Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]5[CH2:54][CH2:53][CH2:52][C@@H:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:23][CH2:24][OH:25])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]5[CH2:54][CH2:53][CH2:52][C@@H:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH:16]=2)[O:22][CH2:23][CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methanesulfonyl chloride (5.80 μL, 0.074 mmol) was added to a solution of Intermediate 78d (40 mg, 0.057 mmol) and DIPEA (30 μL, 0.17 mmol) in DCM (1 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (2 mL) and washed with water (2×2 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound (44 mg, 100%). LCMS (Method 3): Rt: 3.68 min, m/z 777/779 [MH+].
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])C=CC=1)(O)=O.[Na+:79].[Na+].[Na+].[Na+].[Na+].B([C:87]1[CH:88]=[C:89]([CH:97]=[C:98]([F:100])[CH:99]=1)[O:90][CH2:91][CH2:92][CH2:93][C:94]([OH:96])=[O:95])(O)O>>[C:94]([CH2:93][CH2:92][CH2:91][O:90][C:89]1[CH:88]=[C:87](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:26])([CH3:27])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:44])=[O:45])[CH:99]=[C:98]([F:100])[CH:97]=1)([OH:96])=[O:95].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: O=C(O)CCCOc1cc(F)cc(B(O)O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 35 is prepared analogously to compound 8 (Example 8), except that 4-(3-borono-5-fluorophenoxy)butanoic acid is used as a starting material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[CH2:46]([O:48][C:49](Cl)=[O:50])[CH3:47]>O1CCCC1>[CH2:46]([O:48][C:49]([N:13]([CH2:12][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:50])[CH3:47]
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.43 g, 0.85 mmole) and triethylamine (130 μl, 0.93 mmole) in 5 ml of anhydrous tetrahydrofuran, was added dropwise ethylchloroformate (89 μl, 0.93 mmole). The resulting mixture was stirred for about 16 hours at room temperature. The tetrahydrofuran was removed under reduced pressure.
Reaction SMILES: ClC1C=C[C:5]([CH:8]2[CH2:13][CH:12](CN3C=NC=N3)[O:11][C:9]2=[O:10])=CC=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.C(OCC)(=O)C=C.[C-]#N.[Na+]>CN(C)C=O>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]([CH2:5][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C1OC(Cn2cncn2)CC1c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C=CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
This Example illustrates the preparation of -(4-chlorophenyl)-γ-(1,2,4-triazol-1-yl)methyl-γ-butyrolactone (A). ##STR45## Ethyl 3-(4-chlorobenzoyl)propanoate (25.0 g, 83%) was prepared from 4-chlorobenzaldehyde (23.4 g), ethyl acrylate (12.5 g) and sodium cyanide (4.0 g) in dimethylformamide (DMF: 300 ml) by the method described for the preparation of the corresponding methyl ester in Example 1.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:15]([Cl:28])[CH:14]=1.[CH:29](N1CCCCC1)=[O:30].[Cl-].[NH4+]>O1CCCC1>[Si:21]([O:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:29]=[O:30])=[CH:14][C:15]=1[Cl:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution (1.6 M, 8.3 ml) of n-butyl lithium/hexane was added to a solution of 4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene (4.03 g) in tetrahydrofuran (10 ml) under a nitrogen atmosphere at −60° C. and the mixture was stirred for 45 min. The reaction mixture was once heated to 0° C. and then cooled to −40° C. and 1-formyl piperidine (1.63 g) was dropwise added over 3 min. Then, the reaction mixture was heated to 0° C. over 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=30/1) to give the objective compound (2.49 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ccnc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
760 mg (3.25 mmol) 2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 273 mg (8.15 mmol) NaH is added over 5 min. 211 mg (1.63 mmol) 2-Chloropyrimidin-4-amine is then added and the solution stirred at 90° C. over night. 1 mL Water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (52%). ESI-MS m/z 327 [M+H]+.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][OH:15].CCCCCC>O1CCCC1>[CH2:16]([C:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])([CH2:14][OH:15])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(N)(CC)CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(CO)NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Benzoyl isothiocyanate (4.28 mL, 31.8 mmol) was added under nitrogen to a solution of 2-amino-2-ethylbutan-1-ol (3.7315 g, 31.8 mmol), prepared in the previous step, in 100 mL of anhydrous tetrahydrofuran (exotherm on addition). After the addition, the reaction was refluxed for 2.5 h. After cooling to room temperature, 100 mL of hexane was added. The solid that formed was collected by filtration and dried under reduced pressure to give N-({[1-ethyl-1-(hydroxymethyl)propyl]amino}carbonothioyl)benzamide (7.1406 g, 80%) as a white solid. mp 161-163° C.; MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1)=[O:8])([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(N)c2)c1
Yield: 130.5 %

Procedure:
To a solution tert-butyl (3-[{(3-nitrobenzoyl)amino]methyl}phenyl)carbamate (1.50 g, 4.04 mmol) in water (2.91 mL), methanol (16 mL) and acetic acid (6.2 mL) was added iron (0.564 g, 10.1 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 4 h, and the reaction was complete. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a brown solid (1.8 g). LCMS for C19H23N3O3 (M+H)+: m/z=342.1. 1H NMR (400 MHz, CD3OD): δ 7.38 (t, J=2.0 Hz, 1H), 7.28 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.08 (m, 1H), 6.96 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 6.85 (ddd, J=8.0, 2.0, 1.2, 1H), 4.50 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:30]3[CH2:36][CH:35]4[O:37][CH:32]([CH2:33][CH2:34]4)[CH2:31]3)[N:9]=2)=[CH:4][CH:3]=1.ClC(Cl)(O[C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.CN.[N-:52]=[C:53]=O>ClCCl.O1CCCC1>[CH3:53][NH:52][C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:30]3[CH2:31][CH:32]4[O:37][CH:35]([CH2:34][CH2:33]4)[CH2:36]3)[N:9]=2)=[CH:6][CH:7]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1
Reactant: [N-]=C=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (130 mg, 0.26 mmol) in dichloromethane (5 mL) was treated with triphosgene (37 mg, 0.12 mmol) as a solution in dichloromethane (2 mL). After the passage of five minutes, the appropriate nucleophile—in this case, 2.0 M methylamine solution in tetrahydrofuran (2 mL)—was added to the resulting isocyanate mixture. After 30 minutes of stirring at room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile. After the concentration of fractions under reduced pressure, tert-butyl 4-[6-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate was obtained. MS (ES+): 563.4 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:26])=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:26])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)OCc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(Allyloxycarbonyl)oxymethyl]benzoic acid (850 mg, 3.60 mmol) obtained from Example 17-(2) was dissolved in dichloromethane (5 ml), and N,N-dimethylformamide (0.05 ml) and oxalyl chloride (570 mg) were added thereto. The mixture was stirred at room temperature for 1 hour, then toluene was added thereto, and the solution was concentrated under reduced pressure to give crude 2-[(allyloxycarbonyl)oxymethyl]benzoyl chloride.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:12]=O.[CH3:14][NH:15][NH2:16].Cl>C(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:14][N:15]([CH3:12])[N:16]=[C:3]1[CH:2]([F:11])[F:1])=[O:6])[CH3:9]
Reactant: CNN
Reactant: C=O
Reactant: CCOC(=O)CC(=O)C(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CN(C)N=C1C(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
Ethyl 4,4-difluoroacetoacetate (5.0 g, 30 mmol) was dissolved in 35 ml of ethanol and the solution was cooled down to 0° C. A 37% aqueous solution of formaldehyde (2.5 g, 30 mmol) was added and the mixture was stirred for 15 minutes at 0° C. Methylhydrazine (1.4 g, 30 mmol) was added and the reaction mixture was heated to reflux. After reaching the reflux temperature, 0.5 ml of concentrated hydrochloric acid were added, and refluxing was continued for 16 h. Subsequently, the mixture was cooled down and the solvent was removed in vacuo. The remainder was taken up in water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, yielding 1.5 g of 3-difluoromethyl-1-methyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=O)=O.[C-:21]#[N:22].[Na+]>CS(C)=O>[C:21]([CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:22]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CC#N
Temperature: 25 °C
Yield: 76 %

Procedure:
A DMSO (40 ml) solution of ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate and NaCN (1.59 g, 3.24 mmol) was stirred at 45° C. for 4 hours and at 50° C. for 2 days, the progress of the reaction was monitored by LC-MS. After cooling to room temperature, the reaction was quenched by the addition of water (˜60 ml). Reaction mixture was extracted with EtOAc (˜40 ml), two layers were separated, organic layer was washed with brine (˜25 ml), the extraction and wash sequence was repeated for two more times. Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 80:20). Compound (R)-tert-butyl 2-(cyanomethyl)-4,4-difluoropyrrolidine-1-carboxylate was obtained as a colorless oil: 2.10 g (76% yield over 2 steps).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][P:18]([CH2:30][C:31]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:32])([CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[O:14][CH2:15][O:19][P:18]([CH2:30][C:31]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:32])([CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:17]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CP(=O)(O)CCCCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triethylamine (1.9 ml) and chloromethyl pivalate (2.0 ml) are added to a solution of 3.0 g of [[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, benzyl ester in dimethylformamide under an argon atmosphere and the resulting mixture is stirred at room temperature for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product (3.7 g) is chromatographed on silica (80 g) eluting with ethyl acetate/dichloromethane to give 2.96 g of the title compound.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[C:12](=[O:36])[N:11]1[CH3:37])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:35])[F:34])[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[C:12](=[O:36])[N:11]1[CH3:37]
Reactant: CN1C(=O)N(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C[C@@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)N(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C[C@@H]1CO
Yield: 104.5 %

Procedure:
The 7-((R)-4-benzyloxymethyl-3-methyl-2-oxoimidazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (13 mg, 0.025 mmol) prepared in Example 1-35 was dissolved in methanol (5 ml). Thereafter, 10% Pd—C (3 mg) was added to the obtained solution, and the obtained mixture was then stirred in a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was then concentrated. The obtained residue was purified by silica gel TLC used for preparative separation (dichloromethane:methanol=20:1), so as to obtain 7-((R)-4-hydroxymethyl-3-methyl-2-oxoimidazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.9 mg, quantitative) in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: C1CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(CN3CCCCC3)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (250 mg; 0.84 mmol), piperidine (94 mg; 1.1 mmol) and K2CO3 (140 mg; 1.01 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture is cooled to room temperature, diluted with TBME, filtered and evaporated to dryness to deliver the title compound as orange crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[H][H].Cl[C:10]1[N:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([CH2:19][Cl:20])[CH:11]=1>CCCCC.O1CCCC1>[Cl:20][CH2:19][C:12]1[CH:11]=[C:10]([O:6][CH2:3][C:4]#[CH:5])[N:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=1
Reactant: [H][H]
Reactant: C#CCO
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: C#CCOc1cc(CCl)nc(C(C)C)n1

Procedure:
21.5 g of 50% sodium hydride dispersion in oil (0.45 mol of NaH) are suspended briefly in 200 ml of absolute n-pentane under nitrogen. The sodium hydride is then liberated from the oil by decantation and covered with 400 ml of dry tetrahydrofuran. 25.4 ml (0.43 mol) of 2-propynol are then introduced while stirring well, the temperature of the mixture rising to 40° C. After completion of the hydrogen evolution the mixture is cooled to 0° C. and a solution of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61) in 100 ml of tetrahydrofuran is added dropwise during 30 minutes. The mixture is stirred for 16 hours and the major part of the solvent is then removed by evaporation under reduced pressure. The residue is subsequently taken up in 300 ml of methylene chloride and the solution is washed neutral twice with 300 ml of water each time. The organic phase is dried over anhydrous magnesium sulphate and concentrated and the reaction is purified on silica gel with diethyl ether/n-hexane (1:9). In this manner there is obtained 4-chloromethyl-2-isopropyl-6-(2-propynyloxy)-pyrimidine in the form of a yellowish oil, nD24 1.5142.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Br
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)ccc2Br)n1
Temperature: 150 °C
Yield: 36 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-bromo-5-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.029 g (36% yield) of pure product: MS (ES) m/z 523 (M+1).