Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.C(OCC)(=[O:20])C>O1CCOCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=[O:20]
Reactant: COC(=O)c1cc(C(Br)Br)cnc1C(=O)OC
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C=O)cnc1C(=O)OC
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of dimethyl 5-dibromomethylpyridine-2,3-dicarboxylate (8.32 g, 0.0227 mol) in dioxane (60 mL) and water (20 mL) is added silver nitrate (7.85 g, 0.0476 mol). The resulting slurry is heated at reflux for 3 hours. The reaction mixture is cooled to room temperature, filtered through a pad of diatomaceous earth and the diatomaceous earth is rinsed with tetrahydrofuran. The filtrate is concentrated in vacuo to remove the dioxane and tetrahydrofuran. The resultant aqueous solution is made basic by the addition to saturated aqueous sodium bicarbonate (100 mL) and extracted with methylene dichloride. The combined extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Chromatography of said residue using silica gel and 33% ethyl acetate in hexanes as eluant yields the title compound as a white solid, (4.31 g, 85%) mp 75° C.-77° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]([F:15])([F:14])[F:9])=[CH:4][N:3]=1
Reactant: OCCC(F)(F)F
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)CCOc1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.00 g (5.75 mmol) 2-bromo-5-hydroxypyridine, 0.66 g (5.75 mmol) 3,3,3-trifluoro-1-propanol and 1.51 g (5.75 mmol) triphenylphosphine are added to 50 mL THF. Then 1.32 g (5.75 mmol) di-tert-butyl azodicarboxylate are added and the reaction mixture is stirred at 60° C. for 3 h. The solvent is removed in vacuo and the crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[NH:21][N:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>C1COCC1.CN1C(=O)N(C)CC1.[Pd]>[Cl:35][C:31]1[CH:30]=[C:29]([NH:28][C:26]2[N:25]=[CH:24][N:23]=[C:22]3[NH:21][N:20]=[C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[C:27]=23)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CC(C)[C@H](N)C(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
In 4 ml of THF/DMEU 1:3, 40 mg (0.08 mmol) of rac.-3-([N-benzyloxycarbonylvalyl]-amino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Example 8) are hydrogenated in the presence of 10 mg of Pd/C (10%) and 10 μl of 1,2-dichlorobenzene. The catalyst is filtered off, and the filtrate is partially concentrated by evaporation in a rotary evaporator, poured into 30 ml of water and again filtered and the filtrate is concentrated by evaporation under a high vacuum first at RT and finally at 50° C. to yield rac.-4-(3-chlorophenylamino)-3-(valyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=9.2; FAB-MS: (M+H)+=360.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]=[O:9].N12CCC(CC1)CN2.Cl>O.CS(C)=O>[OH:9][CH2:8][C:2](=[CH2:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC
Reactant: C=O
Agent: C1CN2CCC1CN2
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: C=C(CO)C(=O)OCC
Temperature: 100 °C

Procedure:
Into a 2-liter separable flask fitted with a stirrer, a reflux condenser and a thermometer, dimethylsulfoxide (500 parts), water (170 parts), ethyl acrylate (200 parts), paraformaldehyde (purity: 80%, 72.5 parts) and diazabicyclo (2.2.2) octane (15.6 parts) were charged. They were heated to 100° C., and subjected to a reaction for 4 hours. Although the contents were not homogeneous at the time of the charging, they turned into a homogeneous clear mixture around 60° C. Dilute hydrochloric acid (500 parts) was then added, followed by extraction twice with diethylether (200 parts, each). The extract was dried over anhydrous magnesium sulfate. After the thus-dried extract was concentrated in an evaporator, the concentrate was subjected to distillation under reduced pressure. Ethyl 2-(hydroxymethyl)acrylate was obtained (yield: 193 parts). The reaction product was identified to be the target compound by IR and NMR, and its purity was determined to be 98.7% by GC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([CH2:18][C@H:19]([NH:30][S:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(=[O:33])=[O:32])[C:20]([N:22]([CH2:26][C:27]([OH:29])=O)[CH:23]2[CH2:25][CH2:24]2)=[O:21])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:45][O:46][NH2:47].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH:23]1([N:22]([CH2:26][C:27](=[O:29])[NH:47][O:46][CH3:45])[C:20]([C@@H:19]([NH:30][S:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(=[O:33])=[O:32])[CH2:18][C:16]([NH:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)=[O:17])=[O:21])[CH2:24][CH2:25]1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N(CC(=O)O)C2CC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CONC(=O)CN(C(=O)[C@H](CC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)NS(=O)(=O)c1ccc2ccccc2c1)C1CC1
Yield: 53.9 %

Procedure:
500 mg of [[(S)-3-[(S)-1-tert-butoxycarbonyl-piperidin-3-ylmethylcarbamoyl]-2-(naphthalen-2-sulfonylamino)-propionyl]-cyclopropyl-amino]-acetic acid are stirred at room temperature for 20 hours in 10 ml of methylene chloride together with 71 mg of O-methylhydroxylamine hydrochloride, 0.28 ml of N-methyl-morpholine and 376 mg of BOP. The mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and then with water. After drying and evaporation the product is purified over silica gel with ethyl acetate/methanol (9:1). There are obtained 282 mg of tert-butyl (S)-3-[(S)-3-([cyclopropyl-methoxycarbamoylmethyl-carbamoyl)]-3-(naphthalen-2-ylsulfonylamino)-propionylamino-methyl]-piperidine-1-carboxylate, MS (ISP): 646.6 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1COC(c2cccs2)c2cc(Br)ccc2N1
Product: O=C1COC(c2cccs2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chlorobenzeneboronic acid generally according to the procedure described in example 1. 1H-NMR (CDCl3) δ 8.26 (br s, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.42 (dd, J=5.1, 0.9 Hz, 1H), 7.36 (m, 3H), 7.24 (d, J=2.0 Hz, 1H), 7.05 (m, 2H), 6.93 (d, J=3.5 Hz, 1H), 6.24 (s, 1H), 4.56 (d, J=17.0 Hz, 1H), 4.47 (d, J=17.0 Hz, 1H); MS (ES) m/z 356 (M+H)+; Anal. Calc. For C19H14ClNO2S: C, 64.13, H, 3.97; N, 3.94. Found: C, 64.1, H, 3.83; N, 3.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:37][C:38]([F:46])([F:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[O:40]>C1(C)C=CC=CC=1.O>[F:37][C:38]([F:46])([F:45])[C:39]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:40])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CC(Cc1cccnc1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 243 (0.08 g, 0.236 mmol) in toluene was added PTSA (0.090 g, 0.472 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.129 g, 0.590 mmol) was added to the reaction and heated to 100° C. for 16 h. Reaction was cooled to RT, diluted with water, extracted with ethyl acetate twice, the organic layer dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 245. 1HNMR (400 MHz, CDCl3) δ ppm 7.06 (m, 2H), 6.88 (s, 1H), 6.90 (s, 1H), 6.123 (s, 1H), 3.88 (m, 7H), 3.49 (m, 1H), 3.08 (m, 2H), 3.03 (m, 6H), 2.29 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]([CH2:15][CH:16]=[C:17]([CH3:32])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:12](=[O:14])[CH3:13])(=O)C.[Na+].[Cl-]>CO>[C:27]([Si:24]([CH3:25])([CH3:26])[O:23][CH2:22][CH:21]([CH3:31])[CH2:20][CH2:19][CH2:18][C:17]([CH3:32])=[CH:16][CH2:15][CH:11]([OH:10])[C:12](=[O:14])[CH3:13])([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(=O)OC(CC=C(C)CCCC(C)CO[Si](C)(C)C(C)(C)C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(=O)C(O)CC=C(C)CCCC(C)CO[Si](C)(C)C(C)(C)C

Procedure:
400 ml saturated potassium carbonate solution is added to 1.94 g (5.05 mmol) 3-acetoxy-11-(tert-butyl-dimethylsilyloxy)-6,10-dimethyl-5-undecene-2-one in 20.0 ml methanol. After termination of the reaction (accurate DC control, e.g. approx. 10 min at room temperature), 30 ml of the NaCl solution is added and five times extracted with 30 ml diethylether. The combined organic phases are washed again with NaCl solution, and dried over sodium sulfate, the solvent was then removed in the vacuum, and silica gel chromatography was performed with the residue.
Reaction SMILES: [ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.CO>[ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 N solution of HCl in ether (15 ml) was added in stirring solution of compound 5 (10.0 g, 21.9 mmol) in methanol at 0° C. The mixture was allowed to warm to room temperature gradually and continue stirred for 2 hr. Solvent was evaporated under reduced pressure, and the residue was treated with anhydrous ether (120 mL) to precipitate the product 6. The precipitated product was washed with ether (50 mL×2) afforded the titled compound as white solid. [α]D25 −28.19°; 1H NMR (500 MHz, DMSO-d6): δ 8.40 (bs, 2H, D2O exchange, NH2), 7.88 (m, 4H), 7.64 (m, 2H), 7.45 (m, 4H), 5.48 (m, 2H), 5.07 (m, 1H), 3.96 (m, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 2.47 and 2.39 (m, 1H), 1.63 (m, 1H); HR-MS Calcd. For (C20H21NO5)+ 355.1420, found 335.1293.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]([CH2:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)[CH:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([CH2:32][N:28]([CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:34][CH:35]=1
Reactant: CC(C)N(C)Cc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)N(C)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 63.4 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.18 mmol) with 4-[(N-methyl-iso-propylamino)-methyl]-benzylamine (270 mg, 1.41 mmol) in toluene (10 mL). Purify by chromatography on silica gel (75 g) eluting with a gradient of 100% DCM to 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain 7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (350 mg, 64%). MS (APCI) m/z: 468 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(O[CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@:19]1([OH:32])[CH3:31])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([S:11][CH2:17][C@@H:18]2[C@:27]3([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]3)[CH2:21][CH2:20][C@@:19]2([CH3:31])[OH:32])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(S)cc(OC)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(OC)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A mixture of 3,5-dimethoxybenzenethiol (20) (6.74 g, 39.60 mmol), ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (12.62 g, 39.60 mmol), and Cs2CO3 (38.70 g, 118.77 mmol) in CH3CN (560 mL) was stirred at room temperature for 1 h, then refluxed for 24 h. After cooling, the mixture was concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,2R,4aS,8aS)-1-{[(3,5-dimethoxyphenyl)-sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (21) (9.40 g, 60%) as a light yellow sticky mass.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([Cl:9])[N:4]([CH2:10][CH3:11])[N:3]=1.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:7][C:6]1[C:2]([Cl:1])=[N:3][N:4]([CH2:10][CH3:11])[C:5]=1[Cl:9]
Reactant: BrP(Br)Br
Reactant: CCn1nc(Cl)c(CO)c1Cl
Solvent: O
Solvent: CCOCC
Product: CCn1nc(Cl)c(CBr)c1Cl
Temperature: -30 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A solution of 0.82 g (4.2 mmoles) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol dissolved in 50 ml of diethyl ether was cooled to −30° C. Thereto was added 1.3 g (4.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g (yield: 81.8%) of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])[CH:5]=[C:6]([CH3:7])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CC(=O)C=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1Cl
Yield: 62 %

Procedure:
Upon boiling a solution of 18.1 g of 2-chlorobenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 171°C (ethanol) is obtained. Yield: 62 percent of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(OCC)(=O)C>[CH2:17]([O:16][C:12]([CH:13]=[CH:14][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)=[O:15])[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(CC(=O)O)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 4-bromophenylacetic acid (43.0 g, 200 mmol) in dimethyl formamide (400 mL) in a round bottom flask under nitrogen atmosphere at room temperature was added ethyl acrylate (43.3 mL, 400 mmol), palladium diacetate (0.90 g, 4 mmol), triphenylphosphine (2.10 g, 8 mmol), and diisopropylethylamine (87.2 mL, 500 mmol). The reaction mixture was heated to 100° C. for 43 hours, cooled to room temperature, and hydrochloric acid (1N, 1 L) was added. To the reaction mixture was added ethyl acetate (500 mL), the aqueous layer was extracted with ethyl acetate (2×500 mL), and the combined organic layers washed with hydrochloric acid (1N, 500 mL), water (500 mL) and saturated sodium chloride solution (250 mL), then dried over sodium sulfate, filtered and evaporated in vacuo to provide the title compound as a mixture of cis and trans isomers (46.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[H-].[Na+].[CH3:13][N:14]([CH3:30])[S:15]([NH:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([F:26])[C:23](F)=[CH:22][C:21]=1[F:28])(=[O:17])=[O:16]>O1CCCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:6][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:19]([NH:18][S:15]([N:14]([CH3:30])[CH3:13])(=[O:17])=[O:16])=[O:29])=[C:21]([F:28])[CH:22]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
To a solution of 3,4-dichlorobenzyl alcohol (157 mg, 0.884 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60% dispersion in oil, 37 mg, 0.92 mmol). The reaction was stirred at room temperature for 45 minutes and heated to 55° C. for 30 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the residue was added a solution of N-[(dimethylamino)sulfonyl]-2,4,5-trifluorobenzamide (Preparation 3, 100 mg, 0.354 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 3 hours and then partitioned between aqueous 2M hydrochloric acid (5 mL) and ethyl acetate (10 mL). The organic phase was separated and washed with a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was triturated with diethyl ether, filtered and dried in vacuo to afford the title compound as a white solid (56 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:7][CH2:6]1)=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2N)CC1

Procedure:
A solution 0.01 M of trans-4-{[2-(2-Nitro-phenyl)-ethylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2 g, 6.25 mmol) in MeOH (625 mL) with ˜1% of glacial AcOH (6.25 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small type cartridge, full hydrogen mode, flowrate of 1 mL/min). Finally, the solvent was removed under reduced pressure to obtain the titles compound (3.07 g, quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.N1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH:11][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1nc2ccc(F)cn2c1-c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cc1ccc(F)cc1)Nc1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine (compound l, 0.075 g, 0.00033 mol) was dissolved in tetrahydrofuran (5.0 mL) and pyridine (29 uL, 0.00036 mol) was added. Rxn cooled to 0° C. and 4-fluorophenylacetyl chloride (48 uL, 0.00036 mol) was added. The reaction was stirred at 0° C. for 30 minutes. The solvent was removed and the crude product was partioned between water (25 mL) and EtOAc (25 mL). The layers were separated and the organic layer was washed 3×20 mL with water. The organic layer was dried (magnesium sulfate) then chromatographed on silica (70% ethyl acetate/hexanes) to give N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide Rf 0.37, 70% ethyl acetate/hexanes; MS m/z 364 (M+H). SH-SY5Y_EC50 (μM): 0.7321.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1[CH:5]=O.S([O-])([O-])(=O)=O.[Mg+2].C([O-])(=O)C.[NH4+].[N+:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([O-:28])=[O:27]>ClCCl.O>[CH3:33][O:32][C:30](=[O:31])/[C:29](/[N+:26]([O-:28])=[O:27])=[CH:5]\[C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C(=C\c1c(OC)cc(OC)cc1OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4,6-trimethoxybenzaldehyde (20.75 g, 0.105 mol) was dissolved in dichloromethane (300 mL) and to this solution magnesium sulphate (15 g, 0.124 mol), ammonium acetate (10 g, 0.129 mol) and methyl nitroacetate (12.60 g, 0.105 mol) were added and stirred at room temperature for 2 hours. At the end of two hours, water (300 mL) was added to the reaction mass, the organic layer was separated and the aqueous layer extracted with dichloromethane (2×100 mL). The organic layers were combined and concentrated under reduced pressure to give a solid, which was crystallized from methanol (100 mL).