Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[F:25][C:26]1[CH:39]=[CH:38][C:29]([O:30][C@@H:31]2[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32]2)=[CH:28][CH:27]=1>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:36][C@H:33]1[CH2:34][CH2:35][C@@H:31]([O:30][C:29]2[CH:38]=[CH:39][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:32]1
Reactant: O=C[C@H]1CC[C@@H](Oc2ccc(F)cc2)C1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(O[C@@H]2CC[C@H](C=C(Br)Br)C2)cc1
Reaction time: 5 h
Yield: 182.7 %

Procedure:
To a mixture of zinc dust (4.10 g, 63 mmol) and triphenylphosphine (16.5 g, 63 mmol) in CH2Cl2 (100 ml) was added carbon tetrabromide (20.9 g, 63 mmol). After stirring for 5 h, cis-3-(4-fluorophenoxy)cyclopentanecarbaldehyde (4.00 g, 9.2 mmol) was added to the mixture and the whole stirred overnight at room temperature (Tetrahedron Lett., 1972, 3769). The reaction mixture was filtered through a short colummn of silica gel and the filtrate concentrated in vacuo to afford 6.12 g (85%) of title compound as a light yellow oil: 1H NMR δ7.06-6.93 (m, 2H), 6.85-6.73 (m, 2H), 6.45 (d, J=9.2 Hz, 1H), 4.75-4.68 (m, 1H), 2.91-2.76 (m, 1H), 2.44-2.30 (m, 1H), 2.08-1.55 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)#[CH:2].CN(C)[CH2:19][CH2:20]N(C)C>CC(C)=O.[Cu]Cl>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[C:1]#[C:2][C:7]#[C:6][C:5]2[C:4]4[C:3]([CH:1]=[C:20]5[C:19]=2[CH:15]=[CH:14][CH:13]=[CH:12]5)=[CH:16][CH:11]=[CH:10][CH:9]=4)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1c2ccccc2cc2ccccc12
Reactant: CN(C)CCN(C)C
Agent: Cl[Cu]
Solvent: CC(C)=O
Product: C(C#Cc1c2ccccc2cc2ccccc12)#Cc1c2ccccc2cc2ccccc12
Reaction time: 2 h
Yield: 873 %

Procedure:
15 g (0.074 mol) of 9-ethynyl anthracene, 0.36 g (3.7 mmol) copper(I) chloride, 0.43 g (3.7 mmol) of N,N,N′,N′-tetramethylethylenediamine were put into a 500 ml round-bottomed flask equipped with a stirrer, and then dissolved in 200 ml of acetone. The resulting mixture was then vigorously stirred for two hours while purging oxygen gas, to give red-colored solid. After the reaction was completed, the solvent was mostly removed with a small amount remaining. The residue was then precipitated in 5% aqueous hydrochloric acid to obtain red-colored solid. The solid was filtered, washed sufficiently with water and ethanol, and then recrystallized from ethyl acetate, to give red-colored crystal. The red-colored crystal was recovered and then sufficiently dried in a vacuum oven at 40° C., to give 13 g (87.2% yield) of the desired product having a melting point of 280-282° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N>>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[NH2:9]
Reactant: Cc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: Cc1c(N)cc(Cl)cc1Br

Procedure:
This material was prepared from 1-bromo-5-chloro-2-methyl-3-nitrobenzene following the procedure used for SM-9, step 3 (96%): LCMS (m/z): 219.9 (MH+); tR=0.99 minute.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:16]=[CH2:17])(O)[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[BrH:20]>C(O)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:16][CH2:17][Br:20])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C=CC1(O)c2ccccc2CCc2cc(Br)ccc21
Reactant: Br
Solvent: CC(=O)O
Product: BrCC=C1c2ccccc2CCc2cc(Br)ccc21
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A suspension of the above alcohol (1.1 g, 3.49 mmol) in acetic acid (10 mL) was stirred and treated at 15° C. with 15% solution of hydrogen bromide in acetic acid (7 mL) over 15 min. The mixture was stirred at 15° C. for 30 min and then at laboratory temperature for 1.5 h and evaporated in vacuo. The rest of acetic acid was removed by addition of 40 mL xylene and evaporation in vacuo and the residue was chromatographed in a short column of silica gel Fluka 60 (50 g, benzene). The benzene solutions were evaporated in vacuo to yield 1.25 g (95%) of 2-bromo-5-(2-bromo-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: BrC1C=CC(C[N:7]([S:36]([CH3:39])(=[O:38])=[O:37])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][O:27]C2CCCCO2)[CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=CC=1.O1CCCCC1OC([C@H]([C@@H](CC(C)C)C(NNS(C)(=O)=O)=O)C/C=C/C1C=CC=CC=1)=O.[Br:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79]Br)=[CH:77][CH:76]=1>>[Br:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][C@@:10]([C@@H:15]([C:25](=[O:34])[NH:26][OH:27])[CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([NH:8][NH:7][S:36]([CH3:39])(=[O:37])=[O:38])=[O:35])=[CH:77][CH:76]=1
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1ccc(Br)cc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)OC1CCCCO1
Product: CC(C)C[C@](Cc1ccc(Br)cc1)(C(=O)NNS(C)(=O)=O)[C@H](CC=Cc1ccccc1)C(=O)NO

Procedure:
The (E)-2′-(4-bromobenzyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbanoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide by reaction with 4-bromobenzyl bromide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1>C(O)CC>[CH2:1]([NH:4][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:23]1)[CH2:2][CH3:3]
Reactant: Clc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Reactant: CCCN
Solvent: CCCO
Product: CCCNc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Yield: 74 %

Procedure:
50 ml of n-propylamine are added to a solution of 11.6 g (0.03 mole) of 6-chloro-9-[3-(4-phenoxymethylpiperidino)-propyl]-purine in 100 ml of n-propanol and the reaction mixture is heated under reflux for 6 hours. It is then evaporated in a vacuum and the residue extracted with diethyl ether. After evaporation of the solvent and recrystallization of the residue from cyclohexane, there are obtained 9.1 g of N6 -n-propyl-9-[3-(4-phenoxymethylpiperidino)-propyl]-adenine (74% of theory); m.p. 62° - 63° C.
Reaction SMILES: [C:1]1(=[CH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=O)[C:9](=[O:15])[NH:10]3)[CH2:4][CH2:3][CH2:2]1.IC1C=CC=C2C=1C(=O)C(=O)N2.C=C1CC=C1.[CH:34]1[C:39]([NH:40][NH2:41])=[CH:38][CH:37]=[C:36]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:35]=1.Cl>>[C:1]1(=[CH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=[N:41][NH:40][C:39]2[CH:38]=[CH:37][C:36]([S:42]([NH2:45])(=[O:43])=[O:44])=[CH:35][CH:34]=2)[C:9](=[O:15])[NH:10]3)[CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cccc(C=C3CCC3)c2C1=O
Agent: C=C1C=CC1
Agent: Cl
Agent: O=C1Nc2cccc(I)c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=C4CCC4)c32)cc1
Yield: 76 %

Procedure:
By methods described in Procedure L, 4-cyclobutylidenemethyl-1H-indole-2,3-dione was prepared from 4-iodo-1H-indole-2,3-dione and methylene cyclobutene in 25% yield: 1H NMR (DMSO-d6): δ2.08 (quintet, J=7.8 Hz, 2H), 2.91 (m, 2H), 3.06 (m, 2H), 6.67 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 11.00 (bs, 1H); APCI−MS m/z 211 (M−1)−. Condensation of 4-(cyclobutylidenemethyl)-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 76% yield: 1H NMR (DMSO-d6): δ2.11 (quintet, J=7.8 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 3.06 (t, J=7.8 Hz, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.97 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 11.12 (s, 1H), 13.03 (s, 1H); APCI−MS m/z 381 (M−1)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:38])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH3:31])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=2)([OH:38])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH3:31])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Ic1ccc(I)cc1
Reactant: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(c1ccccc1)C(O)(c1ccc(I)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 108.2 %

Procedure:
A solution of 23.4 g of 1,4-diiodobenzene in 124 ml of tetrahydrofuran is mixed drop by drop at -70° C. under nitrogen with 45 ml of a 1.6 molar butyllithium solution, and it is stirred for 5 more minutes. Then, a solution of 18 g of 1-(4-benzyloxy-phenyl)-2-phenyl-butan-1-one [D. W. Robertson; J. A. Katzenellenbogen; D. J. Ellen; A. Rorke; B. S. Katzenellenbogen, J. Steroid Biochem., 1982, 16, 1-13] in 180 ml of tetrahydrofuran is added in drops, allowed to come to room temperature by completing the cooling, and it is stirred for 1 more hour. For working-up, 60 ml of saturated ammonium chloride solution is added, diluted with diethyl ether, washed neutral with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with pentane/diethyl ether. 31.5 g of 1-(4-benzyloxy-phenyl)-1-(4-iodophenyl)-2-phenyl-butan-1-ol is obtained as oil.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][NH2:32])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCc1cccnc1
Product: CCCc1c(OCCCCCC(=O)NCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 3-pyridine propanamine according to procedure A and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[3-(3-pyridinyl)propyl]hexanamide the title compound, mp 83°14 85° (from methylene chloride-ether) in 87% yield.
Reaction SMILES: [N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:20])[C:5](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].[OH2:28].OO.[OH-].[Li+]>C1COCC1>[N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:20])[C:5]([OH:6])=[O:28])=[N+:2]=[N-:3]
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the product from Step C (0.88 g, 2.39 mmol) in THF (30 mL) was added water (10 mL). The solution was stirred at 0° C. for 15 min, and then 30% hydrogen peroxide (1.60 mL, 14.3 mmol) was added followed by slow addition of lithium hydroxide (0.17 g, 7.23 mmol). The resultant mixture was stirred at 0° C. for 4 h. The reaction was quenched by addition of saturated aqueous sodium sulfite solution and stirred at room temperature for 30 min. The aqueous phase was separated and extracted with three portions of dichloromethane. The aqueous phase was then acidified to pH 1 with 3N hydrochloric acid and extracted with three portions of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give the product, which was used in the next step directly. LC/MS 224.1 (M+1).
Reaction SMILES: [CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)#[CH:30]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:30][CH2:29][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#Cc1cccnc1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2cccnc2)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1

Procedure:
To a solution of 0.1 g 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 2.0 ml of TEA is added at room temperature 0.015 g of bis (triphenylphosphine) palladium(II) chloride, 0.002 g cuprous iodide and 0.034 g meta-ethynylpyridine. The mixture is treated at 100° C., 1½ hours at the microwave. The starting material is consumed, as evidenced by HPLC. To the mixture is 1N HCl solution in water and ethyl acetate. The organic layer is washed with sodium bicarbonate and sodium chloride 10% solution in water. The residue is purified by chromatography in silica gel. The intermediate was hydrogenated under a hydrogen atmosphere in the presence of palladium on charcoal to yield after filtration and evaporation of the solvent the title compound as off-white oil, MS (ISP) 487.3 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[BrH:21].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:1]([Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Br
Reactant: CCCCCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Yield: 51 %

Procedure:
To nonadecanol (1.0 g, 3.5 mmol) was added 1500 μL hydrobromic acid (48% wt/vol). After cooling in ice, concentrated sulfuric acid (400 μL) was added and the reaction was allowed to warm to room temperature. A condenser and drying tube were placed over the reaction and the mixture was slowly heated to 120° C. The solution was kept at reflux for five hours and then cooled. The solidified product was resuspended in a mixture of ethyl acetate (50 mL) and water (10 mL). The aqueous layer was removed and the organic layer was washed with water (2×10 mL), then 5% sodium bicarbonate (10 mL) and then one final time with water. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed to provide a crude product which was purified by silica chromatography (hexanes:ethyl acetate, 80:20, as eluant) to give the desired 1-nonadecyl bromide (624 mg, 1.79 mmol, 51%). 1H NMR (CDCl3 , 300 MHz); δ3.40 (t, J=6.9 Hz, 2H), 1.83 (m, 2H), 1.41 (br s, 2H), 1.25 (s, 32H), 0.87 (t, J=6.7 Hz). 13C NMR (CDCl3' 67.93 MHz); δ33.94 32.83, 31.90, 29.65, 29.52, 29.42, 29.33, 28.75, 28.16, 22.66, 14.07. M.S. (EI+); 346 (M+), 267 (M-Br).
Reaction SMILES: [C:1]1([CH:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:30]2[O:34][C@H:33]([C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:48]1([S:54](Cl)(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:1]1([CH:7]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[S:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:56])=[O:55])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:30]2[O:34][C@H:33]([C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCNC(C)C)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN(C(C)C)S(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared from (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (80 mg, 0.12 mmol) (Preparation 12) and benzenesulphonyl chloride (0.0017 ml, 0.14 mmol) by a similar method to that of Example 8.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:21])[N:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]3=[N:14]2)=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>CO>[C:6]([C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:21])[N:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]3=[N:14]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2c(=O)n3c(nc2c1)CNCC3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2c(=O)n3c(nc2c1)CNCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 9-((trimethylsilyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (120 mg) in MeOH (50 mL) was added 1 N KOH (2 mL). The mixture was stirred at room temperature for 1 h. Then the reaction mixture was adjusted pH to 8 and extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4 and concentrated to give the desired product (60 mg), which was purified by column chromatography. MS (ESI): 226 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])[CH:12]2[CH:7]([CH2:8][CH:9]=[CH:10][CH2:11]2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]1[C:6](=[O:25])[CH:7]2[CH:12]([CH2:11][CH:10]=[CH:9][CH2:8]2)[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:16]=2[CH3:24])=[N:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCN1N=C(c2c(C)[nH]c3ccccc23)C2CC=CCC2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1N=C(c2c(C)n(CC(=O)O)c3ccccc23)C2CC=CCC2C1=O
Temperature: 75 °C

Procedure:
The product of step b) was dissolved in DMF (4 mL) and treated with K2CO3 (0.7 mmol, 97 mg) and t-butyl bromoacetate (0.5 mmol, 74 uL). After heating at 75° C. for 2 h, the reaction was cooled, diluted with EtOAc (10 mL) and washed 3× water. The organic solution was concentrated to dryness and treated with 4 mL TFA for 1.5 h. The reaction was concentrated and the title compound was purified by preparative LCMS. 1H NMR (DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.09-6.99 (m, 2H), 5.70 (d, J=10.8 Hz, 1H), 5.63 (d, J=10.8 Hz, 1H), 3.91 (dt, J=6.9, 13.2 Hz, 1H), 3.62 (dt, J=6.6, 13.2 Hz, 1H), 3.36 (quint., J=5.7 Hz, 1H), 2.96 (t, J=5.1 Hz, 1H), 2.79-2.71 (m, 1H), 2.35-1.94 (m, 4H), 1.64 (quint., J=7.1 Hz, 2H), 1.31 (sext., J=7.5 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); MS: ESI (negative): 392 (M−H).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:24]=[CH:23][N:16]4[C:17](=[O:22])[CH2:18][C:19](=O)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(C(C)C)CC)(C)C.[OH:51][CH:52]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53]1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C>[CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:24]=[CH:23][N:16]4[C:17](=[O:22])[CH:18]=[C:19]([N:54]5[CH2:55][CH2:56][CH2:57][CH:52]([OH:51])[CH2:53]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(=O)N2C=CC(C(=O)Nc3nc(C4CCC4)cs3)=CC2=N1
Reactant: OC1CCCNC1
Agent: O=C([O-])O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(C2CCC2)cs1)c1ccn2c(=O)cc(N3CCCC(O)C3)nc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
N8-(4-Cyclobutyl-1,3-thiazol-2-yl)-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]-pyrimidine-8-carboxamide (100 mg, 0.29 mmol) was added with acetonitrile (2 ml) and dimethylformamide (1 ml), cooled to −10° C. with ice, then added with diphenyl chlorophosphate (0.2 ml, 0.96 mmol), and further added dropwise with diisopropylethylamine (0.3 ml, 1.74 mmol). The reaction solution was stirred at −10° C. for 30 minutes, then added with 3-hydroxypiperidine (90 mg, 0.89 mmol), warmed to room temperature, and then further warmed to 80° C. As the reaction was not completed, the reaction solution was further added with 3-hydroxypiperidine (60 mg), stirred for 1 hour, and further added with 3-hydroxypiperidine (70 mg). After the disappear of the starting material was observed, the reaction was stopped with saturated aqueous sodium hydrogencarbonate, and the reaction solution was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 85.2 mg (69%) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Product: COC(=O)c1cc(COCCOC2CCCCO2)cc(C(C)(C)C)c1
Yield: 41.3 %

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (3.5 g) was alkylated analogously to O5.059 with 2-(2-bromoethoxy)tetrahydropyran (3.95 g). However, silica gel chromatography (n-heptane/EA 4:1) was carried out for purification. 2.28 g of the title compound were obtained.