Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]([OH:7])[OH:6])[C@H:3]1[C:8](O)=O.[CH:12]([O:15][C:16]([CH2:18]P1(=O)OC(C)C(C)O1)=[O:17])([CH3:14])[CH3:13]>>[CH3:11][C:2]1([CH3:1])[CH:3]([CH:8]=[CH:18][C:16](=[O:17])[O:15][CH:12]([CH3:14])[CH3:13])[CH:4]1[C:5]([OH:7])=[O:6]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)O
Reactant: CC(C)OC(=O)CP1(=O)OC(C)C(C)O1
Product: CC(C)OC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Using the procedure of Example 6, 0.76 g of the lactone of (1R,cis) 2,2-dimethyl-3-dihydroxymethyl-cyclopropane-carboxylic acid and 1.9 g of 2-isopropoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane were reacted to obtain 1 of (1R,cis,ΔZ) 2,2-dimethyl-3-[3-oxo-3-isopropoxy-1-propenyl]-cyclopropane-carboxylic acid melting at 100° C. and having a specific rotation of [α]D20 =+71°±2° (c=1% in chloroform) and 0.09 g of the corresponding E isomer.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[CH2:11][C:12]#[N:13]>ClCCl>[O:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]1[C:12]#[N:13]
Reactant: O=C1CCCCC1
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CC1OC12CCCCC2
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a stirred mixture of cyclohexanone (5.39 g, 0.055 mol), 50% sodium hydroxide solution (10 ml) and compound 1 (1 mmol) was added dropwise chloroacetonitrile (3.8 g, 0.05 mol) and stirring was continued for further 45 minutes. After that time, the resulting reaction mixture was diluted with dichloromethane (15 ml), the organic layer was separated and the aqueous phase extracted with dichloromethane (3×15 ml). The combined organic portions were dried over magnesium sulphate and evaporated to give a residue which upon distillation under reduced pressure gave 1-oxaspiro[2,5]octane-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].CN(C=O)C>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][C@@H:33]([OH:36])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#C[C@@H](C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: C[C@H](O)C#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (R)-(+)-3-butyn-2-ol (0.047 mL, 0.599 mmol). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 90.7 mg (34%) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:25][NH2:26].C(=O)(O)[O-].[Na+]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH:26][CH3:25])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 130 °C
Yield: 52 %

Procedure:
A mixture of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (50 mg, Example 61) and 40% methylamine methanol solution (5.0 ml) was heated in a sealed tube at 130° C. for 18 hours. After standing to cool, an aqueous saturated sodium bicarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column, to give the title compound (28 mg, 52%) as a pale yellow solid.
Reaction SMILES: [C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35](S(C2C=CC(C)=CC=2)(=O)=O)[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35]([N:48]=[N+:49]=[N-:50])[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](C(O)S(=O)(=O)c2ccc(C)cc2)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1O[C@H](C(O)N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
10 g of compound 2 and 3 g of NaN3 were dissolved in 100 cc of DMF. Reaction was allowed to proceed for 24 hrs at 70° C. after which the reaction mass was poured into 1 liter of water. Compound 5, obtained as a solid, was recrystallized from acetone giving 8 g (quant.) after drying over P2O5. M.p. 111° C.; 1H NMR (CDCl3): δ 8.22, 8.07, 7.92 (d,d,d, 2H each, benzoyl), 7.38-7.66 (m, 9H, benzoyl), 6.0—5.96 (m, 2H, H2,3), 5.8 (m, 1H, H4), 5.13 (d, 1H, H1), 4.47 (m, 1H, H5), 3.69 (s, 3H, OMe), 3.62 (AB, 2H, H6.6′).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1.CN1CCOCC1>C(#N)C>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OC2CCNCC2)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (24 uL, 0.00033 mol) in 0.5 ml of ACN was added to a solution of 1-tert-butyl 2-methyl (1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44 uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. It was stirred at rt for 30 min, then quenched with Water, extracted with EA, and concentrated to give 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([F:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[C:27]([F:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)c1ccc(Cl)nc1F
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using, 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (52 mg, 0.17 mmol) and 2-(6-chloro-2-fluoropyridin-3-yl)propan-2-ol (32 mg, 0.17 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[C:8]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[N:4]2[N:3]=[C:2]([CH3:1])[CH:15]=[C:5]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Product: Cc1cc2nc(Cl)c3cnccc3n2n1

Procedure:
200 g. of 2-methylpyrazolo[1,5-a]pyrido[3,4-e]-pyrimidin-5(4H)-one of Example 1c are refluxed with 800 ml. of phosphorus oxychloride overnight. The excess phosphorus oxychloride is removed in vacuo and the oily residue decomposed by pouring on ice. The acidic aqueous solution is made alkaline with sodium hydroxide. The precipitated 5-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine is filtered off, yield: 143 g. (66%); m.p. 169.8° (ethyl acetate).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.Cl[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[N:2]1[CH2:5][CH:4]([C:6]2[C:15]([C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1cccc(-c2nc3ccccc3nc2C2CNC2)c1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc3ccccc3nc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (311 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1.0 mmol) in DMF (6 mL) was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 2-(1-quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline (256 mg, 0.64 mmol yield 63.7%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[N:50]1([C:56](Cl)=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][N:32]([C:56]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:57])[CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCN(C(=O)N4CCOCC4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 82 %

Procedure:
(3R)-(2,6-Diphenyl-pyridin-4-yl)-[3-(piperazine-1-carbonyl)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.507 mmol, 272 mg) was dissolved in anhydrous dichloromethane and N,N-diisopropylethylamine (2 eq. 180 μl) followed by N-morpholine carbonyl chloride (1 eq. 60 μl ) were added. After 3 hr a further aliquot of N-morpholine carbonyl chloride (40 μl) was added and the mixture was stirred at room temperature for 66 hr. The solution was washed with 0.1M sodium hydroxide solution, dried over anhydrous sodium sulfate, diluted with toluene and evaporated to dryness. The product was purified by chromatography on silica gel eluting with a 2.5% to 10% methanol-dichloromethane gradient to give the title compound (270 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 69.7 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added benzenesulfonyl chloride (0.0099 g, 0.0072 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 35 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (18.6 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 2 H) 7.47 (m, 3 H) 7.61 (m, 4 H) 7.80 (d, J=6.99 Hz, 2 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.87 (dd, J=4.23, 1.29 Hz, 1 H) 10.85 (s, 1 H) 14.08 (br s, 1 H). MS (ESI−) m/z 566 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:12]([O:11][C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:30])=[CH:7][N:6]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A mixture of di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate (Compound 309C, 5.66 g, 18.4 mmol), NBS (3.92 g, 22 mmol), and benzoyl peroxide (0.444 g, 1.84 mmol) in CCl4 (30 mL) was heated at 80° C. for 6 h. The mixture was cooled to room temperature, the solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (EtOAc/heptane: 1:1) to give 4.66 g of di-tert-butyl[5-(bromomethyl)pyridin-2-yl]imidodicarbonate (yield: 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCCBr)cc(Br)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Temperature: 55 °C
Yield: 80.3 %

Procedure:
To a solution of 5-bromo-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (597 mg, 1.72 mmol) in DMF (10 mL) was added pyrrolidine (158 μL, 1.89 mmol), triethylamine (717 μL, 5.15 mmol), and sodium iodide (26 mg, 0.17 mmol). The reaction was heated (55° C.) for 22 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (1×50 mL), brine, dried (Na2SO4) and evaporated to afford 467 mg (80%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1 H), 6.60 (s, 1 H), 2.81 (t, 2 H), 2.40-2.31 (m, 6 H), 1.70-1.59 (m, 6 H), 1.50-1.40 (m, 2 H); ES-MS m/z 338.1 [M+H]+, HPLC RT (min) 1.12.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[C:11](O)(=[O:14])[CH2:12][OH:13].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CO>[OH:14][CH2:11][C:12]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)=[O:13]
Reactant: NCc1csc2cncn12
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)NCc1csc2cncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 4 ml of methanol and 296 mg of THF containing 296 mg of 3-aminomethylimidazo[5,1-b]thiazole, 162 mg of glycolic acid, 26 mg of 1-hydroxybenzotriazole and 439 mg of 1,3-dicyclohexylcarbodiimide were added, and the mixture was then stirred at room temperature for 1 hour. Further, insolubles were removed therefrom by filtration, and after washing with methanol, the filtrate was concentrated under reduced pressure. To the resulting residue, dichloromethane and an aqueous potassium carbonate solution were added, and the crystal was collected by filtration. The organic layer was separated from the filtrate, and the aqueous layer was extracted five times with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was combined with the above crystal, and crystallization was then made from ethyl acetate. To the obtained crystal, 20 ml of water and 2.7 ml of a 1N aqueous hydrochloric acid solution were added, and insolubles were then removed therefrom by filtration. Afterward, anhydrous potassium carbonate was dissolved in the filtrate, and the resulting crystal was collected by filtration, and then washed with dichloromethane and water to obtain 267 mg of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Br.[Br:21][CH2:22][CH2:23][CH2:24][NH2:25]>CC#N>[Br:21][CH2:22][CH2:23][CH2:24][NH:25][C:8]1[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCBr
Agent: Br
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reaction time: 3 h
Yield: 41.7 %

Procedure:
A solution of TEA (0.18 mL, 1.33 mmol) in MeCN (5 mL) was added dropwise to a mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.20 g, 0.67 mmol) and (3-bromopropyl)amine hydrobromide (0.146 g, 0.67 mmol) in MeCN (3 mL). After 45 mins a solution of (3-bromopropyl)amine hydrobromide (0.073 g, 0.33 mmol) and TEA (0.093 mL, 0.66 mmol) in MeCN (5 mL) was added dropwise to the reaction mixture. After 3 h, (3-bromopropyl)amine hydrobromide (0.073 g, 0.33 mmol) and TEA (0.093 mL, 0.66 mmol) was added to the reaction mixture. After 17 h the solvent was evaporated and the residue was purified by silica gel column chromatography using 10-20% EtOAc in petroleum ether mixture as eluant, to yield the title compound (0.112 g, 42%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.69-7.50 (m, 2H), 7.50-7.44 (m, 3H), 5.32 (t, 1H), 3.18 (t, 3H), 3.10-3.04 (m, 2H), 1.90-1.78 (m, 2H), 1.76 (s, 9H); Mass Spectrum M+H+ 403.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC1CCC(O)(c2ccc(Br)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CC=C(c2ccc(Br)cc2)CC1
Yield: 57.8 %

Procedure:
50.1 g of the compound (15), 0.5 g of p-toluenesulfonic acid and 200 mL of toluene were mixed, and the mixture was refluxed under heating for 3 hours while water distilled out was removed. After cooling the resulting reaction mixture to 30° C., 200 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture, which was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and then further purified by recrystallization from Solmix A-11 to obtain 27.2 g of 1-bromo-4-(4-propylcyclohexa-1-enyl)benzene (16).
Reaction SMILES: [CH2:1]([CH:3]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:39][C:40]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[C:41]=1[C:42](Cl)=[O:43]>ClC1C=CC=CC=1>[CH2:1]([CH:3]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:23])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:42]([C:41]1[C:40]([CH3:39])=[CH:48][C:47]([CH3:49])=[CH:46][C:45]=1[CH3:50])=[O:43])[CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3c(C)cc(C)cc3C)cc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Temperature: 65 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To [11-(2-ethylhexyl)-11H-benzo[a]carbazol-5-yl]-(4-fluorophenyl)-methanone (2.00 g, 4.43 mmol) in chlorobenzene (12 mL) are added AlCl3 (1.24 g, 9.30 mmol) and 2,4,6-trimethylbenzoyl chloride (0.85 g, 4.65 mmol) at 0° C. After stirring for 2 hours at 65° C., the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (4:1) to obtain a yellow solid (1.39 g, 52%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83 (t), 0.92 (t), 1.19-1.47 (m), 2.13 (s), 2.26-2.35 (m), 2.35 (s), 4.74-4.78 (m), 6.93 (s), 7.16 (t), 7.56-7.59 (m), 7.67 (t), 7.93-7.98 (m), 8.28 (s), 8.36 (d), 8.55 (br), 8.62 (d); 19F-NMR spectrum (CDCl3). δ [ppm] −105.13.