Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH3:31])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and iodoethane (38 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo. The residue was then purified by preparative HPLC to yield the desired morpholine example 28 as a colorless oil (17 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1ccc2nc(-c3ccc(F)cc3)oc2c1
Yield: 81 %

Procedure:
4-Aminoresorcinol HCl salt (1.61 g) is dissolved in 10 ml of NMP under nitrogen atmosphere. 4-Fluorobenzoyl chloride (1.91 g) is added all at once and the mixture is heated under reflux for approximately 2 hours. After reflux, the mixture is allowed to cool and is diluted with 60 ml of water. Potassium carbonate (3.5 g) is added and the mixture is stirred. The resulting precipitate is filtered and recrystallized from ethanol and water to yield 1.85 g of the above-named product. The product melts at 225° C.-227° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8]P(=O)(OCC)OCC)=[O:7])[CH3:4].C[CH2:18][CH2:19][CH:20]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)C.Cl.O1CC[CH2:34][CH2:33]1>>[CH2:3]([O:5][C:6](=[O:7])[CH:8]=[C:33]([C:28]1[CH:27]=[CH:26][C:25]([CH2:23][CH2:22][CH2:20][CH2:19][CH3:18])=[CH:30][CH:29]=1)[CH3:34])[CH3:4]
Reactant: CCCC(C)CC(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCCc1ccc(C(C)=CC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (28.6 g, content: 63%) was suspended in tetrahydrofuran (1000 ml). Diethyl ethoxycarbonylmethylphosphonate (168 g) dissolved in tetrahydrofuran (500 ml) was added dropwise into the mixture with cooling in an ice-bath over 30 mins. 4-Pentylacetophenone (95 g) in tetrahydrofuran (500 ml) was added to the solution. The solution was stirred overnight at a room temperature and then refluxed at 8 hrs. Tetrahydrofuran was evoporated from the reaction mixture. Diluted hydrochloric acid was added to the residue. The acidic solution was extracted with ethyl acetate. The ertract was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=99:1→98:2→95:5) to give the title compound (128 g) having the following physical data:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved in 80 ml of carbon tetrachloride. A solution of 3.80 g (21.1 mmol) of bromine dissolved in 10 ml of carbon tetrachloride was delivered dropwise into that reaction solution by a dropping funnel. After the dropping was complete, the mixture was stirred for 1 hour at room temperature. After the reaction, a sodium thiosulfate solution was added to stop the reaction. An organic layer was washed with a NaOH solution and a saturated saline solution, and dried with magnesium sulfate. After natural filtration, concentration and dissolving in toluene were conducted. Then, filtration was done through Florisil, Celite and alumina. The filtrate was concentrated, then recrystallized with dichloromethane and hexane. The target substance, 9-bromo-10-phenylanthracene, was obtained in the form of a pale yellow solid, weighing 7.0 g in a yield of 89% (synthesis scheme (j-4)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+]([O-])=O)[CH:11]=2)[N:6]2[C:16]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:5]=12.[Cl:28]CCC1C2C(=CC=CC=2C(F)(F)F)N2C(C3CCCCC3)=NC(C)=C(C)C=12>>[Cl:28][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]1[C:16]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:5]1=[C:4]2[CH2:3][CH2:2][Cl:1]
Reactant: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1cc([N+](=O)[O-])ccc12
Reactant: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1c(C(F)(F)F)cccc12
Product: Cc1nc(C2CCCCC2)n2c(c1C)c(CCCl)c1cc(Cl)ccc12

Procedure:
5-(2-chloroethyl)-1-cyclohexyl-3,4-dimethyl-7-nitropyrimido[1,6-a]indole and 5-(2-chloroethyl)-1-cyclohexyl-3,4-dimethyl-6-trifluoromethylpyrimido[1,6-a]indole.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].N[C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([C:39]([NH:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([O:50][C:51]4[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[C:53]([Cl:59])[CH:52]=4)[C:44]=3[F:60])=[O:40])[NH:36]2)=[CH:32][CH:31]=1.[CH3:61][C:62]([O:65][C:66]([NH:68][CH2:69][C:70]([OH:72])=O)=[O:67])([CH3:64])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:39]([C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([NH:8][C:70](=[O:72])[CH2:69][NH:68][C:66](=[O:67])[O:65][C:62]([CH3:64])([CH3:63])[CH3:61])=[CH:30][CH:38]=3)=[O:40])=[C:44]([F:60])[C:45]=1[O:50][C:51]1[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[C:53]([Cl:59])[CH:52]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(N)cc4[nH]3)c2F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
BOP chloride (0.085 g, 0.334 mmol) was added to a solution of 6-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide (0.065 g, 0.111 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (0.0195 g, 0.111 mmol) and diisopropylethylamine (0.097 mL, 0.557 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr, then extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.031 g, 80% pure). ES MS: m/z 624 (M−1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccccc1)c1cccs1
Product: CN(C)C=C(C(=O)c1cccs1)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-Phenyl-1-(thiophen-2-yl)ethanone (1 g, 4.94 mmol) was treated with dimethylformamide dimethylacetal (5 mL) and heated to 100° C. while stirring. After 4 h, the reaction was allowed to cool down to room temperature. The solid that precipitated out of the reaction mixture was collected by filtration and washed with a 1:1 mixture of diethyl ether and hexanes to afford a yellow crystalline solid (1 g). MS (M+H)+ 258.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7]1.[CH2:23]([NH:26][C:27]1[CH2:31][S:30][C:29](=[O:32])[N:28]=1)[C:24]#[CH:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8](/[CH:11]=[C:31]2/[C:27]([NH:26][CH2:23][C:24]#[CH:25])=[N:28][C:29](=[O:32])[S:30]/2)[CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]pyrrolidine-3-carbaldehyde (1.1 g) in 2-propanol (10 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.782 g) and piperidinium acetate (0.491 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.760 g).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 81.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (4.3 g) and 3-pyridinebutanamine (1.51 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual fashion. The crude product was crystallized from ethyl acetate-hexane to provide 3.6 g of (E)-5,5-bis(4-methoxyphenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 76°-77° C. Anal. Calculated for C28H30N2O3 : C, 75.99; H, 6.83; N, 6.33 Found: C, 76.36; H, 6.97; N, 6.35.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18].C(Cl)CCl>C1COCC1>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of Boc-Aze-OH (5 g, 25 mmol) and HOSu (2.88 g, 25 mmol) in 25 ml of THF was cooled on an ice bath EDC (4.3 ml, 25 mmol) was added and the solution was stirred overnight. It was evaporated, dissolved in ethyl acetate, washed with KHSO4 (aq, 0.3 M), Na2CO3 (aq, 10%), dried (MgSO4) and evaporated. Crystallization from ethyl acetate:petroleum ether afforded 3.78 g (51%) of sub-title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:12][N+:13]([O-:15])=[O:14].[Cl-:16].C[NH2+]C.[F-].[K+]>C1(C)C(C)=CC=CC=1.ClCCl.O>[Cl:16]/[C:12](/[N+:13]([O-:15])=[O:14])=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])CBr
Reactant: CCc1ccc(C=O)cc1
Agent: C[NH2+]C
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1C
Solvent: O
Product: CCc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Reaction time: 15 h

Procedure:
Analogously to the literature method [D. Dauzonne, Synthesis, 1990, 66-70], stir a mixture of 10.0 g (74.5 mmol) of 4-ethylbenzaldehyde, 6.8 ml (13.7 g, 97.6 mmol) of bromonitromethane, 54.7 g (670.7 mmol) of dimethylammonium chloride and 0.6 g (11.2 mmol) of potassium fluoride in 150 ml of xylene on a water separator at 160° C. for 15 hours and then at 175° C. for seven hours. After adding 25 ml of water and 100 ml of dichloromethane, remove the organic phase and extract the aqueous phase three times with 100 ml of dichloromethane each time. Dry the combined organic extracts over sodium sulphate, filter and concentrate under reduced pressure. Chromatograph the residue on silica gel (eluent: cyclohexane/dichloromethane 1:1). 11.9 g (85% purity, 64% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([C@H:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@H:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: N[C@H](Cc1ccccc1)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N[C@H](Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in a yield of 82% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (R)-1,2-diphenylethylamine.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([F:26])[C:11]=1[F:27]>O1CCCC1>[Br:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[C:13]([C:14]([C:16](=[CH:3][N:4]([CH3:5])[CH3:6])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([F:26])[C:11]=1[F:27]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(F)c(Br)c(F)c1F

Procedure:
Dimethylformamide dimethylacetal (11.85 g) was added to a solution of 33.63 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate in 100 ml tetrahydrofuran cooled in an ice-bath. The reaction mixture was then immersed in a warm water bath in order to drive it to completion. The resulting solution was used directly in the next reaction.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[C:10](OC)=[C:9]([C:19]#[CH:20])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(N(CC)CC)C.[C:41](OCC)(=[O:43])C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:20]#[C:19][C:9]2[CH:8]=[C:7]([O:43][CH3:41])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=3[CH:10]=2)=[CH:28][CH:27]=1
Reactant: C#Cc1ccc2c(c1OC)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063 g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.093 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.09 g, 90%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O-:13])([O-])=O.[K+].[K+].ClC1[S:18][C:19]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:20]=2[N:21]=1.[OH-].[Na+].C(OC(C)C)(=O)C>CC#N>[CH3:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:10]([O:13][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][OH:9])=[CH:4][CH:5]=3)[S:18][C:19]=2[CH:25]=1
Reactant: OCCc1ccccc1
Reactant: Cc1ccc2nc(Cl)sc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: Cc1ccc2nc(Oc3ccc(CCO)cc3)sc2c1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of phenethyl alcohol (3.15 g, 22.86 mmol) and K2CO3 (5.26 g, 38.1 mmol) in CH3CN (35 mL) was added 2-chloro-6-methylbenzothiazole (3.5 g, 19.1 mmol). The reaction mixture was heated at 80° C. for 16 h. To the reaction mixture was added 1 N NaOH (30 mL) and isopropyl acetate (40 mL). The layers were separated and the aqueous layer was extracted with isopropyl acetate (2×30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (20% to 90% EtOAc in hexanes) to afford the title compound (3.4 g, 63%). 1H NMR (500 MHz, CDCl3): 7.61 (d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.33-7.28 (m, 4H), 7.20 (d, J=8.3 Hz, 1H), 3.87 (br s, 2H), 2.90 (t, J=6.6 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].BrC1C=CC=CC=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][C:13]1=[CH2:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:16](=[O:17])[CH2:15][C:13](=[CH2:14])[C:12]([OH:18])=[O:19])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: C=C1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Brc1ccccc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 50 g of bromobenzene and the mixture is cooled to 0° C. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 0° C. for two hours and then added to 100 g of ice water. The solid reaction product is filtered off and washed twice with water (50 ml). After recrystallization from ethyl acetate, the product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 50% as a colorless, finely crystalline powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:11]#[N:12].[NH4+].[Cl-]>N1C=CC=CC=1.N>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([C:11]#[N:12])[CH:7]=[N:6][CH:5]=1
Reactant: N#C[Cu]C#N
Reactant: OCc1cncc(Br)c1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: N#Cc1cncc(CO)c1
Temperature: 160 °C
Yield: 71.1 %

Procedure:
A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160° C. After cooling to room temperature, the medium is taken up in 10 mL of concentrated aqueous ammonia and 30 mL of saturated NH4Cl solution and then stirred for 2 hours. The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nnc2n1-c1ccc(NO)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.55 g (0.01 m) of 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, 200 ml of tetrahydrofuran, 100 ml of methanol, 13.6 g of sodium acetate trihydrate and 12 g of stannous chloride dihydrate was stirred at room temperature for 1 hr under nitrogen atmosphere. After addition of 5 ml of conc. aqueous ammonia the inorganic material was separated by filtration over celite. The filter cake was washed with 500 ml of methylene chloride containing 20% of ethanol. The filtrate was evaporated and the residue was stirred with 100 ml of water and 30 ml of methylene chloride. The crystalline material was collected and washed successively with water, ethanol and ether to yield the above-named product. For analysis it was recrystallized from tetrahydrofuran/methanol, mp. 276°-278° dec.
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[C@]1(C(=O)C)O)(=O)C.[ClH:38]>C(#N)C>[ClH:8].[ClH:38].[CH2:1]([N:21]1[C:22]2[C:23](=[O:24])[NH:25][C:26]([NH2:27])=[N:28][C:29]=2[N:19]=[CH:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
Benzyl chloride (2.14 ml, 10.0 equivalents) was added to 3.21 g of an acetonitrile solution containing 0.76 g (corresponding to 1.86 mmols) of triacetylguanosine obtained in Example 1, and the mixture was reacted at 70° C. for 71 hours. The temperature was returned to room temperature, and 3.13 ml (20 equivalents) of conc. hydrochloric acid were added thereto. When the mixture was reacted for 3 hours, the solid was precipitated. Ten milliliters of methanol were added thereto, and the slurry was stirred for 2 hours, and then filtered. The crystals were washed twice with 5 ml of methanol, and dried at 50° C. under reduced pressure for 2 hours to give 0.413 g of crystals in a yield of 70.9%.