Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(C(C)(C)C)(C)C.[H-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:31]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[C:12]([CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:13]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(CCc3ccccc3)c3ccc(O)cc23)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To solution of 5-(t-butyldimethylsilanyloxy)-3-(1-methylpiperidin-4-yl)-1H-indol (285 mg, 0.83 mmol) in tetrahydrofuran (20 mL) stirring at 0° C. was treated with potassium hydride (99 mg of a 35% dispersion in oil, 0.87 mmol). The light yellow solution was stirred for 20 minutes at 0° C. Phenethyl tosylate (2.29 g, 8.30 mmol) was added and stirred at 0° C. for 3 h, and at room temperature overnight. Addition 35% potassium hydride (94 mg, 0.83 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was treated with tetrabutylammonium fluoride (830 μL of a 1M solution in tetrahydrofuran, 0.83 mmol) and was stirred overnight at room temperature, before concentrating in vacuo. Purification by silica gel chromatography 9:1 dichloromethane: methanol gave 175 mg (63%) of the title compound as orange foam: MS (APCI): m/e 335.2 (M+1).
Reaction SMILES: C[N:2]([CH3:5])C=O.Cl[CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1.[C-]#N.[Na+].Cl>O>[C:5]([CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1)#[N:2]
Reactant: O=C(O)c1cccc2c1CCC2Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC1CCc2c(C(=O)O)cccc21
Reaction time: 5 h

Procedure:
In 15 ml. of dimethylformamide is dissolved 1.97 g. of 1-chloroindan-4-carboxylic acid, followed by the addition of 1.47 g. of sodium cyanide. The mixture is stirred for 5 hours, after which 150 ml. of water and 10 ml. of concentrated hydrochloric acid are added. The resultant crystals are collected by filtration and recrystallized from benzene. The described procedure gives 1-cyanoindan-4-carboxylic acid, melting point: 206°-208° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:17]=1[NH2:18].[Cl-].[NH4+]>S(Cl)(Cl)=O.N1C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH:18][C:17]1[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: CCCCCCCCC(Br)C(=O)O
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(Br)C(=O)Nc1c(OC)cc(OC)cc1OC
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
2-Bromodecanoic acid (1 g, 3.8 mmol) was heated under reflux in thionyl chloride (10 ml) for 1 hour. The thionyl chloride was evaporated and the residue was dissolved in dry ether (10 ml) and added dropwise to a solution of 2,4,6-trimethoxyaniline (0.7 g, 3.8 mmol) in pyridine (20 ml) at 0° C. and the mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with ethyl acetate (60 ml). The combined organics were extracted with water and brine and dried and concentrated. Recrystallization from isopropyl ether afforded 1.1 g (65%) of the title compound, m.p. 109°-110° C. This material was used directly in the next step.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC(=O)[NH:25][C:26]1[CH:31]=[C:30]([NH2:32])[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([C:42]3[CH:46]=[C:45]([C:47]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[NH:48])[S:44][C:43]=3[S:57][CH3:58])(=[O:41])=[O:40])[CH:34]=2)=[C:28]([CH3:59])[CH:27]=1>C1COCC1>[C:53]([O:52][C:50](=[O:51])[NH:49][C:47]([C:45]1[S:44][C:43]([S:57][CH3:58])=[C:42]([S:39]([C:35]2[CH:34]=[C:33]([C:29]3[C:30]([NH2:32])=[CH:31][C:26]([NH2:25])=[CH:27][C:28]=3[CH3:59])[CH:38]=[CH:37][CH:36]=2)(=[O:40])=[O:41])[CH:46]=1)=[NH:48])([CH3:56])([CH3:55])[CH3:54]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2N)c1
Temperature: 50 °C
Yield: 121.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF, 1 mL, 1 mmol) was added to a solution of {6-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl}-carbamic acid 2-trimethylsilanyl-ethyl ester ((Example 294: step f) 86 mg, 0.11 mmol) in THF (1 mL). The solution was heated at 50° C. for 12 h, then the solution was partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the organic layer was further extracted with water (5×10 mL) and brine (20 mL). The solution was dried over sodium sulfate and concentrated in vacuo to yield the title compound (71 mg, 84%) which was used without further purification. ESI-MS (m/z): Calcd. for C24H28N4O4S3 (M+H): 533.1; found: 532.7.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1.O>C(O)C>[CH:15]1([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:16]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Following general procedure 2B: To a solution of N-(4-fluoro-3-nitrophenyl)acetamide (15.4 g, 77.7 mmol) in 80% aqueous ethanol (150 mL) was added cyclopropanemethylamine (10 mL) at room temperature. The reaction mixture was heated to reflux overnight. After cooling to room temperature, H2O (300 mL) was added and the desired product precipitated out as an orange solid (18 g, 92%).
Reaction SMILES: CS[CH:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]1.[NH2:22][NH2:23]>O>[CH2:12]([N:11]1[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]/[C:3]/1=[N:22]\[NH2:23])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCN1c2nc(C(F)(F)F)[nH]c2C(=O)NC1SC
Reactant: NN
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 2-(methylthio)-3-pentyl-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (0.61 g, 0.95 mmol), hydrazine (3 mL, 100 mmol) and water (3 mL) was stirred at 100° C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative LCMS. The product fractions were collected and lyophilized to give the desired product (0.25 g, 65%). LCMS calculated for C11H15F3N6O: (M+H) 305.1; found 305.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][O:10][CH2:11][O:12][CH3:13])=[C:7]([C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:15][CH2:16][OH:17])[CH:6]=[CH:5][N:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:20][C@:14]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][O:10][CH2:11][O:12][CH3:13])([CH2:18][CH3:19])[CH2:15][CH:16]=[O:17]
Reactant: CC[C@@](O)(CCO)c1ccnc(OC)c1COCOC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC[C@@](O)(CC=O)c1ccnc(OC)c1COCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a mixture of 7b (0.5 g, 1.78 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (1.2 g, 2.85 mmol). The mixture was stirred at rt for 3 h and then poured into a well-stirred mixture of satd. Na2S2O3 (10 mL) and satd. NaHCO3 (10 mL). The layers were separated after 30 min. The aqueous layer was extracted 3 times with diethyl ether. The combined organic extracts were washed with satd. NaHCO3, brine, dried over MgSO4 and concentrated under vacuum to give the crude aldehyde 8b (0.47 g, 89%) as pale yellow oil. The crude product was sufficiently pure for the subsequent reaction. IR (CH2Cl2, NaCl,cm−1) 3380, 3057, 2982, 1763, 1655, 1596, 1422, 1264, 895, 735, 547; 1H NMR (300 MHz, CDCl3) δ0.82 (t, J=7.4 Hz, 3H), 1.91 (m, 2H), 2.85 (d, J=15.9 Hz, 1H), 3.10 (d, J=15.9 Hz, 1H), 3.41 (s, 3H), 3.96 (s, 3H), 4.74 (s, 2H), 4.98 (q, J=10.9 Hz, 2H), 6.74 (d, J=5.5 Hz, 1H), 8.06 (d, J=5.5 Hz, 1H), 9.73 (s, 1H); 13C NMR (75 MHz, CDCl3) δ7.94, 36.42, 54.23, 55.31, 55.99, 60.93, 77.90, 96.45, 115.82, 117.41, 146.55, 155.59, 163.85, 202.18; HRMS (EI) m/z calcd for C14H22NO5 (M+H) 284.1498, found 284.1498; LRMS (ED) 284(M+H, 15), 265(25), 192(20), 178(72), 148(24), 84(100), 57(26); [α]D23=−11.5 (c=0.125, CH2Cl2).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:26]Cl>CO>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:26])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: ClI
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO3 (1.06 g, 10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) in methanol (10 mL), and stirred overnight at 20 C. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), extracted twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.54 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.55 (m, 1 H), 6.57 (m, 1 H), 3.86 (s, 3H), 3.80 (m, 1 H), 3.60-3.30 (m, 2 H), 3.20-2.80 (m, 4 H), 1.30 (m, 3 H). MS calculated for C14H15F3INO2+H: 414, observed: 414.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]([NH2:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1.CN1CCOCC1>C(O)(C)C>[C:17]([N:16]=[C:8]([NH:29][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)[CH2:27][CH3:28])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Reactant: CCC(N)c1cccc(Cl)c1
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: CCC(NC(=NC#N)Nc1cccnc1)c1cccc(Cl)c1

Procedure:
According to Procedure B, a stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (Step 2) (3.00 g, 0.0126 mol), 1-(3-chlorophenyl)propylamine (2.35 g, 0.0139 mol), N-methylmorpholine (30 mL) and isopropanol (20 mL) was refluxed, under nitrogen, for 2.5 hours. The product was purified by silica gel chromatography with 1% to 3% MeOH-CHCl3 and crystallized from MeOH-EtOAc-hexane to give the product: mp 153°-155 ° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:24]=2[CH:25]=1)=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:30][C:27]2[CH:28]=[CH:29][C:23]3[O:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:25][C:24]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 2-methoxycarbonyl-5-aminobenzofuran gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 9.42 (s, 1H), 9.33 (s, 1H), 9.23 (s, 1H), 8.26 (s, 1H), 8.09 (d, 1H, J=3.6 Hz), 7.59 (m, 3H), 7.13 (m, 3H), 6.53 (d, 1H, J=7.5 Hz), 3.87 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([CH3:12])=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].I[CH3:14].O>CN(C=O)C>[Cl:10][C:9]1[C:4]([NH2:3])=[C:5]([CH3:12])[C:6]([O:11][CH3:14])=[CH:7][CH:8]=1
Reactant: Cc1c(O)ccc(Cl)c1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
NaH, 60% (0.236 mol) was stirred in DMF (500 ml), at room temperature. 3-amino-4-chloro-2-methylphenol (0.236 mol) was added portionwise (exothermic temperature rise to 32° C.). The reaction mixture was stirred for 30 minutes, allowing the temperature to drop to room temperature. Iodomethane (0.236 mol) was added dropwise. The reaction mixture was stirred for one hour at room temperature. Water was added (at first, slowly). This mixture was extracted with toluene. The separated organic layer was dried, filtered and the solvent evaporated, yielding 40.5 g 6-chloro-3-methoxy-2-methylbenzenamine (interm. 22) (quantitative yield; used in next reaction step, without further purification).
Reaction SMILES: C([O-])(=O)C(C)(C)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Zn+])=[CH:11][CH:10]=1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:21]=[O:22])=[CH:11][CH:10]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COc1ccc(C=O)cc1Br
Agent: CC(C)(C)C(=O)[O-]
Product: COc1ccc(C=O)cc1Cc1ccc(F)cc1
Yield: 82 %

Procedure:
(4-Fluorobenzyl)zinc pivalate (11) shows a clean coupling reaction with 3-bromo-4-methoxybenzaldehyde (5m) and afford 3-(4-fluorobenzyl)-4-methoxybenzaldehyde (6s) in 82% yield without observance of any addition products towards the aldehyde functionality (entry 19).
Reaction SMILES: [C:1](#N)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-:22].[Al+3].[OH-].[OH-]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1](=[O:22])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC=Cc1ccccc1
Reactant: [OH-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of 8 g cinnamonitrile in 100 ml tetrahydrofuran, was added dropwise 50 ml of a 1.5M toluene solution of diisobutylaluminum hydride with ice cooling, and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was slowly poured to 200 ml ice water, hydrochloric acid was then added to dissolve the aluminum hydroxide formed, and the organic layer was collected and dried. Distillation of the dried solution under reduced pressure gave 5.2 g (yield: 63.6%) of cinnamaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:13])[C:5](=[O:12])[N:6]2[CH3:11].[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:14][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:13])[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CC1C(=O)N(C)c2cccc(O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cccc2c1C(C)C(=O)N2C
Yield: 86.2 %

Procedure:
A slurry of 1,3-dihydro-4-hydroxy-1,3-dimethyl-2H-indol-2-one (50 g), milled potassium carbonate (60.1 g) and HPLC grade acetone (400 ml) was mechanically stirred at room temperature as dimethylsulfate (41.4 ml) was added dropwise. The addition funnel was replaced with a condenser and the slurry was refluxed for 18 hours. The K2CO3 was filtered off and washed well with acetone. Acetone was evaporated and the residue was purified by column chromatography to yield 46.5 g of an oil. The oil was dissolved in ether and placed in the refrigerator where, upon standing overnight, the product crystallized, m.p. 73°-74° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.056 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 155-157° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:3]1=2.[C:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([OH:27])=[O:26].[OH-].[K+]>>[O:16]=[C:14]([C:6]1[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)/[CH:15]=[CH:32]/[C:31]1[CH:34]=[CH:35][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 72 %

Procedure:
In a similar manner to that of Example 2b, by reacting 770 mg (2.4 mmol) of 1-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)ethanone with 320 mg (2.2 mmol) of 4-carboxybenzaldehyde and 1.2 mL (10 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m=780 mg; yield=72%; m.p.=242° C.).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[CH3:16][N:17]([C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=1)[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][N:17]([CH3:18])[C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][CH:20]=1)[C:25]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:26]
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OC(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 67.1 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (4.00 g, 92% pure, 17.5 mmol), 3-N,N-dimethylaminobenzoic acid (3.13 g, 19.0 mmol), and DMAP (1.85 g, 15.2 mmol) in CH2Cl2 (50 ml) was added N,N′-dicyclohexylcarbodiimine (DCC) (4.31 g, 20.9 mmol) in CH2Cl2 (15 ml). The reaction medium was stirred at room temperature for 70 h. Then, the mixture was acidified with concentrated HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar) and purified by flash-chromatography over SiO2 (cyclohexane/AcOEt=97:3). 4.20 g of product were thus obtained (yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 70 °C
Yield: 93.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with trimethylsilyl acetylene (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trimethylsilanylethynyl-phenyl)-propionic acid methyl ester (615 mg, 93.6%) as an orange solid: mp 72-74° C.; EI-HRMS m/e calcd for C20H28O2Si (M+) 328.1858, found 328.1852.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]#[C:14][CH2:15][N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:16]([CH2:15][C:14]#[C:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CC#CCN2c3ccccc3CCc3ccccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CC#CCN2c3ccccc3CCc3ccccc32)C1
Reaction time: 72 h
Yield: 55.2 %

Procedure:
The above ester (3.5 g, 8.7 mmol) was dissolved in ethanol (40 ml). 5 N Sodium hydroxide (4 ml) was added and the mixture was allowed to stand for 3 days. Ethanol was evaporated in vacuo and the residue was dissolved in water (50 ml). The solution was washed with diethyl ether (30 ml) and acetic acid (3 ml) was added to the aqueous phase which subsequently was extracted with dichloromethane (50 ml). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was filtered through silica gel (20 g) using ethanol as eluent. The solvent was evaporated and acetone was added to the residue. The solid was isolated by filtration and dried to give 1.8 g (55%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:6]2[CH2:7][CH2:8][C:4]([C:3]([F:2])([F:13])[F:14])([C:9]([O:11][CH3:12])=[O:10])[CH2:5]2)=[N:29][CH:30]=1
Reactant: COC(=O)C1(C(F)(F)F)CCNC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCCCCC
Product: COC(=O)C1(C(F)(F)F)CCN(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a solution of methyl 3-(trifluoromethyl)pyrrolidine-3-carboxylate hydrochloride (0.32 g, 1.36 mmol) in EtOH (10.0 mL) was added DIPEA (1.1 mL, 6.79 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.26 g, 1.36 mmol). The reaction was heated up to 70° C. for 1 h. After reaction completion (by TLC), the solvent was evaporated and the crude residue purified over 60-120 M silica-gel using 10.0% EtOAc:hexane to obtain the desired product as a yellow solid (0.30 g, 63% yield). MS: 354.02 [M+H]+.