Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][C:58]([F:61])([F:60])[F:59])=[CH:53][CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:62][OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([O:57][C:58]([F:60])([F:61])[F:59])=[CH:55][CH:56]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:62]=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
Oxalyl chloride (0.21 mL, 2.45 mmol) was dissolved in 5 mL dichloromethane and cooled to −78° C. The mixture was stirred for 15 minutes after 5 mL solution of dimethyl sulfoxide (0.24 mL, 3.26 mmol) in dichloromethane were added. Then 10 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 6m (1.22 g, 1.63 mmol) in dichloromethane were added before the mixture was stirred for 40 minutes. Then the reaction mixture was warmed and stirred for 1.5 hours at room temperature after triethylamine (1.18 mL, 8.15 mmol) was added and partitioned after 10 mL 1 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (10 mL×2) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 6n (1.21 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[C:18]([O:20]CC)=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([S:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[C:18]([OH:20])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)nn(C)c1SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(SCc2ccccc2)c1C(=O)O
Reaction time: 5 h
Yield: 87.6 %

Procedure:
A mixture of 100 ml of ethanol, 7.8 g of potassium hydroxide and 35.0 g of ethyl 5-benzylthio-1,3-dimethyl-pyrazole-4-carboxylate obtained in Reference Example 5 is refluxed while stirring for 5 hours. After evaporating off ethanol, dichloromethane is added to the residue, and the resulting solution is extracted with water. After acidifying the aqueous solution to pH 2 with diluted hydrochloric acid, extracted with dichloromethane, and then dried over anhydrous sodium sulfate. Evaporating off dichloromethane yields 27.7 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1([C:17]2[CH:18]=[C:19]([C:36]([OH:38])=[O:37])[C:20](=[O:35])[N:21]3[C:26]=2[C:25]([CH3:27])=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:23]([F:34])=[CH:22]3)[CH2:16][CH2:15]1.NCC1CCN(C2C(F)=CN3C(C=2C)=C(C2CC2)C=C(C(O)=O)C3=O)C1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[C:23]([F:34])=[CH:22][N:21]4[C:26]([C:25]=3[CH3:27])=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=[C:19]([C:36]([OH:38])=[O:37])[C:20]4=[O:35])[CH2:29][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Cc1c(N2CCNCC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cc1c(N2CCC(CN)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cc1c(N2CCN(C3CCN(C(=O)OC(C)(C)C)C3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
The title compound was prepared as described in Step 1 of Example 9 (1974) except 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was used in place of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazin-1-yl-4H-quinolizine-3-carboxylic acid was used in place of (8-(3-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)(=O)C.O=[CH:9][CH:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:11]#[N:12]>C(O)C>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[CH:9]=[N:3][NH:2][C:11]=1[NH2:12]
Reactant: NN
Reactant: N#CC(C=O)c1cccs1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1[nH]ncc1-c1cccs1

Procedure:
Hydrazine hydrate [7803-57-8] (4.8 mL, 99.0 mmol) then acetic acid [64-19-7] (5.6 mL, 97.8 mmol) were added to a solution of 3-oxo-2-thiophen-2-yl-propionitrile (7.4 g, 49.0 mmol) in ethanol (100 mL). The solution was then heated to reflux for 2 h. The cooled reaction was evaporated to dryness and the resultant solid triturated in water. Product was isolated by filtration, washed with water, and dried to provide 4-thiophen-2-yl-2H-pyrazol-3-ylamine as 7.1 g of fine off white powder, mp. 183-184° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51 (s, 1 H) 7.01-7.10 (m, 2 H) 7.27 (dd, J=5.05, 1.01 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 121.07, 121.47, 127.58, 135.85. LRMS (ESI) m/z 166.0 [(M+H)]+, calc'd for C7H7N3S: 165.22.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:30](O)=[O:31])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][C@H:44]([CH3:46])[C@@H:43]([O:47][Si](C(C)(C)C)(C)C)[C@H:42]([NH:55]C(=O)OC(C)(C)C)[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[NH2:55][C@H:42]1[C@H:43]([OH:47])[C@@H:44]([CH3:46])[CH2:45][N:40]([C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH:33][C:30]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:19](=[CH:18][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]4)=[CH:16][CH:15]=3)[N:14]=2)=[O:31])[CH2:41]1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (0.012 g, 0.028 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.019 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL) was added DIPEA (0.019 mL, 0.11 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. To the resulting residue, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.007 g, 40%). LCMS calc. for C34H39N8O5 [M+H]+: m/z=639.3. found: 639.3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: COc1cccc2c(O)ccnc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(O)c(CO)cnc12

Procedure:
4-Hydroxy-8-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 4-hydroxy-3-hydroxymethyl-8-methoxyquinoline, m.p. >350°.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:29])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:39])[O:35][C@H:34]([C:36]([O-])=[O:37])[CH2:33][O:32]1.[K+].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH2:29][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:36]([C@@H:34]4[CH2:33][O:32][C:31]([CH3:39])([CH3:30])[O:35]4)=[O:37])[CH2:25][CH2:24]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][N:7]=1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CC1(C)OC[C@@H](C(=O)[O-])O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C2CCN(C(=O)[C@@H]3COC(C)(C)O3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To a mixture of 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (257 mg, 0.50 mmol, TFA salt), potassium (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (101 mg, 0.55 mmol) and EDCI (105 mg, 0.55 mmol) in DCM (5 mL) were added 1-hydroxy-1H-benzotriazol hydrate (85 mg, 0.56 mmol) and DIPEA (194 mg, 1.50 mmol). The mixture was stirred for 16 hours at room temperature. Water was added to the mixture and the mixture was extracted with DCM. The organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to give (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg). Mass Spectrum [M+H]+=526. To a mixture of (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg) in DCM (10 mL) at r.t was added dropwise TFA (1.6 ml, 20.77 mmol). The mixture was stirred for 16 h at r.t, concentrated and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as the eluant. The fractions containing the desired compound were evaporated to dryness to afford the title compound (142 mg, 48%) as a white solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.56 (1H, m), 1.70 (1H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]([CH2:14][CH3:15])[C:3]1=[O:16].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:17][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)=[O:13])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH3:15])[C:3]1=[O:16]
Reactant: CCN1C(=O)C(C)(C)c2ccc(C(=O)O)cc21
Reactant: Nc1ccc(F)cc1
Product: CCN1C(=O)C(C)(C)c2ccc(C(=O)Nc3ccc(F)cc3)cc21
Yield: 58 %

Procedure:
By reaction of the 2,3-dihydro-3,3-dimethyl-1-ethyl-2-oxo-(1H)-indole-6-carboxylic acid prepared in Example 34b with 4-fluoroaniline analogously to Example 1c, there was obtained the title compound in a yield of 58% of theory; m.p. 179°-181° C., after recrystallisation from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]([C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])[CH3:22]>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[NH:28][N:27]=2)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CC(C)c1cc(N)n[nH]1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(Cl)nc3c2CCC3)n[nH]1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, Compound (i) (8 g, 42 mmol) in isopropanol (100 mL) was added N,N-diisopropylethyl amine (8.67 g, 67 mmol) followed by 5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (5.89 g, 47 mmol). The reaction mixture was heated to reflux at 100° C. for 16 h. The reaction mixture was cooled to RT. The precipitated product was filtered and washed with hexane to afford 2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine, Compound (iii) (5 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (d, 6H), 1.96-2.07 (m, 2H), 2.70-2.81 (m, 4H), 2.88-3.01 (m, 1H), 6.38 (s, 1H), 9.60 (s, 1H), 12.11 (brs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].I[CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][CH:29]([CH3:32])[CH2:30][CH3:31])[CH3:2]
Reactant: CC[C@H](C)CI
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)CC)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 73.6 %

Procedure:
A solution of (benzhydrylidene-amino)-acetic acid ethyl ester (5.48 g, 20.5 mmol) in tetrahydrofuran (40 mL) was treated with potassium t-butoxide (2.83 g, 25.26 mmol) and stirred at 0° C. for 35 min. At this time a solution of (S)-1-iodo-2-methyl-butane (5.00 g, 25.25 mmol) in tetrahydrofuran (20 mL) was added via syringe and the resulting solution stirred at 0° C. for 10 min and then room temperature overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid. The layers were separated, and the organic layer was washed with brine and concentrated in vacuo. The residue was purified by ISCO flash chromatography (RediSep silica 120 g, 0% to 10% ethyl acetate/hexanes) which afforded (S)-2-(benzhydrylidene-amino)-4-methyl-hexanoic acid ethyl ester (5.09 g, 74%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=2)[C:12]#[N:13])[CH:5]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1.Cl.[F:24][C:25]1(F)[CH2:28][NH:27][CH2:26]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>>[F:24][CH:25]1[CH2:28][N:27]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=3)[C:12]#[N:13])[CH:5]=[C:4]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:3]=2)[CH2:26]1
Reactant: FC1(F)CNC1
Reactant: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Product: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(N3CC(F)C3)n2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 6.8 %

Procedure:
2-((6-Chloro-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile (50.0 mg, 0.159 mmol, 1.00 equiv), 3,3-difluoroazetidine hydrochloride (44.3 mg, 0.318 mmol, 2.00 equiv), sodium tert-butoxide (94.4 mg, 0.953 mmol, 6.00 equiv), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (7.56 mg, 0.0159 mmol, 0.100 equiv), and chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct (13.0 mg, 0.0159 mmol, 0.100 equiv) were added to a 2-dram vial. After purging the vial with nitrogen, dry tetrahydrofuran (1.50 mL) was added and the reaction mixture was left stirring at 80° C. for 14 h. The reaction mixture was then filtered over Celite washing with ethyl acetate (3×3 mL) and concentrated to dryness. Purification by reverse phase column chromatography (30:70 water/acetonitrile with 0.1% ammonium hydroxide) gave the desired product as a white solid (3.8 mg, 6.4% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.26 (s, 1H), 7.21 (dd, J=5.2, 2.0 Hz, 1H), 6.88 (s, 1H), 6.04 (s, 1H), 4.49-4.26 (m, 4H), 4.02-3.86 (m, 2H), 3.52-3.35 (m, 2H), 2.76-2.58 (m, 1H), 1.73-1.59 (m, 4H).
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2>O1CCOCC1.O>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:2])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=[Se]=O
Reactant: Cc1c(Cl)cnc2ccccc12
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(Cl)cnc2ccccc12
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A solution of selenium dioxide (1.90 g) in 1,4-dioxan (5 ml) and water (1.2 ml) was added dropwise over 15 min to a stirred solution of 3-chloro-4-methylquinoline (2.91 g) in 1,4-dioxan (10 ml) at 60-70° C. The mixture was heated at reflux for 6 h, allowed to warm to room temperature, then concentrated in vacuo. The residue was purified by column chromatography (SiO2), eluting with dichloromethane to 5% methanol in dichloromethane by a stepwise gradient, to give the sub-title compound as a yellow solid (1.19 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.25 g, 1.34 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzaldehyde (0.3 g, 1.745 mmol) and sodium triacetoxyborohydride (0.43 g, 2.01 mmol). The mixture was stirred at room temperature for 16 hours. Then the reaction mixture was diluted with dichloromethane and washed with NaHCO3 solution. The organic layer was dried with MgSO4, concentrated, and purified by flash chromatography, eluting with 50% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11]C1C=CC(C=O)=CC=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1.CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][CH2:22][C:5]1[CH:27]=[CH:26][C:25]([CH2:29][OH:28])=[CH:2][CH:1]=1)=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)OCCc2ccc(CO)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (5 mmol) of the aldehyde obtained in Example 45, 50 ml of THF and 50 ml of methanol are introduced into a round-bottomed flask. 100 mg (2.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [I:1]I.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1>O.[NH4+].[OH-]>[I:1][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[OH:3])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(O)c(I)c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O was added at once to a solution of 4-hydroxybenzoic acid (0.58 g; 4.18 mmol) in 25% NH4OH (22 ml). The reaction mixture turn instantly from black to colourless upon stirring at room temperature. This was evaporated under reduced pressure, diluted to 5 ml with H2O and acidified to pH˜5 with 10% citric acid. The solid formed was filtered off, washed with H2O (2×5 ml) and dried to give title compound (0.91 g; 89%), as colourless solid. 1H-NMR (DMSO-d6) 6.9 (d, 1H, J=8.5 Hz); 7.75 (dd, 1H, J=2, 8.5 Hz); 8.17 (d, 1H, J=2 Hz); 11.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([NH2:15])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: NC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.82 mmol) to a solution of 2-fluoro-5-iodobenzamide, (prepared as described in PREPARATION 44), (0.482 g, 1.82 mmol) in triethylamine (7 mL, 53 mmol) and heat at 70° C. After 10 minutes, add toluene (10 mL) to the solidified reaction mixture, heat at 70° C. for 1 h, cool to room temperature and stir overnight. Concentrate and purify the residue by silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes, to give the title compound as a white solid (260 mg, 32%).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[C:11]([O:13][CH2:14][CH2:15][I:16])=[O:12])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>>[NH2:5][S:6]([C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[C:11]([O:13][CH2:14][CH2:15][I:16])=[O:12])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1C(=O)OCCI
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1C(=O)OCCI
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75.3 %

Procedure:
The product from Example 1 (1 g) was added to 8 mL of trifluoroacetic acid, and the clear solution was stirred at room temperature for 4-5 hours. Removal of the volatiles in vacuo afforded an orange oil, which was subjected to silica gel chromatography. Elution with 4:1 hexane/ethyl acetate gave 650 mg of the title sulfonamide as a white powder, m.p. 76°-79° C.; IR (nujol): 1720, 1730, 3290, 3400 cm-1.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].CO.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)[C@@H](C)NC(=O)OCc1ccccc1

Procedure:
Under argon, 885 mg of benzyl [(2R)-3-oxobutan-2-yl]carbamate (Example 151A, 4 mmol, 1 equivalent) were initially charged in 13 ml of THF and 13 ml of methanol and, analogously to Example 133A, reacted with 227 mg of sodium borohydride (6 mmol, 1.5 equivalents) and worked up. This gave 830 mg (92% of theory) of the title compound.