Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][NH:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8].[C:35]([O-])(O)=O.[Na+].CI>CO>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][N:5]([CH3:35])[CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])O
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NCc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)N(C)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To 100 mg of (methyl 2-[(2,6-dichlorobenzyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate) 41 in CH3OH (2.3 ml) are added, at 0° C., NaHCO3 (1 equ.) and CH3I (1 equ.). The reaction is stirred for 1 h at 0° C., and then at room temperature for 2 days. The solvent is evaporated and CH2Cl2 (10 ml) is added to the residue. The solution is washed with water, brine, again water and dried over MgSO4, filtered and evaporated. Due to an incomplete reaction, the protocol is repeated using a tenfold excess of NaHCO3 and CH3I in MeOH (5 ml). After a similar work-up, the residue is purified by silica gel chromatography using hexane/AcOEt 90/10 as eluent to give methyl 2-[(2,6-dichlorobenzyl)(methyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 51.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([S:7]([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])(=[O:28])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Into a 25-mL single-necked round-bottomed flask equipped with a magnetic stir bar were placed 0.63 g (2.0 mmol) of (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine (prepared according to Example 1), 1.04 g (3.0 mmol) 3-chloroperoxybenzoic acid (60%, from Aldrich) and 20 mL chloroform. The reaction mixture was stirred at room temperature for 1 h, washed with 20 mL saturated aqueous Na2S2O3 solution, diluted with 50 mL CH2Cl2, washed with saturated aqueous Na2CO3 solution (2×10 mL) and dried (MgSO4). Filtration and removal of the solvent gave a solid residue which was purified by flash chromatography (ethyl acetate:n-pentane, 2:8) to afford the titled compound (0.62 g, 94%): mp. 85°-87° C.; [α]D20 +18.2° (c 1.0, CHCl3); IR (KBr): 3033.3, 1757.2, 1597.5, 1334.1, 1210.1, 1163.6, 1091.7 cm-1 ; 1H NMR (CDCl3) δ2.44 (s, 3H, CH3), 3.49 (s, 3H, CH3), 3.71 (d, J=7.7 Hz, 1H, CH), 4.12 (d, J=7.6 Hz, 1H, CH), 7.20-7.32 (m, 5H, aromatic), 7.35 (d, J=8.4 Hz, 2H, aromatic), 7.92 (d, J=8.3 Hz, 2H, aromatic); 13C NMR (CDCl3) δ164.5, 145.0, 133.8, 130.9, 129.7, 128.3, 128.0, 127.9, 127.2, 52.3, 45.3, 43.3, 21.6. Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17. Found: C, 61,43; H, 5.17.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:46].O1CCOCC1>CO>[ClH:46].[ClH:46].[ClH:46].[NH2:38][C:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:27]3[N:13]4[C:14]5[CH:26]=[CH:25][CH:24]=[N:23][C:15]=5[NH:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[C:12]4=[N:11][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=3)=[CH:33][CH:32]=2)[CH2:35][CH2:36][CH2:37]1
Reactant: CC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 98 %

Procedure:
tert-Butyl (1-{4-[2-(4-acetylphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (27 mg, 0.045 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 22.5 hours. The mixture was concentrated to afford the desired product (27 mg, 98%) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.66-8.63 (m, 3H), 8.11 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.35-7.35 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.70 (m, 1H), 3.68-3.65 (m, 1H), 2.64-2.53 (m, 5H), 2.24-2.15 (m, 1H), 1.89-1.80 (m, 1H). LCMS: 498 [M+H].
Reaction SMILES: [Br:1][CH:2]1[C:7](=[O:8])[C:6]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>ClCCl>[CH2:9]([CH:6]1[C:7](=[O:8])[C:2]([Br:1])=[CH:3][N:4]=[CH:5]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1C(C(O)c2ccccc2)=CN=CC1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(Br)=CN=CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3-bromo-5-(hydroxyl-phenyl-methyl)pyridin-4-one 11 (0.125 g, 91 mmol), TFA (16 mL) and Et3SiH in anhydrous dichloromethane (30 mL) was stirred at rt for 10 h [Borzilleri, et al., U.S. Pat. 20050245530]. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 0.081 g (69%), white solid. 1H NMR (MeOH— d4, 500 MHz): δ 8.12 (s, 1H), 7.47 (s, 1H), 7.29-7.17 (m, 5H), 3.83 (s, 2H). 13C NMR (MeOH—d4, 125 MHz): δ 175.2, 140.7, 139.5, 136.9, 130.8, 130.0, 130.0, 129.5, 129.5, 127.3, 114.1, 34.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:9][C@@H:7]([C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@@H](O)[C@H]1COC(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (the product of step iv) (0.24 g) in dry THF (10 mL) at 0° C. was added in portions sodium hydride (91 mg as 60% dispersion in mineral oil) followed in portions by 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.50 g). The reaction mixture was stirred at room temperature for 48 h then quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ethyl acetate. The layers were separated and the aqueous layer extracted with further ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 1:9 gradient) as eluent to give the subtitle compound as a pale yellow solid. Yield: 0.42 g.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C@@H:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:22]1[CH2:23][OH:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CC(C)=O.O>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C@@H:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[C@H:22]1[C:23]([OH:3])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 ml of Jones' reagent (chromium trioxide/4N aqueous sulfuric acid: Bowden, Heibron, Jones & Weedon, J. Chem. Soc., 1946, 39) was added, whilst ice-cooling, to a solution of 245 mg (0.74 mmol) of (3R)-1-t-butoxycarbonyl-3-t-butyldimethylsilyloxy-L-prolinol [prepared as described in step (a) above] in 10 ml of acetone, and the mixture was stirred at 0° C. for 2 hours. At the end of this time, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was triturated with hexane, to give 191 mg of the title compound as colorless crystals, melting at 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([S:9](=[O:14])(=[O:13])[N:10]([CH3:12])[CH3:11])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([S:9](=[O:13])(=[O:14])[N:10]([CH3:12])[CH3:11])[C:7]=1[O:8][CH2:34][CH:31]1[CH2:33][CH2:32]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c(S(=O)(=O)N(C)C)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(OCC2CC2)c(S(=O)(=O)N(C)C)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 41.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.75 g, 1.77 mmol) in DMSO (25 mL) were added K2CO3 (367 mg, 2.106 mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (350 mg) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5].[Br:36]Br>C(O)(=O)C>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([C:31]=1[Br:36])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5]
Reactant: BrBr
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Solvent: CC(=O)O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2[nH]c3ccccc3c2Br)s1
Reaction time: 1 h

Procedure:
N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)indole-2-carboxamide (1.0 g, Example 14) was dissolved in acetic acid (12 ml). Bromine (0.1 ml) dissolved in acetic acid (1 ml) was dropwise added under water-cooling, and the mixture was stirred for 1 hour. The solvent was evaporated, and an aqueous sodium thiosulfate solution was added. The mixture was extracted with chloroform. The extract was washed with saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from methanol to give 0.36 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-bromoindole-2-carboxamide.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1)=[O:17]
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc2c(c1)OCO2
Yield: 43.5 %

Procedure:
1,2-Methylenedioxybenzene (1.18 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 1.22 g of 6-bromo-1-(3,4-methylenedioxyphenyl)-1-hexanone.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[CH:13]([CH3:15])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CC(C)COc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(C)COc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isobutoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isobutoxyphenylboronic acid in a manner analogous to Example 2c (0.46 g, 70%). MS=302 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]2>CC(N(C)C)=O>[C:40]([C:35]1[NH:36][C:37]2[C:33]([CH:34]=1)=[CH:32][C:31]([O:30][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:39][CH:38]=2)([OH:42])=[O:41]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C(=O)O)cc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (345 mg, 5.0 mmol), 5-hydroxy-2-indolecarboxylic acid (106 mg, 0.6 mmol) and DMA (2.0 ml) was purged with nitrogen for 5 minutes at 25° C. This mixture was then stirred at 100° C. for 3 hours, allowed to cool to ambient temperature, filtered and the filtrate evaporated under vacuum. The residue was purified on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (as a gradient from 30/69.8/0.2 to 50/49.8/0.2) and the product further purified by silica column chromatography eluting with dichloromethane/methanolic ammonia (7M) (90/10) to give 4-(2-carboxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (85 mg 36%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.70 g, 1.80 mmol) in dimethylformamide (14 ml) was added cesium carbonate (2 g) followed by methyl bromoacetate (2551 μl, 2.70 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate, and the combined organic phases dried over magnesium sulfate and concentrated in vacuo to provide a yellow solid. No further purification was required. Yield: 0.51 g, 61%; LCMS method: basic, RT: 3.77 min, MI: 462 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][CH2:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O)[CH3:12].C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:20]/[C:16]2[N:15]([CH2:14][O:13][CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOCn1cccc1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOCn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 4-chlorophenylacetonitrile (500 mg, 3.30 mmol), 1-ethoxymethyl-1H-pyrrole-2-carbaldehyde (520 mg, 3.39 mmol, 1.03 equiv.), and 18-crown-6 ether as a phase transfer catalyst (87 mg, 0.33 mmol) in toluene (30 ml) was added potassium hydroxide (185 mg, 3.30 mmol) and the mixture was heated to 80° C. for 3 h, then stirred at room temperature overnight. The solution was filtered through a small plug of silica and concentrated to afford an oil (705 mg). This is Compound 7 in Table 8.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:38]=[CH:37][CH:36]=[CH:35][C:16]=1[O:17][CH2:18][CH:19]([OH:34])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=O.Cl>C(O)C>[NH2:4][C:3]1[N:5]=[C:13]([C:15]2[CH:38]=[CH:37][CH:36]=[CH:35][C:16]=2[O:17][CH2:18][CH:19]([OH:34])[CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[CH:12]=[CH:11][N:2]=1
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1nccc(-c2ccccc2OCC(O)CN2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
2.0 g (0.021 mole) of guanidine hydrochloride and 0.042 mole of a 30% strength sodium methylate solution are added to 10.0 g (0.021 mole) of 1-[2-(3-dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl in 250 ml of ethanol, and the mixture is refluxed for 12 hours. The hot solution is filtered and the filtrate is concentrated. The crude product is recrystallized from ethanol, and 3.5 g (38%) of product of melting point 159°-160° C. are isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.N1C=CC=CC=1>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: II
Reactant: Cc1cccc(C)c1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and pyridine (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91.8 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12]1[C:13]([I:27])=[C:14]([C:18]([I:26])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:20]=1[I:21])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][NH:34][CH3:35])[CH3:30]>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:36])[CH2:33][N:34]([C:15](=[O:16])[C:14]1[C:13]([I:27])=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:18]=1[I:26])[CH3:35])[CH3:30]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
840 ml (6.1 Mol) triethylamine is added to a solution of 759 g (1.2 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 276 g (1.8 Mol) sarcosine ethyl ester hydrochloride in 7600 ml N,N-dimethylformamide and stirred for 1 hr. at 60° C. The reaction mixture is cooled to room temperature, the crystallized triethyl ammonium chloride is filtered, washed with N,N-dimethylformamide and reduced under vacuum in a rotary evaporator. The residue is dissolved in 650 ml methanol and added dropwise to 3 l ethyl acetate. The precipitate is crystallized overnight, filtered to a dry state and finally washed with water, 1N hydrochloric acid, cold saturated sodium bicarbonate, water and dried under vacuum at 60° C. Yield: 685 g (80%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)cc2)CC1
Yield: 48.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-chlorophenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 1.0 g of 4-amino-5-chloro-N-((1-(6-(4-chlorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH2:22])=[O:21].[OH-].[Na+]>C(#N)C>[C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][CH:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4])(=[O:21])[NH2:22]
Reactant: NC(=O)c1sccc1N
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A solution of ethyl 2-bromo-2-phenylacetate (349 μl, 2.00 mmol) and 3-aminothiophene-2-carboxamide (284 mg, 2.00 mmol) in acetonitrile (2 ml) was heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was dissolved in EtOH (2 ml). Sodium hydroxide (80 mg, 2.00 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hours. Then ethanol was evaporated, and the residue was taken up with water and washed with EtOAc. The pH of the aqueous phase was adjusted to 3 with HCl, and product was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetic acid (389 mg, 70% yield), which was used in the next step without any further purification.