Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(F)c1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Yield: 70.4 %

Procedure:
Prepared according to Procedure B with 1e (500 mg, 1.89 mmol) and chloroacetyl chloride (0.45 mL, 5.67 mmol) in acetic acid (10 mL). Purified by extraction from aq. K2CO3 and recrystallization from isopropanol to afford 430 mg of an off-white crystalline solid (70%). 1H NMR (CDCl3) δ: 7.76 (dt, J=5.3, 8.2 Hz, 1H); 7.56-7.65 (m, 2H); 7.47-7.56 (m, 3H); 7.16-7.25 (m, 1H); 4.35 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[C:18]([CH:19]3[CH2:21][CH2:20]3)=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([O:22][CH:23]([CH3:25])[CH3:24])[CH:10]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[C:18]([CH:19]3[CH2:21][CH2:20]3)=[CH:17][C:12]([CH2:13][OH:14])=[C:11]([O:22][CH:23]([CH3:25])[CH3:24])[CH:10]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1cc(C2CC2)c(C2CC2)cc1OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1CO
Yield: 98.5 %

Procedure:
A THF (15 mL) solution of methyl 4,5-dicyclopropyl-2-isopropoxybenzoate (5.90 g) was added at 0 C to a mixture of lithium aluminum hydride (1.71 g) and THF (85 mL), and the resultant mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Water (1.8 mL), a 1 M aqueous sodium hydroxide solution (1.8 mL), and water (5.4 mL) were added in this order to the reaction mixture at 0 C. The mixture was filtered through celite, and then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to obtain the title compound (5.22 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([O:24][CH:25]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[OH:30][CH:27]1[CH2:28][CH2:29][CH:25]([O:24][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:23]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(OC3CCC(O)C3)c3ccccc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: OC1CCC(Oc2nc(N3CCNCC3)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (10 ml) is added to 2-[4-(t-butoxycarbonyl)piperazin-1-yl]-4-[(3-hydroxycyclopentan-1-yl)oxy] quinazoline (0.95 g), and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is evaporated to dryness under reduced pressure, and the resulting residue is dissolved in ethyl acetate. The solution is washed with aqueous sodium hydrogen carbonate solution and then with water, and dried over anhydrous sodium sulfate, and then is evaporated to dryness under reduced pressure to give 4-[(3-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (0.55 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([Br:32])[CH:30]=[CH2:31].Br>C(OCC)(=O)C.O.CN(C)C=O>[BrH:32].[CH2:31]([N:20]1[CH2:19][CH2:18][N:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)[CH2:22][CH2:21]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCN1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 2.6 g of potassium carbonate, 2.2 g of allyl bromide, and 75 ml of dimethylformamide was stirred at 70°-75° for 16 hours, and then at ambient temperature for 48 hours. The mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to produce an oil. The oil was dissolved in ethyl acetate and a saturated solution of hydrogen bromide in ethyl acetate was added, dropwise, until the solution was acidic. A precipitate was formed and collected. Recrystallization of the precipitate from ethanol gave 2.3 g (33%) of 3-[4-(2-propenyl)-1-piperazinyl)-1-(4-fluorophenyl)-1H-indazole hydrobromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[F:71][C:72]([F:85])([F:84])[O:73][C:74]1[CH:79]=[CH:78]C(S(Cl)(=O)=O)=[CH:76][CH:75]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:78]=[CH:79][C:74]([O:73][C:72]([F:85])([F:84])[F:71])=[CH:75][CH:76]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)c(=O)n32)cc1
Yield: 41.6 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-(trifluoromethoxy)benzene sulfonyl chloride (39.6 mg, 0.152 mmol) yielded 31.7 mg (41.6%) of 33a. MS (ESI) 651.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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.CCOC(C)=O>[CH3:11][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:12]([OH:14])=[O:13])[CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(C(=O)O)c2)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 96 h
Yield: 36.8 %

Procedure:
To a solution of 2-bromo-5-methylbenzoic acid (5.00 g, 23.3 mmol) in DME (100 mL) were added 3-carboxyphenylboronic acid (3.86 g; 23.3 mmol), a solution of Na2CO3 (9.90 g, 93 mmol) in H2O and tetrakis(triphenylphosphine)palladium. The mixture was stirred at 90° C. for 4 days. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), and washed with a saturated NaHCO3 solution. The aqueous layer was separated, acidified with 10% HCl, and extracted with EtOAc (3×20 mL). The combined extracts were dried over MgSO4 and concentrated. The crude material was purified by column chromatography (9:1 hexanes/EtOAc 1% acetic acid) to afford 4-methyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid (2.20 g, 37%) as a solid: H NMR (DMSO-d6) δ 2.40 (s, 3H), 7.30 (m, 1H), 7.42 (m, 1H), 7.52-7.57 (m, 2H), 7.60 (s, 1H), 7.85 (s, 1H), 7.91-7.92 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[N:39]1[CH:44]=[CH:43][C:42]([CH2:45]Cl)=[CH:41][CH:40]=1.O>O1CCCC1.CN(C)C=O>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:45][C:42]4[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(Cc4ccncc4)CC3)cc2C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) were added 9.1N sodium hydroxide (0.068 ml) and 4-picolyl chloride hydrochloride (51 mg), and the mixture was stirred at 50° C. for 5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1) and dried under reduced pressure to give the title compound (93 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:33]
Reactant: Cc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCOc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A solution of 294 mg (1 mmol) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was treated with 40 mg (1 mmol) of 60% NaH/mineral oil and after 1 hour, 0.15 mL (1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 2 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/hexane to give a total of 235 mg (58% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid ethyl ester, mp, 115-116° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[C:29]12([N:39]=[C:40]=[O:41])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][N:17]([C:40]([NH:39][C:29]23[CH2:38][CH:33]4[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]4)[CH2:36]2)[CH2:30]3)=[O:41])[CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1
Yield: 90.7 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]azetidine (157) (100 mg, 0.30 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (3.01 mmol/g; 100 mg, 0.30 mmol) and 1-adamantyl isocyanate (55 mg, 0.30 mmol). The resultant mixture was shaken at ambient temperature for 5 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. Elution with DCM (6 mL) followed by DCM-MeOH (6 mL), then removal of solvent in vacuo afforded the desired product as a white foam (140 mg, 92%).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)#[CH:20]>CN(C)C=O.C(N(CC)CC)C.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>[CH2:16]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:4](=[CH:3][C:2]([C:20]#[C:19][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=4)=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=2[CH:8]=1)[CH2:17][CH3:18]
Reactant: CCCc1ccc2c(ccc3cc(I)ccc32)c1
Reactant: C#Cc1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1ccc2c(ccc3cc(C#Cc4ccc(F)c(F)c4)ccc32)c1

Procedure:
2-iodo-7-propyl-phenanthrene in dimethylformamide and triethylamine was reacted with 4-ethynyl-1,2-difluorobenzene in the presence of tetrakis(triphenylphosphine)palladium (0), and the product was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol to yield 2-propyl-7-(3,4-difluorophenylethynyl)phenanthrene.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 50 °C
Yield: 37.6 %

Procedure:
(L)-Arginine (103.2 g., 0.6 mole) was dissolved in 600 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (87 mL, 0.6 mole) was added dropwise to the mixture. The reaction mixture was maintained at 50° C. for 2 hours. The mixture was then cooled to room temperature and acidified to pH 2.3 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide and dried by lyophilization to furnish 64.1 g of crude N-cyclohexanoyl-(L)-arginine. The product was purified by column chromatography on silica gel using butanol/acetic acid/water as the eluent system. The products isolated were N-cyclohexanoyl-(L)-arginine and N(α)-N (γ)-dicyclohexanoyl-(L)-arginine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:22][N:15]([C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(c1ccccc1)c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(C)c2ccccc2)ncn1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.14 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.36 g of 4-chloro-6-(N-methyl-N-phenylamino)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 6 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of 4-(N-methyl-N-phenylamino)-6-(2-butynyloxy)pyrimidine (the present compound (93)), m.p.: 57.6° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC#CC)ncn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.27 g of sodium hydride (60% in oil), to which 0.7 ml of a tetrahydrofuran solution containing 0.41 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was then stirred at room temperature for 20 minutes, to which 0.7 ml of a tetrahydrofuran solution containing 0.4 g of 4,6-dichloropyrimidine was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.39 g of 4,6-bis(2-butynyloxy)pyrimidine (the present compound (1)), m.p.: 82.9° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[Si:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[Br:9][C:4]1[CH:3]=[C:2]([Si:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
Into a solution of 1,3,5-tribromobenzene (9.0 g, 28.6 mmol) in diethyl ether (200 mL) was added n-butyllithium solution in hexane (2.5 M, 12 mL, 30.6 mmol) dropwise at −78° C. The reaction was stirred at this temperature for 30 minutes before a solution of chlorotriphenylsilane (9.27 g, 31.4 mmol) in diethyl ether (90 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature and continue to stir overnight, and finally refluxed for 2 hours. After cooling to room temperature, the solid was filtered off. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3,5-dibromophenyl)triphenylsilane (4.0 g, 28%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[F:22].O>C1COCC1.CO>[Br:11][C:12]1[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(Br)cc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of 2-chloropyrimidin-4-amine (1.31 g, 10.08 mmol) in THF (55 mL) at 0° C. was added sodium hydride (60% in oil, 806.69 mg, 20.17 mmol) portion-wise. The reaction mixture was stirred at 0° C. to RT for 10 minutes and 1-bromo-2,5-difluoro-4-nitrobenzene (1.2 g, 5.04 mmol) was added. The reaction mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to RT and water (30 mL) was added. Product extracted into DCM (2×30 mL) and washed with water (20 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM:MeOH gradient (99:1 to 95:05) to afford the title compound as an orange solid (1005 mg, 56% yield); 1H NMR (250 MHz, DMSO) delta 6.87 (1H, d, J=5.83 Hz), 8.08 (1H, d, J=6.31 Hz), 8.18 (1H, d, J=8.35 Hz), 8.27 (1H, d, J=5.83 Hz), 10.32 (1H, br. s.); LC-MS: m/z+348.70 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.CO[C:15](=N)[C:16]([Cl:19])([Cl:18])[Cl:17]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]([C:16]([Cl:19])([Cl:18])[Cl:17])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (12.0 mmol) Methyl-3,4-diamino-benzoate were dissolved in 50 mL concentrated acetic acid. Then 2.09 mL (1.4 equiv.) methyl-2,2,2-trichloroacetimidate were added slowly and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with 100 mL toluene and the solvent was removed under reduced pressure. The residue was taken up in dichloromethane and washed once with a saturated NaHCO3-solution and once with brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give pure methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylate as a light brown amorphous solid. Yield: 3.64 g MS (ES+): m/e=293, chloro pattern.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:12]=3[Br:22])=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(cn1)[nH]c1c(Br)cc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.9 %

Procedure:
285 mg of 6-nitro-β-carbolin-3-carboxylic acid ethyl ester is introduced into 5.8 g of bromine and stirred for 2 days at room temperature. The mixture is then diluted with 15 ml of chloroform and filtered with suction. The residue is recrystallized from pyridine and chromatographed on silica gel with chloroform-methanol (9:1). 65 mg of 8-bromo-6-nitro-β-carbolin-3-carboxylic acid ethyl ester of melting point 291°-292° C. is obtained.
Reaction SMILES: CS(O[CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)(=O)=O.[Na].[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>CN(C=O)C>[NH2:15][C:16]1[N:17]=[N:18][N:19]([CH:6]2[CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[N:20]=1
Reactant: CS(=O)(=O)OC1CN2CCC1CC2
Reactant: Nc1nnn[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1nnn(C2CN3CCC2CC3)n1

Procedure:
3-Methanesulphonyloxy-1-azabicylo[2.2.2]octane (D8) (2.0 g, 9.7 mmol) and the sodium salt of 5-aminotetrazole (D15) (2.5 g, 2.0 eq) were dissolved in dry DMF (50 ml) and the reaction carried out as for Example 10. The product (E11) isolated from column chromatography was a white crystalline solid (124 mg, 6.6%), which was recrystallised from ether, m.p. 132-134° C.