Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([NH:35][CH2:36][C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[NH:35][CH2:36][C:37]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.2 mmol) and BOC-glycine (35 mg, 0.2 mmol) in DMF (1.0 mL) at room temperature was treated with diisopropylethylamine (35 μL, 0.2 mmol) followed by 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (84 mg, 0.22 mmol). The reaction mixture was stirred for 2 h then partitioned between EtOAc (10 mL) and a saturated aqueous NaHCO3 solution (10 mL). The organic component was isolated and further washed with brine (10 mL) then dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 40% EtOAc/hexane as eluant to afford intermediate {2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester as a foam (85 mg, 81%). LC/MS 7.46 min, [M+1]+ 524.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:37]([C:19]1[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[N:14]=[C:13]([C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH3:11])[CH3:12])=[C:3]([CH:4]=2)[C:1]#[N:2])[S:17][N:16]=1)[CH3:38]
Reactant: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCNCC1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)-1-piperidinecarboxylate (D124) (0.089 g, 0.168 mmol) in Dichloromethane (DCM) (10 mL) at room temp was added TFA (0.388 mL, 5.04 mmol). This solution was stirred for 2 hr. This solution was condensed and dried in high vacuum to remove TFA to afford 5-{3-[2-ethyl-3-(4-piperidinyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D125) (72 mg) as a brown oil residue, which was used directly in the next step. MS (ES): C26H30N4S requires 430.2. found 431.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[C:32]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=1)=[O:23])(=[O:34])[CH3:33]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (1.06 g, 83.0%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 79 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanesulfonamide (intermediate A-7) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 79% yield. MS: 371.1 (M+H+).
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CO.B(F)(F)F.N>[N+](C)([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: C[N+](=O)[O-]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C

Procedure:
In 3 ml of nitromethane were dispersed 1.44 g of 7-ACA and 1.19 g of methanol. Then, to the dispersion were sequentially added 8.54 g of a complex of boron trifluoride with methanol (content of boron trifluoride: 51%) and 3.31 g of fluorosulforic acid. The resultant mixture was heated at 25° C. for 15 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 0° C. Then, from the reaction mixture, methanol was distilled off under reduced pressure. To the resultant residue was added 100 ml of water to obtain a solution. The solution was subjected to reversed phase adsorption chromatography using a column filled with HP-20 (tradename of a resin for adsorption produced and sold by Mitsubishi Chemical Industries, Ltd., Japan). The eluate was adjusted to pH 3.5 with 28% aqueous ammonia to thereby form a precipitate. The precipitate was collected by filtration, and washed with 15 ml of ice water and, then, with 5 ml of cold methanol to thereby obtain the desired product, namely 7-amino-3-methoxy methyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.75 g. The yield of the desired product was 55.8%.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1>CCO>[NH2:9][C:10]1[N:15]=[C:14]([S:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CCOC(=O)CS
Reactant: Cc1cc(Cl)nc(N)n1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSc1cc(C)nc(N)n1

Procedure:
Sodium (4.6 g, 0.2 mol) was dissolved in 1 l. abs. EtOH. Ethyl mercaptoacetate (24 g, 0.2 mol) was added and the resultant mixture was stirred 1 hr. at room temperature. The 2-amino-4-chloro-6-methylpyrimidine (0.2 mol) was added and the mixture was heated at reflux for 18 hrs. The reaction mixture was evaporated to a syrupy residue which was portitioned between CHCl3 (1.5 l.) and H2O (100 ml). The CHCl3 phase was dried (MgSO4) and evaporated to give the crude product as an oil, 40.6 g (91%). The straw colored oil crystallized upon standing, m.p. 65°-69°. The analytical sample was obtained by a recrystallization from cyclohexane, 27 g (60%), m.p. 71°-73°.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([C:27]3[CH:28]=[CH:29][C:30]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=4)[CH:18]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([C:27]3[CH:28]=[CH:29][C:30]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=4)[CH:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CNCCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(CCCNCC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
To a suspension of 3-({3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-propylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in anhydrous DCM (2.8 mL) was added trifluoroacetic acid (1.4 mL). The mixture was stirred at rt under N2 for 3 days. The reaction mixture was concentrated and the crude was dissolved in EtOAc. The organic layer was washed with aqueous, saturated NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC [gradient 15 to 90% ACN/H2O+0.1% TFA]. The product containing fractions were collected, and the TFA was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (6 mg, 9%) as a white solid. 1H NMR (300 MHz, MeOD). 8.39 (s, 1H), 7.85 to 7.82 (m, 2H), 7.65 (s, 1H), 7.36 to 7.33 (m, 5H), 7.24 (d, 1H), 6.56 (s, 1H), 5.67 (s, 2H), 4.02 (t, 2H), 3.78 to 3.75 (m, 2H), 3.05 (t, 3H), 2.87 (d, 2H), 2.70 (t, 2H), 2.02 to 1.98 (m, 2H); ES-MS m/z 467.3 [M+H]+, RT (min) 2.82.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: C[C@H](CCl)COc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl (2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 260°-261° C.
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC#CCCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCC/C=C\CCO

Procedure:
Hydrogen gas was blown into a solution prepared by dissolving 126 g of 3-octyn-1-ol in 100 ml of n-hexane with admixture of 10 g of a Lindlar catalyst and 10 g of pyridine and the introduction of hydrogen was continued for about 4 hours when absorption of hydrogen had ceased. Removal of solid matter from the reaction mixture by filtration and stripping of n-hexane gave cis-3-octen-1-ol, which was dissolved in a mixture of 250 g of methylene chloride and 111 g of triethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]=[C:9]=[O:10])=[O:7])([O-:3])=[O:2].[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[N:20][CH:21]=1>O1CCOCC1.O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])=[O:10])=[CH:27][CH:28]=2)=[N:20][CH:21]=1
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Sc2ncc(Br)cn2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-nitrobenzoyl isocyanate (3 g, 0.016 mol) in dry 1,4-dioxane (15 mL) was added dropwise to a solution of 4n (2.93 g, 0.01 mol) in dry 1,4-dioxane (15 mL) with stirring at room temperature. The reaction mixture was stirred for 18 hours and then diluted with water. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, and the organic layer was washed with water 2-3 times, dried, and concentrated to give 1-[4-(5-bromopyrimidin-2-ylsulfanyl)-phenyl]-3-(2-nitrobenzoyl)urea (6n), yield 92%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.35 (br, s, 1H), 8.78 (s, 2H), 8.22 (m, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.67 (m, 2H), 7.57 (m 2H); EI-MS m/z 473 [M]+, 475 [M+2]+; HRMS calculated for C18H12BrN5O4SNa [M+Na]+:495.9685, found: 495.9701. Anal. (C18H12BrN5O4S) C, H, N.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:19])[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1>[NH2:19][C:7]1[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cn2nc(-c3ccco3)nc2c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Temperature: 70 °C
Yield: 67.7 %

Procedure:
A mixture of 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid methyl ester (200 mg; see Example 7 above), LiOH (2 M, 1 mL), and MeOH (a few drops) in THF (20 mL) was heated (at around 70° C.) for 30 minutes. The solvent was removed in vacuo and then the residue was triturated with 0.5 N HCl. The product was dried to afford 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid as a light yellow solid (128 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 6.73(dd, J=3.5, 1.8 Hz, 1H), 7.18(dd, J=3.5, 0.9 Hz, 1H), 7.7(br. s, 2H), 7.94(dd, J=1.8, 0.8 Hz, 1H), 8.68(s, 1H). MS: m/z 246 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH3:13][N:14](CCO)[CH3:15].[Na]>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH2:10][N:14]([CH3:15])[CH3:13])=[O:7])=[CH2:2]
Reactant: CN(C)CCO
Reactant: C=CC1CC1(C#N)C(=O)OCC
Agent: [Na]
Product: C=CC1CC1(C#N)C(=O)OCCN(C)C
Reaction time: 0.58 h

Procedure:
2-(N,N-dimethylamino)ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was prepared by reacting essentially equimolar amounts of ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate and N,N-dimethylaminoethanol. For the reaction, a small amount of sodium metal (1.13 wt. %) was reacted with the N,N-dimethylaminoethanol prior to the addition of the ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate. The reaction mixture was stirred for 35 minutes after which time gas chromatographic analysis indicated the reaction to be 70% complete. After workup of the reaction mixture, the crude product was vacuum distilled to obtain the 2-(N,N-dimethylamino)ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate (B.p. 97° C. at 0.015 mm Hg). The infrared spectrum was consistent with the structure. nmr (CDCl3)τ 3.97-4.85(3 vinyl H, mult.); 5.75(2H, tr.); 7.15-7.60(1H(2 ring position, hidden), mult); 7.37(2H, tr.); 7.74(6H,s); 7.85-8.55(2H(3 ring position), mult.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:29]3[CH2:32][C@H:31]([C:33](N(OC)C)=[O:34])[CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:40])[CH:10]=1)#[N:2].[CH3:41][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[C:33]([C@H:31]1[CH2:32][C@H:29]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:40])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30]1)(=[O:34])[CH3:41]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)N(C)OC)C2)c2nc(C)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide (1.90 g) in tetrahydrofuran (5 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (5.3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50 (volume ratio)] to give the title compound as a colorless amorphous compound (1.38 g, 79%).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])N)[CH3:23].C(O)C>O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([NH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:1]1[S:29][CH2:28][CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])[N:2]=1)=[CH:11]2)(=[O:14])=[O:15]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CSC(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)=N1
Yield: 25.5 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.30 g), cysteine ethyl ester hydrochloride (0.22 g) and ethanol (10 mL) was heated under reflux overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.11 g, yield 25%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 156-157° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: NO
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: Cl
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
The procedure described in Example (1b) is repeated, except that 233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene, 100 g of 37% hydrochloric acid, 200 ml of water and 69.5 g (1.0 mol) of hydroxylamine hydrochloride are used. Working up and subsequent distillation yields 245 g (0,92 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime; yield 92% of theory; boiling point 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[Mg]Br>C(OCC)C.[Cu]I>[F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH2:4][C:5]([C:17]1[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=1[CH3:11])([CH3:7])[CH3:6]
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: Cc1ccc(F)cc1[Mg]Br
Agent: [Cu]I
Solvent: CCOCC
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a slurry of 1,1,1-trifluoro-4-methylpent-3-en-2-one (49.5 g, 0.325 mol) and copper (I) iodide (61.9 g, 0.325 mol) in 700 mL of anhydrous diethyl ether at 0° C. was added a solution of 2-methyl-5-fluorophenyl magnesium bromide (0.5 M in THF, 706 mL, 0.353 mol) dropwise over 1.5 hours. The mixture was warmed to room temperature and stirred for a total of 18 hours. The reaction was quenched by addition of 500 mL of cold saturated ammonium chloride (NH4Cl) solution and the layers were separated. The aqueous layer was extracted with two 300 mL portions of diethyl ether. The combined organic fractions were washed with 300 mL of saturated ammonium chloride solution, three 300 mL portions of water and one 200 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with hexanes) afforded 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (68.1 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:27][C:28](=[O:40])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:40]=[C:28]1[CH2:29][C:30]([C:32]2[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=2)[C:38]#[N:39])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[NH:27]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(OC(F)(F)F)cc4)cc3NC(=O)C2)c1
Yield: 83.8 %

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K30) (170 mg, 0.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a heige solid (112 mg).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1cccc(Br)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.