Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[CH3:26].[C:29](OC(=O)C)(=O)[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:23](=[O:28])[CH:24]=[C:25]([CH3:26])[N:27]=[C:29]1[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=N)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Product: Cc1cc(=O)n(-c2cc(S(=O)(=O)N3CCCCc4ccccc43)ccc2Cl)c(C)n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-imino-butyramide (42 mg, 0.1 mmol) in acetic anhydride (1 mL) was added 4-dimethyl-aminopyridine (6 mg, 0.1 mmol). The mixture was heated at 85° C. under stirring for 16 hrs. The mixture was then subjected to purification by prep. LCMS to afford 3-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-2,6-dimethyl-3H-pyrimidin-4-one 14-1. MS: 443.8 (M+H)+; tR=6.94 min (method 2).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][S:2][CH:3]=1)=[O:8])=[O:21]
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1cccc(Cl)c1)c1ccsc1
Yield: 93.1 %

Procedure:
7.5 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 10.0 g of sodium bicarbonate and 8.86 g of 3-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 11.0 g of N-(3-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1.C(=O)([O-])O.[Na+].Br[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH3:1][N:2]([CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)Cc1cccc(NC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cccc(N(C)Cc2ccccc2C(=O)OCC)c1
Yield: 68.3 %

Procedure:
The starting material employed above had been synthesized in the same manner as described in Example 1. That is, N-methyl-3-ethoxycarbonylmethylaniline (20.7 g), sodium hydrogencarbonate (19 g), water (30 ml) and ethyl 2-bromomethylbenzoate (27.5 g) were used to produce N-methyl-N-(2-ethoxycarbonylbenzyl)-3-ethoxycarbonylmethylaniline (26 g) as a light yellow oil. Then, N-methyl-N-(2-ethoxycarbonylbenzyl)-3-ethoxycarbonylmethylaniline (26 g) so produced, sodium hydroxide (40 g), water (450 ml) and ethanol (150 ml) were used to prepare N-methyl-N-(2-carboxybenzyl)-3-carboxymethylaniline (14.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [Cl-]
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCCl

Procedure:
To 12-bromododecanoic acid (1 g) dissolved in acetonitrile (50 ml) was added calcium chloride (2 g) and tetra-n-butylammonium chloride (1.2 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate-water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 12-chlorododecanoic acid. After a 280 mg portion of 12-chlorododecanoic acid thus obtained, para-nitrophenol (167 mg) and N,N'-dicyclohexylcarbodiimide (245 mg) in N,N-dimethylformamide (DMF) was stirred for 12 hours, precipitates were removed by filtration and DMF was removed by distillation to give an active ester. To the active ester of 12-chlorododecanoic acid dissolved in DMF were added 6- (4'-N-glycyl-spicaminyl-amino)purine hydrochloride (456 mg) and triethylamine (1.2 ml), and the mixture was stirred for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK132 in the yield of 287 mg.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]([NH2:12])=[O:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N:9]1[C:10](=[O:11])[N:12]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=12
Reactant: NC(N)=O
Reactant: O=C1CCCCC1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1N=C2CCCCC2=N1
Temperature: 25 °C

Procedure:
A mixture of 2-bromocyclohexanone (6.23 g, 0.035 mol) and urea (2.1 g, 0.035 mol) is refluxed in a solution of ammonium acetate (10 g), acetic acid (15 mL) and water (50 mL) for 4 h. Upon cooling slowly to room temp, white crystals form in the reaction vessel. The solid is collected by suction filtration, washed thoroughly with water and ether, and dried in vacuo to afford 4,5,6,7-tetrahydro-2-benzimidazolone (Compound 7).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][CH2:10][C:11]1[C:20]2[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([O:22][CH2:23][O:24][CH3:25])=[CH:13][CH:12]=1.N1C=CN=C1>CN(C)C1C=CN=CC=1.O>[Si:5]([O:9][CH2:10][C:11]1[C:20]2[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([O:22][CH2:23][O:24][CH3:25])=[CH:13][CH:12]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COCOc1ccc(CO)c2cccc(C)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Product: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
13.7 g of t-butylchlorodimethylsilane was added to an N,N-dimethylaminopyridine (100 ml) solution of 14 g of 1-hydroxymethyl-4-methoxymethoxy-5-methylnaphthalene, 6.64 g of imidazole, and 0.4 g of 4-dimethylaminopyridine and agitated at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Thereafter, the resultant organic phase was washed with water and then with a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 19 g of the captioned compound as a light brown oily substance.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[C:30]([O-:33])(=[O:32])[CH3:31].[Cs+]>CN(C=O)C>[C:30]([O:33][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)[O-]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC(C)=O)cc23)c1
Yield: 183.8 %

Procedure:
The title product of Example 30 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a residue (285 mg) which was recrystallized from ethylacetate/hexane. (134 mg; M.P. 84°-87° C.; LC-MS: 422 (MH+); anal. RP18-HPLC RT: 4.38 min.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCl.[CH2:22]([O:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[C:42](Cl)[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[C:39]([OH:41])=[O:40])[N:37]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:22]([O:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[CH:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47])[C:39]([OH:41])=[O:40])[N:37]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CCCC(Cl)=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CCCC=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67 %

Procedure:
To a solution of triphenylphosphine (284 mg) in tetrahydrofuran (4 ml) cooled at -15° C. are added a 0.85M solution of chlorine in carbon tetrachloride (1.27 ml), triethylamine (0.152 ml), and a solution of ketodiester (4) (160 mg) in tetrahydrofuran (2 ml). The mixture is warmed to room temperature, stirred for 6.5 hours, subjected to usual work-up, and silica gel chromatography to give chlorodiester (5). Yield: 67%.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C@:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[CH2:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])(C)(C)C.FC(CC(O)=O)(F)F>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C@@:16]2([C:18]([F:20])([F:21])[F:19])[CH2:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-[(R)-4-(3,5-Dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid tert-butyl ester (0.68 g) in dichloromethane (0.7 ml) was added trifluoromethyl acetic acid (“TFA”) (0.07 ml). The reaction mixture was stirred at ambient temperature for 4.5 hours. The dichloromethane was evaporated under reduced pressure and the residue was taken up in ethyl acetate and water. The organic phase was washed with water and brine and evaporated under reduced pressure to afford 4-[(R)-4-(3,5-Dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid which was used as such in the next reaction). LCMS (Method F) RT=2.07 min, [M−H]−=414/416.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][C:8]([S:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>ClCCl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:3][C:2]([CH3:5])([CH3:4])/[CH:1]=[N:13]/[S:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Product: CC(C)(C)/C=N/S(=O)C(C)(C)C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of pivalaldehyde (2 g, 2.56 ml, 23.2 mmol) in dry dichloromethane (150 mL) under argon atmosphere was added 2-methylpropane-2-sulfinamide (3.38 g, 27.9 mmol) and titanium (IV) ethoxide (6.36 g, 5.84 ml, 27.9 mmol) to give a colorless solution. The reaction mixture was stirred at r.t overnight and quenched by slow addition of water while the reaction still stirring until a precipitate formed. The reaction mixture was then filtered through a pad of celite. The filtrate was extracted with water, the organic phase was collected, dried over Na2SO4 and evaporated down in vacuo to give the title compound (3.6 gr, 82%) as crude oil. The crude was used without any further purification for the next step, MS (EI): m/e=190.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][NH:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O.C(P(=O)(OCC)OCC)#N>C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][N:8]([C:37](=[O:38])[C@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH2:9][CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(CNCC(=O)OC(C)(C)C)OCC
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(CN(CC(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 11.0 g of N-(2,2-diethoxyethyl)glycine t-butyl ester, 13.3 g of N-benzyloxycarbonyl-L-phenylalanine and 50 ml of dimethylformamide was cooled to 0° C., and there were added dropwise 9.4 g of diethyl cyanophosphonate, then 5.9 g of triethylamine. The mixture was stirred for one hour at the same temperature, then for 5 hours at room temperature. The reaction mixture was diluted with ethyl acetate, which was poured into ice-water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give a crude product. The crude product was purified by means of chromatography on silica gel using an eluent (n-hexane:ethyl acetate=9:1) to afford 20.0 g of the title compound as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1Cl.C(O)(=[O:17])C>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[OH:17]
Reactant: Clc1cc(-c2ccccc2)nnc1Cl
Reactant: CC(=O)O
Product: Oc1cc(-c2ccccc2)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 19 (158 g, 0.7 mol) and acetic acid (700 mL) was heated under reflux for 5 hrs. The reaction mixture was cooled to room temperature, the precipitate filtered and the bright yellow filter cake washed with water (5×500 mL). The filter cake was recrystallized from ethyl acetate (200 mL), filtered and dried over a medium frit sintered glass funnel in vacuo to give the desired product 20 in 32% yields. HPLC (tr/purity): 15.37 min, >95%. ESI m/z (MeOH): 2073 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.C(#N)CC.CCN(C(C)C)C(C)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:35]([O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2)([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)C1Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (300 mg, 1.06 mmol), prepared as in J. Med. Chem. 2003, 46, 9, 1627-1635, in DMF (1 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (175 μL, 2.271 mmol), tert-butyl acrylate (615 mL, 4.24 mmol), tri(o-tolyl)phosphine (64 mg, 0.21 mmol) and palladium acetate (48 mg, 0.21 mmol). The mixture was stirred at 100° C. overnight. LCMS analysis showed that some unreacted starting material was remaining, so 24 mg of palladium acetate and 64 mg of tri(o-tolyl)phosphine were added. After 5 h at 100° C., the reaction was allowed to come back to room temperature, filtered through Celite pad and rinsed with methanol. The residue obtained after concentration was purified by flash chromatography (eluent: gradient DCM/EtOAc) to give the title compound as an orange solid (115 mg, 32%) contaminated with traces of tri(o-tolyl)phosphine oxide.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[I-].[Na+].[CH2:22](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:23][C:24]#[CH:25]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:25]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH2:24][C:23]#[CH:22]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
A solution of 4-phenylphenol (0.774 g, 4.55 mmol) and potassium tert-butoxide (0.51 g, 4.55 mmol) in toluene (20 mL) was stirred for 1 h at room temperature. Sodium iodide (0.068 g, 0.45 mmol) and toluene-4-sulfonic acid but-3-ynyl ester (1.02 g, 4.55 mmol) were added, and the mixture heated to reflux for 24 hours. The mixture was cooled to room temperature, diluted with diethyl ether (20 mL), washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 3:1, Rf0.57) to give an oil (140 mg, 14%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.50 (m, 4H), 7.46–7.38 (m, 2H), 7.32 (d, 1H, J=7.3), 7.02–6.95 (m, 2H), 4.15 (t, 2H, J=7.0), 2.71 (dt, 2H, J=2.7, 7.3), 2.06 (t, 1H, J=2.7).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO.O>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:13]=[N:12]1
Reactant: CSc1nccc(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2cnn(C)c2)n1
Temperature: 100 °C

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 1.1 eq), Na2CO3 (2.8 g, 3 eq) and Pd(PPh3)4 (500 mg, 0.43 mmol) were combined in a solvent comprised of toluene/EtOH/H2O (4/4/1, 20 mL). The reaction mixture was purged with argon and heated to 100° C. overnight. The reaction was filtered to remove insolubles and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to provide 4-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine contaminated with triphenylphosphine oxide (2.0 g, >100% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.49 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.38 (d, J=5.1 Hz, 1H), 3.89 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][C:17](Cl)=[O:18])[C:14](=[O:20])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:35])[CH2:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1.O.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][C:17]([N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:35])=[O:18])[C:14](=[O:20])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(C(=O)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(4S)-3-benzyloxycarbonyl-5-oxo-oxazolidin-4-yl-acetyl chloride (3.00 g, 10 mmol) in dichloromethane (20 mL) was added dropwise to a solution of tert-butyl-N-phenylglycinate (2.3 mg, II mmol) in pyridine (10 mL) at 0 C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with H2O (100 mL) and EtOAc (150 mL). The organic phase was separated and washed successively with citric acid (10%, 2×100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow viscous oil. Column chromatography (SiO2, 20-50% EtOAc in petroleum ether) gave tert-butyl N-[(4S)-3-benzyloxycarbonyl-5-oxo-oxazolidin-4-yl-acetyl]-N-phenylglycinate as a white foam. MS (APCI) m/z 467 (M+−1,100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:37](N1C=CN=C1)([N:39]1C=CN=[CH:40]1)=O.CNC.C1COCC1>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([N:39]([CH3:40])[CH3:37])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6 (1.68 g, 3.43 mmol) in dry DMF (30 mL) was added carbonyldiimidazole (1.1 g, 6.86 mmol), and the reaction mixture was heated to 60° C. for 1 hr. The reaction mixture was cooled to 0° C. and a solution of dimethylamine in THF (2 M, 8.6 mL, 17.2 mmol) was added and stirred for 18 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was then rinsed sequentially with 10% citric acid (2×50 mL), water (2×50 mL), and brine (20 mL), then dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography using hexane-ethyl acetate (3:7) containing 1% acetic acid. Yield: 1.77 g, 100%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (200 mg, 0.41 mmol) and acetone (2.5 mL, 54 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine), 132 mg (66%) of the title compound.