Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.[O:25]=[C:26]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:27][C:28](O)=[O:29].CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:7]3[CH2:6][C:5]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:8]=3[N:9]([C:28](=[O:29])[CH2:27][C:26]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:25])[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Reactant: O=C(O)CC(=O)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)CC(=O)N1CCCC1)C2

Procedure:
A mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (0.36, 1.0 mmol), 3-Oxo-3-pyrrolidin-1-yl-propionic acid (Compound 28a) (0.157 g, 1.0 mmole), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.24 g, 1.25 mmol), hydroxybenzo-triazole hydrate (HOBT) (0.17 g, 1.25 mmol) and DIEA (0.220 mL, 1.25 mmol) was stirred in 10 mL DMF over night at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The solvent was removed in vacuo and the crude material was prepped on the Gilson. Lyophilization produced a white powder. MS m/z 465.1 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[C@H:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][Si:13]([CH3:37])([CH3:36])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:24]4[CH:23]=[CH:22][C:21]([C:19]5[N:20]=[C:16]([C@H:15]6[N:11]([C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[CH2:12][Si:13]([CH3:37])([CH3:36])[CH2:14]6)[NH:17][CH:18]=5)=[CH:26][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 25.8 %

Procedure:
To a solution of [[(5)-1-((R)-3,3-dimethyl-5-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methylester (51.6 mg, 0.096 mmol; Preparation 11) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (56.7 mg, 0.096 mmol) dissolved in toluene (0.61 mL) and water (0.24 mL) was added potassium carbonate (66.0 mg, 0.48 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (7.02 mg, 0.009 mmol) was added. The reaction mixture was sparged with nitrogen and heated to 90° C. overnight, cooled to RT, diluted with EtOAc, and washed with water and brine to produce a dark colored oil. The residue was purified by silica gel chromatography (12 g silica, 0% to 100% EtOAc/hexane) to produce the title intermediate as a yellowish solid (23 mg; 26% yield) (m/z): [M+H]+ calcd for C44H54ClF3N8O7Si 927.35 found 927.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:10](=[O:12])[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Br:1])([CH3:14])[CH3:13])[CH2:43][CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C(=O)O)c1cc(F)ccc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)NC1CCN(Cc2ccccc2)CC1)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-bromo-5-fluorophenyl)-2-methylpropanoic acid (510 mg, 1.95 mmol, EXAMPLE 44, Step 1) in tetrahydrofuran (20 mL) were added triphosgene (197 mg, 0.66 mmol) and triethylamine (0.288 mL, 2.05 mmol). The mixture was stirred at room temperature for 30 min and was filtered. The filtrate was added drop-wise into a solution of 1-benzyl-4-aminopiperidine (372 mg, 1.95 mmol) and triethylamine (0.288 mL, 2.05 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for overnight.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:21][CH2:20]1
Reactant: OCCN1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(CCO)CC1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (40.5 g) in acetone (375 ml) were added 1-(2-hydroxyethyl)piperazine (31.5 g) and potassium carbonate (63.0 g). The resulting mixture was refluxed with stirring for 3 hours. The reaction mixture was filtered and the filtrate was evaporated. The residual oil was subjected to column chromatography on silica gel, eluting with a mixture of chloroform and methanol (9:1). The fractions containing the object compound were collected and then evaporated to give an oil of N-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]phthalimide (25.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:13])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CO)cc(C)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCl)cc(C)n1
Temperature: 25 °C

Procedure:
In 77 ml of CHCl3 was dissolved 7.00 g (0.0511 mole) of (2,6-dimethyl-4-pyridyl)methanol and with stirring at room temperature, 15.3 ml of thionyl chloride was added dropwise. After completion of the dropwise addition, the mixture was stirred for 3 hours and concentrated. The residue was diluted with aqueous sodium hydrogen carbonate solution and extracted with AcOEt (100 ml×3). The extract was dried over MgSO4 and distilled to remove AcOEt. The procedure gave 6.37 g of (2,6-dimethyl-4-pyridyl)methyl chloride as oil.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[Si:16]([O:23][CH:24]1[CH2:28][C:27](=[O:29])[C:26]([S:30][CH2:31][CH2:32][CH2:33][CH:34]=O)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1C=CC=CC=1>[Si:16]([O:23][CH:24]1[CH2:28][C:27](=[O:29])[C:26]([S:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCC=O)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)/C=C/CCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 75 %

Procedure:
96 mg (2.0 mmoles) of 50% sodium hydride was suspended in 5 ml of dry benzene, and 841 mg (4.0 mmoles) of methyl diethylphosphonoacetate was added. The mixture was stirred for 10 minutes. 600 mg (1.91 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(4-oxobutylthio)-2-cyclopentenone was dissolved in 10 ml of dry benzene. The solution was stirred under ice cooling. To the resulting solution was added the above reaction mixture. The mixture was stirred further for 15 minutes. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was dried over anhydrous dodium sulfate, and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (8/1) as an eluent to give 531 mg (yield 75%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-trans-4-pentenylthio)-2-cyclopentenone.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)([OH:13])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:4][CH:3]=1.[C@@:23]12(O)[N:30](C)[C@@H:27]([CH2:28]C1)[CH2:26][CH:25]=C2>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)([OH:13])[C:7]([O:9][C@@:10]23[N:30]([CH3:23])[C@@H:27]([CH2:28][CH2:12]2)[CH2:26][CH:25]=[CH:11]3)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: CC(C)OC(=O)C(O)(c1ccc(Br)cc1)c1ccc(Br)cc1
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(Br)cc1)c1ccc(Br)cc1)CC2

Procedure:
4.9 is prepared analogously to the method according to II.1. Yield: 2.36 g (19% of theory) starting from 9.9 g (0.023 mol) of commercially obtainable isopropyl 4,4′-dibromobenzilate and 3.21 g (0.023 mol) of tropenol; to purify it, the hydrochloride was precipitated and recrystallized from acetonitrile. TLC: Rf value: 0.30 (eluant as in step II.1); melting point: 205° C.-207° C. (hydrochloride).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:26]=[CH:25][C:17]([CH2:18][N:19]5[CH2:23][CH2:22][CH2:21][C:20]5=[O:24])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cc4)sc23)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The reaction mixture consisting of the nitro compound 203 (580 mg, 1.25 mmol), iron powder (594 mg, 10.64 mmol), and ammonium chloride (57.6 mg, 1.076 mmol) in EtOH/water mixture (16 mL/8 mL) was stirred for 2 hr at 80° C. The reaction mixture was filtered while hot. The filtrate was concentrated to give title compound 204 (542 mg, 100% yield) as a brown solid. MS: 434 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3](CSCCN)=[N:4]C=C[CH:7]=1.C(C=C(OC)OC)#N.[C:21]([CH:23]=[C:24](OC)[NH:25][CH2:26][CH2:27][S:28][CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=1)#[N:22].C(N)C#C>>[C:21]([CH:23]=[C:24]([NH:4][CH2:3][C:2]#[CH:7])[NH:25][CH2:26][CH2:27][S:28][CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=1)#[N:22]
Reactant: COC(=CC#N)NCCSCc1ncccc1Cl
Reactant: NCCSCc1ncccc1Cl
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
When 2-[(3-chloro-2-pyridyl)methylthio]ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene and the resultant 1-cyano-2-methoxy-2-{2-[(3-chloro-2-pyridyl)-methylthio]ethylamino}ethylene is reacted with propargylamine according to the general procedure of Example 1 Step B the title compound is produced.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([O:24]CC)=[O:23])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetate (1.3 g, 2.62 mmol) in THF (15 mL) and MeOH (5 mL) was added 1M sodium hydroxide (5.25 mL, 5.25 mmol). The mixture was stirred at room temperature for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with water (20 mL), acidified with 1M HCl (6 mL) and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with diethyl ether to give the crude product, containing about 5% of the 1-isomer. Further purification by trituration in isopropyl acetate (2×, 80° C. overnight, then room temperature overnight) provided the title compound as a beige powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][CH2:11][CH2:12]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)C(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][Cl:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCCCl
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)C(C)C
Product: CC(=O)N1CCN(CCCl)CC1

Procedure:
1-Acetylpiperazine (1.28 g, 10 mmoles), 1,2-dichloroethane (5 g, 50 mmoles), anhydrous sodium carbonate (2.5 g) and potassium iodide (25 mg) are combined in 40 ml of 3-methyl-2-butanone and refluxed for 16 hours. The reaction mixture is evaporated to dryness in vacuo and the residue distributed between 100 ml of water and 150 ml of methylene chloride. The methylene chloride layer is dried over anhydrous magnesium sulfate and evaporated to dryness to yield 2-(4-acetylpiperazino)ethyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:29])[CH3:30])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(F)(F)F)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.18 g, 0.29 mmol), 4-trifluoromethylphenylboronic acid (0.07 g, 0.36 mmol), sodium carbonate (0.09 g, 0.86 mmol) in THF (26 mL) and water (13 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.02 g, 0.01 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.12 g of (R)-3-(3,5-Dichloro-4′-trifluoromethyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4]C[CH:2]1[C:7]([CH2:9][CH2:10][C:11]#[N:12])=[O:8].ClC1C=CC=C(C(OO)=[O:21])C=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29]>CCCCCC>[C:11]([CH2:10][CH2:9][CH:7]1[O:8][C:4](=[O:21])[CH2:5][CH2:6][CH2:1][CH2:2]1)#[N:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29]
Reactant: N#CCCC(=O)C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCCCCC
Product: N#CCCC1CCCCC(=O)O1
Temperature: 55 °C

Procedure:
A reactor is loaded with 151 g of 3-(2-cyclohexanoyl)propionitrile in 500 ml of n-hexane and 260 g of m-chloroperbenzoic acid (70% titer) dissolved at 50° C. in 2000 ml of n-hexane in 30 minutes. The solution is heated to 55° C. for 15 hours. Cooling of the solution separates, in crystalline form, part of the m-chlorobenzoic acid which is scarcely soluble in the system, together with a heavy liquid phase which is formed by 7-cyanoethyl-2-oxepanone and by m-chlorobenzoic acid. 71.5 g of 7-cyanoethyl-2-oxepanone, impure with m-chlorobenzoic acid, are recovered from the lower phase. 24 g of 7-cyanoethyl-2-oxepanone are recovered from the upper phase by concentration and several crystallizations. Conversion over the initial ketone is 85%. Yield on the converted amount is 57%.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:47][C:48]#[C:49][Si:50]([CH3:53])([CH3:52])[CH3:51].Cl>CN(C=O)C>[F:37][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH2:47][C:48]#[C:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Reactant: C[Si](C)(C)C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 9 h
Yield: 4.4 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (150 mg) and potassium carbonate (43 mg) in DMF (8 ml) are added, at room temperature, potassium iodide (19 mg) and (3-bromoprop-1-yn-1-yl)(trimethyl)silane (64 mg). The reaction mixture is stirred at 80° C. for 9 h. Then dilute hydrochloric acid is added to the mixture, which is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}phenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:18])[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]4=[O:18])=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCOC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then acidifying with TFA and purification of the residue by chromatography (preparative HPLC).
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:20][CH:21]=O)=[CH:16][CH:15]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:20][CH:21]=[CH:36][C:35]3[C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=3[C:29]#[N:30])=[CH:16][CH:15]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Yield: 55.8 %

Procedure:
In 4 ml of ethanol were dissolved 100 mg (0.25 mmol) of 3-[5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-yl]propenal and 87 mg (0.28 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene) propanedinitrile. After the mixture was stirred with heating at 50° C. for 4 hours, the product was separated by filtration and washed with ethanol. The product was purified by silica gel column chromatography to give 97 mg of a black crystal (yield: 55.5%).
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39](O)=[O:40])=[CH:33]2>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]([NH:13][C@@H:12]([C:14]([N:16]1[CH2:17][CH2:18][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:20][CH2:21]1)=[O:15])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:40])=[CH:33]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 5-chloroindole-2-carboxylic acid (54%).