Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32].[CH3:33][NH:34][CH3:35]>ClCCl.CCOCC>[CH3:33][N:34]([CH3:35])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][N:4]2[C:5](=[O:21])[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[C:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:7]=3)[N:2]([CH3:1])[C:3]2=[O:32])=[CH:24][CH:25]=1
Reactant: CNC
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)Cl)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Cn2c(=O)c3cc(C#CCc4ccccc4)ccc3n(C)c2=O)cc1
Reaction time: 16 h

Procedure:
To a solution of 0.5 g (1.1 mmol) of compound obtained in Step 1 in 50 ml of dichloromethane, 10 ml of dimethylamine in ether were added and stirring was continued at room temperature for 16 hours. The reaction mixture was partitioned between 1 M HCl and dichloromethane. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to give 0.4 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([O:22][C:23](=[O:29])[C:24](OCC)=[O:25])[CH3:21].CCOCC>C(O)(=O)C>[CH2:20]([O:22][C:23](=[O:29])[C:24]([CH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25])[CH3:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(OCc2ccccc2)c(C)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1c(OCc2ccccc2)cc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
25.7 g of the thus obtained 2,5-dimethyl-3-nitro-O-benzylphenol are added in portions during stirring to a mixture of 17 g freshly prepared potassium-tert.-butylate and 120 ml oxalic acid diethyl ester. After completion of the addition, the mixture is heated to 60° C. for two hours. After cooling, the composition is mixed with 200 ml ether and carefully acidified with diluted acetic acid. The ether phase is washed with neutral water, dried and evaporated. The still present oxalic ester is distilled off in the water jet vacuum at increased bath temperature. The residue is dissolved in ether and the solution is carefully mixed with ligroin. After aspirating and drying, there is obtained 30.6 g (~85° of theory) 2-benzyloxy-4-methyl-6-nitro-phenyl pyruvic acid ethyl ester; m.p. 80°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([CH2:20][OH:21])[CH:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:23]>C(#N)C.O.[O-]Cl.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([OH:23])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a solution of [4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (17.4 g, 55 mmol) in acetonitrile (235 mL), phosphate buffer (pH 6.7, 220 mL) and 2,2,6,6-tetra-methylpiperidine 1-oxyl radical (TEMPO, 0.6 g) was added and the solution was warmed to 35° C. To this warm solution under argon was added with stirring over 2 h simultaneously a solution of NaOCl2 (12.4 g) in water (58 mL) and NaOCl (0.85 mL, 10% solution) in water (35 mL). Stirring was continued for 20 h at 35° C. after which time the solution was cooled to room temperature and quenched by addition of in sequence water (420 mL), 2 N NaOH solution (65 mL) and Na2SO3 solution (17.1 g in 285 mL water). This mixture was stirred for 30 min and acidified with 2 N HCl (175 mL). The mixture was extracted once with ethyl acetate/THF (800/150 mL), and once with ethyl acetate (500 mL). Organic phases were washed with brine (800 mL), pooled and dried with Na2SO4. The solvent phase was concentrated to a volume of ˜100 mL. n-Heptane (150 mL) was added and the solvent phase was concentrated again to ˜100 mL. This was repeated twice. n-Heptane (100 mL) was added. The product precipitated upon stirring, was filtered off and dried to give the title compound as a white solid (18.4 g, quant.), LC-MS (peak area/EIC) ˜100%, 332.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.O[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:29][C@@:23]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:9][CH:6]4[CH2:5][CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH2:7]4)[CH:14]=3)[CH:19]=2)[CH2:27][O:26][C:25](=[O:28])[NH:24]1
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(=O)N1

Procedure:
In a 40 mL vial, 4-trifluoromethyl-cyclohexanol (713.2 mg, 0.004241 mol) was diluted with tetrahydrofuran (19.0 mL), then (R)-4-(6-hydroxy-naphthalen-2-yl)-4-methyloxazolidin-2-one (0.9462 g, 0.003890 mol) and triphenylphosphine (1.3031 g, 0.0049682 mol) were added. The mixture was stirred and then diisopropyl azodicarboxylate (0.91 mL, 0.0046 mol) was added. The reaction was stirred at room temperature for 38 h. The reaction mixture was concentrated in vacuo, taken up in DCM, adsorbed onto silica gel and chromatographed (0-100% EtOAc/Hexanes). Isolated was 223.5 mg (15%) of product as cis/trans mixture.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[CH:26]=[C:25]([C:35]([O:37]C)=[O:36])[C:24]4=[O:39])[CH2:17][CH2:16]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[OH-].[Na+]>O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[CH:26]=[C:25]([C:35]([OH:37])=[O:36])[C:24]4=[O:39])[CH2:19][CH2:20]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(=O)O)c(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To 1 mL of a methanol solution containing 0.20 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, 0.5 mL of 20% aqueous sodium hydroxide solution was added and stirred for 1 hour. 3 mL of water was added, removed methanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[C:17][C:18]3[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]=3[CH3:26])[CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH3:26][C:19]1[CH2:20][CH2:21][CH2:22][C:23]([CH3:24])([CH3:25])[C:18]=1[C:17]#[C:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14]2
Reactant: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(C#Cc2ccc3cc(C(=O)O)ccc3c2)C(C)(C)CCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.130 g (0.38 mmol) of ethyl-6-[2-(2,6,6-trimethylcyclohex-1-enyl)ethynyl]-2-naphthoate (Compound 3) in 0.7 ml of ethanol was added dropwise under nitrogen 0.9 ml of a 1.86M solution of KOH in ethanol and water. After being stirred at 50 degrees C. for 18 hours, solvent was removed in-vacuo and the residue treated with 1 ml of water and extracted with 1×3 ml portions of ether. The aqueous layer was then acidified with dilute HCl and extracted with 3×3 ml portions of ether. Combined ether extracts were dried (MgSO4), filtered, and concentrated in-vacuo to give the title product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].N>C(O)C.[Ni]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1ccccc1-c1ncc[nH]1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-c1ncc[nH]1

Procedure:
A solution of 2-(1H-imidazol-2-yl)-benzonitrile (50 mg, 0.30 mmol) in ethanol saturated with ammonia (5 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere for 2 h. The reaction mixture was filtered over celite and concentrated to give 2-(1H-imidazol-2-yl)-benzylamine; 1H NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H, J=7.5 Hz), 7.42 (m, 1H), 7.28 (m, 2H), 7.18 (bs, 2H), 3.96 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([NH:12]C(OC(C)(C)C)=O)[CH:5]=1.[ClH:21]>O1CCOCC1>[ClH:21].[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cc(SC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)cc(SC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
3-tert-Butoxycarbonylamino-5-methylsulfanyl-benzoic acid methyl ester (D60) (0.54 g, 1.82 mmol, 1 equiv) was dissolved in dioxan (2 ml) and 4M HCl in dioxan (16 mmol, 4 ml, 8.8 equiv) was added. The solution was stirred at room temperature for 2 h allowing the hydrochloride salt of the amine to precipitate. This precipitate was filtered off, washed with Et2O and dried giving 3-amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62) (0.224 g, 52%). [M+H]+=198.1, RT=2.68 min
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:16])[C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[CH:14][S:13][C:12]=23)[CH:2]=1>ClCCl.[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[CH:14][S:13][C:12]=23)=[O:16])[CH:2]=1
Reactant: OC(c1cccnc1)c1ncn2ccsc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1cccnc1)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.8 %

Procedure:
Manganese dioxide (1.0 g) was added to a solution of 1.02 g of 7-[(pyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole in 40 ml of dichloromethane, and the mixture was stirred at room temperature for 5 hr. The reaction solution was filtered through Celite, followed by washing with dichloromethane. The filtrate was concentrated under the reduced pressure to give 1.10 g of 7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7](Cl)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To the mixture of the 2-iodo-4-chloroaniline (5.0 g, 20 mmol) and triethylamine (8.3 mL, 60 mmol) in methylene chloride (200 mL), the solution of methanesulfonyl chloride (3.4 mL, 44 mmol) was added slowly. The solution then was stirred at room temperature for 2 h. After being washed by HCl solution (0.5 N, 2×100 mL), NaOH solution (0.5 N, 2×100 mL), brine (100 mL), the organic layer was dried over Na2SO4 and concentrated providing the title compound (6.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17]Cl)[C:9]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:28]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>CCCCCCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][N:35]3[CH2:36][CH2:37][CH:32]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]3)[C:9]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC1CCNCC1
Reactant: CC(C)(C)c1ccc2c(c1)N(CCCCl)C(=O)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCN2C(=O)COc3ccc(C(C)(C)C)cc32)CC1
Yield: 87.1 %

Procedure:
6-tert-Butyl-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2248b) (1.39 g, 4.93 mmol), K2CO3 (1.36 g, 9.85 mmol), NaI (1,48 g, 9.85 mmol) and 4-butylpiperidine (0.73 g, 5.17 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2248F) (1.66 g, 87%). 1H NMR (CDCl3) d 7.01-6.98 (m, 2H), 6.91-6.88 (m, 1H), 4.55 (s, 2H), 3.99 (t, J=7.2 Hz, 2H), 2.89 (d, J=6.4 Hz, 2H), 2.42 (t, J=6.8 Hz, 2H), 1.92-1.82 (m, 4H), 1.65 (d, J=9.6 Hz 2H), 1.31 (s, 9H), 1.29-1.17 (m, 9H), 0.88 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) d 164.6, 146.1, 143.3, 128.1, 120.6, 116.6, 112.2, 67.9, 56.5, 54.4, 39.8, 36.4, 35.9, 34.7, 32.6, 31.6, 29.2, 24.8, 23.1, 14.2.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[N:24]=[CH:23][C:22]4=[O:33])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[NH:24][CH2:23][C:22]4=[O:33])[CH2:17][CH2:18]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CN2
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one (Example 72, 0.125 g) in ethanol (4 mL) was added sodium borohydride (40 mg). After 3 hour at room temperature, additional sodium borohydride (47 mg) was added. After 30 minutes the reaction was quenched with acetone and concentrated. Chromatography on silica gel with a gradient of dichloromethane to 20% methanol in dichloromethane gave 108 mg of the product as a colorless solid.
Reaction SMILES: [NH2:1][C:2](=[O:37])[CH:3]([OH:36])[CH:4]([NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2Cc3ccccc3C2)n1
Solvent: CCOC(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2Cc3ccccc3C2)n1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-(isoindolin-2-ylmethyl)-1H-pyrazol-1-yl)nicotinamide (1.05 g, 2.115 mmol) as described in example 1.4, treatment of the crude product with ethyl acetate gave the title compound as white amorphous solid; 421 mg, ESI-MS [M+H]+: 495.2. 1H-NMR (400 MHz, DMSO), 6 [ppm]: 8.97 (m, 1H), 8.55 (m, 1H), 8.32 (m, 1H), 8.03 (m, 1H), 7.79 (m, 1H), 7.72 (m, 1H), 7.42 (m, 1H), 7.29-7.15 (m, 9H), 6.47 (m, 1H), 5.42 (m, 1H), 3.80 (s, 4H), 3.68 (m, 2H), 3.15 and 2.87 (each dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 70 %

Procedure:
After dissolving 1-methyl 2-aminoterephthalate (8.00 g, 41.1 mmol) in dimethylformamide (80 ml), anhydrous potassium carbonate (6.25 g, 45.1 mmol) and benzyl bromide (4.12 ml, 43.1 mmol) were added and the mixture was stirred at room temperature for 15.5 hours. An excess of triethylamine was added, and after stirring for an additional 10 minutes at room temperature, ice water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration was performed with silica gel-alumina and the solvent was distilled off under reduced pressure. IPE was added to the obtained oil for crystallization, and the crystals were filtered off. The filtrate was concentrated and then the same procedure was repeated twice to yield the title compound (8.21 g) as a light yellow powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH:28]([CH2:39][OH:40])[CH2:27]3)=[O:25])=[C:17]2[CH:16]=1>O1CCOCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH:28]([CH2:39][OH:40])[CH2:27]3)=[O:25])=[C:17]2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1CO
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12)N1CCNC(CO)C1
Reaction time: 4 h

Procedure:
4M HCl solution (in Dioxane) (5 mL) was added to a stirred solution of tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-(hydroxylmethyl)piperazine-1-carboxylate (150 mg, 0.276 mmol) in Dioxane (2 mL) and stirring was continued at 20-35° C. for 4 h. After which the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by Preparative HPLC [Column:LUNA-C18-250*21.2 mm, Mobile phase-A: 0.1% TFA in water, B: ACN, Gradient (Time/% B): 0/30, 2/30, 10/60 and Flow rate: 20 mL/min] 110 mg of the title compound.
Reaction SMILES: [Cl:1]C(OCC)=O.CCN(C(C)C)C(C)C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>C(Cl)Cl>[CH3:16][C:17]1[C:18]([Cl:1])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: Cc1ccc2c(c1)C1CNCC1C2C
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)C(C)C1CNCC21
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH2Cl2 (3×15 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 10-60% EtOAc-hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C16H21NO2+H: 260, observed: 260.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:6][CH2:5]2.O.[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:6][CH2:5]2)#[N:18]
Reactant: CCC(=O)NC1CCc2cc(Br)ccc21
Reactant: CN1CCCC1=O
Solvent: O
Product: CCC(=O)NC1CCc2cc(C#N)ccc21
Reaction time: 1 h
Yield: 50 %

Procedure:
3.64 g of N-(5-bromoindan-1-yl)propionic acid amide were dissolved in 30 ml of 1-methyl-2-pyrrolidone. 1.8 g of cuprous cyanide were added to this solution followed by heating and refluxing for 2 hours. After returning the reaction solution to room temperature, the reaction solution was poured into water, and stirred for 1 hour. The resulting reaction mixture was filtered with CELITE and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 1.46 g of the target compound. Yield: 50%
Reaction SMILES: Cl[CH:2]([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)(O)[O-].[K+].[I-].[K+]>CC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:2]([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4])=[CH:11][CH:10]=1
Reactant: CCC(Cl)C(C)=O
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(Oc1ccc(Cl)cc1)C(C)=O
Yield: 62.1 %

Procedure:
A solution of 3-chloro-2-pentanone (10 g) in acetone (50 ml) was added dropwise to a stirred mixture of 4-chlorophenol (11 g), potassium bicarbonate (20 g) and potassium iodide (1 g) in acetone (100 ml). After the addition was completed the mixture was heated under reflux for 6 hours. The mixture was then filtered, washed with acetone and the acetone was evaporated under reduced pressure. The residue was dissolved in ether (150 ml), and the ethereal mixture was washed with 300 ml of a 10% aqueous solution of sodium hydroxide followed by 300 ml of water. The mixture was then dried over magnesium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 3-(4-chlorophenoxy)-2-pentanone (10.96 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C@H:23]([CH3:24])[CH2:22][CH2:21][C@@H:20]([CH2:25][OH:26])[CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C@H:23]([CH3:24])[CH2:22][CH2:21][C@@H:20]([CH:25]=[O:26])[CH2:19]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CN2C[C@H](CO)CC[C@H]2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C[C@H](C=O)CC[C@H]2C)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of DMSO (1.75 mL, 24.7 mmol) in CH2Cl2 was cooled at −78° C. and treated with oxalyl chloride (2.16 mL, 24.7 mmol) dropwise. The solution was stirred at −78° C. for 20 mins and then treated with a solution of [(3R,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]methanol (4.10 g, 16.4 mmol) in CH2Cl2 (15 mL) dropwise. After stirring at −78° C. for 1 h, the reaction was allowed to warm to ambient temperature and triethylamine (11.5 mL, 82.0 mmol) was added. After stirring overnight, the reaction was diluted with CH2Cl2 and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-10% MeOH in CH2Cl2 to provide (3R,6R)-1-(4-methoxybenzyl)-6-methylpiperidine-3-carbaldehyde as an orange oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 266.4 for M+H3O+.