Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=O)[CH:12]([CH3:16])[O:11][C:10]=2[CH:17]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][CH2:13][CH:12]([CH3:16])[O:11][C:10]=2[CH:17]=1
Reactant: CC1Oc2cc(Br)ccc2NC1=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC1CNc2ccc(Br)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Borane dimethyl sulfide complex (2 M solution in THF, 0.414 mL, 0.828 mmol) was added at room temperature to a solution of 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one A-2 (100.0 mg, 0.414 mmol) in anhydrous THF (4.10 mL) under an atmosphere of argon. The reaction mixture was heated to reflux for 2 h, cooled to room temperature, quenched with methanol (1.0 mL), stirred for 30 mins and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine A-3 (92.9 mg, Yield=98%). MS (ESI) [M+1]+ 228, 230.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.BrC1C=CC([C:16]2[C:21]([C:22]([C:24]3[C:25]([C:30]4[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=4)=NC=CC=3)=O)=CC=[CH:18][N:17]=2)=CC=1.C(Cl)Cl.[O:40]1CCCC1>CCCCCC>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([C:25]([OH:40])([C:24]2[CH:18]=[N:17][CH:16]=[CH:21][CH:22]=2)[CH2:2][C:1]#[N:3])=[CH:35][CH:34]=1
Reactant: C1CCOC1
Reactant: O=C(c1cccnc1-c1ccc(Br)cc1)c1cccnc1-c1ccc(Br)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CCC(O)(c1ccc(Br)cc1)c1cccnc1
Reaction time: 0.25 h

Procedure:
A mixture of 6.5 g (0.16 mole) of acetonitrile and 50 ml of dry tetrahydrofuran (THF) was slowly added under N2 -atm to a mixture of 100 ml of 1.5 M n-butyllithium in hexane and 50 ml of dry THF at -50° C. After stirring for 35 minutes a solution of 36.5 g (0.14 mole) of 4-bromophenyl-3-pyridylketone in 250 ml of dry THF was added at -50° C. The temperature was kept at -70° C. for 15 minutes, then the reaction mixture became viscous and it was allowed to reach ambient temperature. The product was poured into a stirred mixture of 500 g of icewater and 500 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with 2×200 ml of CH2Cl2. The combined organic layers were washed with water and dried. The solvent was evaporated giving 39.7 g of an oil. It was dissolved in 550 ml of hot i-PrOH and a solution of 35 ml of 4M HCl-ether (0.14 mole) in 100 ml of i-PrOH was added. After cooling there was collected 34.6 g (74%) of the hydrochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile. M.p. 158°-161° C. ##STR33##
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[O:5])[CH3:2].[C:12]12([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:12]23[CH2:13][CH:14]4[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]4)[CH2:21]2)[CH2:19]3)=[CH:27][CH:26]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCCCCl
Product: CCOC(=O)CCCCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the procedure describe in Example 5, the use of 5-chloro-pentanecarboxylic acid ethyl ester and p-(1-adamantyl)-phenol as starting materials gives 5-[4-(1-adamantyl)-phenoxy]-pentanecarboxylic acid ethyl ester of boiling point 170°-180° C (0.05 mm).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:57]1([N:60]2[CH2:65][CH2:64][N:63]([C:66]3([CH2:72][NH:73][C:74](=[O:81])[C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][CH2:61]2)[CH2:59][CH2:58]1>ClCCl.CN(C=O)C>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:69]2[CH2:68][CH2:67][C:66]([CH2:72][NH:73][C:74](=[O:81])[C:75]3[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=3)([N:63]3[CH2:62][CH2:61][N:60]([CH:57]4[CH2:58][CH2:59]4)[CH2:65][CH2:64]3)[CH2:71][CH2:70]2)=[O:23])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)COCCN(C1CC1)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1(N2CCN(C3CC3)CC2)CCN(C(=O)COCCN(C2CC2)S(=O)(=O)c2ccccc2C(F)(F)F)CC1)c1ccncc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-2-(trifluoromethyl)phenylsulfonamido)-ethoxy)acetic acid AC9 (0.472 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 55%. MS, Rt=2.8 min, m/z=693.5 [MH]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:10][S:9][C:8]2[S:11][CH:12]=[CH:13][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH2:17]([Li])CCC.CI>O1CCCC1.CCCCCC>[CH3:17][C:12]1[S:11][C:8]2[S:9][CH2:10][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH2:6][C:7]=2[CH:13]=1
Reactant: [Li]CCCC
Reactant: CCCN(CCC)C1CSc2sccc2C1
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CSc2sc(C)cc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g of N,N-dipropyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine in 40 ml of tetrahydrofuran is treated with 4 ml of 2.5 M n-butyl lithium in hexane at 0°. After 30 minutes at 0°, 1.5 g of methyl iodide is added and the mixture is kept at room temperature for 1 hour. Dilution with ether and washing with water followed by drying and removal of the solvent in vacuo affords 2-methyl-N,N-dipropyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(NCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(NCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Yield: 21.5 %

Procedure:
N4-(2-morpholin-4-yl-ethyl)-naphthalene-1,4-diamine (190 mg, 701 μmol), 3-fluoro-5-morpholinyl benzoic acid (236 mg, 1.05 mmol), HBTU (531 mg, 1.4 mmol) and diisopropylethylamine (0.37 ml, 2.1 mmol) are stirred at room temperature in dimethylformamide (10 ml) for 12 hours. The mixture is poured into ethyl acetate (100 mL) and washed with water (100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 5% methanol in ethyl acetate to give 3-fluoro-5-morpholin-4-yl-N-[4-(2-morpholin-4-yl-ethylamino)-naphthalen-1-yl]-benzamide (72 mg). 1H NMR 300 MHz (CDCl3) 7.7-8.0 (m, 3H), 7.4-7.6 (m, 3H), 7.3 (m, 1H), 7.05 (m, 1H), 6.7 (m, 1H), 6.6 (m, 1H), 5.35 (m, 1H), 3.65-4.0 (m, 8H), 3.2-3.4 (m, 6H), 2.8 (m, 2H), 2.4-2.55 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.N1(C2C=CN=CC=2)CCCC1>C(#N)C.O>[F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Reactant: C1CCNC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CC#N
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Temperature: 22 °C
Yield: 92.9 %

Procedure:
A solution of 3,3,3-trifluoro-N-(4-flurosulfonylphenyl)-2-hydroxy-2-methylpropanamide (0.25 g), pyrrolidine (0.28 g), and 4-pyrrolidinopyridine (12 mg) in dry acetonitrile (3 ml) was heated at reflux for 24 hours. After cooling to 22° C., the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl, brine, dried (Na2SO4) and evaporated to give an oil which crystallized upon suspension in hexane to yield the title compound as an off-white crystalline solid (0.27 g); mp 183°-186° C.; MS: m/z=367(M+1); NMR: 1.59 (s,3), 1.62 (m,4), 3.12 (m,4), 7.56 (s,1), 7.75-7.77 (m,2), 8.00-8.03 (m,2), 10.40 (s,1). Analysis for C14H17F3N2O4S: Calculated: C, 45.89; H, 4.68; N, 7.65; Found: C, 45.98; H, 4.76; N, 7.56.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH2:12]=[O:13].C(#N)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[K+]>[CH2:17]([O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: C=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nc(C(F)(F)F)c(CO)c1OCc1ccccc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 was dissolved in 35.0 g (0.15 mole) of a 24% aqueous potassium hydroxide solution. To the solution being stirred at room temperature was dropwise added 9.7 g (0.12 mole) of a 37% formalin solution, followed by stirring at the same temperature for 1 hour. Then, there were added 70.0 g (0.3 mole) of a 24% aqueous potassium hydroxide solution and 100 ml of acetonitrile. Thereto was dropwise added 20.5 g (0.12 mole) of benzyl bromide at room temperature in 1 hour, followed by stirring at room temperature for 12 hours to give rise to a reaction. After the reaction, the organic layer which appeared by phase separation, was concentrated under reduced pressure to obtain 26.1 g (purity: 80.0%, yield: 73.1%) of a crude solution of title compound. The crude solution was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain a title compound as a light yellow transparent solution.
Reaction SMILES: [N:1]1([C@@H:10]2[O:14][C@H:13]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C@@H:12]([OH:27])[CH2:11]2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:28]([O:27][C@H:12]1[CH2:11][C@H:10]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[O:14][C@@H:13]1[CH2:15][O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])(=[O:30])[CH3:29]
Reactant: CC(C)[Si](OC[C@H]1O[C@@H](n2ccc3cnccc32)C[C@@H]1O)(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2ccc3cnccc32)O[C@@H]1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3-ol (0.487 g, 1.25 mmol) and a catalytic amount of DMAP in pyridine (1.6 mL) at 0° C. was added acetic anhydride (0.130 mL, 1.38 mmol) dropwise. The reaction was stirred overnight, concentrated, dissolved in EtOAc, washed with 1 M aq HCl (1×), water (1×) and brine (1×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated to give the title compound (0.464 g, 95%) which was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:37]3[C:38]4[CH:39]=[C:40]5[C:27]6([CH2:30][O:31][C:32]5=[CH:33][C:34]=4[CH2:35][CH2:36]3)[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]6)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(C3=NCCO3)cc2C)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(C2=NCCO2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Yield: 35 %

Procedure:
This was prepared from methyl 4'-(4,5-dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylate (D114) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine (D8) following the procedure of Example 12. This gave the title compound (35%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:16]#[N:17].C[Si](Cl)(C)C.[CH2:30]([Mg]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[F:12][C:13]1[CH:14]=[C:15]([C:16]([C:4]2[O:3][C:2]([CH3:1])=[CH:6][CH:5]=2)([NH2:17])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: Cc1ccco1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven-dried round bottomed flask was added 2-methylfuran (0.5 mL, 5.58 mmol) in Et2O (4 mL) at −30° C. nBuLi (2.5 M in hexanes, 0.95 ml, 2.38 mmol, 1.17 eq) was added dropwise at −30° C. under N2. The reaction mixture was slowly warmed up to room temperature and stirred at room temperature overnight. To the resulting light tan solution, cooled at −40° C., was added an Et2O solution (5 mL) of 3-fluoro-5-trifluoromethyl-benzonitrile (1.05 g, 5.58 mmol), added dropwise. The resulting solution was stirred −50 to −10° C. for 3 h. Pretreated TMSCl (0.78 ml, 1.1 eq) was added dropwise at −78° C. The dry ice bath was removed, and the mixture was stirred at r.t. for 1.5 h. It was cooled back to −78° C., and benzylmagnesium chloride (2.7 ml, 5.4 mmol, 0.97 eq) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min, and then at r.t. for 2 h. The reaction mixture was quenched by adding sat'd NH4Cl and 1N HCl, and stirred for 10 min. The resulting solution was extracted with EtOAc, washed with 1N NaOH, sat'd NaHCO3, H2O, brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methylfuran-2-yl)-2-phenylethanamine eluted with 15-30% EtOAc in hexanes) to give pure 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methylfuran-2-yl)-2-phenylethanamine as light brownish gum (1.1 g, yield: 71.4%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=3.16 min, 347.13 (M−NH2+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.42 (s, br, 1 H), 7.25 (d, J=10.0 Hz, 1 H), 7.14-7.04 (m, 4 H), 6.77-6.70 (m, 2 H), 5.97 (d, J=3.0 Hz, 1 H), 5.86-5.80 (m, 1 H), 3.41 (d, J=13.2 Hz, 1 H), 3.09 (d, J=13.2 Hz, 1 H), 2.21 (s, 3 H). 1H NMR (xx MHz, CDCl3) δ ppm −63.05 (CF3), −111.53 (F).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.CON(C)[C:15](=[O:19])[CH2:16][O:17][CH3:18]>O1CCCC1.CCCCCC>[CH3:18][O:17][CH2:16][C:15](=[O:19])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: COCC(=O)N(C)OC
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(=O)C#C[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.42 h
Yield: 79.7 %

Procedure:
A solution of 14.75 ml of trimethylsilylacetylene (103.62 mmol) in 250 ml of tetrahydrofuran is cooled to −70° C. and then 64.76 ml of a 1.6 M solution of n-BuLi (103.62 mmol) in hexane are added. The mixture is stirred for 25 minutes at −70° C. and then a solution of 13.14 g of N-methoxy-N-methyl-2-methoxyacetamide (98.69 mmol) in 250 ml of tetrahydrofuran is added rapidly. During the addition, the temperature rises to −50° C., and then the cold bath is removed and the mixture is stirred for 2 hours at ambient temperature. A 1N solution of HClaq is added and then extraction is carried out 4 times with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered, and concentrated under vacuum. 13.4 g of 1-methoxy-4-(trimethylsilyl)but-3-yn-2-one are obtained in the form of a light brown oil which is used without subsequent purification (crude yield=80%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C1COCC1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([NH:25][S:26](=[O:38])(=[O:37])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]>CN(C=O)C>[CH2:1]([O:4][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([NH:25][S:26](=[O:37])(=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[CH:2]=[CH2:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOc1nc(-c2ccncc2)nc(NS(=O)(=O)Nc2ccc(C(C)C)cc2)c1Oc1ccccc1OC
Temperature: 80 °C

Procedure:
To a mixture of allyl alcohol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silicagel with EtOAc/Hex=3:2 to give 4-i-propyl-phenyl sulfamic acid-[6-allyloxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (10 mg). tR=5.36 min, (LC); [M+H]+=548.46 (ES+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][F:23])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:30])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][F:23])[C@@H:13]3[C@H:18]([F:30])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1c(C2=NN3CC[C@@H](F)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.1 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-3-(2-fluoroethoxy)-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained in example 16 (120 mg, 0.36 mmol) in DCM (5 mL) at 0° C. was added DAST (0.05 mL, 0.43 mmol) and stirred at room temperature for 14 h. Once the starting material had disappeared (monitored by TLC) reaction mixture was diluted with DCM, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 50% EtOAc in Hexane) provided the title compound (60 mg, 50%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].[OH-].[Na+]>>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:14])[C:7]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:6]=3[C:5]=2[CH:4]=1)[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc2c(c1)c1c(n2C=C(C)c2ccncc2)CCN(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-N, 2-dimethyl-5-(2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indol-8-amine (23 mg) was charged in round bottom flask and acetic anhydride (0.7 mL) was added. The contents were stirred at RT for 30 min. The reaction mixture was basified with 1N NaOH and compound extracted with EtOAc (2×25 mL). The organic layer was concentrated under vacuum and recrystallized in DCM:Hexane (1:3) to yield 2.38 mg of desired compound. 1H NMR (CDCl3, free base) δ (ppm): 8.62 (d, 2H), 7.42 (d, 2H), 7.25 (s, 1H), 7.10 (dd, 2H), 6.98 (d, 1H), 3.70 (s, 2H), 3.30 (s, 3H), 2.82 (m, 4H), 3.60 (s, 3H), 2.04 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1)=[O:6].CO.O1CCCC1>O>[C:22]([O:21][C:19]([N:9]1[CH2:10][C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[C@H:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Add lithium hydroxide (0.50 g, 12 mmol) to a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.80 g, 2.08 mmol) in a 1:2:1 mixture of MeOH:tetrahydrofuran:water (8 mL). Stir the mixture at room temperature for 3 h then concentrate under reduced pressure to remove volatile organics. Wash the concentrated aqueous mixture with EtOAc and then acidify to pH 5 using a 0.5 M solution of citric acid. Extract the mixture with EtOAc, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to provide 0.53 g of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:19])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc([N+](=O)[O-])cc1
Yield: 84 %

Procedure:
3-(4-nitrophenyl)propanoic acid (500 mg, 2.56 mmol) was dissolved in MeOH (10 ml). SOCl2 (0.374 ml, 5.12 mmol) was added at 0° C., and the reaction was refluxed for 2 hours. The solvent was evaporated under vacuum, and the crude product was triturated in petroleum ether to give methyl 3-(4-nitrophenyl)propanoate (450 mg, 2.151 mmol, 84% yield).