Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C(CBr)=C(C(C)=C(OC(=O)C)C=1)C(OCC(Cl)(Cl)Cl)=O)(=O)C.OC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS.[C:43]([O:46][C:47]1[C:48]([CH3:83])=[C:49]([C:58]([CH2:65][S:66][C@@H:67]([NH:69][C:70](=[O:82])[C@@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:72][OH:73])[CH3:68])=[C:59]([O:61][C:62](=[O:64])[CH3:63])[CH:60]=1)[C:50]([O:52]CC(Cl)(Cl)Cl)=[O:51])(=[O:45])[CH3:44]>>[C:43]([O:46][C:47]1[C:48]([CH3:83])=[C:49]([C:58]([CH2:65][S:66][CH:67]([NH:69][C:70](=[O:82])[C@@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:72][OH:73])[CH3:68])=[C:59]([O:61][C:62](=[O:64])[CH3:63])[CH:60]=1)[C:50]([OH:52])=[O:51])(=[O:45])[CH3:44]
Reactant: CC(=O)Oc1cc(OC(C)=O)c(CS[C@H](C)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c(C(=O)OCC(Cl)(Cl)Cl)c1C
Agent: CC(=O)Oc1cc(OC(C)=O)c(CBr)c(C(=O)OCC(Cl)(Cl)Cl)c1C
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCCS
Product: CC(=O)Oc1cc(OC(C)=O)c(CSC(C)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c(C(=O)O)c1C

Procedure:
2,2,2-Trichloroethyl 3,5-diacetoxy-2-bromomethyl-6-methylbenzoate was reacted with t-butyl [(S)-2-hydroxy-1-[(2-mercaptoethyl)carbamoyl]ethyl]carbamate in a manner analogous to the procedure given in Example 1(f), and the resulting 2,2,2-trichloroethyl 3,5-diacetoxy-6-[[((R)-2-[(S)-2-(t-butoxyformamido)-3-hydroxypropionamido]-2-ethyl]thio]methyl]-2-methylbenzoate product was subjected in analogous manner to the procedure described in Example 1(g) to give 3,5-diacetoxy-6-[[[2-[(S)-2-(1-t-butoxyformamido)-3-hydroxypropionamido]-2-ethyl]thio]methyl]-2-methylbenzoic acid as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH2:10][CH:9]1[CH2:28][O:29][CH2:32][CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)N2CCN(Cc3ccccc3)C(CO)C2)cc(OC)c1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1Cc1ccccc1
Reaction time: 0.08 h

Procedure:
In N,N-dimethylformamide (2 ml) is dissolved 1-benzyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (1.0 g). The solution is added dropwise to a mixture of sodium hydride (0.15 g) and N,N-dimethylformamide (4 ml) taking 5 minutes at 0 ° C while stirring. To the mixture is further added ethyl iodide (0.5 g) at 0° C., followed by stirring for 30 minutes at room temperature. The reaction mixture is poured into icewater and extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure to afford 1-benzyl-2-ethoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine as a colorless oily product (1.0 g). This product is led to its hydrochloride, followed by recrystallization from acetone to give colorless needles, m.p. 130-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Temperature: 25 °C
Yield: 100 %

Procedure:
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)isoindole-1,3-dione which was used directly in the following step (assumed 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=5)(=[O:42])=[O:41])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c1

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-methoxy-benzenesulfonyl chloride. White solid; EI-HRMS m/e calculated for C30H28FN5O5S (M+) 589.1795, found 589.1801.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1.Br[C:12]1C=CC(I)=C(CC)C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH2:10][CH3:12])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1C
Reactant: CCc1cc(Br)ccc1I
Agent: C=C[Si](C)(C)C
Product: C=Cc1ccc(Br)cc1CC
Yield: 77 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 4-bromo-2-ethyl-1-iodobenzene (2.1 g, 6.9 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 175° C. for 45 min to yield 36A (1.1 g, 77%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.58 Hz, 3 H) 2.51 (q, J=7.66 Hz, 2 H) 5.15 (dd, J=10.99, 1.14 Hz, 1 H) 5.47 (dd, J=17.31, 1.14 Hz, 1 H) 6.74 (dd, J=17.43, 11.12 Hz, 1 H) 7.08-7.20 (m, 3 H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25]([CH:35]4[CH2:8][CH:36]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a 6 ml DMSO suspension of 200 mg of 60% sodium hydride was added 1.1 g of trimethylsulfoxonium iodide, followed by stirring for 30 minutes. To the reaction mixture was added 242 mg of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate, followed by stirring at room temperature for 1 hour and at 60° C. for 1 hour. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg of ethyl 2-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]cyclopropanecarboxylate.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH:17]2[CH2:22][C:21](=[O:23])[C:20]([C:24](=[N:28][O:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])=[C:19]([OH:32])[CH2:18]2)=[C:11]([CH3:33])[C:10]=1[CH3:34])C1C=CC=CC=1>[Pd].Cl.C(OCC)(=O)C>[CH2:30]([O:29][N:28]=[C:24]([C:20]1[C:19](=[O:32])[CH2:18][CH:17]([C:12]2[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([CH3:34])[C:11]=2[CH3:33])[CH2:22][C:21]=1[OH:23])[CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)c(C)c(OCc3ccccc3)c(C)c2C)CC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)c(C)c(O)c(C)c2C)CC1=O
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Palladium on activated carbon (0.14 g), followed by concentrated hydrochloric acid (2 drops), were added to a solution of 5-(4-benzyloxy-2,3,5,6-tetramethylphenyl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (see Example 37) (1.40 g; 3.0 mmole) in ethyl acetate (50 ml). The mixture was hydrogenated at atmospheric pressure for 2 hours, then filtered, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oily residue, which was purified by column chromatography over silica gel (eluant dichloromethane) to give 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(4-hydroxy-2,3,5,6-tetramethylphenyl)cyclohex-2-en-1-one (0.34 g; 30.1%) as a colourless solid, mp 134° C.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CCOCC.N.[Li]>O1CCCC1.C(O)C>[CH2:1]1[CH:13]2[CH:5]([C:6]3[CH2:7][CH:8]=[CH:9][CH2:10][C:11]=3[CH2:12]2)[CH2:4][CH2:3][CH:2]1[N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: c1ccc2c(c1)CC1=C2CCC(N2CCCC2)C1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: C1=CCC2=C(C1)CC1CC(N3CCCC3)CCC21
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
A solution of 20.1 g (0.084 moles) of 1-(1,2,3,4-tetrahydrofluoren-2-yl)pyrrolidine, prepared as per Example 7, in 400 ml of tetrahydrofuran and 100 ml of ether is added to 2.5 l of liquid ammonia. 12.25 g (1.72 g-atoms) of lithium ribbon is added over 25 min and the mixture stirred for 15 minutes. 160 ml of ethanol is added over 2.5 hr., the ammonia evaporated and the residue added to 1 liter of cold water. The layers are separated and the aqueous layer is extracted with ether (2 × 300 ml). The combined ether layers are washed, dried and evaporated in vacuo to give 20.2 g of oil of the above title.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[C:21](OC)=[O:22]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[CH2:21][OH:22]
Reactant: COC(=O)c1ccnc2cc(OC)c(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2nccc(CO)c2cc1OC
Temperature: -78 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
Lithium aluminum hydride (262 mg, 6.90 mmol) was suspended in tetrahydrofuran (20 mL) then cooled to −78° C. A solution of methyl 6,7-dimethoxyquinoline-4-carboxylate (1.55 g, 6.27 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 4 hours. The reaction was quenched with ethyl acetate (6 mL) then added sodium sulfate decahydrate and warmed the mixture to room temperature, stirring overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The remaining solid was triturated with dichloromethane, filtered and dried under high vacuum to give 1.2 g of (6,7-dimethoxyquinoline-4-yl)methanol as a light yellow solid. MS (ESI, pos. ion) m/z: 220.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1)[CH3:3].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH3:3])[C:30]=1[C:31]#[N:32]
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3cncc(F)c3)n12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3cncc(F)c3)n12

Procedure:
A solution of (S)-methyl 2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate (0.151 g, 0.480 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.089 g, 0.576 mmol) and DIEA (0.252 mL, 1.441 mmol) in n-butanol (2.40 mL) was stirred at 110° C. for 2 h. The mixture was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-7% MeOH in DCM) to afford the methyl 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(5-fluoro-3-pyridinyl)imidazo[1,2-a]pyridine-5-carboxylate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.65 Hz, 3H) 3.33 (s, 3H) 5.41 (quin, J=6.65 Hz, 1H) 7.16 (d, J=7.24 Hz, 1H) 7.23 (br. s., 2H) 7.38-7.50 (m, 2H) 7.75-7.90 (m, 2H) 7.95 (dd, J=8.61, 1.57 Hz, 1H) 8.42 (br. s., 1H) 8.62 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 433.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12]>>[NH2:13][C:11]1[S:12][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)c1csc(N)n1
Temperature: 100 °C
Yield: 152.6 %

Procedure:
According to literature reference (Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633), ethyl bromopyruvate (10.0 mL, 79.7 mmol) and thiourea (5.5 g, 72.3 mmol) are combined neat in a 100 mL flask and slowly heated to 100° C. over a 1 hour period. At approximately 70° C. a vigorous reaction occurs and the mixture becomes homogeneous. After reaching 100° C. the reaction is heated for an additional 20 minutes and then cooled to room temperature. Upon cooling the reaction product solidifies affording 19.0 grams of a crude ethyl 2-amino-4-thiazolecarboxylate which is used without further purification.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.[CH3:8][C:9]1([CH3:29])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:21]=2)[O:10]1.CCN(CC)CC.C(Cl)(=O)CC>C(Cl)Cl>[CH3:8][C:9]1([CH3:29])[C:13]([CH3:14])([CH3:15])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[CH2:1][CH3:3])[CH2:20][CH:21]=2)[O:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
TFA (14.75 g, 9.966 mL, 129.4 mmol) was added to a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5000 mg, 16.17 mmol) in DCM (40 mL) at 0° C. and the reaction stirred at this temperature for 1.5 hours. The solvent was removed in vacuo and the residue azeotroped with MeCN (×3). The residue was re-dissolved in DCM (50 mL) and cooled to 0° C. Et3N (6.545 g, 9.015 mL, 64.68 mmol) was added followed by a solution of propionyl chloride (1.646 g, 1.546 mL, 17.79 mmol) in DCM (5 mL). The reaction mixture was allowed to warm to ambient temperature over 1 hour. The mixture was diluted with DCM and washed with 1:1 1M HCl/brine (×2), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 120 g column, eluting with 20 to 80% EtOAc/Petroleum Ether) to give the sub-title product as a white solid (3.87 g, 90% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.15 (t, 3H), 1.27 (s, 12H), 2.20-2.44 (m, 4H), 3.47 (t, 1H), 3.64 (s, 1H), 4.06 (d, 2H) and 6.48 (d, 1H) ppm; MS (ES+) 266.3.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2I)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of 1.50 g (3 mmole) of the intermediate obtained in Step A in toluene was treated with 1.48 g (15 mmole) of trimethylsilyl acetylene, 87.1 g (0.86 mol) of triethylamine, 0.1 g (0.15 mmol) of bis(triphenylphosphine) palladium(II) chloride, 0.2 g (0.8 mmole) of triphenyl phosphine and 0.2 g (1.17 mmole) of copper iodide. This reaction mixture was stirred at rt for 1 hr and heated at 90° C., in a sealed reaction vessel, for 16 hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which upon purification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. 1H NMR (300 MHz, CDCl3): δ 0.0 (s, 9 H), 0.93 (t, J=7.0, 61), 1.32 (d, J=6.6 Hz, 6 H), 1.33 (d, J=6.6 Hz, 6 H), 3.18 (septet, J=6.6, 2 H), 3.90 (q, J=7.0 Hz, 4 H), 7.20-7.50 (m, 4 H).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[OH:4])#[CH:2].I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[C:1]#[C:2][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Yield: 68.2 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.4 g (6 mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol with 1.6 g (6 mmol) of methyl 4-iodobenzoate, 1.5 g (68%) of the expected ester was obtained in the form of an orange-colored oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(I)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc(I)cc1
Yield: 134.5 %

Procedure:
A mixture of 2.1 g of 4-iodobenzamide, 30 ml of tetrahydrofuran, and 2 g of Lawesson's reagent was heated to reflux for 1 hour. It was partitioned between toluene and 10% aqueous sodium carbonate solution. The organic phase was dried and evaporated. The crude product was passed over a plug of silica gel using acetone/hexane 1:1 for elution. Crystallization from methylene chloride/hexane gave 1.75 g of yellow crystals with m.p. 163-165° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:4]1)=O.Cl.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:40][CH:41]=[CH2:42])[CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl.CCOC(C)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[N:5]1[CH2:6][C@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:3]([CH2:1][N:46]2[CH2:47][CH2:48][CH:43]([N:39]([CH2:40][CH:41]=[CH2:42])[C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[CH2:44][CH2:45]2)[CH2:4]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCN(c1cccnc1)C1CCNCC1
Reactant: O=C[C@H]1CN([C@@H]2CCCCC2CC(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN(c1cccnc1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2ccccc2)CC1
Yield: 70.9 %

Procedure:
A solution of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)cyclohexaneacetic acid, benzyl ester (35 mg, 0.086 mmol; prepared above as Aldehyde 4), 4-(N-(pyrid-3-yl)-N-allylamino)piperidine dihydrochloride (28 mg, 0.103 mmol, from Step B), sodium triacetoxyborohydride (44 mg, 0.206 mmol) and triethylamine (0.03 mL, 0.206 mmol) were stirred in 2 mL 1,2-dichloroethane for 12 h. The mixture was diluted with 25 mL EtOAc and washed with water and sat'd aq. NaCl. The organic phase was dried over Na2SO4 and concentrated. Flash chromatography (5 grams silica, 0→2% MeOH/CH2Cl2 eluent) afforded 37 mg (70%) of the title compound. M/z; (M+H)=607.4 (obs), 607.4 (calc.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[N:7][C:6]=1Cl.[OH-].[K+]>C1C=CC=CC=1>[Cl:11][C:9]1[C:8]([Cl:12])=[N:7][C:6]2[O:1][CH2:2][CH2:3][NH:4][C:5]=2[N:10]=1
Reactant: OCCNc1nc(Cl)c(Cl)nc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Clc1nc2c(nc1Cl)OCCN2
Yield: 29.1 %

Procedure:
(2-Hydroxyethylamino)-trichloropyrazine (12.1 g, 0.05 mol) and crushed KOH (5 g, 85% assay, 0.075 mol) were contacted in refluxing benzene overnight. The solid phase was filtered out and stirred in water, CH2Cl2, and IPA and refiltered after each wash to give 3 g (30% yield) of an off-white solid.
Reaction SMILES: N([O-])=O.[Na+].Cl.[CH3:6][C:7]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:8]=1N.[C:18]([O-])(=[O:20])C.[K+].C=O.Cl.NO.S([O-])([O-])=O.[Na+].[Na+]>O.Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:6][C:7]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:8]=1[CH:18]=[O:20]
Reactant: Cc1cc(C(C)C)cc(C)c1N
Reactant: CC(=O)[O-]
Agent: [Cu+2]
Agent: C=O
Agent: Cl
Solvent: O
Product: Cc1cc(C(C)C)cc(C)c1C=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A solution of NaNO2 (1.75 g, 25 mmol) in water (4 mL) was added to a stirred solution of 2,6-dimethyl-4-isopropylaniline hydrochloride (Schubert, W. M. et al. J. Amer. Chem. Soc. 1954, 76:1) (5 g, 25 mmol) in concentrated HCl (4.5 mL) at 0° C. The mixture was allowed to stir at 0° C. for 1.5 hours. Potassium acetate (6 g) was then added. At the same time, a solution of paraformaldehyde (1.15 g), hydroxylamine hydrochloride (2.63 g, 37.84 mmol) and potassium acetate (5.1 g) in water (17 mL) was heated under reflux for 15 min. To this solution, cooled to 10-15° C., was added potassium acetate (16.5 g) in water (18 mL), copper sulfate (0.625 g) and sodium sulfite (0.1 g). The neutral diazonium solution was then added immediately to the paraformaldehyde mixture and the resulting solution was allowed to stir at room temperature for 2 hours. The mixture was acidified with 20 mL of concentrated HCl and heated at reflux for 2 hours. The cooled mixture was extracted with ether (3×30 mL) and the solvent was removed under reduced pressure. The yellow liquid was purified by column chromatography using as eluent hexane-EtOAc (97:3) to give 0.72 g (16%) of the title compound as a white liquid.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([F:23])[F:22].C(C1C=CC(N)=CC=1)(C)(C)C>>[F:20][C:21]([F:23])([F:22])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([S:24]([C:21]([F:23])([F:22])[F:20])(=[O:25])=[O:26])=[CH:28][CH:29]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Agent: CC(C)(C)c1ccc(N)cc1
Product: O=S1(=O)N=C(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedure of Example 1C, substituting the product of Example 7B (0.1476 g, 0.450 mmol) for the product of Example 1B and substituting 4-aminophenyl trifluoromethyl sulphone (0.2571 g, 1.14 mmol) for 4-tert-butylaniline. MS (ESI+) m/z 536 (M+H)+, m/z 534 (M−H)−; 1H NMR (CD3OD) δ 7.73 (dd, J 4.7, 8.1, 1H), 7.99 (d, J 8.2, 1H), 8.12 (s, 1H), 8.19 (d, J 9.2, 2H), 8.38 (m, 3H), 8.46 (d, J 7.8, 1H), 8.92 (d, J 4.4, 1H).