Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1>CN(C=O)C.O>[CH2:2]([CH:3]([O:6][C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-pentanol (0.093 ml, 0.86 mmol) in DMF (2 ml) was added sodium hydride (60% in oil, 34 mg, 0.86 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (64.8 mg, 0.20 mmol). The mixture was stirred at 60° C. for 1.5 hours, then diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 52 mg (69%) of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2cccc(Cl)c2N1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCc2cc([N+](=O)[O-])cc(Cl)c2N1
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a solution of 8-chloro-3,4-dihydro-2(1H)-quinolinone (5.08 g) in acetic anhydride (50 ml) was dropwise added a solution of nitric acid (d=1.40, 2.97 g) in acetic acid (20 ml) over the period of 10 minutes with stirring under ice-cooling. The mixture was stirred for 2 hours at ambient temperature and then for 6 hours at 50° C., and was allowed to stand for 60 hours at ambient temperature. The resulting precipitates were collected, washed with acetic anhydride and ethyl acetate successively and dried to give 8-chloro-6-nitro-3,4-dihydro-2(1H)-quinolinone (3.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-])=O)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:24](OCC)=[O:25]>C(OCC)(=O)C>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([OH:10])=[C:12]([C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:25])[CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 180 °C

Procedure:
A suspension of 0.60 mL of 4-chlorobenzylamine and 0.200 g of ethyl 4-hydroxy-7-nitro-3-quinoline carboxylate is heated to 180° C. for 1 h. The reaction is cooled to room temperature. Ethyl acetate is added and the resulting solid is collected and washed with ethyl acetate to yield 0.071 g of the title compound as a tan solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:26]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)(=[O:24])=[O:25])[CH3:27]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: CCS(=O)(=O)c1ccc(Br)cc1
Product: CCS(=O)(=O)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133 step 3) and 1-bromo-4-ethylsulfonylbenzene as light yellow solid. MS (m/e): 380.153 [MH+].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:18]2[N:17]=[C:16]([NH2:24])[CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:18]2[N:17]=[C:16]([NH:24][C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH:15]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
In a 250 ml round-bottomed flask was added (+/−)-trans-2-phenylcyclopropanecarbonyl chloride (1.9 g, 10 mmol) in pyridine (94 ml) to give a yellow suspension. 7-Chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 1.7 g, 9.4 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. After 30 min, reaction was complete and was quenched with saturated sodium bicarbonate solution. The layers were extracted with ethyl acetate (3×100 mL), and the organic layers were washed with saturated sodium bicarbonate solution and concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated to obtain the product N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 1.9 g, 62%) as an orange solid. 1H NMR (DMSO-d6) δ: 11.39 (s, 1H), 7.99 (s, 1H), 7.27-7.34 (m, 2H), 7.15-7.25 (m, 3H), 6.39 (s, 1H), 2.46 (td, 1H), 2.41 (s, 3H), 2.30-2.37 (m, 1H), 1.50-1.58 (m, 1H), 1.46 (ddd, J=8.2, 6.6, 4.2 Hz, 1H). ESI-MS: m/z 327.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1.CCOCC>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([B:16]([OH:17])[OH:15])=[CH:7][N:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(B(O)O)cn1
Temperature: -78 °C
Yield: 60.9 %

Procedure:
To a solution of 5-bromo-2-(tert-butyl)pyridine (1 g, 4.67 mmol) and triisopropylborate (1.29 mL, 5.60 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 2.06 mL, 5.14 mmol). The reaction was stirred at −78° C. for 2½ hours then allowed to warm slowly to −10° C. over 1 hour. The reaction was quenched by the addition of water (10 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous suspension was diluted with water (30 mL) and washed with ether (30 mL). The aqueous phase was acidified to pH 6 by the addition of acetic acid and the resulting milky suspension extracted with ether (2×20 mL). The combined organic extracts were washed with saturated brine (2×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a white foam. Ether (5 mL) and hexanes (40 mL) were added and the resulting suspension stirred vigorously for 30 minutes then filtered to give 2-(tert-butyl)pyridine-5-boronic acid (0.5093 g, 61% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[O:21][N:20]=1>>[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[CH:23]=2)[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2cc(CCl)no2)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)on1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-(chloromethyl)-5-[3,5-bis(trifluoromethyl)phenyl]isoxazole (Example 323C): MS (ES) m/z 518 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](Cl)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[S:22]([NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:14](=[O:15])[CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)(=[O:24])=[O:23]
Reactant: O=C(Cl)CN1CCN(c2ccncc2)CC1
Reactant: NCCCNS(=O)(=O)c1ccc2ccccc2c1
Product: O=C(CN1CCN(c2ccncc2)CC1)NCCCNS(=O)(=O)c1ccc2ccccc2c1
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride was reacted with N-(3-aminopropyl)naphthalene-2-sulphonamide to give N-[3-(2-naphthalenesulphonamido)propyl]-2-[4-(4-pyridyl)piperazin-1-yl]acetamide in 34% yield;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]([C:11]1[S:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1)[C:8]([NH2:10])=[NH:9].C(OCC)(=O)C.O>O1CCCC1>[NH:7]([C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)[C:8]([NH2:10])=[NH:9]
Reactant: CCOC(=O)c1csc(NC(=N)N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N=C(N)Nc1nc(CO)cs1
Yield: 62.2 %

Procedure:
To a suspension of lithium aluminum hydride (0.5 g) in dry tetrahydrofuran (260 ml) is portionwise added 2-guanidino-4-ethoxycarbonylthiazole (3.6 g) at 0° C. with stirring in half an hour, and the resultant mixture is refluxed under stirring for 4 hours. Ethyl acetate and water are added to the reaction mixture for decomposing excess lithium aluminum hydride. The organic layer is separated and the residual layer is extracted with methanol. The methanolic extract is combined with the organic layer, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate:methanol (4:1, v/v). The eluate is concentrated in vacuum to give 2-guanidino-4-hydroxymethylthiazole (1.8 g) as crystals melting at 163°-165° C. The yield is 62.2%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[C:5]2[C:21]([CH3:22])=[N:20][NH:19][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])#[N:2]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[N:7]=[C:6]3[NH:19][N:20]=[C:21]([CH3:22])[C:5]3=[C:4]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[C:3]=2[C:1]#[N:2])=[C:10]([F:18])[CH:11]=1
Reactant: Cc1n[nH]c2nc(-c3ccc([N+](=O)[O-])cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1n[nH]c2nc(-c3ccc(N)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 0.15 g (0.27 mmol) of tert-butyl 4-(4-(5-cyano-6-(2-fluoro-4-nitrophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in 15 ml of ethanol are added 0.037 g (0.035 mmol) of 10% Pd/C. The mixture is stirred at room temperature for 18 h under hydrogen atmospheric pressure. The mixture is then concentrated, re-dissolved in dichloromethane, filtered through Celite, and concentrated. The residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 0 to 5%) to yield 0.020 g (14%) of tert-butyl 4-(4-(6-(4-amino-2-fluorophenyl)-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of yellow crystals.
Reaction SMILES: [CH2:1]([C:10]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:23][O:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:26]=1[NH2:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:10]1([C:20]([NH:27][C:26]2[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=2[O:24][CH3:23])=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCC1(C(=O)Cl)CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(OC)cc(OC)cc2OC)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according to the procedure described in Example 65, except that 422 mg 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride, 247 mg (1.3 mmole) 2,4,6-trimethoxyaniline, and 165 mg (1.3 mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirred at room temperature for 20 hours. There was obtained 421 mg product (68% yield). IR(CHCl3) 1670 cm-1. 1H NMR: δ 0.87 (t, 3H); 1.25 (c, 12H); 1.5 (c, 3H); 1.85 (c, 2H); 2.21 (c, 1H); 2.8 (c, 2H); 3.0 (c, 1H); 3.3 (d, 1H); 3.66 (s, 6H); 3.75 (s, 3H); 6.06 (s, 2H); 6.56 (s, 1H); 7.1 (s, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[CH3:21][C@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[CH2:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC1CCCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: C[C@H]1CCCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 108 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 7.93 (s, 1H), 7.86 (d, 1H), 7.36 (m, 2H), 6.99 (d, 2H), 6.92 (d, 1H), 6.63 (d, 2H), 5.26 (t, 1H), 4.05 (d, 1H), 3.70 (d, 2H), 3.28 (d, 1H), 2.75 (m, 4H), 2.37 (s, 1H), 1.63 (m, 2H), 1.39 (m, 3H), 1.20 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)(O)=[O:2].C(C[N:17]1C(S)=NN=N1)(O)=O>>[C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)(=[O:2])[NH2:17]
Reactant: O=C(O)Cn1nnnc1S
Reactant: O=C(O)CCCn1nnnc1S
Product: NC(=O)CCCn1nnnc1S

Procedure:
When an equivalent amount of 1-(3-carboxypropyl)tetrazole-5-thiol was substituted in the procedure of Example 5 for 1-carboxymethyltetrazole-5-thiol, 1-(3-carbamoylpropyl)tetrazole-5-thiol was obtained, m.p. 133°-136°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[C:11]1(C)[CH:16]=CC=C[CH:12]=1>[Pd].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.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>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1)[CH:11]=[CH2:12]
Reactant: COc1ccc(Br)cc1F
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
4-Bromo-2-fluoroanisole (3 g, 14.6 mmol) was dissolved in toluene (100 ml) and treated successively with tetrakis-(triphenylphosphin)-palladium (0.84 g, 0.73 mmol) and allytributylstannane (5.8 ml, 19 mmol). Reaction mixture was refluxed for 23 hours. After evaporation of the solvent, the residue was dissolved in ether (150 ml) and stirred in the presence of sat. KF (20 ml) at room temperature for 0.5 hour. Solid was filtered and H2O (100 ml) was added to the filtrate. The aqueous phase was extracted with ether (2×100 ml), combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexan-ethyl acetate 19:1) to provide 4-allyl-2-fluoro-1-methoxy-benzene (1.26 g, 52%) as a colorless oil MS: m/e=166 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=4[F:24])[CH:19]=[O:20])=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.[CH3:26][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.C(OCCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[CH3:26])[CH:21]=[CH:22][C:23]=4[F:24])=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)c(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(O)c1ccc(F)c(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Temperature: 0 °C

Procedure:
470 mg of 3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-4-fluorobenzaldehyde are placed in a round-bottomed flask and dissolved in 90 ml of diethyl ether and 45 ml of tetrahydrofuran. The solution is cooled to 0° C. with an ice bath and 4 ml of a 1M solution of methylmagnesium bromide in dibutyl ether are added dropwise thereto. The mixture is stirred in the ice bath for 1 h 30 and 22 ml of a saturated aqueous ammonium chloride solution are added. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture. 401 mg of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:17]Br>ClCCl>[Br:17][CH:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(2,4-dichlorophenyl)-3-oxopropanoate (3.95 g, 15.1 mmol) in dichloromethane (150 mL) was added a solution of bromine (0.935 mL, 18.2 mmol) in dichloromethane (20.0 mL) dropwise at 0° C. The solution was then stirred at room temperature for 1 hour. The reaction was quenched with 10% aqueous potassium carbonate solution, and then the layers were separated. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oil was used directly in the next step (5.27 g, quantitative). LCMS: (AA) ES+, 341. 1H NMR (400 MHz, d1-chloroform) (2 sets of signals, keto and enol): 12.78 (s, 1H), 7.73-7.28 (m, 2 sets of 3H), 5.73 (s, 1H), 4.37 (q, J=7.28 Hz, 2H), 4.29 (q, J=7.28 Hz, 2H), 1.41 (t, J=7.03 Hz, 3H), 1.29 (t, J=7.03 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[CH:12])[CH2:4][CH2:5][CH3:6].[I:14]I.ClCl>CO.O>[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[C:12][I:14])[CH2:4][CH2:5][CH3:6]
Reactant: C#CCOC(=O)NCCCC
Reactant: II
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNC(=O)OCC#CI
Reaction time: 1 h
Yield: 166.2 %

Procedure:
At 8° C., 10.1 g of sodium hydroxide (0.244 mol) and 19.0 g of propargyl butylcarbamate (0.122 mol) are introduced as initial charge in 48 g of methanol and 50 g of water. At this temperature, 15.5 g of iodine (0.061 mol) are added in portions. Chlorine (5.6 g, 0.079 mol) is then slowly introduced into the reaction mixture so that the temperature still remains below 8° C. When the metered addition is complete, the mixture is stirred for 1 h at this temperature and then 105 g of water are added. The precipitated solid is isolated by filtration, washed with water and dried in vacuo. This gives 28.5 g of 3-iodo-2-propynyl N-butylcarbamate (purity: 95.0% (HPLC), polyiodized compounds: 0.3% (HPLC), yield: 79%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48.1 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 35 mg (0.2 mmol) of 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of dry pyridine under nitrogen in the presence of 30.4 mg (0.2 mmol) of DBU under reflux conditions. The solvent was removed under reduced pressure and to the orange viscous oil water was added and the solid was collected which was further purified from methanol to yield 20 mg of the desired product, m.p. 228°-230° C. 1H NMR (TFA) δ: 9.28 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1.4Hz, 1H), 5.9-5.75 (m, 4.14 (m, 5H), 3.1-2.72 (m, 5H), 1.7-1.2 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].[NH4+].[Cl-].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH2:18])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(N)=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 3-bromo-4-(methoxycarbonyl)benzoic acid (2.5 g, 9.69 mmol), NH4Cl (1.04 g, 19.38 mmol), HATU (5.5 g, 14.5 mmol), and DIPEA (5.2 mL, 29.1 mmol) in DCM (50 mL) was stirred for 3 h at rt. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (3:1) to give methyl 2-bromo-4-carbamoylbenzoate (1.3 g; yield 52%) as a white solid. MS: m/z=257.9 (M+1, ESI+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:19]C=[N+](C)C>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([Cl:19])[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(O)nc(N[C@@H](C)c2ccccc2)n1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)nc(N[C@@H](C)c2ccccc2)n1
Yield: 18.3 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-hydroxy-6-methylpyrimidine (100 mg, 0.436 mmol, 1 eq) in chloroform (2 mL) was added (chloromethylene)dimethylammonium chloride (Vilsmeier reagent) (55.9 mg, 0.436 mmol, 1 eq). After 1 hour the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (eluted with 3:1 hexanes/acetone) to give 19.8 mg of the title compound. Mass spectrum (NH3/CI): 248.1 (M+1).