Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccccc1CNC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccccc1CNC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-{[2-(methyloxy)phenyl]methyl}-3-piperidinecarboxamide (200 mg, 0.421 mmol), EtOH (5 mL), Hunig's base (0.074 mL, 0.421 mmol), and hydrazine anhydrous (0.08 mL, 2.5 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.16 (d, J=6.82 Hz, 3H), 1.66 (m, 2H), 1.71-1.95 (m, 2H), 2.31-2.45 (m, 1H), 2.95 (m, 1H), 3.82 (s, 3H), 4.12-4.41 (m, 2H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 6.87-7.08 (m, 2H), 7.14-7.30 (m, 2H), 7.52-7.62 (m, 1H), 7.70 (m, 1H), 7.94 (s, 1H), 8.24-8.38 (m, 1), 11.50 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([F:22])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([F:22])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(F)c1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O

Procedure:
(3-fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-carbamic acid t-butyl ester (1 ml) was put into 25 ml round-bottom flask and dissolved in methylenechloride. To the solution was added trifluoroacetic acid (1 ml) and stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (236.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2CCNC3C)o1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:13][CH:14]=2)[CH:9]1[C:28]1([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)=[NH:7].Cl>C(#N)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:28]2([CH:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH:11]=4)[CH2:16][CH2:17][N:8]3[C:6]3[NH:5][CH:4]=[CH:3][N:7]=3)[CH2:29][CH2:30][CH2:31]2)=[CH:37][CH:36]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)NCC(OC)OC)CC2
Agent: Cl
Solvent: CC#N
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(c1ncc[nH]1)CC2
Temperature: 25 °C

Procedure:
The crude N-(2,2-dimethoxyethyl)-1-[1-(4-fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-carboximidamide (see above) was dissolved in acetonitrile (5 mL). Concentrated aqueous hydrochloric acid was added until the reaction mixture remained at pH 1. After stirring at room temperature over night the solvent was evaporated in vacuo. Water (10 mL) was added and the mixture was neutralized with aqueous saturated NaHCO3 solution. The mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=80:1). Yield: 2.8 mg (5.5 μmol, 2%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:20][O:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:21]([O-])=O>CO.[Pd]>[NH2:21][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:18][O:19][CH2:20]3)[CH2:13][CH2:12]2)[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: N#Cc1cc(OC2CCN(C3COC3)CC2)c(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(N)c(Cl)c(OC2CCN(C3COC3)CC2)c1
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
A mixture of 4-chloro-3-nitro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (430 mg, 1.272 mmol) and Pd/C (271 mg, 0.127 mmol) in methanol (20 mL) was hydrogenated at 20 psi for 1.5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g gold column, eluting with 1-5% 2 N ammonia in methanol/dichloromethane). 3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (50 mg) was obtained as a foaming solid.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:43][C:42](=[O:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(OCC)C.Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:43][C:42](=[O:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[CH:45][CH:46]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3noc(=O)[nH]3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(-c3noc(=O)[nH]3)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 500 mg (0.81 mmol) of methyl 4-((3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-{2-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]ethyl}but-3-en-1-yl)benzoate in 5 ml of THF and 5 ml of water is mixed with 38.8 mg (1.62 mmol) of lithium hydroxide and stirred at 50° C. for 12 h. Cooling is followed by addition of water and extraction with diethyl ether. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. The resulting organic phase is washed with sodium chloride solution, dried over sodium sulfate and concentrated. 420 mg (0.7 mmol, 79% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:16]=1[CH3:32].C(N(CC)CC)C.ClC(OCC)=O.[NH2:46][OH:47]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:46][OH:47])=[O:31])=[O:22])[C:16]=1[CH3:32]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (201 mg, 44%) as a red solid. LC-MS (m/z) 457 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH2:8][OH:9].[H][H]>C(O)C.[Pt]=O>[NH2:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH2:8][OH:9]
Reactant: COc1ccc([N+](=O)[O-])c(CO)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(N)c(CO)c1

Procedure:
This alcohol (2.1 g.) was dissolved in ethanol (100 ml.), Adams' platinum oxide catalyst was added, and the mixture was shaken with hydrogen at ambient temperature and pressure until 950 ml. of hydrogen had been absorbed (theoretical quantity=900 ml.). The hydrogenated mixture was filtered through "Supercel" (trademark) kicselguhr, and the solvent was evaporated to give 2-amino-5-methoxybenzyl alcohol as a brown solid;
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:35]([NH:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1)[CH3:36]>>[CH2:35]([N:37]([C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1)[C:32]([C@H:20]1[CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[C:20]([CH3:32])([CH3:21])[CH3:19])[CH2:23][NH:18][CH2:19]1)=[O:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CCNc1ccc2c(c1)N(CCCOC)C(=O)CO2
Product: CCN(C(=O)[C@@H]1CNC[C@H](NC(=O)C(C)(C)C)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2

Procedure:
The title compound is prepared analogously as described in Example 92A. using (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester and 6-ethylamino-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one. The product is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 ml/min); tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.47 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[C:34]([NH:37][CH2:38][CH2:39][NH2:40])(=[O:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[C:34]([NH:37][CH2:38][CH2:39][NH:40][C:23]([C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:10])[C@H:13]([O:31][CH2:32][CH3:33])[CH2:14]2)[S:19][C:20]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:25])(=[O:36])[CH3:35]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: CC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCNC(C)=O
Yield: 57.4 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (200 mg, 0.40 mmol), N-acetylethylenediamine (0.08 mL, 0.80 mmol), WSC hydrochloride (230 mg, 1.20 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol), to obtain 134 mg of the title compound as a white solid (57%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: NCC(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(Cl)c4)c4cccc(Cl)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(3-chlorophenyl)ethanamine (J. Med. Chem., 1988, 31 (7), 1282) using a similar method to that of Preparation 64.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C@@:36]1([C:52]([F:55])([F:54])[F:53])[CH2:51][N:39]2[C:40](=[O:50])[CH:41]=[C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:43]=[C:38]2[NH:37]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:35][C@@:36]1([C:52]([F:55])([F:53])[F:54])[CH2:51][N:39]2[C:40](=[O:50])[CH:41]=[C:42]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[N:43]=[C:38]2[N:37]1[CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][CH:11]=1
Reactant: OCCc1ccc(N2CCOCC2)cc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
135 mg of 2-(4-morpholinophenyl)ethanol and 223 mg of polymer-supported triphenylphosphine (3 mmol/g) are added to a solution of 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]-pyrimidin-5-one (Example 1j) in 5 ml of tetrahydrofuran. After stirring for five minutes at ambient temperature, 0.12 ml of diethyl azodicarboxylate is added. The resulting reaction mixture is then stirred overnight at ambient temperature. After filtration, the filtrate is evaporated under reduced pressure. The residue obtained is purified by silica column chromatography (eluent: dichloromethane/methanol 97/03), so as to give 40 mg of (S)-2-methyl-7-morpholin-4-yl-1-[2-(4-morpholin-4-yl-phenyl)ethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2([C:20](OCC)=[O:21])[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[N:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[C:3]=1[C:38]#[N:39].[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2([CH2:20][OH:21])[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[N:5]=[C:4]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[C:3]=1[C:38]#[N:39]
Reactant: CCOC(=O)C1(n2nc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2N)CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(C2(CO)CCN(Cc3ccccc3)CC2)c1N
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a solution of ethyl 4-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidine-4-carboxylate (52 mg, 0.1 mmol) in MeOH (5 mL) was added NaBH4 (8 mg, 0.2 mmol). After 10 min, the reaction was quenched with water (5 mL) and extracted with EA (10 mL×3). The organic combined layers was dried over Na2SO4 and concentrated to give the crude product (34 mg, 70.9%) as an off-white solid. MS (ESI, m/e) [M+1]+ 480.0.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]([OH:35])[CH:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[OH:28])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:26](=[O:35])[C:27]([C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(C(O)C(O)c2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(C(=O)C(=O)c2ccncc2)c1
Temperature: 0 °C
Yield: 62.2 %

Procedure:
To a stirring solution of methyl sulfoxide (11.8 g, 10.7 mL, 150 mmol) in dichloromethane (150 mL) at -78° C. was added trifluoroacetic anhydride (23.7 g, 16 mL, 113 mmol) dropwise. After ten minutes, 1-(3-methoxyphenyl)-2-pyridin-4-ylethane-1,2-diol (8.5 g, 34 mmol) in dichloromethane (60 mL) was added dropwise. After another ten minutes, triethylamine (21.3 g, 29.4 mL, 211 mmol) was added dropwise and the reaction mixture was immediately warmed to 0° C. and poured into saturated aqueous sodium hydrogen carbonate solution (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The resulting oil was chromatographed on silica gel eluting with 1:3 ethyl acetate:hexane to give the dione as a yellow solid (5.1 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:12]=[O:11])[C:14]=1[CH:21]=[O:22]
Reactant: COc1cccc(CO)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cccc(C=O)c1C=O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of DMSO (63.35 g, 810.8 mmol, 4.4 equiv) in CH2Cl2 (190 ml) was slowly added at −78° C. under an atmosphere of argon to a solution of oxalyl chloride (51.46 g, 405.4 mmol. 2.2 equiv) in CH2Cl2 (600 ml). A solution of (2-hydroxymethyl-6-methoxy-phenyl)-methanol (30.97 g, 184.3 mmol) in CH2Cl2 (250 ml) was added dropwise, while maintaining the temperature of the reaction mixture below −68° C. 90 minutes after completed addition, triethylamine (335.65 g, 3.317 mol, 18 equiv) was slowly added at −78° C. The reaction mixture was warmed to room temperature over 2 hours, at which point TLC analysis indicated complete conversion. Water (500 ml) was added, and the mixture was extracted with CH2Cl2 (4 liters in total). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 0:100) afforded 28.78 g of a orange-brown solid, which was recrystallized from CH2Cl2/hexane to give a first crop of pure title compound (brown solid, 9.68 g). Further purification of the mother liquor via flash chromatography and recrystallization afforded another 7.95 g of pure title compound (total: 17.63 g, 58%). 1H NMR (400 MHz, CDCl3): δ=10.64 (s, 1H), 10.42 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.23 (dd, J=8.5/0.9 Hz, 1H), 3.97 (s, 3H). MS (ES+): 165 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:17](Cl)([CH3:20])(=[O:19])=[O:18].O>C(Cl)Cl.CCCCCCC.CCOC(C)=O>[CH:1]1([CH2:7][CH2:8][O:9][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: O
Product: CS(=O)(=O)OCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
150 mg (1.17 mmol, 1 eq) of 2-cyclohexylethanol were diluted in 4 mL of DCM, 214 μL (1.52 mmol, 1.3 eq) of triethylamine were added. The mixture was cooled to 0° C. and 100 μL (1.29 mmol, 1.1 eq) of mesyl chloride were added. The mixture was stirred for 15 min at 0° C. then water was added. The aqueous phase was extracted with dichloromethane. The organic phase was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product (241 mg) was used directly for synthesis of 2. TLC: Rf: 0.48 (eluant: Heptane/EtOAc: 1/1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(-n2cccn2)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-pyrazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.208 ml, 1.20 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 73.6 mg (28.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:35](Cl)=[O:36].C(N(CC)CC)C.O>N1C=CC=CC=1>[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:35]([NH:18][C:15]1[CH:16]=[N:17][C:12]([C:2]2([CH3:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:10][CH2:11]2)=[CH:13][CH:14]=1)=[O:36]
Reactant: CC1(c2ccc(N)cn2)CCC2(CC1)OCCO2
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(C3(C)CCC4(CC3)OCCO4)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 50 °C
Yield: 90 %

Procedure:
[6-(8-Methyl-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]amine (340 mg) was added to a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (491 mg) described in Reference Example 180 in pyridine (7.0 ml) and stirred at 50° C. for an hour. After completion of the reaction, triethylamine (1.5 ml) and water was added and the precipitated solid was collected by filtration to give 5-methyl-N-[6-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (618 mg) as a white solid.