Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@:9]1([C:40]([F:43])([F:42])[F:41])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:11][CH2:10]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[C:24]3[CH:25]=[C:17]4[CH2:16][CH2:15][CH2:14][C@@H:13]5[CH2:33][C@@:9]([OH:8])([C:40]([F:42])([F:41])[F:43])[CH2:10][CH2:11][C@@:12]5([CH2:34][NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:18]4=[CH:19][C:20]=3[CH:21]=[N:22]2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of N-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)methanesulfonamide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4=Methanesulfonyl, Rx=Benzyl) (40 mg, 0.065 mmol) in DCM (3 mL) was cooled to about 0° C. and treated with BBr3 (1M in hexane, 0.23 mL, 0.23 mmol). The mixture was stirred for about 30 min at rt. The reaction was quenched by addition of MeOH (5 mL) and warmed to rt for about 90 min. Solvents were removed under reduced pressure and the residue was dissolved in DCM (20 mL) and concentrated onto silica gel (1 g). The residue was purified on silica gel (12 g) using a gradient of 30-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL), diluted with water (3 mL) and reduced in volume to about 3 mL under reduced pressure. The product was filtered off and dried under vacuum at about 50° C. to yield N-(((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)methanesulfonamide (36, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4=Methanesulfonyl) (23 mg, 67%) as an off-white solid. LC/MS, method 2, Rt=2.49 min, MS m/z 526 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.25 (d, J=0.6 Hz, 1H), 7.84 (s, 1H), 7.79-7.72 (m, 2H), 7.55 (s, 1H), 7.42-7.34 (m, 2H), 6.29 (t, J=6.7 Hz, 1H), 5.89 (s, 1H), 3.90-3.81 (m, 1H), 3.36-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.00-2.90 (m, 1H), 2.61 (s, 3H), 2.28-2.20 (m, 1H), 2.14-2.03 (m, 1H), 2.02-1.73 (m, 5H), 1.72-1.53 (m, 3H), 1.44-1.30 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[N:9][CH:10]=1)=[N+]=[N-].[ClH:19]>CO.[Pd]>[ClH:19].[F:18][C:13]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(OCC(F)(F)C(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a stirred solution of 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (110 mg, 2.1 mmol, Step-2) in methanol (3.5 mL) and 2M hydrochloric acid (0.2 mL) is added palladium 10% on carbon (10 mg). The mixture is stirred at room temperature under hydrogen atmosphere (1 atm) for 4 hours. The mixture is filtered through a pad of celite and washed with methanol. The filtrate is concentrated in vacuo to give 110 mg (93% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: OC1CCNCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCC(O)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and piperidin-4-ol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: C([Li])CCC.[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.Br[CH2:23][C:24]([CH3:26])=[CH2:25]>C1COCC1>[CH3:25][C:24](=[CH2:23])[CH2:26][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:13]([OH:15])=[O:14]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamino (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and coolling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](O)([CH3:19])[C:16]([OH:18])=[O:17].C1C2SC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(C(OCC)=O)=O.[Al+3].[Cl-].[Cl-].[Cl-].C1(C(=O)C(O)=O)C2SC3C(=CC=CC=3)SC=2C=CC=1.C[Mg]I.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl.CCOCC.C1(C)C(C)=CC=CC=1>[CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:19])[C:16]([OH:18])=[O:17]
Reactant: CC(O)(C(=O)O)c1ccc2c(c1)Sc1ccccc1S2
Agent: CCOC(=O)C(=O)Cl
Agent: C[Mg]I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ccccc1S2

Procedure:
33 g. of the ethyl ester of 2-(2-thianthrenyl)-2-hydroxypropionic acid (obtainable by reacting thianthrene with ethoxalyl chloride in 1,2-dichloroethane in the presence of AlCl3 at 10°-20° and reacting the thus-obtained ethyl ester of 2-thianthrenylglyoxylic acid (m.p. 68°-69°) with CH3MgI in ether) is dissolved in 500 ml. of xylene; 1 g. of p-toluenesulfonic acid is added thereto, and the mixture is refluxed for 31/2 hours with the use of a water trap. After cooling, the reaction mixture is washed with sodium bicarbonate solution and water, separated, dried over sodium sulfate, and evaporated. The thus-produced oily ethyl ester of 2-(2-thianthrenyl)-acrylic acid is dissolved in 270 ml. of ethanol and hydrogenated on 8 g. of 4% palladium charcoal at 50° and under 6 atmospheres until the hydrogen absorption is terminated (3 hours). The product is filtered, concentrated by evaporation, and the ethyl ester of 2-(2-thianthrenyl)-propionic acid is thus obtained, b.p. 225°-229°/0.2 mm.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:11]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2>ClCCl.CC(O)C.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:10]=[C:9]([N:8]3[CH:1]4[CH2:7][CH2:6][CH:5]3[CH2:4][O:3][CH2:2]4)[N:14]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(NC3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ccc(-c2nc(NC3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 16 h
Yield: 90.5 %

Procedure:
In a 250 mL round bottom flask was placed 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (82 mg, 0.199 mmol) in dichloromethane (7 mL) and 2-propanol (7 mL). A catalytic amount of palladium on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was diluted with dichloromethane, filtered over Celite™ and concentrated to give 69 mg (0.18 mmol, 91%) of a tan solid. HRMS: 382.2236 [M+H]+. For [M+H]+ mass error=−0.1 mDa or −0.35 ppm.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CO[CH:7](OC)[CH2:8][N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)S(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[CH:20]=[N:9][CH:8]=[CH:7]2
Reactant: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1ccc2cnccc2c1
Reaction time: 8 h
Yield: 29.8 %

Procedure:
41.6 g of AlCl3 were suspended in 400 mL of dichloromethane. At room temperature, a solution of 22.95 g N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the layers were separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) was purified by silica gel chromatography to yield 2.74 g of compound 3. Rt=0.30 min (Method C). Detected mass: 148.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:16]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:20]=[N:16][NH:17][CH:18]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: OB(O)c1cn[nH]c1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3cn[nH]c3)n2n1
Temperature: 160 °C
Yield: 63.3 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (100 mg, 0.37 mmol), (1H-pyrazol-4-yl)boronic acid (90 mg, 0.45 mmol), dichloro-bis(triphenylphosphino) palladium (II) (15 mg, 0.021 mmol), potassium phosphate (80 mg, 0.56 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford butyl-[3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine (60 mg, 62%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (s, 1H), 7.59 (d, J=9.6 Hz, 1H), 6.67 (d, J=9.6 Hz, 1H), 3.44 (t, J=7.1 Hz, 1H), 1.70-1.80 (m, 1H), 1.46-1.59 (m, 1H), 1.03 (t, J=7.3 Hz, 1H); LCMS (ESI) m/e 257.3 [(M+H)+, calcd for C13H17N6 257.1].
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48])=[O:19])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Reactant: COC(=O)[C@H](O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1

Procedure:
A solution of 44.4 mg product from Step D Example 1, 28.8 mg EDC, 20.3 mg HOBt, 31.1 mg methyl (2R)-3-amino-2-hydroxypropanoate hydrochloride from Step C above and 70 μL DIEA in 1 mL DMF was stirred at room temperature over night. The title compound was isolated by preparative HPLC using 55˜75% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column as a white solid after lyophilization. LC-MS: 2.55 min. (M+H=546.3).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[O:7]=[CH:8][CH2:9][CH2:10][C:11](OCC(C)C)=O>>[O:5]=[C:4]1[CH2:3][N:2]2[C:8](=[O:7])[CH2:9][CH2:10][CH:11]2[NH:6]1
Reactant: NCC(N)=O
Reactant: CC(C)COC(=O)CCC=O
Agent: Cl
Product: O=C1CN2C(=O)CCC2N1
Yield: 22.6 %

Procedure:
Glycinamide hydrochloride (4.2 g, 38 mmol) and isobutyl 4-oxobutanoate (5 g, 31.6 mmol) were reacted together according to the procedure of example 2, to give the title compound 1 g (22.6%), m.p. 154°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1.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>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: OCc1ccc(Br)cc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(Br)cc1

Procedure:
To a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 52 mg 4-bromobenzyl alcohol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 2 h at room temperature 36 mg of triphenylphosphine and 25 mg of diisopropylazo-dicarboxylate were added, and after 16 h again 36 mg of triphenylphosphine and 25 mg of diisopropylazodicarboxylate were added. After additional 24 h the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 96 mg of 2-{[1-(4-bromo-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:7]>[Ti](Cl)(Cl)(Cl)Cl>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:10]=[O:14])=[C:3]([OH:2])[CH:9]=1)[CH3:7]
Reactant: COC(Cl)Cl
Reactant: CCc1cccc(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCc1ccc(C=O)c(O)c1
Reaction time: 0.75 h
Yield: 65.3 %

Procedure:
Titanium(IV) chloride (100 mL, 100 mmol, 1M in CH2Cl2) followed by dichloromethyl methyl ether (7.47 mL, 82.5 mmol) was added to a cooled 0° C. solution of 3-ethylphenol (6.11 g, 50 mmol). The reaction mixture was stirred for 45 mins. The mixture was poured into ice and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a bright pink oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave 4-ethyl-2-hydroxy-benzaldehyde (4.9 g, 65%) followed by 2-ethyl-4-hydroxy-benzaldehyde (1.32 g, 18%). A: 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=7.6 Hz, 3H), 2.67 (d, J=7.6 Hz, 2H), 6.82 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 9.83 (s, 1H), 11.05 (s, 1H). B: 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.6 Hz, 3H), 3.03 (d, J=7.6 Hz, 2H), 6.68 (s, 1H), 6.78 (s, 1H), 6.82 (d, J=8.3 Hz, 1H), 7.77 (t, J=8.3 Hz, 1H), 10.10 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][N:22]1[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]1>C(#N)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:24][CH2:23]1
Reactant: CN1CCN(C)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 49.1 %

Procedure:
A solution of 11-(2-chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (5 g) and N,N'-dimethylpiperazine (4 g) in acetonitrile (100 ml) was heated to reflux for 2 hours. The mixture was evaporated and the residue, crystallized from methanol, yielded 3 g (42.9%) of 11-[2-(4-methylpiperazin-1-yl)-acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one N1 -chloromethylate melting at 198°-200° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:6](O)=[O:7])#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C1COCC1.C(Cl)Cl.O.CCOC(C)=O>[C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:6]([N:29]=[N+:30]=[N-:31])=[O:7])#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccc(C(=O)O)c(F)c1C#N
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(=O)N=[N+]=[N-])c(F)c1C#N
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a stirred solution of the above benzoic acid intermediate (3 g, 14.34 mmol) and triethylamine (4.5 g, 44.47 mmol) in dry THF (30 mL) at −10° C. was added ethyl chloroformate (2.5 g, 23.04 mmol). The reaction was stirred for 1 h and monitored by TLC (20% EtOAc in CH2Cl2). A solution of NaN3 (2.3 g, 35.34 mmol) in water (15 mL) was added dropwise to the mixture and stirred for 2 h. The mixture was diluted with water (40 mL) and extracted with toluene (3×20 mL). The extract was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give 3-cyano-4-ethoxy-2-fluoro-benzoyl azide (2.5 g, 39.2%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(OCI)OC1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 74.7 %

Procedure:
In the same manner as in Example 81, 372 mg of the title compound was prepared from 374 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 336 mg of cyclohexyloxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][C:40](F)=[C:39](F)[CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[N:33](C)[CH3:34])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC=CC=3)C=C(C(=O)NC[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])C=2)C=1CCC(=O)NOCC)C.[OH-].[Na+]>C1COCC1.CCO>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Reactant: CCONC(=O)CCc1c(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)cccc1OCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)c1CCC(=O)O
Yield: 80 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-bi phenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbamoyl-ethyl)-phenoxy]-butyric acid ethyl ester (176 mg, 0.23 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (129 mg, 80%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCO.CCO.CCO.CCO.[Ti].C(O)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:8][C:7]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 6 h

Procedure:
A mixture of 3.59 g (10 mmol) of tert.butyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 1.5 g (6 mmol) of tetraethyl orthotitanate and 30 ml of benzyl alcohol is stirred at 130° for 6 hours, a small amount of solvent being distilled off in vacuo twice. The mixture is subsequently evaporated in a high vacuum, the residue is taken up in 40 ml of chloroform, the solution is treated with 40 ml of concentrated hydrochloric acid/water (1:1) and the mixture is stirred until both phases are clear. The chloroform solution is washed successively with 20 ml of 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from ethyl acetate and there is obtained benzyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 180°-182°.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S1C=CC=C1>C1(C)C=CC=CC=1.[Rh]>[C:15]1([CH:14]([NH:21][CH:5]2[CH:6]3[CH2:11][C:2]4([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]2[CH2:3]4)[CH2:7]3)[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: C[C@H](N)c1ccccc1
Agent: [Rh]
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: c1ccsc1
Solvent: Cc1ccccc1
Product: CC(NC1C2CC3CC1CC(O)(C3)C2)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Commercially available 5-hydroxyadamantan-2-one (0.1 mol), L(-)-Alpha-methyl-benzyl amine (0.105 mol), aluminium isopropoxide (0.1 mol) and Rhodium on active carbon (20 mol %) were suspended in 500 ml of toluene, 20 ml of the 4% thiophene solution were added. The reaction mixture was stirred at 50° C. for 24 h.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:20][CH2:19][CH2:18][CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCN1CCCC1
Reactant: Clc1ccc2ncc(Br)n2n1
Product: Brc1cnc2ccc(NCCCN3CCCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(pyrrolidin-1-yl)propan-1-amine according to general procedure 1 providing the intermediate (227 mg, 81%) as a clear oil; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=9.6 Hz, 1H), 7.44 (s, 1H), 6.40 (brs, 1H), 6.35 (d, J=9.6 Hz, 1H), 3.52 (quart, J=5.2 Hz, 2H), 2.67 (t, J=6.2 Hz, 2H), 2.57-2.54 (m, 4H), 1.86 (quin, J=6.3 Hz, 2H), 1.84-1.78 (m, 4H); ES-MS: (M+H)=324, 326 m/z.