Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[CH:10]=1.[Na]>O1CCCC1>[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C1CCNC1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of pyrrolidine (7.3 mL, 87 mmol) in dry tetrahydrofuran (5 mL), a solution of 3-bromomethyl-benzoic acid methyl ester (2.0 g, 8.7 mmol) in 5 mL of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 4 hours. The reaction mixture was then poured into 100 mL of saturated aqueous solution of sodium hydrogenocarbonate, extracted with 100 mL of ethyl acetate, dried over sodium sulfate and evaporated to dryness affording the title compound as yellow oil (1.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N-:16]=[C:17]=[O:18].[K+]>C(O)(=O)C>[CH3:14][C:6]1([CH3:15])[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:17]([NH2:16])=[O:18])=[CH:3][CH:4]=2)[C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)c2cc(NC(N)=O)ccc21

Procedure:
1.3 g. (6.3 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione was suspended in 30 ml. 2N acetic acid, mixed with 1.0 g. (12.5 mMole) potassium isocyanate and stirred for 6 hours at 80° C. The reaction mixture was cooled and the precipitate was filtered off with suction and washed with water. The residue was dissolved in dilute aqueous sodium hydroxide solution, the solution was neutralised with dilute hydrochloric acid, the residue was filtered off with suction and, for purification, worked up with ethanol and filtered off with suction. Yield: 0.6 g. (38.5% of theory); m.p. 260°-264° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[O:17]=[C:13]1[N:12]([C:6]2[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=2)[CH2:16][CH2:15][O:14]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1OCCN1c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under N2, chlorosulfonic acid (1.5 g, 12.87 mmol) was diluted in CCl4 (2 mL) and cooled to 0° C. Then 3-phenyl-1,3-oxazolidin-2-one (280 mg, 1.72 mmol) was diluted in CCl4 (2 mL) and added slowly to the reaction mixture. The reaction mixture was stirred for two hours at 0° C. The reaction was then slowly quenched with ice water (4 mL) and extracted with CCl4 (3×4 mL). The organic extracts were dried over sodium sulfate and concentrated to give 4-(2-oxo-1,3-oxazolidin-3-yl)-benzenesulfonyl chloride which was used without purification.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=1.C(OC(C)C)(=O)C>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)c1cnc(Br)s1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: CC(=O)OC(C)C
Product: C[C@@H](c1ccc(-c2ncc(C(=O)N(C)C)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 2-bromo-N,N-dimethylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.215 min, m/z=450.1; 1H NMR (CD3OD) 0.92 (s, 3H), 1.22 (s, 3H), 1.53 (d, 3H), 2.11 (s, 2H), 2.19-2.28 (m, 1H), 2.40-2.58 (m, 2H), 3.00-3.31 (m, 4H), 5.56 (m, 1H), 7.02 (d, 2H), 7.26-7.39 (m, 5H), 7.69 (d, 2H), 8.08 (s, 1H). The compound was dissolved in refluxing isopropyl acetate and allowed to cool slowly to rt to afford a solid with mp 110-111.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C[Si]([C:19]#[N:20])(C)C.CCN(CC)CC>CC#N>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: O=[N+]([O-])c1ccc2c(ccc[n+]2[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 75 °C
Yield: 35.9 %

Procedure:
To a suspension of compound 45A (400 mg, 2.1 mmol) in MeCN (15 mL) was added trimethylsilylcyanide (0.34 mL, 2.5 mmol), followed by a slow addition of Et3N (0.65 mL, 4.6 mmol). The reaction mixture was heated to 75° C. for 30 min, then cooled to rt, concentrated, dried under vacuum, and purified by silica gel flash chromatography, eluting with CH2Cl2 to give the title compound (150 mg, 36%) as a white solid. LC/MS m/z 200 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(=O)C)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 72.6 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (1.0 g; 3.14 mmol) in 95% ethanol (10 ml) is treated with a solution of sodium hydroxide (2.5 g; 62.9 mmol) in water (5 ml) and the heterogeneous mixture heated at 75 C. for three hours. The ethanol is removed in a rotary evaporator and the residue is diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml) and chloroform (3×20 ml). The organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/dichloromethane gradient (5%-30%) containing 5% triethylamine afforded the product as an orange solid (0.63 g; 73%). HNMR (CD3OD): 7.34 (dd, 2H, J=8.7; 5.6 Hz), 6.80 (t, 2H, J=8.7 Hz), 4.29 (s, 2H), 2.82 (m, 2H), 2.66 (m, 1H), 2.41 (m, 2H), 1.76 (m, 2H), 1.49 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36]([O-])=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+]>CO.C(Cl)Cl>[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])=[C:3]([C:13]2[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=2)[CH:4]=1)(=[O:11])[NH2:12]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 82 %

Procedure:
The title compound was prepared by the coupling procedure of Example 7, step (e) using 3-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-propionamide (as prepared in the previous step, 75.0 mg, 0.307 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 103 mg, 0.338 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (124 mg, 82%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.3 (M+H). found 522.1.
Reaction SMILES: [NH2:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:4][CH:3]1[CH2:5][OH:6].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>ClCCl>[OH:6][CH2:5][CH:3]1[CH2:4][C:2]1([NH:1][C:26](=[O:27])[O:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Step b) To a solution of ((1RS,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)methanol (2.85 g, 13.7 mmol, Eq: 1.00) in dichloromethane (27.4 ml) was added at 5° C. diisopropylethylamine (2.65 g, 3.59 ml, 20.5 mmol, Eq: 1.5) and methyl chloroformate (1.42 g, 1.17 ml, 15.1 mmol, Eq: 1.1) dropwise via syringe. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a brown oil which was purified by silica gel flash chromatography with 0-100% EtOAc in heptane to give the title methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (3.52 g, 13.2 mmol, 96.6% yield) as a light brown oil.
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])=[CH:16][CH:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37]O)=[CH:32][CH:31]=1>O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37][O:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]3[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=3)[CH:20]=2)=[CH:32][CH:31]=1
Reactant: CCC(C)(CO)c1ccc(F)cc1
Reactant: OCc1cccc(Oc2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(COCc1cccc(Oc2ccc(F)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To 20 ml of toluene were added 2 ml of concentrated sulfuric acid, 2.7 g of 3-(4-fluorophenoxy)benzyl alcohol and 2.3 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol, and the mixture was refluxed for 6 hours (water formed by reaction was removed). The mixture was cooled to room temperature, and water was added to the mixture and the toluene layer was separated, washed with water, dried, and evaporated under reduced pressure, and the obtained crude ether was purified by column chromatography on 100 g of silica gel (1:1 mixed solvent of toluene and n-hexane was used as eluent) to give 2.2 g of the desired ether (the yield was 46% of the theoretical yield).
Reaction SMILES: [CH3:1][N:2]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=O)[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[CH3:1][N:2]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=[S:46])[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 95.4 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 125 mg of N-methyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound B10) and 104 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 123 mg of the title compound as a waxy solid. ESI-MS: 528.9 (MH+). TLC: Rf=0.43 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: CC1(C)O[CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:19])[N:15]3[CH3:18])=[CH:10][C:9]=2[O:20][CH3:21])CO1.COC1C=C2C(=CC=1CC[N:37]1[CH2:42][CH2:41][CH:40]([N:43]3[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]([NH2:54])=[O:53])[CH:50]=4)[CH:45]=[CH:44]3)[CH2:39][CH2:38]1)NC(=O)CC2>>[CH3:21][O:20][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[CH2:7][CH2:5][N:37]1[CH2:38][CH2:39][CH:40]([N:43]3[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]([NH2:54])=[O:53])[CH:50]=4)[CH:45]=[CH:44]3)[CH2:41][CH2:42]1)[N:15]([CH3:18])[C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)NC(=O)CC2
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)C(=O)CC2

Procedure:
The subject compound was synthesized from 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-one according to the method described in Example 56, (5).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:11](SC)[C:12](Cl)=O>>[CH3:8][C@H:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][NH:9]1
Reactant: CSC(Cl)C(=O)Cl
Reactant: C[C@H](N)c1ccccc1
Product: C[C@@H]1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-2, except that 25.6 ml of (S)-1-phenylethyl-amine(0.20M) and 34.8 g of α-chloro-α-(methylthio)-acetyl chloride(0.22M) were used as starting materials, 8.8 g of the title compound was obtained in oil form.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0. mmole) in dry DMF (150 mL) at was added 4-benzyloxybenzylchloride (14.85 g, 63.8 mmole). After 10 min, 60% NaH (2.78 g, 69.6 mmole) was added and the reaction slurry was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a waxy solid. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (27.13 g, 93%) as a white solid: MS (ES) m/e 503 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si](Br)(C)C.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][P:27](=[O:28])([OH:34])[OH:31])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)NC)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)N1CCc2cc(N(CP(=O)(O)O)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C

Procedure:
1.2 g diethyl {[(3,5-dichloro-phenylsulphonyl)-(1-methylcarbamoyl-2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 30 ml dichloromethane. 1.2 ml of trimethylsilylbromide are added with stirring. Then the mixture is refluxed for 2 hours and after cooling to ambient temperature combined with 30 ml of methanol. The mixture is stirred for 1 hour, the solvents are eliminated in vacuo, another 30 ml of methanol are added and the mixture is stirred for a further 10 minutes. Then the solvent is eliminated in vacuo and the residue is dried in vacuo at 80° C. Then it is extracted from diethyl ether, the solid is suction filtered and dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH2:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:32]([NH:34][C@@H:35]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6](=[O:24])[CH:7]([NH:23][C:36](=[O:37])[CH:35]([NH:34][C:32]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccncc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccncc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a manner similar to that described in Example 25, the product from Example O and the product from Example Z were coupled to give the title compound.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([O:22][CH2:23][C@H:24]([NH:28]C(OC(C)(C)C)=O)[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:28][C@@H:24]([CH2:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:14][CH:13]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(OC2CCCCC2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(OC2CCCCC2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(cyclohexyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(cyclohexyloxy)phenyl)propanamide (200 mg, 50%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=C(c2cnn(Cc3ccccc3)c2)CCC1
Temperature: 110 °C
Yield: 55.6 %

Procedure:
To 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (406 mg, 1.43 mmol), 3-bromocyclohex-2-enone (200 mg, 1.14 mmol), and Pd(PPh3)4 (132 mg, 0.114 mmol) in toluene (2 mL) was added 2M Na2CO3 (1 mL). The reaction mixture was purged with nitrogen and heated at 110° C. for 16 h. The reaction was diluted with water (10 mL) and extracted DCM (3×15 mL), dried over Na2SO4 and purified by flash chromatography (24 g silica gel) using hexanes/EtOAc (0-50% over 15 min, flow rate 35 mL/min) to isolate Intermediate 45A (160 mg, 0.634 mmol, 55.5% yield) as a tan solid. LC-MS (ESI) 253.0 (M+H), RT=1.70 min (Method B).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]1([N:17]2[CH:18]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[N:15]=[N:16]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(1-phenyl-1,2,3-triazol-4-yl)-1,2,3,6-tetrahydropyridine (816 mg, 2.5 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) and the reaction stirred at room temperature for 35 minutes. The solvent was evaporated in vacuo and the residue basfied by addition of aqueous sodium hydroxide (1M, 30 ml). Water (30 ml) was added and the mixture extracted with dichloromethane (3×30 ml). The combined organic layers were washed with saturated brine (20 ml), dried (K2CO3) and evaporated in vacuo to yield the title compound as a buff solid (486 mg, 86%). δH (CDCl3) 2.59-2.53 (2H, br s, tetrahydropyridinyl CH2), 3.14 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.56-3.58 (2H, br s, tetrahydropyridinyl CH2), 6.60 (1H, br s, tetrahydropyridinyl 5-H), 7.40-7.45 (1H, m, ArH), 7.50-7.54 (2H, m, ArH), 7.72-7.75 (2H, m, ArH), 7.84 (1H, s, triazolyl 5-H).
Reaction SMILES: [Br-].[C:2](/[CH:5]=[CH:6]/[C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)([OH:4])=[O:3].[C:33]([C:36]1[CH:41]=[CH:40][N:39]([C:42]2[CH:43]=[CH:44][C:45]([CH:48]=O)=[N:46][CH:47]=2)[CH2:38][CH:37]=1)(=[O:35])[CH3:34]>>[C:33]([C:36]1[CH:37]=[CH:38][N:39]([C:42]2[CH:43]=[CH:44][C:45]([CH:48]=[CH:11][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:2]([OH:4])=[O:3])=[CH:32][CH:31]=3)=[N:46][CH:47]=2)[CH2:40][CH:41]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)C1=CCN(c2ccc(C=O)nc2)C=C1
Reactant: O=C(O)/C=C/c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(=O)C1=CCN(c2ccc(C=Cc3ccc(/C=C/C(=O)O)cc3)nc2)C=C1
Yield: 95.3 %

Procedure:
Production Example 108, step 4, {4-[(E)-2-carboxyvinyl]benzyl}(triphenyl)phosphonium bromide (503.9 mg, 1.001 mmol) and 5-(4-acetylpyridin-1-yl)pyridine-2-carbaldehyde (257.3 g, 1.103 mmol) were condensed to give (2E)-3-(4-{2-[5-(4-acetylpyridin-1-yl)pyridin-2-yl]vinyl}phenyl)prop-2-enoic acid (355.1 mg, yield 94.0%) as a pale-brown solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[NH:6][C:7]=1[CH3:8].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH3:8][C:7]1[NH:6][C:5]2[N:4]([C:3]=1[CH3:2])[C:23](=[O:26])[CH:24]=[CH:25][C:9]=2[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: C#CC(=O)OC
Reactant: COc1cccc(C(=O)Cc2nc(C)c(C)[nH]2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cccc(C(=O)c2ccc(=O)n3c(C)c(C)[nH]c23)c1

Procedure:
The compound is prepared as described in example 20 with 55 mg (0.02 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methoxyphenyl)ethanone hydrochloride (example LV), 250 mg (4.62 mmol) of sodium methylate and 74 mg (0.89 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH:25]1([CH2:28][N:29]2[CH:33]=[C:32](I)[CH:31]=[N:30]2)[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH:25]4[CH2:27][CH2:26]4)[CH:33]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: Ic1cnn(CC2CC2)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC4CC4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-cyclopropylmethyl-4-iodo-1H-pyrazole.