Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CCO>[CH2:17]([N:19]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:20][CH3:21])[CH3:18]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-ethylethanamine (0.50 ml, 4.8 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 77 (4), 58 (6).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[O:5][CH2:6][C@@:7]2([N:34]=1)[C:20]1[CH:19]=[C:18]([C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16][C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:11][CH:12]=1.[Cl-].[NH4+]>CO.C(OCC)(=O)C.O>[NH2:3][C:4]1[O:5][CH2:6][C@@:7]2([N:34]=1)[C:20]1[CH:19]=[C:18]([CH:21]([OH:27])[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH:17]=[CH:16][C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)CC(=O)c1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(O)c1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (33.1 mg, 874 μmol) was added at RT to a solution of 1-((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-3,3-dimethyl-1-butanone (312 mg, 728 μmol) in methanol (5 ml) and the mixture was stirred for 1 hr at ambient temperature. Saturated ammonium chloride solution (3 ml) was added, the mixture was diluted with ethyl acetate (5 ml) and water was added to dissolve solids. The organic layer was washed with brine, dried and concentrated to give pink solid which was purified by chromatography on silica gel (12 g Redi-Sep column, 15-75% DCM/MeOH/NH4OH 90:10:1 in DCM) to afford (1RS)-1-((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-3,3-dimethyl-1-butanol as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:37]=[CH:36][C:28]([CH2:29][C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:24][C:25]1[CH:37]=[CH:36][C:28]([CH2:29][C:30]2[S:34][C:33]([NH:35][C:19]([C:18]3[CH:17]=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14][CH:9]([CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][CH2:11]4)=[CH:23][CH:22]=3)=[O:21])=[N:32][N:31]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(Cc2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 73.1 %

Procedure:
0.3 g of 4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid (0.94 mmol, 1 eq.) is placed in a mixture of 5 mL of dichloromethane and 2 mL of dimethylformamide at room temperature. 0.394 g of 5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-amine (1.88 mmol, 2 eq.), 1.054 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (2.26 mmol, 2.4 eq.) and 0.66 mL of diisopropylethylamine (3.76 mmol, 4 eq.) are successively added. The reaction mixture is stirred for 6 days at room temperature, diluted in ethyl acetate, washed with saturated aqueous ammonium chloride solution, and washed twice with water and once with brine. The organic phase is concentrated and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 33%. 0.35 g of tert-butyl (4-{4-[5-(4-fluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH2:16]([C:19]1[CH:20]=[N:21][C:22](Cl)=[N:23][CH:24]=1)[CH2:17][CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]3[N:23]=[CH:24][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][N:21]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: CCCc1cnc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-(5-propylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 5-propyl-2-chloropyrimidine (0.5 mL) in a similar manner as described above to give 5 mg (5%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.86 (s, 1H), 8.17 (s, 2H), 7.53 (s, 1H), 7.30 (d, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 5.30-5.23 (m, 1H), 2.63-2.56 (m, 2H), 2.36 (t, 2H), 2.06-1.96 (m, 2H), 1.84-1.73 (m, 2H), 1.56-1.47 (m, 2H), 0.88 (t, 3H); MS m/z (M−1) 383, 385.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 87.5 %

Procedure:
Following a procedure similar to that described in Example 74(a), but using 2.04 g of 2-butyl-4-pivaloylimidazole-5-carbonitrile (prepared as described in Preparation 40), 5.6 g of 4-[2-(trityltetrazol-5-yl)-phenyl]benzyl bromide and 1.06 g of potassium t-butoxide, 5.43 g of the title compound were obtained as crystals, melting at 103°-105° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(dimethylaminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C26H25N3O3
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(C)=O)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask were placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of acetyl chloride (19.8 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 ml, of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17]CC)=[O:16])=[CH:4][N:3]=1.[OH-].[Na+].Cl>CCO.O>[OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:10])([F:11])[F:12])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Yield: 98.4 %

Procedure:
A solution of ethyl 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylate (4.0 g, 13 mmol) and NaOH (1.60 g, 39 mmol) in EtOH (20 mL) and H2O (45 mL) was heated at reflux for 1 h. The solution was cooled and acidified (conc. HCl). The resulting solid was filtered and dried to provide 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylic acid (3.3 g, 98% yield); 1H-NMR (DMSO-d6) δ 9.90 (bs, 1H), 8.43 (s, 1H).
Reaction SMILES: [F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].C1C=C(C([Cl:22])=O)C(C(Cl)=O)=CC=1>>[F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([Cl:22])=[O:4]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCCC[C@](F)(C(=O)O)C(F)(F)F
Product: CCCC[C@](F)(C(=O)Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
A mixture of 8.0 g of (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoic acid and 24.0 g of phthalyl chloride was stirred at 80° C. for 24 hours. Subsequently, the reaction mixture was distilled under reduced pressure, thereby obtaining 8.2 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl chloride having the physical properties as mentioned hereinbefore.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]4([CH2:16][CH2:15]4)[C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]4([CH2:16][CH2:15]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C12CC2
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C12CC2

Procedure:
The title compound is prepared from a mixture of 8′-chloro-2′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]1([OH:25])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C1COCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([C:11]#[C:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([O:25][C:31]([O:32][CH3:33])=[O:34])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C(C)(C)C)CC1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)OC1(C#CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (500 mg, 1.353 mmol) in 30 mL of anhydrous THF was added dropwise n-BuLi (0.65 mL, 1.623 mmol) at −78° C. under N2. After stirring for 1 h at −78° C., methyl carbonochloridate (176.2 mg, 1.623 mmol) in THF (1 mL) was added dropwise to the above solution at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 2 h, then allowed to warm to r.t. and stirred for another 8 h. The reaction mixture was cooled to −78° C. and quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 453 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 4.40 (s, 2H), 4.26-4.15 (m, 2H), 3.80-3.67 (m, 2H), 3.41-3.28 (m, 2H), 2.27-2.14 (m, 2H), 2.00 (ddd, J=13.1, 9.2, 3.9 Hz, 2H), 1.48 (s, 9H), 1.33 (t, J=7.1 Hz, 4H), 0.92 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: Cl.CC1(C)[O:7][C@@H:6]2[CH2:8][CH2:9][C@@H:10]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]4=[N:13][CH:12]=3)[C@@H:5]2[O:4]1>CO>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@@H:10]3[CH2:9][CH2:8][C@@H:6]([OH:7])[C@H:5]3[OH:4])=[CH:12][N:13]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(N)nccn23)O1
Agent: Cl
Solvent: CO
Product: Nc1nccn2c([C@@H]3CC[C@@H](O)[C@H]3O)cnc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Concentrated HCl (4 mL) was added to 3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (2-10) (1.20 g, 4.37 mmol, 1 equiv) in methanol (20 mL) and the mixture was heated to 65° C. After 8 hours, no more starting material was present and the mixture was concentrated to afford desired (1R,2S,3S)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)cyclopentane-1,2-diol (2-11) as a tan solid. 1H NMR (500 MHz, CD3 OD): δ 8.06 (d, J=5.8 Hz, 1H); 7.82 (s, 1H); 7.27 (d, J=5.7 Hz, 1H); 4.14 (s, 1H); 4.04 (dd, J=9.3, 4.5 Hz, 1H); 3.55 (q, J=9.1 Hz, 1H); 2.40-2.29 (m, 1H); 2.22-2.10 (m, 1H); 1.92-1.80 (m, 2H). LRMS m/z (M+H) 235.1 found, 235.1 required.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH:4]=[CH:5]OC.Cl.O.[NH2:13][NH2:14].[OH-].[Na+]>O.C(O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[CH:5][NH:14][N:13]=1
Reactant: COC=CC(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cc[nH]n1
Yield: 92 %

Procedure:
2.71 kg of 1,1,1-trifluoro-4-methoxy-but-3-en-2-on, 2.44 kg of ethanol and 3.10 kg of water were charged into a reaction vessel. 20 ml of concentrated hydrochloric acid and 0.80 kg of hydrazine hydrate were successively added and the mixture was heated to reflux for 4 h. The mixtures was allowed to cool and neutralized by addition of 10% aqueous NaOH to about pH 4-5. Then the mixture was evaporated. Toluene was added and the mixture was again evaporated to yield 2 kg of raw 3-trifluoromethyl-pyrazole with a purity of >85%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34]C)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:26][C@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([OH:34])=[O:33])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H]3CCC[C@H]3C(=O)O)cn2)C1

Procedure:
(1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1-carboxylic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.68 (s, 2H), 8.08 (d, 1H), 7.02 (d, 1H), 6.89 (m, 3H), 4.51 (m, 1H), 4.28 (m, 2H), 3.95 (m, 3H), 3.75 (m, 2H), 2.90 (m, 1H), 1.89 (m, 8H), 1.51 (m, 2H), 1.23 (t, 3H). MS (ES+) 455.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH2:31])[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:14])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+:32]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O-:29])=[O:28])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:14])=[CH:9][CH:10]=1.[Na+:32]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(O)cc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 90 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 4 (4.5 g), 1 mol/L of an aqueous sodium hydroxide solution (33 mL), and methanol (300 mL), to give the captioned compound (3.7 g, 90%) as crystals.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:18]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To anhydrous pyridine (120 ml), methyl 3-aminobenzoate (5.00 g) was dissolved, and valeryl chloride (4.13 ml) was added while cooling on ice. The mixture was stirred at room temperature for 4 hours. Distilled water was added to the solution. The whole was extracted with ethyl acetate, washed with 5% sodium hydrogencarbonate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (Kieselgel 60=170 g, hexane/ethyl acetate=3/1) to obtain the above-captioned compound ([6]-(62)-90) (7.70 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>C(Cl)Cl>[CH2:11]([O:10][C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 147 g of 1,4-diaminobutane in 490 ml of methylene chloride, a solution of 41 ml of benzyl chloroformate in 84 ml of methylene chloride was added dropwise at 0° over a period of 1 hour. The mixture was stirred at 0° for 1 hour, then washed twice with water and extracted four times with 150 ml of 4N hydrochloric acid. The acidic extracts were washed with methylene chloride, basified with 450 ml of 22% of sodium hydroxide and extracted four times with methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated to give 4-benzyloxycarbonylamino-1-butylamine, having NMR peaks at δ=7.3, 5.05 and 2.6 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][N:26]([CH3:31])[C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(CN3CCNC3=O)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(Cc2ccc(CN3CCN(C)C3=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was added P-374 (21 mg, 0.05 mmol), THF (1 mL) and the solution was cooled to 0° C. Sodium hydride (3 mg, 0.076 mmol) was added and after 15 minutes at room temperature, methyl iodide (6 uL, 0.101 mmoL) was added. The reaction was stirred for 30 minutes at room temperature and then 1 mL of water was added. The THF was evaporated and the product was extracted with ethyl acetate and concentrated. The residue was passed through a silica gel plug eluting with methanol, which afforded P-375 (18.1 mg, 82%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=1.6 Hz, 1H), 7.60 (dd, J=2.0, 7.9 Hz, 1H), 7.50-7.39 (m, 2H), 7.37 (s, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.31 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 3.24 (s, 4H), 2.67 (s, 3H) ppm. LC/MS=97.8%, 440.1 (APCI+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 83.6 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (233 mg, 0.958 mmol), methyl 6-chloronicotinate (164 mg, 0.988 mmol) and potassium carbonate (265 mg, 1.92 mmol) in DMF (5.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (303 mg, 79%) as a white solid. MS: m/e=379.2 [M+H]+.