Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](=[O:29])[NH:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: Nc1ccncc1
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)Nc3ccncc3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one and 4-aminopyridine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Br:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34]N>>[Br:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccc(F)cc1Br
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1Br

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2-bromo-4-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=496.9 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][NH:32]C(OCC1C=CC=CC=1)=O)=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[ClH:43].[H][H]>CO.[Pd]>[ClH:43].[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][NH2:32])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCN
Yield: 107.1 %

Procedure:
A mixture of the product from Example 28B (0.53 g, 0.93 mmol) and 10% Pd/C (0.053 g, 0.047 mmol) in methanol (50 mL) and conc. HCl (86 μL, 1.02 mmol) was hydrogenated under 60 psi of hydrogen gas at ambient temperature for 1 h. The resulting mixture was filtered and concentrated to obtain title compound (0.47 g, quantitative yield). 1H NMR (DMSO-d6) δ: 1.28 (s, 9H), 1.84 (m, 1H), 2.46 (m, 1H), 2.85 (m, 1H), 2.94 (m, 1H), 4.65 (dd, 2H), 5.18 (q, 1H), 6.96 (d, 1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.51 (t, 1H), 7.69 (d, 1H), 7.91 (d, 1H), 8.02 (br s, 2H), 8.59 (s, 1H), 9.19 (s, 1H). 1H NMR (methanol-d4) δ: 1.32 (s, 9H), 1.91 (m, 1H), 2.59 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.45 (dd, 2H), 4.71 (dd, 21H), 5.30 (t, 1H), 7.28 (s, 2H), 7.32 (s, 1H), 7.57 (t, 1H), 7.67 (d, 1H), 7.90 (d, 1H), 8.48 (s, 1H). MS (ESI) m/z: 436.2 [M+H]+ Anal Calcd for C24H29N5O3.HCl.1.8 H2O: C, 57.15; H, 6.71; N, 13.88. Found: C, 57.21; H, 6.55; N, 13.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(ccn2Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (49 mg, 0.13 mmol) in DMF (1 mL) and add sodium hydride (17 mg, 0.42 mmol). Stir the mixture at room temperature for 30 min then add 2-bromomethyl-pyridine hydrobromide (35 mg, 0.14 mmol). Stir the mixture at room temperature for 5 h, then dilute with EtOAc (30 mL) and wash with saturated NaHCO3 (10 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 20% to 80% EtOAc/hexanes as eluent, to give the title compound (32 mg, 52%). MS (ES+) 471.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.55-8.53 (m, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.73 (dt, 1H, J=7.7, 1.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.57-7.55 (m, 2H), 7.45 (d, 1H, J=8.8 Hz), 7.30-7.26 (m, 1H), 7.10 (dd, 1H, J=8.6, 2.0 Hz), 7.03 (d, 1H, J=7.9 Hz), 6.52 (d, 1H, J=3.5 Hz), 5.53 (s, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.27 (t, 2H, J=7.0 Hz).
Reaction SMILES: C([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)CCC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:13][CH:5]=1
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cnc2[nH]cnc2c1

Procedure:
A solution of 6-[(1-oxopentyl)amino)]-2-butylimidazo[4,5-b]pyridine, K2CO3 (956 mg, 6.92 mmol), and 4'-bromomethylbiphenyl-2-tert-butylsulfonamide 1.65 g, 3.46 mmol) in DMF (15 mL) was stirred for 12 h at r.t. The reaction mixture was poured into H2O (50 mL), extracted with EtOAc (2×50 mL), concentrated, and purified (SiO2, 4:1 EtOAc/hexanes) to give 740 mg of 2-butyl-3-[2'-(N-tert-butyl-aminosulfonyl)[1,1']biphenyl-4-yl]methyl-6-[(1-oxopentyl)amino)]-3H-imidazo[4,5-b]pyridine as a foam.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:20]O>>[CH3:20][O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CO
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (26 mg) in anhydrous methanol (1 ml) at 0° C. is treated with ethereal CH2N2 until a yellow color persists. The mixture is stirred 15 more minutes in the cold and then evaporated in vacuo. Chromatography of the residue on silica gel provides benzyl 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]1[C@H:41]2[C@H:37]([O:38][CH2:39][CH2:40]2)[O:36][CH2:35]1)[C@H:9]([OH:30])[CH2:10][N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([S:12]([N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][C@@H:9]([OH:30])[C@@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]2[C@H:41]3[C@H:37]([O:38][CH2:39][CH2:40]3)[O:36][CH2:35]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc(N)c1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (239 mg, 0.394 mmol) in absolute ethanol (3 mL) was combined with Palladium on carbon (10 wt %, 25 mg) and reduced under a Hydrogen atmosphere over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(3-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (153 mg, 67%) as a white solid. H1-NMR (chloroform-D3): 0.96 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.76 (m, 2H), 3.96 (m, 6H), 4.19 (m, 1H), 4.88 (m, 1H), 5.07 (m, 1H), 5.69 (d, 1H), 6.95 (d, 1H), 7.14 (s, 1H), 7.28 (m, 7H). MS(ESI): 600(M+Na).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1.I[CH3:16]>CO>[CH3:16][S:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1
Reactant: OCCCn1c(S)nc2ccccc21
Reactant: CI
Solvent: CO
Product: CSc1nc2ccccc2n1CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered over hyflo and the filtrate is alkalized with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 2-(methylthio)-1H-benzimidazole-1-propanol as a residue.
Reaction SMILES: [O:1]=[C:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[C:14]([F:17])([F:16])=[CH2:15]>>[O:1]=[C:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O:7][C:14]([F:17])([F:16])[CH3:15])(=[O:6])=[O:5]
Reactant: C=C(F)F
Reactant: O=C(C(F)(F)F)C(F)(F)S(=O)(=O)O
Product: CC(F)(F)OS(=O)(=O)C(F)(F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A metal tube containing 2-oxopentafluoropropanesulfonic acid (23.8 g, 0.10 mol) was cooled below -40° C. and vinylidene fluoride (1,1-difluoroethene) (13 g, 0.20 mol) was added. The mixture was shaken and warmed to 25° C. where it was kept for 4 hours. Distillation of the liquid product gave 20.4 g (0.07 mol, 70%) of 1,1-difluoroethyl 2-oxopentafluoropropanesulfonate, bp 62°-63° C. (50 mm Hg): λmax (CCl4) 5.54 (C=O), 6.96 (SO2O) and 7.5-9 μm (CF, SO2); 1H NMR, δ2.06 ppm (t J=14.3 Hz) CH3 ; 19F NMR, -58.3 (q J=14.3 Hz, each member t J=7.1 Hz) 2F, OCF2, -75.0 (t J=8.0 Hz) 3F, CF3 and -106.1 ppm (q J= 8.0 Hz, each member t J=7.1 Hz) 2F, CF2SO2.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[O:15][C:16]3[N:17]=[C:18]([S:27][CH3:28])[N:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[C:21]=3[N:22]=2)=[CH:9][C:8]=1[CH3:29]>ClCCl>[CH3:13][C:12]1[CH:11]=[C:10]([C:14]2[O:15][C:16]3[N:17]=[C:18]([S:27][CH3:28])[N:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[C:21]=3[N:22]=2)[CH:9]=[C:8]([CH3:29])[C:7]=1[OH:6]
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reaction time: 1 h

Procedure:
At −20° C., 0.70 ml of boron tribromide was added slowly to a solution of 2.5 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-7-propoxyoxazolo[5,4-d]pyrimidine in 50 ml of dichloromethane. After 1 h at −20° C. and 2 h at room temperature, the mixture was quenched by addition of saturated aqueous sodium bicarbonate solution, with the temperature being kept below 5° C. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried and concentrated under reduced pressure. This gave 2.0 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13](C(OC(C)(C)C)=O)[CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>CO.[OH-].[Na+]>[F:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[NH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[nH]cc(-c3cc4c(-c5cnc(C6(O)CCC6)s5)c(F)cnc4[nH]3)c2c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-methoxy-1H-indole-1-carboxylate (Example 93B) (140 mg, 0.203 mmol) in methanol (2.00 mL) and 2N sodium hydroxide solution (670 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v ammonium acetate and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.19 (bs, 1H), 11.52 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.41 (d, J=3.51 Hz, 1H), 7.01 (s, 1H), 6.89 (d, J=3.51 Hz, 1H), 6.68 (s, 1H), 3.87 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 435.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.CC[O-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:6]1[CH:7]=[C:3]([C:2]([F:9])([F:8])[F:1])[N:4]=[CH:5]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.0 g (14.7 mmol) 4-(trifluoromethyl)-1H-imidazole are initially introduced into 5.5 ml (4.7 g, 14.7 mmol) 21% strength sodium ethylate solution in ethanol and 1.8 ml (2.7 g, 16.2 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and the filtrate is concentrated in vacuo. Diisopropyl ether is added to the residue, the mixture is filtered again, the filtrate is concentrated again on a rotary evaporator and the residue is dried in vacuo. The product is obtained as a 9:1 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[CH:9][CH:10]=2)[N:5]=1>C(O)C.O1CCCC1>[Cl:3][C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2cc(C=O)c(Cl)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2cc(CO)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a stirred solution of 6.9 g (180 mmol) of sodium borohydride in 250 ml of absolute ethanol, a solution of 15 g (73 mmol) of 2-chloro-3-formyl-7-methylquinoline in 250 ml of dry tetrahydrofuran was added over 15 minutes without cooling. During the addition a slight H2 -evolution and a temperature rise to +28° C. was observed. The reaction mixture was stirred at room temperature for 4 hours and then 4 ml of the reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate, extracted with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo to give a residue of 100 mg. 1H-NMR indicated complete conversion to the alcohol. After 5 hours the whole reaction mixture was worked up in the same way to give 14.8 g 2-chloro-3-hydroxymethyl-7-methylquinoline after evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[NH:16][N:15]=NN=2)[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:20][C:19]([CH2:18][Cl:17])=[N:15][N:16]=2)[CH:3]=1
Reactant: Cn1ncc2c(-c3nnn[nH]3)cc(Br)cc21
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: Cn1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Temperature: 110 °C
Reaction time: 46 h
Yield: 74.4 %

Procedure:
6-Bromo-1-methyl-4-(1H-tetrazol-5-yl)-1H-indazole (604.6 mg, 2.166 mmol) was dissolved in chloroform (20 ml). Chloroacetyl chloride (0.520 ml, 6.49 mmol) was added and the mixture stirred at 110° C. for 46 h. Further chloroacetyl chloride (0.174 ml, 2.166 mmol) was added and the reaction continued stirred at 110° C. for 26 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant white solid was washed with DCM, the solvent removed under vacuum and the solid dried under high vacuum for 18 h to give the title compound as a white solid (528 mg).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].[C:17]([C:20]1[C:21]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>C1COCC1>[OH:19][C:17]([C:20]1[C:21]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:18])[CH2:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C)(O)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 9.5 mL (2.1 eq) of LDA in 15 mL THF at −78° C. was added 2.0 mL of t-butyl acetate (2.1 eq.). The resulting mixture was stirred at −78° C. for 30 minutes after which a solution of N-(3-acetylpyridin-2-yl)pivalamide (1.52 g, 6.90 mmol) in THF was added in a dropwise fashion. The resulting reaction mixture was then stirred at −78° C. for 30 minutes and was brought up to room temperature. The reaction mixture was then quenched with saturated NH4Cl. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with H2O (2×20 mL), brine (lx 20 mL), dried over MgSO4 and concentrated to give the title compound (1.40 g, 61%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.33 (s, 9 H) 1.44 (s, 9 H) 1.58 (s, 3 H) 2.65 (d, J=16.70 Hz, 1 H) 3.06 (d, J=16.70 Hz, 1 H) 5.54 (s, 1 H) 6.96 (dd, J=7.76, 4.83 Hz, 1 H) 7.43 (dd, J=7.91, 1.76 Hz, 1 H) 8.45 (dd, J=4.98, 1.76 Hz, 1 H) 10.29 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]([N:14]1[CH2:17][CH:16]([F:18])[CH2:15]1)=[O:13])[CH2:9][CH2:10][CH3:11])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:9][CH2:10][CH3:11])[C:12]([N:14]1[CH2:15][CH:16]([F:18])[CH2:17]1)=[O:13]
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@@H](N)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester (200 mg, 0.66 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1.6 ml, 20.8 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to provide (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-pentan-1-one trifluoroacetate as a pale brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:26])([CH2:21][C:22](OC)=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>CCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:26])([CH2:21][CH:22]=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC=O)O2
Reaction time: 1 h

Procedure:
A solution of 31.17 g. of (±)-methyl 6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetate in 3.11. of pentane was cooled under N2 to -70° Diisobutylaluminum hydride (24.4% in toluene; 87.3 ml.) in 87 ml. of pentane was added over 14 minutes. After 1.0 hour at -70°, another 8.73 ml. of diisobutylaluminum hydride was added and stirring was continued an addtional 0.25 hour. The reaction was quenched by the careful addition of 250 ml. of methanol at -70° . The mixture was diluted with 1.01. of ether, washed with 0.5 N HCl, H2O, and brine and dried over sodium sulfate. Solvent removal gave a light yellow oil, which was filtered through 500 g. of silica gel with 90:10 benzene-ethyl acetate. Crystallization of the resulting oil from hexane - 30°-60° petroleum ether gave (±) 6-benzyloxy-2,5,7,8-tetramethylchroman - 2-acetaldehyde as a white solid, m.p. 70°-75°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8](OS(C(F)(F)F)(=O)=O)=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:20].[I-:21].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:21])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:20]
Reactant: [I-]
Reactant: O=C1CCc2c(Cl)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c21
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cc(Cl)c(I)c21
Temperature: 25 °C
Yield: 60.8 %

Procedure:
4,6-Dichloro-7-trifluoromethylsulfonyloxyindan-1-one (56.0 g., 0.160 mole), sodium iodide (133.1 g., 0.8 mole), and DMF (320 ml) in a dry apparatus were stirred under nitrogen at a bath temperature at 130° C. for four days, cooled to room temperature, and poured into 1 L of ice-water. The crystals were collected, washed with water, dried overnight in a vacuum oven at 50° C., then sublimed at 170°-190° C. at 0.05 mm to give 38.3 g. of crude product which was recrystalized from toluene to give 31.8 g of the title compound, mp. 170°-172° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][C:17]#N)=[O:14])=[O:8])(=[O:3])[CH3:2].[O:29](CCO)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCC#N)c1
Reactant: OCCOc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCOc2ccccc2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 51.9 %

Procedure:
Cyanomethyl 3-[(2 acetylthiomethyl-3-phenylpropionyl)amino]benzoate (compound of Example 116) (4 g), 2-phenoxyethanol (3 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2 g) are mixed, and the mixture is stirred at 60° C. for 15 hours and extracted with ethyl acetate (50 ml). The extract is washed with 10% hydrochloric acid and water, and ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 50% aqueous acetonitrile and purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate (100 ml). The extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (2.5 g).