Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=C[CH:11]=1.[CH2:16]([O:18][C:19]([C:21]1[C:26](=[O:27])[N:25]2C(C)CCC[C:24]2=[N:23][CH:22]=1)=[O:20])[CH3:17].C(OC(C1C(=O)N2CC(C)CCC2=NC=1)=O)C>>[CH2:16]([O:18][C:19]([C:21]1[C:26](=[O:27])[N:25]2[CH2:24][CH:14]([CH3:13])[CH2:15][C:10](=[N:9][NH:6][C:5]3[CH:7]=[CH:8][CH:2]=[CH:3][CH:4]=3)[C:11]2=[N:23][CH:22]=1)=[O:20])[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2
Agent: CCOC(=O)c1cnc2n(c1=O)CC(C)CC2
Product: CCOC(=O)c1cnc2n(c1=O)CC(C)CC2=NNc1ccccc1
Yield: 60.2 %

Procedure:
The process according to Example 6 is carried out except that p-chloro-aniline is replaced by aniline and ethyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate is replaced by ethyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate, respectively. Thus ethyl-9-(phenyl-hydrazono)-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate is obtained with a yield of 60.2%. Mp.: 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
The compound (1.6 g) obtained in Example 50 was suspended in a mixture of ethanol (20 mL) and tetrahydrofuran (15 mL), and 1N aqueous sodium hydroxide (5.9 mL) was added at room temperature, followed by stirring for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 mL), the solvent was distilled away under reduced pressure, and the residue was washed with water and diethyl ether to give the title compound (1.19 g).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[I:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1ccccc1I
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Ic1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-iodobenzyl chloride (396 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 270 mg of the product 222. 1H NMR (DMSO-d6) δ 11.43 (s, 2 H), 8.00 (d, 1 H), 7.82 (d, 1 H), 7.48 (t, 1 H), 7.30-7.00 (m, 7 H), 7.00-6.80 (m, 4 H), 5.82 (s, 2 H), 4.88 (s, 2 H); MS: m/z 471 (M++1).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>ClCCl>[CH3:21][N:22]([CH:24]=[N:18][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[N:10][C:11]=12)=[O:17])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cnn2c(-c3ccccc3)ccnc12
Solvent: ClCCl
Product: CN(C)C=NC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 600 mg of 7-phenylpyrazolo(1,5-a)-pyrimidine-3-carboxamide (Example 7), 5.0 ml of N,N-dimethylformamide dimethyl acetal and 25.0 ml of dichloromethane are heated on a steam bath for 2 hours with complete solution taking place. The solution is evaporated in vacuo to give a solid. The solid is then recrystallized from acetone to give 58 mg of the desired product as yellow needles, mp 198°-201.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][OH:21].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][O:21][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 118 mg of 4,4-dimethyl-2-pentyn-1-ol, to which 43 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(4,4-dimethyl-2-pentynyloxy)-6-(2,3-difluorophenyl)pyrimidine (the present compound (119)).
Reaction SMILES: C[Mg]Cl.CON(C)[C:7]([C@@H:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:8].[C:25](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:7]([C@@H:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:8])[CH3:25]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(=O)N(C)OC)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with a solution of methylmagnesium chloride in THF (0.805 L, 3 M). The solution was purged with nitrogen and cooled to 0° C. In a separate flask, the title compound from Example 4 (250.0 g, 0.805 mol) was dissolved in dry THF (1.0 L). This solution was added to the solution of methylmagnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was complete upon the disappearance of the starting material (approx. 20 minutes after completing the addition). The reaction mixture was slowly added into a 10% citric acid solution (1 L) at a rate that maintained a temperature of less than 25° C. The mixture was diluted with water, and the THF was removed by distillation at 70° C. (80° C. external) and 1 atm. The product was extracted with ethyl acetate, and the organic phase was separated and concentrated by distillation at 76° C. (95° C. external) and 1 atm to a final volume of ˜800 mL. The solution was allowed to cool to room temperature, and n-heptane was added to give a precipitate. The suspension was stirred for 30 minutes, and the solid was isolated by filtration and dried in a vacuum oven at 40° C. overnight to afford the title compound (170 g, 80%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:16]([NH2:18])[CH3:17])[CH2:10][CH2:9][CH:8]([S:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:18][CH:16]([C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][CH:8]([S:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH2:9][CH2:10]1)[CH3:17])=[O:23]
Reactant: CC(N)C1(CC2CC2)CCC(SCC2CC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1ccc(Cl)cc1Cl)C1(CC2CC2)CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)amine (0.1 g; 0.3745 mmol), 2,4-dichlorobenzoyl chloride (0.1174 g; 0.56175 mmol) and triethylamine (0.0567 g; 0.56175 mmol) were dissolved in dichloromethane and stirred for one hour at room temperature. The reaction was evaporated and partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was dried and evaporated and the residue was purified by silica chromatography using ethyl acetate hexanes to yield 2,4-dichloro-N-(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)benzamide. (130 mg, 79%)
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.C[N:19]1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37]>C1COCC1>[CH3:34][N:35]([C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:19])[O:36][CH3:37]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)[C@H](CC(C)C)N(N)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of Boc-Leu-OH.H2O (80.3 mmol) and N-methyl morpholine (88 mmol) in THF (35 ml) was added to a pre cooled solution of isobutyl chloroformate (88 mmol) in THF (65 ml) under nitrogen at between -10 and -15° C. over 40 minutes. The reaction was stirred at -10° C. for 1 hour after which time N-methyl morpholine (88 mmol) was added followed by N,O-Dimethylhydroxylamine hydrochloride (88 mmol) portion wise between -10 and 0° C. The reaction was then stirred at -10° C. for 1 hour and then allowed to warm up to room temperature over night. The THF was then removed under vacuum and water (50 ml) and ethylacetate (200 ml) added. The organic layer was then washed with 0.1 M citric acid solution (4×50 ml), then saturated sodium bicarbonate (4×50 ml), dried over magnesium sulphate and then concentrated under vacuum to give the product.
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:17])=O>>[CH2:1]([C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)s1
Reactant: O=S(Cl)Cl
Product: CCCCCCc1ccc(C(=O)Cl)s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
10 ml of thionyl chloride was added to 1.0 g (4.72×10-3 ml) of 5-hexylthiophene-2-carboxylic acid, followed by stirring for 4 hours under heating at 80° C. and removal of excessive thionyl chloride by reduced-pressure distillation to obtain 5-hexylthiophene-2-carboxylic chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[C:12](\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH2:28]([NH:30][CH2:31]C)C>C(O)C>[CH3:14][CH2:13]/[C:12](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)\[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]([CH3:31])[CH3:28])=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCl)cc1)c1ccccc1
Solvent: CCO
Product: CC/C(=C(/c1ccc(I)cc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of E-1-[4-(2-chloroethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene (3.05 g) in 33% diethylamine in ethanol (60 ml) was boiled under reflux for 20 hours. The mixture was concentrated, a procedure made necessary only because of escape of the gaseous dimethylamine under these conditions, further 33% dimethylamine solution (60 ml) was added and reflux was continued for a further 20 hours. The mixture was again concentrated and the residue partitioned between ether (50 ml) and aqueous sodium hydroxide (1M; 50 ml). The ether solution was concentrated and the residue applied to a column of silica gel (Merck 15111, 40 g). Column chromatography was need to remove a small amount of unreacted starting material from the product which could not be removed by recrystallisation. This problem and the concentration step during addition of dimethylamine could have been overcome by carrying out the reaction in a sealed bomb. Elution with 5% methylamine in 1:1 ether-light petroleum (b.p. 40°-60° C.) gave 4-iodotamoxifen, which was further purified by recrystallisation from light petroleum (b.p. 40°-60° C.) (2.60 g, 84% yield), identical to that of Example 1.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH3:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:26]#[CH:27].BrC(C1C=CC=CC=1)C.C([Si](C)(C)C)#C.[N-]=[N+]=[N-]>>[C:28]1([CH:25]([C:26]2[N:1]([C@H:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:27]=2)[CH3:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)c1ccccc1
Agent: C#C[Si](C)(C)C
Agent: CC(Br)c1ccccc1
Agent: [N-]=[N+]=[N-]
Product: CC(c1ccccc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from both enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and (1-methylprop-2-yn-1-yl)benzene prepared from (1-bromoethyl)benzene and ethynyltrimethylsilane. The resulting diastereoisomeric esters derived from the chiral azide with the retention time of 10.3 min from EXAMPLE 6 were separated by flash chromatography using a gradient of 10-70% EA/Hex to afford after standard hydrolysis EXAMPLE 29.1 and 29.2. The resulting diastereoisomeric esters derived from the chiral azide with the retention time of 11.5 min from EXAMPLE 6 were separated by flash chromatography using a gradient of 10-70% EA/Hex to afford after standard hydrolysis EXAMPLE 29.3 and 29.4 respectively. MS (+ESI) m/z: 405.1.
Reaction SMILES: C1([C:7]23[CH2:15][CH:11]4C[CH:13]([CH2:14]2)[C:9]([C:16](=[O:18])C)([CH2:10]4)[CH2:8]3)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:25].[Na+].Cl.C([O:34][CH:35]([CH3:37])[CH3:36])(C)C>O.[Ru](Cl)(Cl)Cl.O.C(#N)C>[C:35]([C:36]12[CH2:14][CH:7]3[CH2:8][C:9]([C:16]([OH:18])=[O:25])([CH2:10][CH:11]1[CH2:15]3)[CH2:13]2)(=[O:34])[CH3:37]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Reactant: CC(C)OC(C)C
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C12CC3CC1CC(C(=O)O)(C3)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a stirred mixture of 1-(1-Phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone (8.0 g, 33.3 mmol) as obtained in preparation 1, carbontetrachloride (66 mL), acetonitrile (66 mL) and water (100 mL), cooled to 0° C., was added sodiumperiodate (31.9 g, 149 mmol) and ruthenium (III) chloride hydrate (0.44 g, 1.7 mmol). The reaction mixture was gradually warmed to ambient temperature and stirred for 2 h. The reaction mixture was diluted with diisopropylether (100 mL) and stirred for 15 minutes to precipitate black RuO2. The reaction mixture was then filtered through a pad of celite and the organic layer was extracted with 1N NaOH solution (3×25 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum to obtain unreacted starting material (3.04 g 12.67 mmol). The aqueous layer was acidified with conc. HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylic acid (4.0 g) as off-white solid in 57% yield. M.R: 90-95.0° C. m/z (M+1) 209. IR cm−1 2935, 1694, 1413, 1357, 974, 746. 1H NMR (CDCl3) 300 MHz δ 2.77-2.73 (m, 1H), 2.54-2.48 (m, 1H), 2.44-2.34 (m, 1H), 2.20 (s, 3H), 2.18-2.09 (m, 1H), 7.38-7.19 (m, 5H), 2.86-2.80 (m, 1H), 2.59-2.50 (m, 1H), 2.32-2.25 (m, 1H), 2.23 (s, 3H), 2.18-2.09 (m, 1H), 2.06-1.74 (m, 7H), 1.73-1.61 (m, 1H). 13C NMR (CDCl3) 75 MHz δ 211.0, 181.3, 61.5, 50.3, 47.9, 45.9, 45.6, 42.6, 41.9, 36.8, 35.6, 26.4.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.S([CH2:21][N+:22]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[ClH:30].[CH2:31]([CH2:34]OC)OC>C(O)(C)(C)C.CO>[ClH:30].[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH:31]([CH3:34])[CH2:21][NH2:22])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COCCOC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CC(CN)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a −15° C. solution of 50.0 g (251.2 mmol) of 4-bromoacetophenone and 49.0 g ( 251.2 mmol) of tosylmethyl isocyanide in 800 mL of dry dimethoxyethane was added a hot solution of 50.7 g 452.2 mmol) of potassium tert-butoxide in 230 mL of tert-butyl alcohol dropwise at a rate to maintain the temperature below 0° C. The reaction was stirred at −5° C. for 45 min after addition was complete. The cooling bath was removed and the reaction stirred for 2.5 h more. The mixture was concentrated in vacuo to a volume of 200 mL and diluted with 500 mL of water. The aqueous mixture was extracted four times with diethyl ether, and the combined organic portions were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in 55 mL of tetrahydro-furan and heated to reflux. To the refluxing solution was added slowly dropwise 27.6 mL ( 276.3 mmol) of 10.0 M borane-dimethylsulfide complex. Refluxing was continued for 20 min after addition was complete. The mixture was cooled to ambient temperature and methanol saturated with hydrogen chloride was added very slowly until pH 2 was achieved. The mixture was concentrated in vacuo and the residue was dissolved in methanol and concentrated in vacuo again. The solid residue was suspended in 125 mL of ethanol, filtered, rinsed with ethanol then diethyl ether. The white solid was dried in vacuo to afford 25.4 g (40%) of the title compound. The filtrate was concentrated in vacuo and suspended in diethyl ether. The solid was filtered, rinsed with diethyl ether and dried in vacuo to afford another 15.6 g (25%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:19].O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([NH2:19])=[O:14])[CH2:6][CH2:5]2
Reactant: [NH4+]
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1CCc2cc(I)ccc2O1
Reaction time: 3 h

Procedure:
The crude carboxylic acid of Example 7 (30.4 g, 100 mmol) and CDl (19.5 g, 120 mmol) were stirred in N,N-dimethylformamide (300 mL) at room temperature for 2 hours to obtain a yellow solution. To this solution was then added ammonium acetate (23.1 g, 300 mmol). The resulting mixture was stirred for 3 hours. It was then cooled in an ice-water bath and water (400 mL) was then added dropwise to the reaction mixture to obtain a fine white precipitation which was stirred for 12 hours. The solid was collected by vacuum filtration, washed with water and dried by suction (25.8 g, 85%): 1H NMR (DMSO-d6) δ1.75-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.55-2.80 (m, 2H), 4.43-4.47 (dd, J=8.7, 3.3 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 7.35 (m, 2H). CI-MS m/z 304 (M +H+).
Reaction SMILES: Cl.O1CCOCC1.C([O:12][C:13](=[O:39])[CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:38])=[C:24]([O:26][CH:27]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=3[Cl:37])[CH3:28])[CH:25]=2)[N:17]=[CH:16]1)(C)(C)C>ClCCl>[NH2:38][C:23]1[N:22]=[CH:21][C:20]([C:18]2[N:17]=[CH:16][N:15]([CH2:14][C:13]([OH:39])=[O:12])[CH:19]=2)=[CH:25][C:24]=1[O:26][CH:27]([C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=1[Cl:37])[CH3:28]
Reactant: CC(Oc1cc(-c2cn(CC(=O)OC(C)(C)C)cn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(Oc1cc(-c2cn(CC(=O)O)cn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 48 h
Yield: 108.4 %

Procedure:
A 4 M solution of hydrochloric acid in dioxane (0.22 mL, 0.89 mmol) was added to a solution of (4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-imidazol-1-yl)-acetic acid tert-butyl ester (86 mg, 0.18 mmol) in dichloromethane (2 mL). After stirring for two days the reaction was concentrated by rotary evaporation and the residue was dissolved in a minimum amount of methanol. This solution was added dropwise to ether and the resulting mixture allowed to stand overnight. The mixture was filtered and the precipitate was washed with ether and air dried to give (4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-imidazol-1-yl)-acetic acid (83 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1coc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1coc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Ethyl 2-bromo-1,3-oxazole-4-carboxylate (2.5 g, 11.36 mmo) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (22.73 ml, 22.73 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, diluted with water and pH was adjusted to 2. Formed precipitate was filtered and dried to yield the title compound (1.1 g). The filtrate was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness to yield the title compound 0.85 g. Total yield 88%. m/z [192.0+1]
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH3:10])[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a stirred mixture of 5-bromo-3-methylthiophene-2-carboxylic acid (1.70 g, 7.69 mmol), 1-hydroxybenzotriazole (1.56 g, 11.54 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.21 g, 11.54 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added N,N-diisopropylethylamine (4.10 mL, 23.54 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.78 mL, 7.69 mmol). The resulting reaction mixture was stirred at ambient temperature for 16 h, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 7% methanol in dichloromethane to afford 5-bromo-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide as an off-white solid (1.92 g, 80%): MS (ES+) m/z 311.1 (M+1), 313.1 (M+1).