Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](O)=[O:6])[CH2:3][CH2:2]1.CSC.B>C1COCC1>[CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: C[C@H](N[C@H](C(=O)O)C1CC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]acetic acid (400 g, 1.82 mol) in dry THF (5.2 L) at 0° C. was added borane dimethylsulfide (neat) (485 g, 6.39 mol) with vigorous stirring. The reaction mixture was stirred overnight at room temperature. Reaction progress was monitored by HPLC. Stirring was continued until the acid was consumed completely (18-20 h). Upon completion the reaction mixture was cooled to 0° C. and methanol (6 L) was added dropwise. The mixture was concentrated under vacuum and the residue was dissolved in chloroform (5 L). The organic layer was washed with 10% aqueous NaHCO3 solution (2×1 L) followed by brine, dried over Na2SO4, filtered and concentrated to afford a tan-yellow oil. The oil was distilled under reduced pressure to afford (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (166 g, 44% yield) as a colorless oil: by 175-184° C., 0.1 mm Hg; [α]25D −52.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.91-3.86 (m, 1H), 3.67 (dd, JAB=10.6, JAX=3.8 Hz, 1H), 3.39 (dd, JBA=10.6, JBX=4.3 Hz, 1H), 2.40 (s br, 2H), 1.70-1.65 (m, 1H), 1.35 (d, J=6.6 Hz, 3H), 0.88-0.82 (m, 1H), 0.47-0.37 (m, 2H), 0.05-−0.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.8, 127.6, 126.2, 125.9, 63.0, 60.5, 54.4, 24.4, 13.3, 3.0, 1.5; LRMS (ESI) m/e 206.3 [(M+H)+, calcd for C13H20NO 206.2].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cccc(NC(C)=O)c2c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of N-(7-hydroxynaphthyl)acetamide (175.4 g, 0.872 mol), potassium carbonate (301 g, 2.18 mol), and acetone (1 l) was added iodomethane (270 mL, 4.36 mol). The reaction mixture was refluxed for 6 hr, cooled to room temperature, and the solvent removed. The residue was filtered through silica with ethyl acetate and triturated with ethyl acetate to yield 161.6 g (86%) of a gray solid. An analytical sample was further purified by preparative reverse phase HPLC to yield the title compound as a white solid: mp 154-155° C.; 1H NMR (DMSO-d6): δ 2.19 (3H, s), 3.90 (3H, s), 7.19 (1H, dd, J=2.39 Hz, J=8.94 Hz), 7.29-7.34 (2H, m), 7.39 (1H; d, J=1.86 Hz), 7.75-7.68 (2H, m), 7.87 (1H, d, J=8.96 Hz), 9.82 (1H, s); MS (ESI) m/z 216 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[S:12][C:11]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>O>[N:1]1([CH2:6][CH2:7][C:8]2[S:12][C:11]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(CCn2ccnc2)s1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(CCn3ccnc3)s2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4.2 g of 4-{5-[2-(1-imidazolyl)-ethyl]-thien-2-yl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.8 g of hydrazine hydrate are added and the mixture is stirred at 90° C. for 2 hours. After the mixture has been cooled, it is extracted with chloroform. The chloroform phase is washed with water, dried over Na2SO4 and concentrated to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2C[C@@H]3C[C@H]2CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg, 0.848 mmol) and DIPEA (271 μL, 1.554 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (1S,45)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (148 mg, 0.428 mmol, 60.6% yield). LC-MS (M+H)+=346.1. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2H, m), 7.00-7.08 (2H, m), 5.11-5.21 (1H, m), 4.69-4.74 (1H, m), 4.15-4.26 (1H, m), 3.88-3.94 (2H, m), 3.68-3.86 (2H, m), 3.11-3.21 (1H, m), 2.56-2.69 (1H, m), 1.92-2.11 (2H, m), 1.24-1.42 (2H, m).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[CH3:6][C:7]([CH:9]1[CH2:11][CH2:10]1)=[O:8].CC(C)=O>>[CH3:6][C:7]([OH:8])([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)[CH3:9].[CH:9]1([C:7]([OH:8])([C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)[CH3:6])[CH2:11][CH2:10]1
Reactant: CC(=O)C1CC1
Reactant: C#CC1CC1
Solvent: CC(C)=O
Product: CC(C)(O)C#CC1CC1
Product: CC(O)(C#CC1CC1)C1CC1

Procedure:
Another reaction which is known is the ethynylation of cyclopropylacetylene with acetone or cyclopropyl methyl ketone to give 2-methyl-4-cyclopropyl-3-butyn-2-ol or 2,4-dicyclopropyl-3-butyn-2-ol (Izvetiya Akademii Nark SSSR, Seriya Khimicheskaya, pages 1339-1344 (1978)), but no description for the reverse reaction is provided.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([SH:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:34]([O:36][CH:37]([O:42][CH2:43][CH3:44])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35]>C(Cl)Cl>[CH2:43]([O:42][CH:37]([O:36][CH2:34][CH3:35])[CH2:38][CH2:39][CH2:40][NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([SH:19])([CH3:18])[CH3:17])[CH3:44]
Reactant: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCCN)OCC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(CCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a round bottom flask was added (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.68 g, 16.52 mmol), HOBT (2.53 g, 16.52 mmol), EDC (3.17 g, 16.52 mmol), DCM (50 mL), TEA (2.302 mL, 16.52 mmol) and 4,4-diethoxybutan-1-amine (2.66 g, 16.52 mmol). The reaction was stirred at rt overnight. The reaction was diluted with DCM (150 mL). The organics was washed with water (2×150 mL), saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-benzyl 1-(4,4-diethoxybutylamino)-3-mercapto-3-methyl-1-oxobutan-2-ylcarbamate (6.90 gm, 16.2 mmol, 98% yield) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:16]1[CH2:20]OC[CH2:17]1.C(Cl)(=O)C(Cl)=O.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH2:20]([O:14][C:13]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)=[O:15])[CH:16]=[CH2:17]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nitroterephthalic acid (6.33 g) in methylene chloride 475 ml) and THF (15 ml) was converted to the mono acid chloride using oxalyl chloride (2.63 ml), DMF (2.55 ml) and N-methylmorpholine (7.95 ml) at −10° C. After 1 hour the solvents were removed and, without further purification, the product was dissolved in allyl alcohol (20 ml) and THF (10 ml) and stirred overnight at ambient temperature. The solvents were removed and the residue partitioned between EtOAc and aqueous NaHCO3. Acidification of the NaHCO3 solution and extraction with EtOAc gave the product, 4-allyloxycarbonyl-2-nitrobenzoic acid (6.8 g). Nmr (CDCl3): δ 4.89 (d, 2H); 5.31-5.49 (m, 2H); 5.95-6.15 (m. 1H); 7.94 (d, 1H); 8.36 (dd, 1H); 8.54 (d, 1H). Without purification, this acid was converted by the method above to the acid chloride which was dissolved in THF (100 ml) at 0° C. Ammonia gas was bubbled into the solution until the reaction was completed. The solution was partitioned between EtOAc and water, and the product from the organic fraction purified on silica, eluting with methylene chloride followed by EtOAc. The product (4 g), containing a small impurity, was reduced with SnCl2 by a similar method to that in example 12 giving 4-allyloxycarbonyl-2-aminobenzamide. Nmr (DMSO-d6): δ 4.79 (d, 2H); 5.22-5.46 (m, 2H); 5.91-6.13 (m, 1H); 7.02 (dd. 1H); 7.37 (d, 1H); 7.61 (d, 1H).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].[ClH:31]>ClCCl.C(O)C>[ClH:31].[ClH:31].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17](=[O:19])[C:16]1[CH:21]=[CH:22][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)[CH3:24]
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 16 h

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl]benzoate (2.2 g, Example 7) and N,N-diethylethylenediamine (7 ml) was boiled under reflux for 5 hours. The mixture was cooled and stood for 16 hours at ambient temperature. Petroleum ether, b.p. 60-80° C. (50 ml) was added and then decanted off to leave a gum which was further treated with petroleum ether as above and the residual gum dissolved in dichloromethane and purified by flash column chromatography on silica using dichloromethane/IMS/triethylamine (25:2:1) as the mobile phase to give a solid which was dissolved in ethanol (70 ml) and then dry hydrogen chloride gas was passed through the solution. The precipated solid was collected by filtration, washed with ethanol and dried to give N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]-pyrazol-3-yl)- benzamide dihydrochloride, m.p.230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:33])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde (Example 102, Step E) (267 mg, 0.604 mmol) in acetone (4 mL) was added freshly prepared Jones reagent (0.5 mL) at rt. The reaction mixture was stirred at room temperature for 15 min. before it was diluted with EtOAc and washed with water and sat. aq. NaCl solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound as a colorless film as a 3.6:1 mixture of diastereomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)[CH2:4][CH3:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:28]>>[ClH:28].[CH2:1]([N:3]([CH2:6][C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][NH:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: ClCCl
Reactant: CCN(CC)C[C@@H]1COCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C[C@@H]1COCCN1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
(R)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 90, STEP 1) was dissolved with TFA/DCM, (6 ml, 1:1 v/v) and the resulting mixture was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure and the concentrate was treated with 4N HCl in dioxane (3 ml), stirred for 10 minutes and the volatiles were removed under reduced pressure. The resulting semi solid was triturated with diethyl ether (2×30 ml) and dried to give the title product (140 mg, yield: 58%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][NH:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:27]=1)(=[O:16])=[O:15].C(N(CC)CC)C.CN1CCCC1=O>O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:25]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:27]=[C:17]([S:14]([CH3:13])(=[O:15])=[O:16])[CH:18]=[CH:19][C:20]=3[CH2:26]2)[CH:11]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCCNC2
Reactant: Clc1cc(Cl)c2ccccc2n1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3ccccc3n1)C2
Temperature: 100 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol), 7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (144 mg, 0.637 mmol), triethylamine (0.106 mL, 0.765 mmol) and N-methyl-2-pyrrolidone (2 mL) was heated with stirring in a sealed tube for 4 hours at 100° C. The resulting mixture was diluted with water and extracted with ethyl acetate (15 mL×3). The organic layers were combined and washed with brine (15 mL×3), and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to afford 55.6 mg of product as a white solid (yield was 22.5%). MS obsd. (ESI+) [(M+H)+] 387.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]=[C:26]1[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:30][CH2:29][O:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:25])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=O)CN1CCOCC1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)CN1CCOCC1=O
Reaction time: 1 h
Yield: 8.7 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.400 g, 1.14 mmol) was dissolved in THF (4 mL) and 2-(3-oxomorpholino)acetohydrazide (0.295 g, 1.71 mmol) was added. T3P (1.09 g, 1.71 mmol) was added dropwise followed by DIPEA (220.80 mg, 1.71 mmol) at −60° C. and the reaction mixture was stirred for 1 h. The reaction mixture was transferred into 25 mL iced-water and extracted with EtOAc (2×25 mL) Combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product which was purified by chromatography (0-4% MeOH/CH2Cl2) to give 0.05 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3-oxomorpholino)acetyl)acrylohydrazide (Yield: 8%). 1H NMR (400 MHz, DMSO-d6) δ 10.33 (bs, 2H), 9.63 (s, 1H), 8.57 (s, 2H), 8.30 (s, 1H), 7.50-7.52 (d, J=8 Hz, 1H)), 6.01-6.03 (d, J=8 Hz, 1H), 4.08-4.12 (m, 4H), 3.85-3.87 (m, 2H), 3.41-3.44 (m, 2H). LCMS m/z 507.13 [M+H]+, tR 1.950 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([OH:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N1CCCC1.CC(O[C:22]([NH:24][C@@H:25]([C:29]([OH:31])=O)[CH:26]1[CH2:28][CH2:27]1)=[O:23])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:48]([N:50]1[CH:54]=[C:53]([C:55]2[N:60]=[C:59]3[C:61](C(O)=O)=[CH:62][N:63](COCC[Si](C)(C)C)[C:58]3=[N:57][CH:56]=2)[CH:52]=[N:51]1)[CH3:49].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1>>[CH:26]1([C@@H:25]([NH:24][C:22]([C:61]2[C:59]3[C:58](=[N:57][CH:56]=[C:55]([C:53]4[CH:52]=[N:51][N:50]([CH2:48][CH3:49])[CH:54]=4)[N:60]=3)[NH:63][CH:62]=2)=[O:23])[C:29]([N:6]2[CH2:5][CH2:4][C:3]([OH:9])([C:2]([F:1])([F:10])[F:11])[CH2:8][CH2:7]2)=[O:31])[CH2:27][CH2:28]1
Reactant: OC1(C(F)(F)F)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Solvent: C1CCNC1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(O)(C(F)(F)F)CC4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 4-trifluoromethyl-piperidin-4-ol (Example 74, step 2) for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. MS: (M+H)+=506.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH2:25])[NH:18][N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:33]([C:35]1[O:36][C:37](=[O:60])[C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]3[O:55][C:54]([CH3:57])([CH3:56])[C:53]([CH3:59])([CH3:58])[O:52]3)[CH:46]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:34].Cl>CN(C=O)C.CCOC(C)=O>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:33]([C:35]3[O:36][C:37](=[O:60])[C:38]4[C:43]([C:44]=3[C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]5[O:52][C:53]([CH3:59])([CH3:58])[C:54]([CH3:57])([CH3:56])[O:55]5)[CH:46]=3)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH3:34])[N:17]=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[C:24]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
In a 100 ml round bottomed flask 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 400 mg, 1,194 mmol) was dissolved in 7 ml of dry DMF then K2CO3 (254 mg, 1.837 mmol) was added. After stirring for 5 min a solution of 3-(1-bromoethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (Intermediate C26, 420 mg, 0,918 mmol) in 7 ml of dry DMF was added and the clear brown mixture was heated at 60° C. for 30 min. The mixture was cooled to r.t. then 30 ml of HCl 0.5 M and 50 ml of EtOAc were added and stirred for 15 min. Phases were separated and the crude material was purified by chromatography eluting with DCM\MeOH (80/20) in DCM to give the title compound (820 mg) as a brown oil. This material was used in the next step without any further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1)=[O:16])(=[O:30])=[O:31]
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2-(3-pyridyl)-pyrimidine-5-carboxylic acid hydrochloride (237 mg 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (15 mL) is treated with diisopropylethylamine (0.36 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc. The resulting solid is filtered, washed with ether to afford 2-(3-pyridyl)-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (185 mg, 48%). MS: 384 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (d, 3H), 4.65 (d, 2H), 7.45-7.55 (q, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.72-8.80 (m, 2H), 9.35 (s, 2H), 9.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1N.C(O)(=O)C.N([O-])=O.[Na+].[CH:21]([CH:23]=[CH2:24])=[O:22].[ClH:25]>O.CC(C)=O.Cl[Cu]>[Cl:25][CH:23]([CH2:24][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1[Cl:1])[CH:21]=[O:22]
Reactant: Cl
Reactant: C=CC=O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=CC(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Yield: 50 %

Procedure:
195.5 g (1 mole) of 2-chloro-5-trifluoromethylaniline are added to a mixture of 280 ml of concentrated HCl and 280 ml of acetic acid. After the mixture has been cooled to 0° C., 75 g of NaNO2 dissolved in 150 ml of water are slowly added to the mixture, the temperature being maintained between 0° and 3° C. At the same temperature, a mixture of 5 g of CaO and 60 g of acrolein dissolved in 250 ml of acetone is then introduced. A solution of 1 g of CuCl in 20 ml of concentrated HCl is then added; the temperature is maintained between 5° and 10° C. The evolution of nitrogen ceases after a reaction time of 1 hour. The α-chloro-β-(2-chloro-5-trifluoromethyl-phenyl)propionaldehyde is extracted by ether and washed in water. After drying and removal of the solvent the product is distilled at a reduced pressure. 135 g, corresponding to a 50% yield, of a slightly yellowish oil distilling between 98° and 100° C. at a pressure of 0.5 mm are obtained.