Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:17][CH:15]([CH2:16]2)[O:14][C:13](=[O:18])[NH:12]3)=[CH:7][CH:6]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C(N(CC)CC)C>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:17][CH:15]([CH2:16]4)[O:14][C:13](=[O:18])[NH:12]5)=[CH:7][CH:6]=3)[N:33]=[C:29]2[N:28]=1
Reactant: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Reactant: COc1ccnc(N)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C45CC(C4)OC(=O)N5)cc3)nc2n1
Temperature: 100 °C

Procedure:
A mixture of crude 5-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.5 g), 4-methoxypyrimidin-2-amine (1.26 g), triethylamine (0.84 mL) and ethanol (62 mL), under argon, was heated at 100° C. (bath temperature) for 6 hours. On cooling the reaction was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried and concentrated. Purification was achieved by chromatography on silica gel followed by preparative reverse phase HPLC to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C2=NN(CCc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(CCc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-Phenethyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.07 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.20 (m, 5H), 6.91 (m, 2H), 4.56 (s, 2H), 4.11 (t, 2H), 3.12 (t, 2H), 2.21 (s, 3H) ppm. MS calculated for C26H22FN3O4S—H: 490, observed: 490.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:33]([C:28]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=2)(=[O:35])=[O:34])=[CH:15][C:14]=1[Cl:20]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 3,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][C:11]1[C:19]3[C:18]([C:20]([O:22]C)=[O:21])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][N:12]=1)[CH2:2]2.O.O.[OH-].[Li+:27]>C1COCC1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][CH2:10][C:11]1[C:19]3[C:18]([C:20]([O-:22])=[O:21])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][N:12]=1)[CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate (1.8 g, 5.7 mmol) from Step A above in THF (30 ml) and H2O (30 ml) was added lithium hydroxide monohydrate (721 mg, 17.2 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (R)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 301 (M+H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C-:20]#[N:21].C([Al+]CC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]#[N:21]
Reactant: N#CCc1ccccc1
Reactant: [C-]#N
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[Al+]CC
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(N)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
10 millimoles (1.17 g) of benzyl cyanide are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. 15 millimoles of 1.5 M toluenic solution of diisobutylaluminum hydride (10 ml) are added, dropwise, at this temperature. The temperature is maintained at 0° C. for one hour, then 13.7 ml (viz 1.5 eq) of diethyl-aluminum cyanide are added. The reaction mixture is stirred for 3 hours while the temperature reaches the room temperature. Then it is hydrolyzed with 10 ml of methanol, and with a slurry of sodium sulfate. After purification of the so-obtained α-aminonitrile, by ethyl acetate/petroleum ether, there are obtained 0.95 g of 2-amino-3-phenyl-propionitrile, in the form of an orange-colored oil, yield: 65%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:24]N(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.CO>[C:14]1([C@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]2[C:20]([O:22][CH3:24])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](C(=O)O)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of (3S,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid (1.12 g) in DMF (12 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.41 g), N,N-dimethylaminopyridine (992 mg), triethylamine (1.02 ml) and methanol (595 μl), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (1.00 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:19]([CH3:20])[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:2]=2[CH:7]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Product: Cc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 1-Bromo-5-fluoro-2-nitrobenzene and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown solid (75 mg, 66%). 1H NMR (DMSO) δ 2.50 (s, 3 H), 7.11 (d, 1 H), 7.21-7.29 (m, 1H), 7.59-7.69 (m, 5 H), 7.79 (br s, 1 H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:24])[C@H:19]1[CH2:23][S:22][CH2:21][NH:20]1)[CH3:16].C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH2:15]([O:17][C:18](=[O:24])[C@H:19]1[CH:23]([C:12](=[O:14])[CH2:11][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[S:22][CH2:21][NH:20]1)[CH3:16]
Reactant: CCOC(=O)[C@H]1CSCN1
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: CCOC(=O)[C@@H]1NCSC1C(=O)C[C@H]1CCc2ccccc2C1
Yield: 83 %

Procedure:
Colorless crystals of 3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioproline ethyl ester were prepared in the same manner as in Reference Example 1, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and D-thioproline ethyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 83%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl.[CH3:10][O:11][C:12]1[C:30]([O:31][CH3:32])=[CH:29][C:15]([CH2:16][CH2:17][NH:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:14][C:13]=1[OH:33].[BH4-].[Na+]>CO>[CH3:32][O:31][C:30]1[CH:29]=[C:15]2[C:14](=[C:13]([OH:33])[C:12]=1[O:11][CH3:10])[CH:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[NH:18][CH2:17][CH2:16]2
Reactant: COc1cc(CCNC(=O)Cc2ccc(F)cc2)cc(O)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(c(O)c1OC)C(Cc1ccc(F)cc1)NCC2
Temperature: 55 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Phosphoryl chloride (370 μl, 3.97 mmol) was added to a chloroform (6 ml)solution of N-(4,5-dimethoxy-3-hydroxyphenethyl)-4-fluorophenylacetamide (437 mg, 1.31 mmol) at room temperature, and the mixture was stirred undera nitrogen atmosphere at 55° C. for 8 hours. The solvent and the excess phosphoryl chloride were removed under reduced pressure and the resultant residue was dissolved in methanol (25 ml). Sodium borohydride (65 mg, 1.72 mmol) was added to this methanol solution under ice cooling and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, brine (50 ml) was added to the resultant residue, and the mixture was extracted three times with chloroform (30 ml). The organiclayer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resultant residue was recrystallized from ethyl acetate-hexane to give 199 mg (yield: 48%) of the captioned compoundas a colorless solid. Melting point: 195°-200° C. FAB-MS (m/z, (C18H20NO3F+H)+): 318 1H-NMR (300MHz, CD3OD, δ ppm): 2.97-3.08 (3H, m), 3.22-3.34 (1H, m), 3.46-3.55(2H, m), 3.78 (3H,(2H, m), 7.34-7.38 (2H, m)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].CN1CCCC1=O.CCN(C(C)C)C(C)C>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(O)CN
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(NCC(C)(C)O)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A 20 mL reaction vial equipped with a stir bar was charged with 4-fluoro-2-methoxy-1-nitrobenzene (0.5 g, 2.92 mmol), 1-amino-2-methylpropan-2-ol (0.313 g, 3.51 mmol), N-methyl-2-pyrrolidinone (7.3 mL) and Hunig's base (N,N-diisopropylethylamine) (0.76 g, 5.84 mmol). The vessel was sealed and the reaction was heated on a thermal block at 80° C. for 24 hours. The reaction was cooled to ambient temperature, treated with water (40 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (2×25 mL), dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash chromatography on a 10 g silica gel column eluting with 1% methanol/CH2Cl2 to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 1.16 (s, 6H) 3.10 (d, 2H) 3.84 (s, 3H) 4.58 (s, 1H) 6.35 (m, 2H) 6.96 (m, 1H) 7.83 (d, 1H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2)[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:11]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH2:10][CH2:9][OH:8])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]=2[CH:23]=1
Reactant: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: OCC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of [(S)-3-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]-(9H-purin-6-yl)amine (296 mg, 0.6 mmol) in anhydrous DCM (6 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron tribromide (1.0 M in DCM, 1.2 mL, 1.2 mmol). The reaction mixture was stirred at 0° C. for 1 h. MeOH was then added and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 187 (160 mg, 66%). LCMS (Method K): RT 3.10 min [M+H]+ 404.1 1H NMR (DMSO-d6, 400 MHz): δ 12.55 (1H, s), 8.28-7.83 (3H, m), 7.81-7.44 (6H, m), 7.16-7.01 (1 m), 6.91-6.79 (1H, m), 5.56 (1H, br s), 4.60 (1H, br s), 3.57-3.38 (2H, m), 2.23-2.00 (2H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH:2]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>O>[C:15]([C:9]1[CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([CH2:11][CH:10]=1)[C:1]([O:13][CH3:14])=[O:12])(=[O:17])[CH3:16]
Reactant: COC(=O)C1CC=CCC1C(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C1CC=C(C(C)=O)CC1C(=O)OC

Procedure:
10 g dimethyl 1,2,3,6-tetrahydro-phthalate (II) was treated at -5° C. with 25 ml of acetic anhydride in the presence of 9 ml of tin tetrachloride. The reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and was then evaporated to dryness under vacuum. The obtained oil was dissolved in benzene, treated with a methanolic solution of hydrogen chloride. The solution was evaporated to dryness and the residue was purified by chromatography on column of silica gel to give 9 g of the title compound in 75% overall yield. mass spectrum: m/z 240 (M+.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6](Cl)(=[O:8])=[O:7].[NH2:13][C:14]1[C:15](=[O:29])[N:16]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([CH3:20])=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6]([NH:13][C:14]1[C:15](=[O:29])[N:16]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Product: Cc1ccc(NS(=O)(=O)Cc2cccc(Cl)c2)c(=O)n1CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 3-chlorobenzylsulfonyl chloride (113 mg, 0.5 mmol), as prepared in the preceding step, and 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (120 mg, 0.5 mmol), as prepared in step 3 of Example 1, using the procedure in step 4 of Example 1, as a white solid (180 mg, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.37 (d, J=7.6 Hz, 1H), 7.30 (m, 4H), 7.20 (s, 1H), 6.02 (d, J=7.7 Hz, 1H), 4.78 (s, 2H), 4.27 (s, 2H), 2.27 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:11][C:10]([C:18]([OH:20])=[O:19])=[N:9]1.C(OC(C1C=C(N)N(C2C=CC=CC=2F)N=1)=O)C>>[C:3]1([N:8]2[C:12]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[CH:11][C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cc(N2CCCC2)n(-c2ccccc2F)n1
Agent: CCOC(=O)c1cc(N)n(-c2ccccc2F)n1
Product: O=C(O)c1cc(N2CCCC2)n(-c2ccccc2)n1

Procedure:
According to this procedure 1-(2-Fluoro-phenyl)-5-pyrrolidin-1-yl-1H-pyrazole-3-carboxylic acid is prepared starting from 5-Amino-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2([OH:17])[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][C:22]1[C:27]2[O:28][C@H:29]([CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:30][O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[C:27]2[O:28][C@@H:29]([CH2:32][N:16]3[CH:11]4[CH2:12][CH2:13][CH:14]3[CH2:15][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=3)([OH:17])[CH2:10]4)[CH2:30][O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CC2CCC(C1)N2
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1cccc(C(F)(F)F)c1)C3)CO2
Yield: 68 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(3-trifluromethylphenyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 68%, white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([SH:32])=[N:30][N:31]=2)[CH:28]=1.BrC1C=CC2N(C(SC3C=CC4N(C=C(NC(C5CC5)=O)N=4)N=3)=NN=2)C=1>>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([S:32][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[N:30][N:31]=2)[CH:28]=1
Reactant: COCCOCc1ccc2nnc(S)n2c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Product: COCCOCc1ccc2nnc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
The title compound was prepared from N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide and 6-((2-methoxyethoxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol following the procedure described for the synthesis of Compound 4. 1H NMR (METHANOL-d4, 400 MHz): δ=8.75-8.78 (m, 1H), 8.15 (dd, J=9.3, 1.0 Hz, 1 H), 8.04-8.11 (m, 1 H), 8.02 (d, J=9.3 Hz, 1 H), 7.94 (s, 1 H), 7.56 (d, J=9.3 Hz, 1 H), 4.71 (d, J=1.0 Hz, 2 H), 3.61-3.67 (m, 2 H), 3.47-3.53 (m, 2 H), 3.29 (s, 3 H), 1.80-1.87 (m, 1 H), 0.88-1.01 ppm (m, 4 H). ESI-MS:m/z 440.2 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[OH:9])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Oc1ccnc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1c(Br)cnc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
N-Bromosuccinimide (1.3 g) was added to a DMF solution (15 ml) of 4-hydroxy quinoline (1.0 g) and the mixture was stirred at room temperature for 15 hours. A sodium hydrogencarbonate aqueous solution of 25% sodium sulfite was added to the mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was dissolved in a mixture of ethyl acetate and methanol, and an insoluble matter was removed by filtration. The filtrate was condensed under reduced pressure, and the residue was washed with ethyl acetate and dried to give the title compound (1.1 g) as a white powder.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:44]([O:46][CH3:47])=[O:45])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]3[C:36]4[C:35](=[O:37])[CH2:34][C:33]([CH3:39])([CH3:38])[CH2:32][C:31]=4[O:30][C:29]4[CH2:28][C:27]([CH3:41])([CH3:40])[CH2:26][C:25](=[O:42])[C:24]3=4)[C:16]=2[CH3:43])=[CH:13][CH:14]=1)C1C=CC=CC=1>[C].[Pd].C1COCC1>[OH:8][C:9]1[C:10]([C:44]([O:46][CH3:47])=[O:45])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]3[C:24]4[C:25](=[O:42])[CH2:26][C:27]([CH3:40])([CH3:41])[CH2:28][C:29]=4[O:30][C:31]4[CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](=[O:37])[C:36]3=4)[C:16]=2[CH3:43])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A 10% palladium carbon catalyst (wet) (3.15 g) was added to a solution of the methyl 3-(benzyloxy)-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 11-2 (3.15 g, 4.95 mmol) in THF (63 ml) at room temperature, and the mixture thus obtained was then stirred under a hydrogen atmosphere at room temperature for 3 hours. A solid was removed from the reaction solution by filtration, and the solvent was then distilled away from the filtrate thus obtained under reduced pressure to obtain the title compound (2.58 g, yield: 95%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[I-].[O:10]1[CH2:15][CH2:14][CH:13]([Zn+])[CH2:12][CH2:11]1.C(OCC)(=O)C.[Cl-].[NH4+]>CC(N(C)C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:7]1[C:2]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: [Zn+]C1CCOCC1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Clc1nccnc1C1CCOCC1
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A mixture of copper(I) iodide (0.066 g, 0.35 mmol), Pd(dppf)Cl2 (0.14 g, 0.18 mmol), and 2,3-dichloropyrazine (0.52 g, 3.50 mmol) in DMA (3 mL) was placed under argon atmosphere using 3 evacuation/backfill cycles. A solution of (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (about 3.50 mmol, prepared in example 6, step 1) was added dropwise via syringe and the mixture was heated to 80° C. for 4 h, then cooled to RT. Ethyl acetate and saturated aqueous ammonium chloride were added, the resulting layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 2-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (0.20 g, 1.03 mmol, 29% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([O:43]C)=[O:42])[CH2:24][C:25]4[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[C:27]([CH3:40])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:45]=1.[Li+].[OH-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@@H:23]([C:41]([OH:43])=[O:42])[CH2:24][C:25]4[CH:26]=[C:27]([CH3:40])[C:28]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[C:29]([CH3:31])[CH:30]=4)=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:45]=1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(N2CCc3cc(OC)ccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)C(=O)O)CC1)C(=O)N2

Procedure:
Prepared analogously to Example 21b from 0.65 g (1.06 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 38.4 mg (1.60 mmol) LiOH.