Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]3[C:8]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 80 °C
Yield: 99.7 %

Procedure:
To a solution of N-{4-[8-chloro-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (744 mg, 1.71 mmol) in ethanol (25 mL) was added tin(II) chloride dihydrate (1.62 g, 8.57 mmol). The mixture was heated at 80° C. for 4 hours. The solution was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. Dichloromethane was added and the organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 to 1:2 hexanes:ethyl acetate) provided 4-[2-(3-aminophenyl)-8-chloroimidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (690 mg, 99%) as a foam. 1H NMR (CDCl3): δ 9.54 (broad, 1H), 8.10 (d, 1H), 7.39 (d, 1H), 7.16 (t, 1H), 7.05 (m, 1H), 6.97 (d, 1H), 6.84 (t, 1H), 6.72 (m, 1H), 6.51 (d, 1H), 5.18 (d, 1H), 4.33 (m, 1H), 3.72 (broad, 2H), 2.14–2.06 (m, 2H), 1.82–1.54 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:17](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[CH:17][NH:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: O=CO
Product: N#Cc1ccccc1-c1ccc2nc[nH]c2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (0.04 moles, 8.3 g) was refluxed in 100 ml formic acid for 3 hours. The solution was concentrated in vacuo, triturated with toluene, and dissolved in water. The pH of the solution was adjusted to 7.5 with 2N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The solid was triturated with 25% ethyl acetate/75% hexane, filtered and purified by HPLC on silica gel eluted with a gradient of 50-75% ethyl acetate in hexane. The reaction yielded 7.3 g of 5-(2-Cyanophenyl)benzimidazole. (MS)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccc(OC)cc4)c3)cn2)CC1

Procedure:
5′-(4′-Methoxy-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 4-methoxyphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2386.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C#N)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of 2-(4-cyano-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (111 mg, 0.34 mmole) and glycine (512 mg, 6.82 mmole) in 0.5 M sodium methoxide/methanol (13 ml, 6.48 mmole) was refluxed for 45 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (35 ml) and extracted with methyl tert-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The suspension was extracted with chloroform/isopropanol (3:1, 35 ml). The organic suspension was concentrated, washed with water and dried in vacuo to give the title compound as a brown solid (52 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.52 (t, 1H), 8.90 (s, 1H), 8.30 (d, 1H, J=8.2 Hz), 8.04 (d, 1H, J=8.2 Hz), 4.00 (d, 2H, J=5.8 Hz); MS: (+) m/z 355.22 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH:26]([C:28]2[C:33]3[N:34]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=5[Cl:48])[C:35]4=[N:36][C:32]=3[CH:31]=[CH:30][CH:29]=2)[OH:27])[CH2:25][CH2:24]1>ClCCl.C(=O)([O-])O.[Na+]>[CH:23]1([C:26]([C:28]2[C:33]3[N:34]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=5[Cl:48])[C:35]4=[N:36][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24]1
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
Dess-Martin reagent (925 mg, 2.18 mmol) was added to a stirred solution of cyclopropyl[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (770 mg, 1.98 mmol) in dichloromethane (8.0 mL) at 0° C., and the mixture was stirred at 0° C. for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (226 mg, 0.585 mmol, 30%).
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:43])[CH2:9][N:10]([C:15](=[O:42])[C@H:16]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:17][S:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[CH3:32][O:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:33][CH3:34])[CH:22]=[C:21]([S:18]([NH:17][C@H:16]([C:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([OH:43])=[O:7])=[O:42])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:19])=[O:20])[CH:30]=[CH:29]2
Reactant: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonly)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatograhed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.43 g (79 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid, I.R. (KBr): 3,360, 3,140, 1,622 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]([CH:27]([CH3:29])[CH3:28])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:10]([O:25][CH3:26])[CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>O1CCOCC1>[CH3:37][S:38]([C@@:2]([NH2:1])([CH:27]([CH3:29])[CH3:28])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:10]([O:25][CH3:26])[CH:9]=1)=[O:4])(=[O:40])=[O:39]
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCCCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CCNC(=O)[C@](N)(C(C)C)S(C)(=O)=O)ccc1OCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-2-amino-N-(2-{4-[3-(4-chloro-phenyl)-propoxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide (2 g) and triethylamine (0.9 ml) in dioxane (30 ml) is added methanesulfonyl chloride (0.4 ml). The reaction mixture is stirred overnight at room temperature. Water (200 ml) is then added. It is extracted with ethyl acetate (2×200 ml). The organic layers are washed with brine (2×200 ml), dried (MgSO4) and evaporated. (S)-2-Methanesulfonyl-aminoN-(2-{3-methoxy-4-[3-(4-chloro-phenyl)-propoxy]-phenyl}-ethyl)-3-methyl-butyramide is obtained.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[C:26]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:32]([I:39])[CH:31]=[CH:30][C:27]=1[CH:28]=O>C1(C)C=CC=CC=1>[CH2:35]([O:34][C:33]1[CH:26]=[C:27](/[CH:28]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:30]=[CH:31][C:32]=1[I:39])[CH2:36][CH2:37][CH3:38]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1c(I)ccc(C=O)c1C
Solvent: Cc1ccccc1
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Yield: 87.2 %

Procedure:
65.08 g (0.195 mol, 2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 29.60 g (0.097 mol, 1 eq) of methyl-3-butoxy-4-iodobenzaldehyde in 360 ml of toluene. The reaction mixture is refluxed for 2 hours. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (50/50 heptane/dichloromethane). 30.47 g of methyl (E)-3-(3-butoxy-4-iodophenyl)acrylate are obtained in the form of pale yellow crystals. Yield=87%
Reaction SMILES: [CH:1]1([C:5]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[C:10](=[O:18])[NH:9][C:8]=3[N:7]([CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N-:28]=[N+:29]=[N-:30].C([Sn](=O)CCCC)CCC.N>C1(C)C=CC=CC=1>[CH:1]1([C:5]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[C:10](=[O:18])[NH:9][C:8]=3[N:7]([CH2:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([C:23]4[NH:30][N:29]=[N:28][N:24]=4)[CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Cn2nc(C3CCC3)c3c4c(c(=O)[nH]c32)CCCC4)c1
Agent: CCCC[Sn](=O)CCCC
Agent: N
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(c(C3CCC3)nn2Cc2cccc(-c3nnn[nH]3)c2)c2c1CCCC2
Temperature: 100 °C

Procedure:
To a suspension of Example 95A (150 mg) and trimethylsily azide (582 mg) in toluene (20 ml) was added dibutyltin oxide (28 mg). The mixture was heated at 100° C. for 3 days. Solid material was collected by filtration, washed with methanol and dried to give Example 95. Yield: 100 mg. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.81 (s, 2H), 1.92 (m, 1H), 2.02-2.11 (m, 1H), 2.35-2.44 (m, 4H), 2.51 (m, 2H), 2.91 (br s, 2H), 3.84-3.90 (m, 1H), 5.37 (br s, 1H), 5.51 (s, 2H), 5.51 (s, 2H), 7.30 (m, 2H), 7.97 (m, 2H),
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][C:14](OC)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].BrC[C:23]([O:25]CC)=[O:24]>O1CCCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:23]([OH:25])=[O:24])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-n2ccnc2)cc1
Yield: 54 %

Procedure:
A solution of methyl 4-(1H-imidazol-1-yl)-β-oxobenzenepropanoate (6.1 g, 0.025 mol) in tetrahydrofuran (65 ml) is added slowly to a stirred suspension of 50% NaH (1.2 g, 0.025 mol) in tetrahydrofuran (20 ml) and the solution is stirred for one additional hour. Ethyl bromoacetate (4.5 g) is added followed by refluxing the mixture for 7 to 8 hours. The tetrahydrofuran is removed, the residue is treated with water, and the organic material is extracted with ether. The residue obtained after removal of ether is hydrolysed by heating with 6 N HCl for 7 to 8 hours. The crude acid is finally crystallized from dimethylformamide to yield 3.3 g of the product 4-(1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid.
Reaction SMILES: [CH:1]12[N:7]([C:8]3[CH:9]=[CH:10][C:11]([N+:20]([O-])=O)=[C:12]([C:14]#[C:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:13]=3)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2>C(O)(=O)C.O.CO.[Zn]>[CH:1]12[N:7]([C:8]3[CH:9]=[CH:10][C:11]([NH2:20])=[C:12]([C:14]#[C:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:13]=3)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1N
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
3-[5-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-nitro-phenyl]-N,N-dimethyl-prop-2-yn-1-amine (75 mg, 0.25 mmol) was dissolved in a mixture of glacial acetic acid (940 μL) and water (230 μL). Zn dust (164 mg, 2.51 mmol) was added at room temperature. The solution was stirred for 10 min. The reaction was diluted with methanol (5 mL), filtered and concentrated. The residue was dissolved in ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and dried down to a light orange solid. Purification by silica gel chromatography (5-15% methanol/dichloromethane) provided 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)aniline as a light orange oil (20 mg, 30% yield). LC/MS m/z 270.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:38])[CH2:28][CH2:29][S:30][CH2:31][C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:38])[CH2:28][CH2:29][S:30][CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:8]=2)[S:35][CH:36]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CCSCc1csc(N)n1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
3-{2-[3-(4-Fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-ylmethylsulfanyl}-propionic acid ethyl ester was prepared from 3-(4-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: C[O:2]C(=O)C=C.C(P)C(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:24]([P:28]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])[CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:25]([CH3:27])[CH3:26].OO>C1(C)C=CC=CC=1>[CH2:24]([P:28](=[O:2])([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:25]([CH3:27])[CH3:26]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CCP(CCC(=O)OC)CC(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)CP
Agent: OO
Solvent: Cc1ccccc1
Product: CC(C)CP(=O)(CCC(=O)O)CCC(=O)O
Reaction time: 2.5 h

Procedure:
A solution of 688 parts of methylacrylate in 285 parts of toluene is reacted with 450 parts of 80% isobutylphosphine in the presence of 3.9 parts of (azobisisobutyronitrile) initiator at 74°-93° C. for 7 hours. The resulting isobutylbis(carbomethoxyethyl)phosphine is oxidized with 600 parts of (10% excess) of 25% aqueous hydrogen peroxide. The reaction is complete within 2-3 hours at 65° C. and the resultant phosphine oxide is isolated as an oil following distillation of toluene and water from the mixture. The recovered phosphine oxide is hydrolyzed in 4 liters of 5% aqueous sulfuric acid solution by refluxing over a 7 hour period. On cooling, the product, isobutyl bis(β-carboxyethyl)phosphine oxide is isolated as a white crystalline solid in 70% yield and purified by recrystallization from water, m.p. 186°-187° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:19]1[CH:20]=[C:15]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2cc[n+]([O-])cc2)s1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)s1
Reaction time: 8 h

Procedure:
A mixture of 1.90 g (6.33 mmol) of 4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine 1-oxide and 40 ml of phosphoryl chloride is heated under reflux. After 8 h, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 150 ml of dichloromethane and 50 ml of ice-water are added. The organic phase is separated off and once more washed with 50 ml of water, dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 1.35 g (65%) of the desired product; 1H-NMR(DMSO-d6) δ: 8.35 (d, 1H), 7.49 (m, 2H), 7.35 (s, 1H), 7.25 (d, 1H), 7.19 (m, 2H), 3.06 (q, 2H), 1.37 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CNCCNCCNCCN1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(CN2CCNCCNCCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
In 50 ml of chloroform was added 3.5 g (20.3 mmole) of 1,4,7,10-tetraazacyclododecane and 1.7 g (7.87 mmole) p-nitrobenzyl bromide and the mixture stirred under nitrogen for 24 hours at 25° C. The chloroform slurry of hydrobromide salt was then applied to a 1 in.×17 in. column of flash silica gel (Solvent System 3). There was obtained 2.13 g (6.93 mmole) of the title product as a pale yellow solid of analytical purity in 88 percent yield (Rf =0.58, Solvent System 3), MP=128°-129° C., and further characterized by:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21](B(O)O)[CH:20]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:20]=[N:19][C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnc4ccccc4c3)cccc2c1N
Yield: 78.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3-quinoline boronic acid (168 mg, 0.97 mmol) were reacted to afford the title compound (93 mg, 80.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.24 (d, J=2.2 Hz, 1H), 8.50-8.60 (m, 2H), 8.18 (d, J=8.6 Hz, 1H), 7.88-7.98 (m, 3H), 7.82 (d, J=8.2 Hz, 1H), 7.76 (m, 1H), 7.59 (m, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=358 (M+H) HPLC 1.88 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:31])=[N:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[C:21]=4[CH3:22])=[CH:15][N:14]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH:43]=1>[N+](C1C=C(C=CC=1)CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)([O-])=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:31])=[N:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[C:21]=4[CH3:22])=[CH:15][N:14]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:33])=[O:34])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 79.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.333 mmol) was reduced with palladium hydroxide (250 mg) in ethyl acetate/ethanol 10/10 mL to afford 200 mg (80% yield) of the titled compound. MS: m/z=752.9 (M+1).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].S1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:29])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1>O.CO.O1CCCC1>[O:2]=[S:3]1(=[O:5])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:29])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(N)c2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N)c2c1
Reaction time: 2 h

Procedure:
To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which was cooled below 0° C. in an ice-bath, was added a solution of 2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) dropwise. The resulting mixture was stirred below 0° C. for 2 hours. The formed precipitate was collected by filtration, washed with water and dried in vacuo to afford the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 355, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.86 (m, 2 H), 7.77 (s, 1 H), 7.64-7.60 (t, J=16.0 Hz, 1 H), 7.51-7.48 (m, 2 H), 7.37-7.35 (d, J=8.0 Hz, 1 H), 5.06 (s, 2 H), 4.37 (s, 2 H), 3.59 (s, 2 H), 2.31 (s, 3 H).