Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31]Br.[I-].[K+]>C1COCC1.CN1CCCC1=O>[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH2:4][CH2:5][CH2:6]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
NaH (60% dispersion in oil, 800 mg, 20 mmol) was added at 0° C. to a solution of ethyl {4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}acetate (2 g, 6.3 mmol) in THF (25 ml) and N-methylpyrrolidinone (2 ml) under nitrogen. The reaction was stirred at 0° C. for 15 minutes. Bis(2-bromoethyl)ether (1.2 ml, 9.54 mmol) and potassium iodide (500 mg, 3 mmol) were added and the mixture stirred at 0° C. for 45 minutes. The reaction was then warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0° C., quenched with ice and solid carbon dioxide. The mixture was diluted with water and extracted with ethyl acetate (100 ml and 20 ml). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:diethylamine (99:1 by volume) to provide the title compound (870 mg, 36%) as a pale yellow oil. LRMS APCI+ m/z 388 [MH]+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(4-fluorophenyl)piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(=O)N(C)c1cc(Br)cc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
0.04 g (0.00009 mol) of N-[3-bromo-5-(4-nitrobenzenesulphonyl) -phenyl]-N-methylacetamide was dissolved in 5 ml of ethanol, treated while cooling with a solution of 0.085 g (0.00045 mol) of SnCl2.2H2O in 0.34 ml of HCl (37%) and stirred at room temperature for 18 hrs. Then, the solvent was removed and the residue was adjusted to pH 8 with sat. NaHCO3 solution. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and freed from solvent. There was obtained 0.021 g (61%) of N-[3-bromo-5-(4-aminobenzenesulphonyl)-phenyl]-N-methylacetamide as a light yellow oil. MS (ISN): me/e=443, 441 (C15H15BrN2O3S- +NaOAc).
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]C5CCCCO5)[CH:25]=4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:35])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:36].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:35])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:36]
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)c(F)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1ncc2c(F)c(Cc3cnc4ccc(-c5cnn(CCO)c5)nn34)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4,6-difluoro-1-methyl-1H-indazol-5-ylmethyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 285.1, 30 mg, 0.061 mmol) in dioxane (2 mL) stirred at 0° C. was added a solution of HCl in dioxane (4 M, 0.152 mL). The RM was stirred 1 h at rt, poured in a solution 10% NaHCO3, and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, hexane/EtOAc=100:0->80:20) to afford the title compound as a white powder (tR 3.68 min (conditions 3), MH+=410.2, 1H-NMR in DMSO-d6: 8.38 (s, 1H); 8.19 (s, 1H); 8.06 (s, 1H); 8.04 (d, 1H); 7.53-7.46 (m, 3H); 4.97 (t, 1H); 4.40 (s, 2H); 4.18 (t, 2H); 3.97 (s, 3H); 3.76 (q, 2H)).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:21])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
To a mixture of 4-isopropylbenzoic acid (191 mg, 1.16 mmol) and pyridine (0.12 mL, 1.5 mmol) in toluene (10 mL) was added thionyl chloride (0.11 mL, 1.5 mmol). After heating at 80° C. for 3 h, the reaction mixture was cooled and concentrated in vacuo to give 4-isopropylbenzoyl chloride. A solution of this material (1.16 mmol) in methylene chloride (10 mL) was added to a mixture of 2-amino-N-(4-methoxyphenyl)benzamide (200 mg, 0.83 mmol) and pyridine (0.07 mL, 0.87 mmol) in methylene chloride (15 mL) cooled to 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was partitioned between methylene chloride (25 mL) and 1 N hydrochloric acid (10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to give 262 mg (81%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.[NH+]1C=CC=CC=1.CO.CCOCC.CCCCCCC>CN1C(=O)CCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[S:15][C:14]([C:16]3[N:23]=[N:24][NH:25][N:17]=3)=[N:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Fc1ccc(Br)c(OC2CCN(c3nnc(-c4nn[nH]n4)s3)CC2)c1

Procedure:
The title compound was prepared in a similar manner as described in Example 1, Step 3, with 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2-carbonitrile (15.6 g), NaN3 (13.2 g, 204 mmol) and pyridinium hydrochloride (9.47 g, 82.0 mmol) in NMP (70 mL), and purification by trituration with a mixture of MeOH/Et2O/heptane to afford the desired product as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.Cl>O1CCOCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:19]2[O:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:36])=[O:4])[C:13]=3[C:20]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccc(F)cc3)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccc(F)cc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 1 ml 1 N sodium hydroxide solution to a solution of 169 mg (0.37 mmol) 6-{[6-(4-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 5 ml dioxan and stir for 16 h at RT. After adding 3 ml 1 N hydrochloric acid, concentrate the reaction solution by vacuum evaporation. Mix the residue with diethyl ether, filter, and dry under vacuum. 165 mg (99% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17]Cl)[C:6]2=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17][N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]2=[O:19]
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: COc1cc2ncn(CCCCl)c(=O)c2cc1OC
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CCN(CCCn2cnc3cc(OC)c(OC)cc3c2=O)Cc2ccccc2)cc1OC

Procedure:
1-(6,7-Dimethoxy-4(3H)-quinazolinone-3-yl)-3-[N-benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane was prepared analogous to Example 1 (a) by reaction of 1-(6,7-dimethoxy-4(3H)-quinazolinone-3-yl)-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-benzyl amine in chlorobenzene. Rf -value (chloroform/methanol = 9.1) : 0.75.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:36][C:33]1[C:34]2[CH:35]=[C:27]3[C:26]4[N:39]=[C:22]([C:21]5[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:3][C:4]6[O:8][C:7]([C:9]7[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=7)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=6[CH:20]=5)[CH:23]=[CH:24][C:25]=4[O:38][CH2:37][N:28]3[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1000 mg, 1.914 mmol) and pyridine (1.548 mL, 19.14 mmol) in dichloromethane (30 mL), methylsulfonyl chloride (0.741 mL, 9.57 mmol) was added dropwise at 0° C. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was quenched with NaHCO3 and 20 mL dichloromethane was added. Solid crushed out, the mixture was filtered and washed with water. The crude solid was dried under vacuum and gave the crude product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1100 mg, 96% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](OC1C=CC(O)=CC=1CCCC1C=CC(C(OC)=O)=CC=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: COC(=O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Product: COC(=O)c1ccc(C)cc1O

Procedure:
Methyl 2-hydroxy-4-methylbenzoate was prepared from 2-hydroxy-4-methylbenzoic acid by the process described in Example 6 for the synthesis of methyl 4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl]-benzoate.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=1)=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=3)=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(3-chlorophenyl)ethanone and isolated as white solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH2:19]1COC[CH2:20]1.C([Mg]Br)C.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[CH:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=C1c2cc(Br)ccc2Oc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 250 mL RBF was charged with 2-bromo-7-methoxy-9H-xanthen-9-one (10.20 g, 33.4 mmol) and 100 mL dry THF. The mixture was stirred for 10 min at RT and the resulting suspension was placed in an ice-methanol bath for another 10 min. Ethylmagnesium bromide, 1.0 M in THF (43.5 mL, 43.5 mmol) was added to the mixture dropwise. After 30 min, the mixture was carefully quenched with saturated aqueous ammonium chloride (100 mL) at 0° C. and diluted with EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude material was dissolved in 100 mL of chloroform, treated with pyridine 4-methylbenzenesulfonate (0.115 g, 0.669 mmol), and heated to reflux for 4 hr then 50° C. overnight. The mixture was cooled to RT, diluted with DCM, and washed with saturated sodium bicarbonate and brine. The organic fraction was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 5-40% Hexanes:EtOAc to afford 2-bromo-9-ethylidene-7-methoxy-9H-xanthene as a yellow oil, MH+=317.0/319.0@3.35 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH2:14][OH:15]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH:14]=[O:15]
Reactant: OCc1cc(-c2ccccn2)ccc1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccn2)ccc1Cl
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A solution of (2-chloro-5-(pyridin-2-yl)phenyl)methanol (129 mg; 0.72 mmol) in anh. THF (7 ml) was treated with MnO2 (975 mg; 11.22 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 6.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with THF. The filtrate was concentrated to dryness under reduced pressure giving 2-chloro-5-(pyridin-2-yl)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.43 min.; no ionisation.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].O=[C:12]([CH2:18][C:19](=O)[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:7]([N:9]1[C:19]([CH3:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
N-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 ml) was cooled in an ice-bath and treated with ethyl 2,4-dioxovalerate (11.24 ml). After addition was complete the mixture was stirred at room temperature; after ca. 45 min the mixture was warmed to dissolve insoluble ethylhydrazine oxalate. The mixture was stirred for a further 2 h and then poured into water(ca. 300 ml)/ethyl acetate (ca. 700 ml) and solid K2CO3 was carefully added, with stirring, until the pH was neutral. After separation the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), and the solvents removed to leave an oil. Chromatography on silica gel, loading in CH2Cl2 /hexane and eluting with a gradient elution of ethyl acetate/hexane mixtures (from 2:8 to 1:1) gave ethyl 1-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2 g); νmax (CH2Cl2) 1717, 1446, 1389, and 1219 cm-1 ; δ (CDCl3) 1.38 (3H, t, J 7.2 Hz), 1.42 (3H, t, J 7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3 Hz), 4.38 (2H, q, J7.1 Hz), 6.55 (1H, s); (Found m/z 182.1055. C9H14N2O2 requires m/z 182.1055).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=2)[CH:11]=1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccco3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ccco3)ccc2n1
Yield: 74.9 %

Procedure:
384 mg of ethyl 6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 256 mg of 6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:15])[C:10]([CH3:14])=[CH:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(C)=O>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9](=[O:15])[C:10]([CH3:14])=[CH:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC=C(C)C(O)CCc1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCC=C(C)C(=O)CCc1ccccc1
Temperature: 85 °C

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 168 g of 65% 1-Phenyl-4-Methyl-4-Hepten-3-ol, 51 g of 98% Aluminum Isopropoxide, (obtained from the Acros Organics) and 200 g of Acetone and 200 g of Toluene were added and stirred. The reaction mixture was slowly heated at reflux to 85° C. The samples were collected every our when the temperature of the reaction mixture was between 70° C. and 80° C. The NMR spectrum of the 1-Phenyl-4-Methyl-4-Hepten-3-one is as follows: 1.0 ppm (t, 3H); 1.8 ppm (s, 3H); 2.2 ppm (m, 2H); 2.9-3.0 ppm (m, 2H); 6.6 ppm (t, 1H) 7.2 ppm (m, 3H); 7.28 ppm (s,1H), 7.3 ppm (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[C:33](=[O:42])[C:34]([CH3:41])=[CH:35][NH:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:32]=2[C:33](=[O:42])[C:34]([CH3:41])=[CH:35][NH:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Cc1c[nH]c2cccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 5-amino-3-methylquinolin-4(1 H)-one (Compound 203A). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (t, J=7.07 Hz, 6 H), 1.98 (s, 3 H), 3.24-3.31 (m, 2 H), 3.75 (s, 3 H), 3.94-4.04 (m, 4 H), 6.90 (d, J=7.83 Hz, 1 H), 7.04 (s, 1 H), 7.08 (d, J=8.34 Hz, 1 H), 7.34-7.44 (m, 1 H), 7.50 (d, J=7.83 Hz, 1 H), 7.94 (s, 1 H), 8.37 (s, 1 H), 8.48 (br. s., 1 H), 8.91 (s, 1 H), 11.86 (br. s., 1 H), 14.41 (s, 1 H). MS (ES+): tniz 592.14 [MH+] (TOF, polar).
Reaction SMILES: C(OC(=O)NC(C(=O)[NH:14][CH:15]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:16][C:17](=[O:31])[N:18]1[CH2:23][CH2:22][N:21]2[C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=[C:20]2[CH2:19]1)CC(C)C)(C)(C)C.[ClH:44]>>[ClH:44].[O:31]=[C:17]([N:18]1[CH2:23][CH2:22][N:21]2[C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=[C:20]2[CH2:19]1)[CH2:16][CH:15]([NH-:14])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: [NH-]C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F

Procedure:
Analogously to example 2 the compound, [3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloride (Formula 10) is prepared by saltification of the compound of formula 9 (0.52 gm) using hydrochloric acid. (Yield: 0.45 gm, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:27]=[N:26][CH:25]=[C:24]([F:28])[C:21]=1[CH:22]=[O:23].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:27]=[N:26][CH:25]=[C:24]([F:28])[C:21]=2[CH:22]=[O:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: O=Cc1c(F)cncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(F)c2C=O)cc1Cl
Temperature: 100 °C
Yield: 18 %

Procedure:
To the solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (264 mg, 1.00 mmol), 3-bromo-5-fluoroisonicotinaldehyde (204 mg, 1.00 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol) in DMF (3 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction and separation, the combined extracts were concentrated and purified by SNAP10 g (10% MeOH/DCM 0-15% gradient) to give 2-chloro-4-(5-fluoro-4-formylpyridin-3-yl)benzonitrile (47 mg, 18%) as a white solid; ESI-MS m/z: 293 [M+MeOH+1]+, Retention time 1.15 min. 1H-NMR (CDCl3, 400 MHz) δ 7.33 (dd, J=8.0, 1.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.78 (d, J=1.2 Hz, 1H), 10.27 (s, 1H).
Reaction SMILES: C([O:5][CH2:6][CH:7]([Cl:13])[CH2:8][C:9]([F:12])([F:11])[F:10])(=O)CC.CO.S(=O)(=O)(O)O>>[Cl:13][CH:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH2:6][OH:5]
Reactant: CCC(=O)OCC(Cl)CC(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC(Cl)CC(F)(F)F
Reaction time: 2.5 h

Procedure:
2-Chloro-4,4,4-trifluorobutyl propionate (1) (9.58 g, 95.8 mmol), methanol (92 ml, 2.3 mol) and concentrated sulfuric acid (0.53 g, 10 mmol) are loaded into a 250-ml three-necked flask equipped with a condenser, a thermometer, a septum and a magnetic stirrer. The reaction medium is heated to reflux (between 60 and 65° C.). The mixture is left stirring for 2.5 hours. Distillation is performed at atmospheric pressure to remove the methanol and the methyl acetate. The residue is distilled at reduced pressure (38 mmHg).