Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)Cl.C(O)(=O)C>[Br:21][C:11]1[S:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1
Reactant: BrBr
Reactant: CSc1ccc(-c2sccc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ccc(-c2sc(Br)cc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 3-(4-fluorophenyl)-2-(4-methylthiophenyl)thiophene (15 g, 50 mmole) in methylene chloride (150 ml) was diluted with 150 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (55 ml, 1.1 equiv.) was then added dropwise. The reaction mixture was stirred at 0° for 1.5 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (15.4 g), m.p. 113°-116°.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([CH3:20])=[C:15]2[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30]C)=O.O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([CH3:20])=[C:15]2[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([NH:4][CH2:2][CH3:3])=[O:30]
Reactant: CCN
Reactant: COC(=O)c1cccc(Oc2cccc(-c3c(C)cnc4c(Cl)cccc34)c2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cccc(Oc2cccc(-c3c(C)cnc4c(Cl)cccc34)c2)c1
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of ethylamine hydrochloride (41 mg, 0.50 mmol) in toluene (2 mL) at ambient temperature under nitrogen is added 2.0M trimethylaluminum in toluene (0.25 mL, 0.50 mmol). After 0.5 h, methyl 3-[3-(8-chloro-3-methylquinolin-4-yl)phenoxy]benzoate (101 mg, 0.25 mmol) is added and the reaction heated at 60-65° C. for 16 h. The cooled reaction is treated with water (2 mL), then 2M aq HCl (1 mL) and extracted with dichloromethane (2×5 mL). The combined extracts are dried (MgSO4), concentrated in vacuo, and the resulting oil is chromatographed on silica gel using 50:50, then 75:25 ethyl acetate:hexane as eluent. The title compound is isolated as a glass (Rf˜0.3 in first solvent system, 101 mg). MS (ES) m/z 417.2; HRMS: calcd for C25H21ClN2O2+H+, 417.13643; found (ESI, [M+H]+), 417.1357.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Product: COCCc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.54 mmol) of the compound from Example 128A and 128 mg (0.81 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 138 mg (56% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.[C:17](O[Na])([CH3:19])=[O:18].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[O:12][C:17](=[O:18])[CH3:19])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: C=CCc1c(O)c(C)cc2ccc(=O)oc12
Reactant: CC(=O)O[Na]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CCc1c(OC(C)=O)c(C)cc2ccc(=O)oc12
Yield: 129.2 %

Procedure:
In such a manner a mixture of 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g), anhydrous AcONa (1.5 g) and acetic anhydride (40 ml) was refluxed for 1 h. The reaction mixture was gently diluted with water (40 ml), refluxed for 10 min and then poured into H2O (300 ml) yielding a precipitate, which was collected by filtration and washed several times with H2O. The dried product was crystallized from MeOH yielding 6-methyl-7-acetoxy-8-allylcoumarin (X) (6.1 g; m.p. 110°-11° C.). ##STR16##
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:17]([O-:19])[CH3:18].[Na+].[Na].Cl>C(O)C>[CH2:17]([O:19][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCOC(=O)c1cc2cccc(CBr)c2o1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOCc1cccc2cc(C(=O)OCC)oc12
Temperature: 25 °C
Yield: 69 %

Procedure:
4.67 g (16.5 mmol) of ethyl 7-bromomethyl-benzofuran-2-carboxylate were added to a solution of sodium ethanolate in anhydrous ethanol (freshly prepared from 400 mg (17.4 mmol) of sodium in 40 ml of anhydrous ethanol) and the mixture was heated at reflux for one hour. After cooling to room temperature the mixture was poured into 100 ml of 1N HCl and extracted twice with 150 ml of dichloromethane. After drying over magnesium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane). There were obtained 2.8 g (69%) of ethyl 7-ethoxymethyl-benzofuran-2-carboxylate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([F:22])[CH:15]=3)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:29])[CH:3]=1.Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([F:22])[CH:15]=3)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:29][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1F
Reactant: BrCC1CCCC1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-2-fluoro-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless solid (50%). MS (Turbo Spray): m/z=496.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2ccncc2c1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](Oc2ccc3ccncc3c2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesised from (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (CAS Reg. No. 170850-75-6) and isoquinolin-7-ol using the same method as preparation 11 and gave the title compound as an oil in 15% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1[F:9])=[CH2:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: C=Cc1cc(OC)ccc1F
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(OC)ccc1F
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 9 g of 3-ethenyl-4-fluoroanisole in 200 ml of ethanol was added 0.9 g of palladium/carbon. The resulting mixture was stirred under hydrogen atmosphere overnight, and filtered through Celite. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography (developer: 50% ethyl acetate/n-hexane) to give 7.0 g of the title compound as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(N(CC)CC)C>[O:1]([CH2:8][C@@H:9]([OH:10])[CH2:11][NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CCNC[C@H](O)COc2ccccc2)cc1
Yield: 39.3 %

Procedure:
7.71 g of (S)-2-phenoxymethyloxirane and 10.34 g of 2-(4-nitrophenyl)ethylamine hydrochloride were subjected to a ring-opening reaction in the presence of 5.20 g of triethylamine to obtain 6.35 g of (S)-1-phenoxy-3-[[2-(4-nitrophenyl)ethyl]amino]-2-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (I3) (2.00 g, 7.96 mmol), (R)-quinuclidin-3-ol (1.21 g, 9.55 mmol), HOBt (1.46 g, 9.55 mmol), and DCC (1.97 g, 9.55 mmol) in dry THF (70 ml) was stirred at RT overnight. Then THF was evaporated and the crude was taken up with DCM and washed twice with 2M K2CO3 and brine. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=95/5) to get (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (1.68 g; 58.5% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:55][C@@H:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:58][C@@H:57]1[OH:69].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:62]([N:59]1[CH2:60][CH2:61][C@@H:56]([NH:55][C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:13](=[O:14])[C:12]3[CH:29]=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:37][CH2:38]4)=[CH:32][C:11]=3[O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)(=[O:17])=[O:18])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])[C@@H:57]([OH:69])[CH2:58]1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@@H]5CCN(Cc6ccccc6)C[C@@H]5O)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of EXAMPLE 187A (0.158 g), (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049 g), and triethylamine (0.1 mL) in dioxane (2 mL) was heated at 100° C. overnight. The solvent was removed, and the residue was re-dissolved in 1:1 methanol:dimethylsulfoxide (3 mL). It was then purified by reverse phase Prep HPLC. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 20-80% acetonitrile/0.1% TFA in water. The desired fractions were collected, and the organic solvent was partially removed under reduced pressure. The resulting mixture was treated with saturated aqueous NaHCO3 mixture. It was then extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give the desired product. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.77 (dd, 1H), 7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13 (m, 1H), 7.13 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 5.21-5.22 (br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (br s, 4H), 2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (br s, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(C2CCCc3cncn32)cc1
Product: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21

Procedure:
In a manner analogous to that described in example 11, reaction of 5-p-cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with ethyl chloroformate yields the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C:30]1[CH:31]=[C:32]([CH:61]=[CH:62][C:63]=1[F:64])[C:33]([NH:35][NH:36][C:37](=[O:60])[C@H:38]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[C:52](Cl)[C:51]=1C)[C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:40])=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[CH2:65]([Cl:67])Cl>>[Si:42]([O:41][C@@H:39]([CH3:40])[C@@H:38]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]#[N:57])=[C:65]([Cl:67])[C:55]=1[CH3:54])[C:37]1[O:60][C:33]([C:32]2[CH:61]=[CH:62][C:63]([F:64])=[C:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:31]=2)=[N:35][N:36]=1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (331 mg, 1.26 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (321 mg, 1.26 mmol) and TEA (256 mg, 2.53 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (410 mg, 0.631 mmol) in 15 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (400 mg). 1H NMR (500 MHz, CDCl3, δ in ppm): 7.69 (m, 3H), 7.54 (d, J=9 Hz, 1H), 7.35 (t, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.56 (d, J=9 Hz, 1H), 4.99 (m, 1H), 4.74 (m, 1H), 2.37 (s, 3H), 1.62 (d, J=6 Hz, 3H), 1.20 (s, 9H), 1.06 (s, 9H), 0.40 (s, 6H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]>O1CCCC1>[C:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)C
Temperature: 0 °C

Procedure:
To a stirred ice-cooled solution of 2-isopropylamino-nitrobenzene (19.5 g, 0.1 mole) and triethylamine (15 ml 0.11 mole) in tetrahydrofurane (THF, 200 ml) was dropwise added ethoxalyl chloride. The ice bath was removed and the mixture was heated to reflux for 3 hours. The precipitated triethylammonium chloride was filtered off and the filtrate was evaporated in vacuo to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=[C:5]2[CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cn2ccc(CC)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1ccn2cc(C(=O)O)nc2c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of ethyl 7-ethylimidazo[1,2-a]pyridine-2-carboxylate (1.1 g) in ethanol (6 ml) and water (6 ml) was added sodium hydroxide (806 mg) at ambient temperature, and the mixture was stirred for 1 hour. The reaction mixture was adjusted to pH 3.0 with conc. hydrochloric acid. After evaporation of ehtanol, the residual crystal was collected, washed with cold water and dried to give 7-ethylimidazo[1,2-a]pyridine-2-carboxylic acid (0.77 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH2:37][CH3:38]>CN(C=O)C.CO>[ClH:1].[CH2:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:38]
Reactant: CCI
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg) in DMF (1 mL) was added sodium hydride (60%, 10 mg). The mixture was stirred for 15 minutes, then iodoethane (11 □L) was added. The mixture was stirred for 90 minutes then diluted with methanol (5 mL) and purified by ion exchange chromatography [SCX-2; MeOH—(1M NH3/MeOH): (100:0) →(0:100)]. The basic washings were concentrated in vacuo and purified by column chromatography [SiO2; cyclohexane-EtOAc-MeOH: (1:1:0)→(0:10:1)] and converted to the hydrochloride salt according to the description given in the general procedure (D6) to give the title compound (49 mg).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[CH3:21]O>C(Cl)Cl>[CH3:21][O:19][C:18](=[O:20])[C@@H:16]([NH2:17])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1OC
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
Thionyl chloride (3.2 g, 2.0 mL, 26.8 mmol) was added dropwise to a suspension 3-(3,4-dimethoxyphenyl)-L-alanine 1 (2.0 g, 8.9 mmol) in anhydrous MeOH (50 mL) at 0° C. under a nitrogen blanket. The mixture was slowly warmed to room temperature, then stirred for 72 hours. The solvent was removed under reduced pressure to provide a solid. The crude product was taken up in CH2Cl2, then washed with saturated NaHCO3 and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to yield a light brown oil (1.97 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[C:17]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]=3[O:23][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10].Cl>C(OCC)C.C(OCC)(=O)C>[ClH:1].[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[C:17]3[CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[O:23][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3c(oc12)CCNC3
Reaction time: 8 h

Procedure:
To the suspension of N-(3,5-dichloropyridin-4-yl)-2-(tert-butyloxycarbonyl)-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carboxamide (from step 4) (600 mg) in dry diethyl ether (10 ml), ethyl acetate saturated with HCl (4 ml) was added and stirred overnight. Reaction mixture was concentrated and the residue obtained was stirred in dry diethyl ether and filtered. The solid obtained was further purified by refluxing in isopropanol overnight. Yield=400 mg
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 59.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 1 ml of water and 9 ml of ethanol in place of the methanol and 214 mg of 3-methylaniline in place of the 3-(tert-butyl)aniline. 196 mg of N-(3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)=O)=[CH:4][CH:3]=1.CCN(CC)CC>ClCCCl>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:22][C:6]([C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:12][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(NNC(=O)c1ccc(CBr)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(-c2nnc(-c3ccc(Cl)cc3)o2)ccc1CBr
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a 100 mL round-bottom flask was added 2.1 g (12.3 mmol) of 4-chlorobenzoic acid hydrazide, 3.20 g (12.3 mmol) of 4-bromomethyl-3-nitro benzoic acid, 3.54 g (18.5 mmol) of EDC, and 200 mL of DCM. Allowed to stir at room temperature for 18 h. Removed ⅔ of DCM, added water and filtered off white solid and washed with Et2O to give 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 1H) 5.12 (s, 1H) 7.59-7.64 (m, 2H) 7.91-7.95 (m, 2H) 7.96 (d, J=8.21 Hz, 1H) 8.22-8.29 (m, 1H) 8.57 (dd, J=6.57, 1.77 Hz, 1H) 10.76 (s, 1H) 10.94 (dd, J=5.18, 0.88 Hz, 1H). MS (m/z) 413.9 M (+1), tR=1.28, Meth 10. To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE. To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40° C. for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30% EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time=1.51, Method 10.