Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17](=[O:18])[NH2:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NCCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NCCC(N)=O)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
In 10 ml of DMF, 1.0 g (4.9 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then 668 mg (5.37 mmol) of β-alanineamide hydrochloride and 1.09 g (10.7 mmol) of triethylamine were added thereto under ice cooling. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.05 g (yield: 79.8%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][CH:26]3[CH2:31][N:30]4[N:32]=[CH:33][C:34]([C:35]([OH:37])=O)=[C:29]4[CH2:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1.C[CH2:39][N:40]=[C:41]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][CH:26]3[CH2:31][N:30]4[N:32]=[CH:33][C:34]([C:35](=[O:37])[N:40]([CH3:41])[CH3:39])=[C:29]4[CH2:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1
Reactant: O=C(O)c1cnn2c1CCC(NC(=O)c1cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc13)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cnn2c1CCC(NC(=O)c1cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc13)C2
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (45 mg, 0.08 mmol) in dry DMF (1 mL) was added EDCI (28.7 mg, 0.09 mmol), HOBt (12 mg, 0.88 mmol) and stirring was continued at 25° C. for 15 min. To the above reaction added dimethylamine hydrochloride (7.8 mg, 0.1 mmol) followed by DIPEA (0.05 ml, 0.26 mmol), stirring was continued at 25° C. for 16 h. Reaction mixture was diluted with DCM (50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford title compound as white solid. MS (ESI): m/z 534.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl.NC(N)=O>C(OCCCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:20](=[O:21])[N:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:7]2=[O:9]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: NC(N)=O
Solvent: CCCCOC(C)=O
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
21.6 g of 5-bromoanthranilic acid and 15.4 g of 4-chlorophenyl isocyanate were reacted in a similar procedure as described in Example 1 in 200 ml of butyl acetate at 100° C. and with a further stirring time of 4 hours. 18 g of hydrogen chloride gas were then introduced into the suspension of the urea formed in the course of 30 minutes and the mixture was then further stirred at 100° C. for 3 hours. For the work-up of the reaction mixture, sufficient butyl acetate was first distilled off at atmospheric pressure until a thick suspension had resulted, then 200 ml of water were added and the product precipitated out was filtered off. After drying, 31.5 g (90% of theory) of 6-bromo-3-(4-chlorophenyl)-quinazoline-2,4-dione were obtained having a melting point of 212-214° C. (decomposition).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:12])(=O)=O.O.ClCCl>CS(C)=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:11]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH3:12])[CH2:10][CH2:9][C:1]#[N:2])=[CH:30][CH:29]=1
Reactant: CSCc1cccc2c(C(C)(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
128 mg (1.96 mmol) of potassium cyanide were added to 430 mg (0.98 mmol) of the compound from Example 114A in 8 ml of DMSO. The mixture was stirred at 80° C. for 8 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 280 mg (77% of theory) of the target compound were obtained.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([CH:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1(/[C:7](/[N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:6]\[C:5]2[CH:13]=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: c1ccccc1
Product: C(=C(\c1ccccc1)n1c2ccccc2c2ccccc21)\c1ccccc1

Procedure:
N-Phenylbenzaldimine (1.35 g, 0.0075 mol) and 9-benzylcarbazole (1.29 g, 0.0077 mol) were heated at 75° C. for 30 min in dimethylformamide (dry), 50 mL, and potassium tert-butoxide (0.10 g, 0.00089 mol). Based on reversed-phase HPLC results, the reaction was complete after 3 min. Aqueous work-up as above and recrystallization of the precipitate from methanol gave needles mp 160°-2° C. (81%). 1H NMR (200 MHz, CDCL3) δ(assignment): 6.85-7.09 (m, 2 H, aromatic). MS [m/e (70 eV, % of base peak)]C26H19N 345 (M+·, 100), 267 (M+· --PhH, 25.8), 178 PhCCPh+·, 47.5), 167 (carbazole+·, 63.6). HRMS (m/z) for C26H19N (M+·) calcd. 345.1517 found 345.1513. FTIR (CDCl3): 3083, 3064, 3027, 1624, 1598, 1493, 1479, 1450, 1384, 1335, 1314, 1232 cm-1 . Analysis: calcd. for C26H19N: C 90.40, H 5.54, N 4.05%; found: C 90.25, H 5.66, N 4.20%.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.[C:21]1([CH2:27][C:28]([Cl:30])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:30].[CH2:27]([C:28]1[O:17][C:11]2[C:10]([N:18]=1)=[CH:9][C:8]1[CH:7]3[CH2:16][CH:14]([CH2:15][NH:5][CH2:6]3)[C:13]=1[CH:12]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: O=C(Cl)Cc1ccccc1
Product: Cl
Product: c1ccc(Cc2nc3cc4c(cc3o2)C2CNCC4C2)cc1

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone and phenyl-acetyl chloride were converted to the title compound following the procedures described in Example 47. 1H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 7.58 (s, 1H), 7.36–7.24 (5H), 4.29 (s, 2H), 3.46 (d, J=2.5 Hz, 2H), 3.39 (d, J=12.0 Hz, 2H), 3.18 (2H), 2.42 (m, 1H), 2.15 (d, J=11.5 Hz, 1H). APCI MS m/e 291.2 [(M+1)+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC#N.C(O)(C(F)(F)F)=O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: NCCCO
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Yield: 51.8 %

Procedure:
To a solution of 2-chloro-6-(4-ethylphenyl)-3-(trifluoromethyl)pyridine (Example 315, 0.36 g, 1.25 mmol) and 3-amino-1-propanol (0.38 g, 5.00 mmol) in CH3CN (2 mL), TFA (0.5 mL) was added. The mixture was stirred at reflux for 18 h, and then concentrated under reduced pressure. The product (0.21 g, 52%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.72 (d, 1H), 7.27 (d, 2H), 7.10 (d, 1H), 3.72 (t, 2H), 3.66 (t, 2H), 2.69 (q, 2H), 1.90 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]12[CH2:34][CH:33]1[CH2:32][CH2:31][CH:30]([CH2:35][O:36][C:37]1[C:45]([CH:46]3[CH2:48][CH2:47]3)=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:49])[CH:38]=1)[CH2:29]2.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:28]12[CH2:34][CH:33]1[CH2:32][CH2:31][CH:30]([CH2:35][O:36][C:37]1[C:45]([CH:46]3[CH2:48][CH2:47]3)=[CH:44][C:40]([C:41]([NH:61][S:58]([CH:55]3[CH2:57][CH2:56]3)(=[O:60])=[O:59])=[O:42])=[C:39]([F:49])[CH:38]=1)[CH2:29]2
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a solid (0.043 g, 21%): 1H NMR (300 MHz, CDCl3) δ8.69 (d, J=16.4 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 3.94-3.84 (m, 2H), 3.15-3.06 (m, 1H), 1.96-1.68 (m, 7H), 1.48-1.40 (m, 2H), 1.26-1.11 (m, 2H), 1.06-0.99 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 408.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[C:39]([O-])(O)=[O:40].[Na+]>C(O)=O>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH:39]=[O:40]
Reactant: O=C([O-])O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (88 mg, 0.43 mmol) (Example 20) in 80% formic acid (3 mL) was heated to and maintained at reflux for 24 hours. The reaction was then cooled to room temperature, poured into saturated NaHCO3 (30 mL), and, after neutralization was complete, extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 15% EtOAc/hexanes afforded [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}formamide. Rf=0.20 (15% EtOAc/hexanes). LCMS=578.3 (M+1)+. 1H NMR (CD2Cl2, 600 MHz, rotamers present, ratio of major:minor ˜3:1. Data for major rotamer given.) δ 6.86-8.31 (m, 10H), 4.24-4.47 (m, 4H), 3.71 (s, 3H), 2.87 (m, 1H), 1.27 (m, 6H).
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1)C.[OH-].[K+].O.C(O)(=O)C>C(O)C>[OH2:3].[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([OH:29])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:44])=[O:9])=[CH:13][CH:14]=3)[CH2:23][CH2:24]2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reactant: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 3.7 g (0.0073 mole) of the free base of 4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzeneacetic acid ethyl ester oxalate [1:1], 0.8 g (0.0145 mole) of potassium hydroxide, 10 ml of water and 50 ml of 95% ethanol was heated at reflux under a nitrogen atmosphere for 1.5 hr. The solution was poured into a mixture of 1.3 g (0.022 mole) of glacial acetic acid in 500 ml of ice water and let stand at ambient temperature overnight. The solid which had precipitated was collected by filtration, washed with water, air dried, and recrystallized from 2-propanol to yield 2.9 g (78%) of the title compound as a white solid, mp 113°-121° C. (dec).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH2:5]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14](=[O:15])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14]([O:13][CH3:12])=[O:15]
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCO
Temperature: 25 °C
Yield: 85 %

Procedure:
Sodium methoxide was generated by the addition of sodium metal (2.4 g, 104.3 mmol, 5.0 eq) to methanol (130 mL) at 0° C. with stirring. The mixture was warmed to room temperature and stirred until all of the sodium was consumed. ω-Pentadecalactone (5.0 g, 20.8 mmol, 1.0 eq) was added in a single portion, and the solution was stirred at 80° C. for 3 hours. The reaction was quenched with hydrochloric acid (1 M, 175 mL) and diluted with water (175 mL). The aqueous layer was extracted with ether (3×100 mL), and the combined organic layers were washed with water (150 mL), brine (150 mL), and dried over magnesium sulphate. The product was purified by silica gel chromatography (2:1 hexane:ethyl acetate), yielding methyl 15-hydroxypentadecanoate (4.24 g, 85%) as a colourless solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[I-].[NH2:31][N+:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:9]3[CH:14]=[N:13][C:12]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[CH:11][CH:10]=3)=[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]3[N:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[n+]1ccncc1
Reactant: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a mixture of 5-(phenylethynyl)-2-(phenylsulfonyl)pyridine (6.00 g) and K2CO3 (13.0 g) in DMF (120 mL) was added 1-aminopyrazin-1-ium iodide (12.6 g) and the mixture was stirred at room temperature for 1 h, then stirred at 60° C. for 8 h. To the reaction mixture was added K2CO3 (7.80 g) and 1-aminopyrazin-1-ium iodide (8.38 g) and stirred at room temperature for 1 h, then stirred at 60° C. for 12 h. To the reaction mixture was added further K2CO3 (7.80 g) and 1-aminopyrazin-1-ium iodide (8.38 g) and stirred at room temperature for 1 h, then stirred at 60° C. for 26 h. The mixture was poured into ice water and extracted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 3:1 to CHCl3-MeOH 20:1) to give 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (4.14 g) as an amorphous solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:12][CH2:11][C:6]3(OCC[O:7]3)[CH2:5][CH2:4]2)[CH2:2]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(C(F)(F)F)=O>[CH2:2]1[C:3]2([CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: C1COC2(CCC3(CC3)CC2)O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC2(CC1)CC2
Yield: 138.8 %

Procedure:
A solution of 7,10-dioxa-dispiro[2.2.4.2]dodecane (6.25 g, approx. 29 mmol) in THF (25 mL), water (20 mL) and TFA (10 mL) is stirred at rt for 2 h. The mixture is neutralized by adding 2 N aq. NaOH and sat. NaHCO3 solution and extracted with diethyl ether. The organic extracts are washed with water, dried over Na2SO4, filtered and the solvent of the filtrate is removed to give spiro[2.5]octan-6-one (5.0 g) as a colourless oil containing remainders of toluene (product volatile). 1H NMR (CDCl3): δ 2.14 (t, J=6.4 Hz, 4H), 1.40 (t, J=6.4 Hz, 4H), 0.21 (s, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][C:52]1[C:57]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:56][CH:55]=[CH:54][N:53]=1>CN(C=O)C.O>[CH3:51][C:52]1[C:57]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ncccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 45.3 %

Procedure:
DIPEA (193 mg, 1.5 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (127 mg, 0.5 mmol) in DMF (2 mL) followed by HOBt (67 mg, 0.5 mmol) and EDCI.HCl (105 mg, 0.55 mmol). After 2 minutes 2-methyl-3-(piperidin-4-yloxy)-pyridine hydrochloride (100 mg, 0.5 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, and the solid was collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 95 mg (47.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-methyl-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 420, 96.7%. 1H NMR (300 MHz, DMSO-d6): δ 8.3 (m, 1H), 8.2 (b, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (b, 1H), 4.9 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.5 (m, 3H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32]>CO.CCO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2

Procedure:
A slurry of ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21, 0.39 g, 0.91 mmol) in a mixture of MeOH (5 mL) and a 33% solution of methanamine (15 mL, 0.91 mmol) in EtOH was stirred at rt over night giving clean conversion to the amide. The reaction mixture was concentrated under reduced pressure giving the title compound (0.370 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([CH3:21])=[C:12]([CH2:14][C:15]([CH3:20])([N+:17]([O-])=O)[CH3:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([CH3:21])=[C:12]([CH2:14][C:15]([NH2:17])([CH3:16])[CH3:20])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CC(C)(C)[N+](=O)[O-])c(C)[nH]2)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc(CC(C)(C)N)c(C)[nH]2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a solution of 2-(3-fluoro-4-methyl-phenyl)-5-methyl-4-(2-methyl-2-nitro-propyl)-1H-imidazole (1.6 g) in acetic acid (32 ml) was added in 2 equal portions of Zn dust (5.2 g) in 15 minutes at 20-25° C. The slightly exothermic reaction was stirred at RT for 1.5 h, the inorganic salts filtered off, and washed with acetic acid. The filtrate was concentrated almost to dryness, the residue quenched with cold conc. NaOH and brine, and extracted with ethyl acetate. The organic phase washed with brine, dried over magnesium sulphate and evaporated to dryness to obtain 2-[2-(3-fluoro-4-methyl-phenyl)-5-methyl-1H-imidazol-4-yl]-1,1-dimethyl-ethylamine (1.16 g) as a light yellow foam, pure enough to be used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][C:30](Cl)=[O:31].N1C=CC=C[CH:34]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:34][CH2:28][CH2:29][C:30]5=[O:31])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)CCCl
Reactant: c1ccncc1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reaction time: 2 h
Yield: 16 %

Procedure:
Under ice cooling, a mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), 3-chloropropionyl chloride (70 mg) and pyridine (5 ml) was stirred for 2 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol system) to give the title compound (30 mg) as a white powder (yield: 16%).