Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as starting materials in 35% yield. LCMS for C32H31ClN9O2 (M+H)+: m/z=608.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
A solution of 3.34 g (13.96 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 100 ml CH2Cl2 was treated at 0° C. with 1.2 ml (15.4 mmol) of methanesulfonylchloride, 1.7 ml (20.93 mmol) of pyridine and 1.71 g (13.96 mmol) of DMAP. The reaction mixture was warmed up to RT for 3 h, treated with water (10 ml) and stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 4.05 g (90%) of 4-(3-Methanesulfonyloxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 317 (M).
Reaction SMILES: C1(C([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[O:39][C:38]([CH3:40])=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[O:39][C:38]([CH3:40])=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12
Reactant: Cc1ccc(Cn2nnnc2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(Cn2nnnc2C2N3C(=O)C(N)[C@H]3SC2(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of 1.827 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam in 3 ml. of acetone is added a solution of 0.59 g. of p-toluenesulfonic acid monohydrate in 2 ml. of acetone. The mixture is stirred at ambient temperature for 30 minutes, and then the precipitate which has formed is filtered off. This affords 0.87 g. (54% yield) of the title compound as its p-toluenesulfonate salt. The NMR spectrum of the product (CDCl3) shows absorptions at 7.28 ppm (q, 4H), 6.50 ppm (d, 1H), 6.01 ppm (s, 1H), 5.86 ppm (s, 2H), 5.71 ppm (s, 1H), 5.68 ppm (d, 1H), 5.09 ppm (d, 1H), 2.00 ppm (2s, 6H), 1.66 ppm (s, 3H) and 0.88 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2′,4′-dimethoxy-2-methylbiphenyl-4-carboxylate obtained in step 2 (2 g; 6.99 mmol) in EtOH (60 mL) at RT was treated with sodium hydroxide (4.19 mL; 5 M; 20.96 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a brown solid that was taken up in water (40 mL) and the aqueous phase was washed twice with EtOAc and then acidified with HCl to pH 2. Then it was concentrated until precipitation (⅕ of the volume). The suspension was filtered off and dried under vacuum affording the title compound as an orange solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.59 (br s, 1H), 7.58-7.51 (m, 2H), 6.97-6.95 (d, J=8.03 Hz, 1H), 6.81-6.79 (d, J=8.39 Hz, 1H), 6.44-6.37 (m, 2H), 3.59 (s, 3H), 3.49 (s, 3H), 1.88 (s, 3H). LC/MS (Method A): 272.9 (M+H)+; 270.9 (M−H)−. HPLC (Method A) Rt 3.87 min (Purity: 99.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH:15]([NH:18][C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=O)[CH2:16][CH3:17])=[N:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:16][CH3:17])[N:18]=[C:19]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(-c3ccc(Br)cc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 2.34 g (5.77 mmol) N-{1-[3-(4-bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclopentanecarboxamide, 4.43 g (28.9 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: [CH3:1][Ge:2]([CH3:16])([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])OCC[O:10]2)=[CH:5][CH:4]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O>[CH3:15][Ge:2]([CH3:1])([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:10])[CH3:14])=[CH:5][CH:4]=1
Reactant: CC1(c2ccc([Ge](C)(C)C)cc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc([Ge](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 420 mg (1.5 mmol) of 2-(4-trimethylgermylphenyl)-2-methyl-1,3-dioxolane and 56 mg (0.19 mmol) of pyridinium p-toluenesulfonate (PPTS) in 1.35 g (62.5 mmol) of water and 10 ml of acetone was refluxed for 2 hours and stirred at room temperature for 1.5 days. The reaction mixture was extracted with petroleum ether. The extract was washed successively with 2N hydrochloric acid, water and sat.aq.NaHCO3, dried and evaporated.
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][OH:13].[BrH:15].O>C1(C)C=CC=CC=1>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: Br
Reactant: OCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCCCCCCCBr

Procedure:
To a stirred solution of dodecane-1,12-diol (8.365 g, 42.75 mmol), 48% HBr in water (9.7 ml, 85.50 mmol) and toluene (120 ml) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then concentrated, the crude compound was dissolved in DCM (150 ml), washed with water, NaHCO3 brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (5% EtOAc in hexane) to obtain 12-bromododecan-1-ol as an off-white low melting solid (8.87 g, 78%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)=[O:22]>>[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:20]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: CC(=O)c1cccc(N)c1
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-aminoacetophenone gave the title compound as an off-white solid, mp 191-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13]C.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:11])[CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1cc2c(cc1Cl)C(C)(C)CC2
Agent: BrB(Br)Br
Product: CC1(C)CCc2cc(O)c(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-5-methoxy-1,1-dimethyl-indan by treatment with BBr3 as in Example 11.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1C=CC([Cl:26])=CC=1C(O)=O>>[Cl:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: O=C(O)c1cc(Cl)ccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-bromo-5-chlorobenzoic acid. MS (ESI) 224 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([F:12])([F:21])[F:22])=[O:9]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccccc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 58 %

Procedure:
Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, white solid (80 mg, 94%), MS (ISP) m/z=341.3 [(M+H)+], mp 264° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:30])([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[NH:25][O:26][C:27](=[O:29])[N:28]=2)[CH:19]=1)[C:14]([F:17])([F:16])[F:15].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[N:31]1([C:36]([N:28]2[C:27](=[O:29])[O:26][N:25]=[C:24]2[C:20]2[CH:19]=[C:18]([C:13]([F:12])([F:30])[C:14]([F:15])([F:17])[F:16])[CH:23]=[CH:22][N:21]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=c1nc(-c2cc(C(F)(F)C(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)C(F)(F)F)ccn2)noc1=O
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To 2 ml of pyridine were added 0.16 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.14 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-(1-pyrrolidinecarbonyl)-3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (63)).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([S:9]([NH:12]C(C)(C)C)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>FC(F)(F)C(O)=O>[Br:1][CH2:2][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(CBr)cccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(CBr)cccc1S(N)(=O)=O
Yield: 80.5 %

Procedure:
A solution of 5.7 g of 3-bromomethyl-2-carboethoxy-N-(1,1-dimethylethyl)benzenesulfonamide in 60 mL of trifluoroacetic acid was stirred at room temperature for 16 hours. Concentration provided a viscous oil which was triturated with n-butyl chloride. The solids were collected to yield 3.91 g of a white solid, m.p. 138°-140° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCSc1ccc(C(F)(F)F)cn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCSc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
4-geranyloxybenzoic acid(6.17 g) was dissolved in chloroform(80 ml) and triethylamine(6.24 ml), and then diphenylphosphinic chloride(4.29 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylthio)-5-(trifluoromethyl)pyridine(5.00 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 9.02 g of the aimed compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[I-].[K+]>C(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:22]2[CH2:23][CH2:24][N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:20][CH2:21]2)[CH:8]=1
Reactant: O=C(CCCCl)c1cccnc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCN(c2ccccn2)CC1)c1cccnc1
Yield: 44.1 %

Procedure:
A solution of 4-chloro-1-(3-pyridinyl)-1-butanone (Example B) (9 g, 0.049 mol), 1-(2-pyridinyl)piperazine (24 g, 0.147 mol), and potassium iodide (0.8 g, 0.005 mol) is heated to 120° C. for 5 minutes. The residue is taken up in chloroform (40 mL) and the precipitate is filtered. The filtrate is evaporated in vacuo and purified by column chromatography (silica gel, 2% methanol/dichloromethane). The major product is crystallized from 2-propanol/diethyl ether to give 6.7 g 1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone as a white solid; mp 89° C.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH:8]=[CH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2c3sccc3cc[n+]12
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Reaction time: 1 h

Procedure:
ca) 22.9 g of 3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 13.6 ml of methyl propiolate were heated together under argon in 1000 ml of toluene until the starting material was completely taken up. The solvent was removed in vacuo and the residue was stirred in 500 ml of ether/methanol (9:1) for 1 hour. The yellow crystals obtained were removed by filtration under suction. There was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 153°-154° (dec.). An additional portion of product of m.p. 151°-152° (dec,) can be obtained by chromatography of the filtrate on silica gel.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](C(C)(C)C)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:32]1[CH:37]=CC=C[CH:33]=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:33][CH2:32][CH3:37])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: Cl
Product: CCCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 1), 251(17), 250 (100), 163 (6), 121 (34), 114 (9), 107 (6), 90 (17), 78 (9), 77 (10), 71 (17).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33]>CN(C=O)C>[CH3:17][N:8]1[C:6]2=[N:7][C:2]([NH:33][CH2:32][C:31]([O:30][CH3:29])=[O:34])=[CH:3][C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9]1
Reactant: COC(=O)CN
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(Br)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Temperature: 100 °C
Yield: 32 %

Procedure:
To a stirred mixture of 6-bromo-1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.15 g, 0.422 mmol) and Na2CO3 (0.135 g, 1.267 mmol) in dry DMF (6.0 mL), glycine methylester×HCl (0.08 g, 0.633 mmol) was added at it and heated to 100° C. for 6 h. The reaction mixture was cooled to it and poured into rapidly stirred ice cold water. The crude compound was extracted with EtOAc and purified by column chromatography (eluent: 10% EtOAc in hexane) to yield the title compound as a colorless solid (0.05 g, 32%). [1H-NMR (CDCl3, 300 MHz) δ 7.55-7.38 (m, 5H), 6.68 (s, 1H), 5.42 (t, 1H), 4.32 (d, 2H), 4.05 (s, 3H), 3.75 (s, 3H); LCMS RtC=0.469 min; [M+H]+=364.8]
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[Br:21]Br>C(O)(=O)C>[Br:21][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(Br)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
The method of Siegel, J. S. et al. (Org. Lett., 2006, 8, 4989-4992) was used. 3-Nitro-2′-trifluoromethyl-biphenyl-4-ylamine (302 mg, 1.07 mmol, as prepared in Example 6, step A) was placed in an 8 mL vial equipped with a magnetic stir bar, and glacial acetic acid (2 mL) was added via pipette. The solid was allowed to dissolve, and bromine (1.07 eq., 59.0 μL, 1.14 mmol) was added dropwise via microsyringe. The reaction was tightly capped and stirred at RT for 30 min, during which time a precipitate formed. The reaction was poured into crushed ice, and the precipitate was isolated by filtration. The precipitate was washed with water (50 mL), dissolved in DCM (40 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure. The crude material was chromatographed on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 20 min, yielding 341 mg (88%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.14 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.70 (br. s., 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][C:27](=[O:29])[CH3:28])[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(O)c2)c(OC)c(OC)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OC(C)=O)c2)c(OC)c(OC)c1OC
Yield: 60 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (97 mg, 0.2679 mmol) was dissolved in acetic anhydride (20 ml) and the resulting solution was refluxed under heating for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to obtain the titled compound (65 mg, 0.1608 mmol, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:16])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C1C=CN=CC=1.ClCCl.O.C(Cl)(Cl)Cl>[CH3:3][C:1]([C:5]1[C:6]2[O:11][C:13](=[O:14])[C:12](=[O:16])[C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: CN(C)c1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cccc2c1OC(=O)C2=O
Yield: 47987 %

Procedure:
A mixture of 2-tert-butylphenol (15 g, 0.1 mmol) and 4-dimethylaminopyridine (0.5 g) is stirred under nitrogen in 300 ml of dichloromethane. Oxalyl chloride (20 ml, 0.22 moles) is added dropwise, then the mixture is heated to reflux. After ten hours the mixture is cooled and the solvent is removed under reduced pressure. The residue is taken up in 100 ml of 1,2-dichloroethane and added dropwise under nitrogen to a suspension of aluminum chloride (40 g, 0.3 mmol) in 300 ml of 1,2-chloroethane. After 20 hours at room temperature the mixture is slowly diluted with water until all solids dissolve. The organic layer is separated and dried over molecular sieves, and the solvent is evaporated to leave a syrup which is taken up in chloroform and filtered through a short column of silica gel. The filtrate is stripped of solvent under reduced pressure to leave the product (9.8 g) as a syrup suitably pure for subsequent reactions.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:10][O:9][C:7]1([O:11][CH3:12])[CH2:8][CH:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(OC)CC(CO)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester, (J. Org. Chem. 1988, 53, 3841 and J. Org. Chem. 1996, 61, 2174) (15.0 g, 86.1 mmol) in 40 mL of tetrahydrofuran at 0° C. (ice/water bath) was added dropwise a solution of lithium aluminum hydride (103.3 mL, 1M tetrahydrofuran). After the addition was complete the reaction was warmed to room temperature and stirred 12 hours. The reaction was worked-up using the method of Feiser and Feiser, and then filtered through a plug of Celite and concentrated under reduced pressure to yield (3,3-dimethoxy-cyclobutyl)-methanol (12.4 g, 99% crude yield) as a colorless oil. This material was used without further purification.