), 2.55 (d, 1H), 2.48 (dd, 1H), 2.37 (dd, 1H), 2.31 (d, 1H), 2.25 (dd, 1H), 1.95 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH:12]([CH3:16])[C:13](O)=[O:14]>>[Cl:11][CH:12]([CH3:16])[C:13]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)=[O:14]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC(Cl)C(=O)O
Product: CC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1

Procedure:
81.1 g (600 mmol) 2-benzoxazolinone are dissolved at 80° C. in 720 g polyphosphoric acid. Then 66.1 ml (720 mmol) 2-chloropropionic acid are added dropwise and the mixture is heated for 3 h to 125° C., then the reaction mixture is poured onto ice water, the precipitated product is suction filtered, washed with water and dried at 98° C. in the circulating air dryer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:11][CH3:12])[NH2:8]
Reactant: CSc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(N)cc1Cl
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
To a mixture of the compound from stage (i) (14.08 g, 69 mmol) in acetic acid (300 mL) and water (60 mL) was added Fe powder (23 g, 412 mmol) and the reaction mixture was swirled until all the starting material had dissolved. The mixture was left to stand for 1.5 h and the acetic acid was then removed under reduced pressure. The residue was taken up in sat NaHCO3 (aq) (500 mL) and EtOAc (500 mL) and filtered through Arbacel®. The layers were separated, the aqueous phase was extracted with EtOAc (300 mL) and the combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (11.52 g, 96%) as a beige solid; δH (400 MHz, CDCl3) 2.38 (3H, s), 3.66 (2H, br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d); MS m/z (ES+) 174 (MH+).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F-].[K+].[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27](O)([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl>[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27]([F:7])([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)C1C(=O)NC1CC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a -78° cold solution of 3 ml of diethylaminosulphurtrifluoride and 1.7 g of potassium fluoride in 80 ml of dichloromethane is added a solution of 3.2 g of (3SR,4RS)-3-(1-hydroxy-1-methyethyl)-2-oxoazetidine-4-yl acetic acid benzylester in 170 ml of dichloromethane. This mixture is stirred for 15 minutes at -78° and then mixed with water. After addition of further dichloromethane the phases are separated and the organic phase washed with saturated NaCl, dried over MgSO4 and evaporated to dryness. Chromatography of the residue over silica gel (ethylacetate/cyclohexane=1/1) yields the title compound m.p. 112°-116°.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
0.5 g (1.1 mmole) of Z-L-Tyr-Gly-Gly-OMe was dissolved in 3 mL of methanol. Two equivalents of 4 N NaOH were added, and the reaction was stirred for 2 hours, at which time TLC revealed all the starting material had been consumed. (Rf :Z-Tyr-Gly-Gly-OMe, 0.76: Z-Tyr-Gly-Gly-OH, 0.32.) The pH was adjusted to neutrality with 6N HCl and the reaction concentrated under vacuum. 0.5 mL of water was added and the pH dropped to 2. This aqueous solution was washed (4x) with ethyl acetate and the combined ethyl acetate fractions were dried over MgSO4, then concentrated under vacuum. The residue was crystallized from CH2Cl2 /hexanes. Yield 450 mg (95%). M.P. 213°-214° C. (lit. 214°-215° C.). [α]D -23.9 (c 1.2, DMF). Amino acid analysis: tyr1.0, gly1.9.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)=O.[NH3:28]>CO>[C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)(=[O:2])[NH2:28]
Reactant: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Reactant: N
Solvent: CO
Product: CC(COc1ccc(CC(N)=O)cc1Cl)NCC(O)c1cccc(Cl)c1

Procedure:
A solution of 2 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Example 22) dissolved in 50 ml of methanol was saturated with gaseous ammonia in a reaction vessel, whilst ice-cooling, after which the reaction vessel was tightly stoppered and allowed to stand at room temperature for one week. At the end of this time, the solvent (methanol) was removed by distillation under reduced pressure, and the residue was recrystallized from ethyl acetate, to give 0.55 g of the title compound as crystals, melting at 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:20]=[C:21]([CH:26]=[C:27]([CH3:29])[N:28]=4)[C:22](OC)=[O:23])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[AlH4-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:20]=[C:21]([CH2:22][OH:23])[CH:26]=[C:27]([CH3:29])[N:28]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1cc(C)nc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of methyl 2-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)-6-methylisonicotinate (prepared as described for Example 13, using methyl 2-bromo-6-methylisonicotinate) (55.0 mg, 0.137 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) at 0° C. was slowly added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.20 mL). The reaction was stirred at 0° C. for 30 minutes, and then quenched by the sequential addition of 8 μL water, then 8 μL 15% aq NaOH, then 23 μL water. The resulting mixture was diluted with dichloromethane and stirred at room temperature for 10 minutes, then dried with MgSO4 and filtered through celite. The solution was evaporated in vacuo and the crude product was purified via reverse phase HPLC and lyophilized to yield 20.8 mg (41%) of (2-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)-6-methylpyridin-4-yl)methanol. LCMS (ESI): RT (Min)=4.542, M+H=374.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.10 (s, 1H), 8.54 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.5, 1.6 Hz, 1H), 7.42-7.29 (m, 1H), 7.22-7.06 (m, 3H), 6.68 (s, 1H), 5.29 (t, J=5.4 Hz, 1H), 4.46 (d, J=4.7 Hz, 2H), 2.47 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(-c2cccs2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)c(-c2cccs2)c1
Yield: 75.5 %

Procedure:
3 g (13.5 mmol) of 4-nitro-2-(2-thienyl)phenol are dissolved in 40 ml ethanol and hydrogenated at 25° C. after addition of 600 mg of a palladium activated carbon catalyst (10%). The catalyst is removed by filtration after up-take of the theoretically required amount of hydrogen. After concentrating the solution in a rotary evaporator the reaction mixture is poured into 20 ml of cold diethyl ether. The precipitated product is separated from the solution by filtration and dried. 1.95 g (75% of theoretical yield) of 4-amino-2-(2-thienyl)phenol are obtained with a melting point of 130 to 132° C.
Reaction SMILES: [C:1](=[O:20])([O:5][CH:6]([N:8]1[N:12]=[N:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[I:19])=[N:9]1)[CH3:7])[O:2][CH2:3][CH3:4].C(=O)(O[C@@H](N1N=NC(C2N(C)N=CC=2I)=N1)C)OCC>>[C:1](=[O:20])([O:5][C@H:6]([N:8]1[N:12]=[N:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[I:19])=[N:9]1)[CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOC(=O)OC(C)n1nnc(-c2c(I)cnn2C)n1
Agent: CCOC(=O)O[C@H](C)n1nnc(-c2c(I)cnn2C)n1
Product: CCOC(=O)O[C@@H](C)n1nnc(-c2c(I)cnn2C)n1
Yield: 99.22 %

Procedure:
407.5 g of Preparation 23, ethyl 1-[5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazol-2-yl]ethyl carbonate was processed according to Chiral Preparative Chromatography Method 3, followed by concentration of each enantiomer to dryness in vacuo to give isomer 23a (177.4 g, 99.22%, 99.79% e.e.; tR=2.12 min) and isomer 23b (177.74 g, 98.83%, 98.46% e.e; tR=2.59 min).
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[O:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 270-271° C. (diethyl ether).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[CH:11][C:12]([F:27])=[C:13]([N:15]2[C:24](=[O:25])[N:18]3[CH2:19][CH2:20][CH:21](O)[CH2:22][N:17]3[C:16]2=[O:26])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[CH:11][C:12]([F:27])=[C:13]([N:15]2[C:24](=[O:25])[N:18]3[CH2:19][CH2:20][CH:21]([Cl:30])[CH2:22][N:17]3[C:16]2=[O:26])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n2n1CCC(O)C2
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n2n1CCC(Cl)C2
Yield: 90.1 %

Procedure:
A mixture of 212 mg (0.523 mmol) of 2-(5-benzyloxy-4-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-6-hydroxy-1H-[1,2,4]triazolo[1,2-α]pyridazine-1,3(2H)-dione (0.523 mmol), 76 μL of CCl4 (0.784 mmol), and 206 mg of triphenylphosphine (0.784 mmol) in 8 mL of dichloromethane was warmed under reflux for 2h. The mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1: 1 v:v mixture of ethyl acetate and n-hexane to give 200 mg of the title product of Step C, a compound of the invention, as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 2.3 (m, 2H), 3.5 (m, 2H), 3.9 (m, 2H), 4.4 (m, 1H), 5.1 (s, 2H), 7.0 (d, 1H), 7.4 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:35][CH:34]=1
Reactant: OC(CC1CCCCC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 8 h
Yield: 31.2 %

Procedure:
A solution of (±)-2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethanol (0.184 g, 0.527 mmol), 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (0.136 g, 0.608 mmol), and triphenylphosphine (0.208 g, 0.791 mmol) in toluene (8.0 mL) is treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.206 g, 0.817 mmol) and stirred overnight. The reaction mixture is filtered through Celite® diluted with EtOAc, washed with water (2×), brine (1×), dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 25% EtOAc to 100% EtOAc giving (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid methyl ester (0.091 g, 31%) as a white foam. MS (ES): 554.0 [M+H]+.
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C)[C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:23]2[C@@H:18]([NH:19][C:20]([NH:22]2)=[O:21])[CH2:17][S:16]1)=[O:8].[OH-].[Na+]>CO>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:23]2[C@@H:18]([NH:19][C:20]([NH:22]2)=[O:21])[CH2:17][S:16]1)=[O:8]
Reactant: CCCCCCC(=O)N(C(=O)CCCCCC)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(=O)N(C(=O)CCCCC)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 4.5 h

Procedure:
To a solution of 610 mg (0.819 mmol) of N,N-bis-(methyl 6-hexanoyl)-biotinamide in 35 ml of methanol was added 5.0 ml of 1N aqueous sodium hydroxide. The mixture was stirred at 15°-25° C. for 4.5 hours and then concentrated. The residue was diluted with 50 ml of deionized water acidified to pH 2 with 1N aqueous hydrochloric acid at 4° C. The product, which precipitated out as a white solid, was isolated by vacuum filtration and dried under vacuum to afford 482 mg (84%):