Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].Cl.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[C:4]([C:3]([NH:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:12]=1)=[O:29])([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6]
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)O
Reactant: CNC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid (Example 253 a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e=463.4 [M+NH4]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[N:34]([CH3:40])[C:35]([CH2:38][OH:39])=[CH:36][CH:37]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:39][CH2:38][C:35]3[N:34]([CH3:40])[C:33]([CH2:32][C:31]([O:30][CH3:29])=[O:41])=[CH:37][CH:36]=3)=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:26])([F:27])[F:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(CO)n1C
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COC(=O)Cc1ccc(COc2ccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)cc2)n1C

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (5-hydroxymethyl-1-methyl-1H-pyrrol-2-yl)-acetic acid methyl ester according to the procedure of Example 69. MS (ESI) m/z 545.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Li+].Cl>CO>[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:17])=[O:2])[CH2:8][CH2:9]1)(=[O:16])[CH3:15]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](NC(C)=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@H](C(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of trans-2-(4-acetylamino-cyclohexyl)-2-methyl-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is neutralised with 1M HCl and extracted with ethyl acetate (3×50 ml)—the combined organic phases are concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60 F) based on its Rf value.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[CH3:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[N:16][C:15]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:19]([C:17]1[S:18][C:14]([CH3:13])=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1)(=[O:20])=[O:21])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: Cc1sc(S(=O)(=O)Cl)nc1-c1ccccc1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc(-c2ccccc2)c(C)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-methyl-4-phenyl-thiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 7.68 (d, 2H), 7.51 (t, 2H), 7.44 (t, 1H), 4.05 (q, 2H), 3.26 (s, 2H), 3.10 (t, 2H), 2.64 (s, 3H), 2.63 (t, 2H), 1.16 (t, 3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: Fc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-6-fluoro-benzothiazole (0.65 g, 3.5 mmol) and 4-bromoaniline (0.61 g, 3.5 mmol) in n-butanol (6 mL) was heated at 60-70° C. under nitrogen to obtain a solution, to which 4 M HCl in dioxane (0.43 mL, 1.73 mmol) was slowly added dropwise. The reaction mixture was then heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with ethanol and collected by filtration. This yielded 0.98 g (88%) of the title compound. LC/MS m/z 323.0 (MH+); retention time 3.74 min. 1H NMR (CD3OD) δ 7.10-7.30 (m, 1H), 7.39 (d, 1H), 7.45 (d, 2H), 7.58-7.61 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=1)[C:30]#[N:31].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:33][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[CH2:10][CH2:11]3)[C:16]2=[O:20])=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: N#Cc1cc(CBr)ccc1Cl
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4ccc(Cl)c(C#N)c4)C3=O)CC2)cc1

Procedure:
To a mixture of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.232 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (80 mg, 0.347 mmol) in THF (1 mL) and DMF (0.1 mL) was added NaH (46.3 mg, 1.16 mmol, 60%). The reaction was concentrated in vacuo then taken up in dichlormethane and MeOH and filtered through a short plug of silica gel. The pooled fractions containing the title material were pooled, concentrated and neutralized with NaHCO3. MeOH was added and the solution was cooled in a freezer. The title compound was obtained by collecting the white solid via filtration (45 mg). HRMS calculated for C25H26ClN3O3 451.1671. found (ESI, [M+H]+) 452.1744.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CO>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound of step P.i of Preparation P; 8.0 g, 39.5 mmol) in EtOH/H2O 9-1 (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1
Product: Cc1nc(N2CCOCC2)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1

Procedure:
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (1.3 g) and morpholine (10 mL) were combined under nitrogen and refluxed for 6 hrs. The reaction mixture was concentrated by rotovap and the residue was purified by flash chromatography (CH2C2:MeOH, 50:1; silica) to yield a yellow solid (0.54 g). MS (M+H)+416, 418.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:10](O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[CH2:10][Cl:29])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cn1nnnc1C(CCl)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a solution of dry (0.1 mmHg at 80° C.) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)2-propenoic acid 3.8 g (11.0 mmoles) in 20 mL of dry methylene chloride was added 4 mL (46.0 mmoles) of purified oxalyl chloride (redistilled over CaH2) in one single portion. The reaction mixture was warmed gradually to reflux temperature for two hours. The mixture was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride was removed under vacuum (20 mmHg) at ambient temperature for 2 hours and under high vacuum (0.1 mmHg) at 50° C. for 16 hours to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]=3[CH:31]=2)[CH:7]=1.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:4]1[C:5]([OH:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:12]=3[CH:31]=2)[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)ccc3O)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)cc(Br)c3O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of di-tert-butyl [5-(5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate (2.00 g, 4.34 mmol) in acetonitrile (45 mL) was added N-bromosuccinimide (0.811 g, 4.56 mmol). The mixture was stirred at ambient temperature for 0.5 h and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5-15% gradient of ethyl acetate in hexanes) to afford di-tert-butyl [5-(3-bromo-5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate as an orange solid in 35% yield (0.83 g): 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.95-7.93 (m, 1H), 7.89-7.86 (m, 2H), 7.69 (d, J=2.6 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 1.39 (s, 18H); MS (ES−) m/z 536.9 (M−1), 538.9 (M−1), 540.9 (M−1).
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:17][S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCl>[C:11]1([CH2:10][CH:9]([P:4](=[O:3])([OH:5])[OH:8])[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(=O)(OCC)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of diethyl phosphonate (xii) (745 mg; 1.8 mmol) in dichloromethane (8 mL) at 0° C. was slowly added bromotrimethylsilane (2 mL; 15.2 mmol). The reaction was gradually warmed to room temperature and the following day the solution was evaporated. The residue was redissolved in dichloromethane (10 mL), evaporated and the process repeated once more. Methanol (10 mL) was added to the residue and the solution stirred at room temperature for 30 minutes, then the solution was filtered and concentrated. The oily residue was triturated with 1:1 ether-hexanes and the orange solid collected by filtration. Finally, the orange solid was boiled in dichloromethane (5 mL), cooled and filtered to yield pure phosphonic acid (xiii) (512 mg, 80%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 2.71 (dt, J=14, 10 Hz, 1 H, CHPh), 3.13 (ddd, J=4, 8, 14 Hz, 1 H, CHPh), 3.89 (ddd, J=4, 10, 14 Hz, NCHP), 6.86 (dd, J=3.5, 5 Hz, 1 H, Ar—H), 7.07–7.15 (m, 6 H, Ar—H), 7.53 (dd, J=1.5, 5 Hz, 1 H, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 261 (M+, 75), 184 (46), 108 (95), 92 (100), 65 (70), 39 (45).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](N)([CH3:23])([CH3:22])[CH3:21].Cl>[Cu](Cl)Cl.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[C:16]([C:21]1[C:15]([OH:19])=[CH:14][CH:13]=[C:23]3[C:20]=1[CH:22]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:10]=[CH:11]3)[C:15]([OH:19])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Agent: Cl[Cu]Cl
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccc(OCc3ccccc3)cc2c1-c1c(O)ccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a mixture of 55.8 g (0.223 mol) of 7-benzyloxy-naphthalene-2-ol, 60.0 g (0.446 mol) of copper chloride (II), and 1.5 L of methanol was added a methanol (500 mL) solution of 130.5 g (1.78 mol) of t-butylamine, followed by 20 hours of stirring at room temperature. The reaction liquid was cooled on an ice bath and after addition of 500 mL of 6N hydrochloric acid, methanol was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate (1.5 L) and the resulting solution was washed with saturated brine. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 47.3 g of the title compound. Yield 85%.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C:6]1=[O:21].CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>O1CCCC1>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2=O)c1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
A solution of benzyl 4-(2,3-dimethylphenoxy)-3-oxopiperidine-1-carboxylate (10.0 g, 28.0 mmol) in tetrahydrofuran (60 ml) was treated at room temperature with K-selectride (10.0M in tetrahydrofuran, 56 ml, 56.0 mmol). On completion of addition the mixture was stirred at room temperature for 18 h. The mixture was concentrated to dryness in vacuo and diluted carefully by addition of ice-water (100 ml). Extraction with dichloromethane (2×200 ml) was followed by washing the combined organics with aqueous hydrochloric acid (100 ml, 0.1N), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark oil which was purified by silica gel chromatography using isohexanes:ethyl acetate (5:1) as eluent to furnish cis-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (5.01 g, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].[F:14][C:15]1[C:16](I)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])/[C:18]/2=[CH:25]\[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[C:21]2[C:17]=1/[C:18](=[CH:25]/[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31])/[C:19](=[O:24])[NH:20]2)[CH3:2]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCC(NC(C)=O)C(=O)OCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)NC(C)=O

Procedure:
Using Method C above, 2-(acetylamino)-4-pentynoic acid ethyl ester (92.6 mg, 0.51 mmol) (Bachem) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give rac-(Z)-2-(acetylamino)-5-[5-fluoro-2,3,dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid ethyl ester. (Yield 70 mg, 81%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:39])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][C:19]=4[N:32]4[CH2:36][CH2:35][CH2:34][S:33]4(=[O:38])=[O:37])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:40]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:39])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:40])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][C:19]=4[N:32]4[CH2:36][CH2:35][CH2:34][S:33]4(=[O:37])=[O:38])=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2N2CCCS2(=O)=O)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 73.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-(1,1-dioxoisothiazolidin-2-yl)phenyl}-4-hydroxymethyloxazolidin-2-one (778 mg) described in Example 317 and methyl iodide (238 mg), the title compound (586 mg) was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[CH:17]2[Si:22]([CH:25]1[C:33]2[C:28](=[C:29](Br)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35])([CH3:24])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[CH:17]2[Si:22]([CH:25]1[C:33]2[C:28](=[C:29]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:11])[CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35])([CH3:24])[CH3:23]
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3c(C)cc(C)cc3C)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3c(C)cc(C)cc3C)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF. 13.0 ml of 1.0 M mesitylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.60 g (94%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH2:19])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26]>CO>[C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH:19][CH2:26][CH2:25][C:24]([NH2:28])=[O:27])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reactant: C=CC(N)=O
Solvent: CO
Solvent: CCO
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 100 °C
Yield: 38.1 %

Procedure:
To (1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propan-1-amine (0.1 g, 0.34 mmol) in a microwave tube was added ethanol (0.4 ml) water (0.4 ml), acrylamide (0.025 g, 0.35 mmol) and MnCl2 (0.056 g, 0.28 mmol) heated 100° C., 200 W for a total of 1 hour. The reaction was diluted with MeOH and filtered and filtrate evaporated then purified by Prep HPLC to give 3-{[(1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propyl]amino}-propanamide (0.047 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1cccc(F)c1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 3-fluorobenzoyl chloride in a similar manner as described above to give a white solid (24% yield). 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 8.97 (d, 1H), 7.85-7.81 (m, 1H), 7.81-7.74 (m, 1H), 7.62 (d, 1H), 7.59-7.50 (m, 1H), 7.46-7.37 (m, 1H), 7.29 (d, 1H), 7.17 (dd, 1H), 5.38 (m, 1H), 2.68 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H); MS m/z 387 (M−1).
Reaction SMILES: N#N.[CH2:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH3:21])[C:19]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[F-].[Cs+]>O1CCOCC1>[CH2:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[N:15]=[N:16][C:17]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[C:18]([CH3:21])[C:19]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Cl)nnc(NCCNCc2ccccc2)c1C
Agent: N#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1c(NCCNCc2ccccc2)nnc(-c2ccc(F)cc2)c1C
Temperature: 95 °C

Procedure:
Treat a N2 degassed mixture of N1-benzyl-N2-(6-chloro-4,5-dimethylpyridazin-3-yl)ethane-1,2-diamine (6.40 g, 22.0 mmol), 4-fluorophenylboronic acid (9.24 g, 66.0 mmol) and CsF (10.0 g, 66.0 mmol) in 1,4-dioxane (220 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (2.70 g, 3.30 mmol). Heat the reaction mixture at 95° C. overnight. Cool, and partition between saturated NaHCO3 (aq) and EtOAc. Separate the layers, and extract the aqueous layer with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 6% 2M NH3/MeOH in CH2Cl2) to afford the title compound as a waxy solid (4.91 g, 64%). ES/MS m/z 351.2 (M+1).