Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: COCCN
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: COCCNc1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 100 °C
Yield: 16.3 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, 2-methoxy-ethylamine (0.029 mL, 0.343 mmol) was added and the contents heated at 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 15 mg of free base. 1H NMR (CDCl3, free base) δ (ppm): 8.60 (d, 2H), 7.40 (d, 2H), 7.10 (s, 1H), 6.96 (d, 1H), 6.62 (d, 2H), 3.80 (m, 2H), 3.64 (t, 2H), 3.40 (s, 3H0, 3.30 (t, 2H), 2.95 (m, 2H), 2.82 (m, 2H), 2.62 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C(C)=CC=CC=1N)CC2.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=4)[CH2:65]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=4)[CH2:65]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CCC(c1c(C)cccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1c(C)cccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cccc(C)c1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenylamine and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (565 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (437 mg). This compound (435 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (253 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:20][CH:21]=[CH2:22])[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(#N)C>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:19])[N:15]([CH2:20][CH:21]=[CH2:22])[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[N:18]1
Reactant: COC(=O)CCl
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O

Procedure:
13.87 g (100.35 mmol) of potassium carbonate are added to 21.50 g (91.2 mmol) of 5-(4-chlorophenyl)-4-allyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 210A and 11.88 g (109.5 mmol) of methyl chloroacetate in 350 ml acetonitrile and the mixture is heated under reflux for 5 hrs with stirring. It is then concentrated and the residue taken up in ethyl acetate is washed with 1 N hydrochloric acid and then with saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtration, the filtrate is concentrated in vacuo. After purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) 24.00 g (85% of theory) of the target compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH:26]1([C:2]2[C:3]([NH:12][C@H:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1

Procedure:
A suspension of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (2.44 g, 5.73 mmol), cyclopropylboronic acid (2.46 g, 28.6 mmol), potassium carbonate (3.17 g, 22.9 mmol) and tetrakis(triphenylphosphine)palladium (0.662 g, 0.57 mmol) in 1,4-dioxane (15 ml) and water (4 ml) was subjected to microwave irradiation at 140° C. for 2 hours. The reaction was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:22])[C:14]=2[N:13]=[C:12]1[CH2:23][O:24][CH2:25][CH3:26]>>[NH2:22][C:15]1[C:14]2[N:13]=[C:12]([CH2:23][O:24][CH2:25][CH3:26])[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:19]=2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: CN(C)C(=O)Cl
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N(C)C

Procedure:
Using the method of Examples 94-105, dimethylcarbamyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 349.2340.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:10]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])[C:8]#[N:9]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
900 mg (4 mmol) of 2-chloro-4-cyanobenzenesulfonic acid chloride is dissolved in 3 mL of pyridine and, after the addition of 0.5 mL (5.8 mmol) of pyrrolidine, stirred for one hour at 80° C. Then the mixture is cooled, mixed with ice, and adjusted to pH 5-6 with 1 molar hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried. Yield: 1.1 g (100% of theory); Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate=4:1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[OH:17])([CH3:3])[CH3:2].Br[CH2:19][C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH2:19][C:20]#[N:21])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(O)cc1-c1cscn1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)C)c(OCC#N)cc1-c1cscn1
Yield: 72 %

Procedure:
The crude 2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenol from step 4 and bromoacetonitrile (0.33 g, 2.72 mmol) together with K2CO3 (0.94 g, 6.81 mmol) in anhydrous actonitrile (30 ml) was heated at 60° C. for 3 hrs. The reaction mixture was partitioned between EtOAc and water. The combined organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (10 to 20% EtOAc in Hexanes) gave (2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy)-acetonitrile (0.47 g, 72%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:24]([C:14]1[CH:15]=[N:16][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[CH3:12])=[O:25]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnn(-c3ccccc3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.46 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide as a white solid (40 mg, 26%). LRMS (M+H+) m/z: calcd 336.16. found 336.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3[O:41]CCOC=3C=2)C(F)=CN=1.OCCN>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:25][OH:41])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Solvent: NCCO
Product: OCCNc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-hydroxyethylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.7 (bs, 1H), 7.32 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H, J=2.4 and 9 Hz), 6.75 (d, 1H, J=8.9 Hz), 4.21 (s, 4H), 3.67 (t, 2H, J=5.7 Hz), 3.38 (t, 2H, J=5.4 Hz); 19F NMR (CD3OD): −48518; LCMD: ret. time: 15.54 min.; purity: 100%; MS (m/e): 307 (MH+).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C=CC=CC=1.Cl>O.[Zn]>[C:5]([CH2:4][CH2:3][CH2:2][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([OH:7])=[O:6]
Reactant: COc1ccc(Cl)cc1C(=O)CCC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1CCCC(=O)O
Temperature: 80 °C

Procedure:
The acid compound of step 1 above is added to a stirring mixture of toluene (22 ml), conc HCl (41 ml), water (17 ml) and the recovered product of mossy zinc (22.2 g) and mercuric chloride (2.2 g) stirred in an aqueous HCl solution for about 10 minutes. The mixture is stirred under reflux for about 16 hours, diluted with water, extracted with ethyl acetate and the organic layer is dried filtered and evaporated. The residue is taken up in 10% aqueous NaOH, and dimethyl sulfate (about 25 ml) added to the mixture which is heated to 80° C. The mixture is stirred at a constant temperature for about 4 hours, cooled, acidified and the resulting precipitate is filtered dried and used in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([NH:15]C(=O)C)[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1>[OH-].[K+]>[NH2:15][C:13]1[CH:14]=[C:10]2[N:11]([C:2](=[O:1])[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=32)[N:12]=1
Reactant: CC(=O)Nc1cc2c3ccccc3[nH]c(=O)n2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C

Procedure:
10.0 g of N-(5,6-dihydro-5-oxopyrazolo[1,5-c]quinazolin-2-yl)acetamide is suspended in 973 ml of 10% ethanolic potassium hydroxide and refluxed for 3 hours. The reaction mixture is concentrated, cooled to room temperature, diluted with water and neutralized with acetic acid. The product is filtered off and dried.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([CH3:45])[C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=1>>[CH3:24][N:25]([CH3:45])[C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:33]=[C:28]2[N:27]=1
Reactant: CN(C)c1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)nc(N(C)C)n5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and dimethyl-[3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-amine (Stage 70.1.1) to give the title compound as a white solid. (HPLC: tR 2.21 min (Method A); M+H=468 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.17-8.06 (m, 3H), 7.96-7.90 (m, 1H), 7.72-7.67 (m, 1H), 7.56-7.52 (m, 1H), 3.91 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 3.06 (s, 6H), 1.97 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([CH3:44])(=[N:35][C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:37])=[O:34])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:45](I)[CH3:46]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([CH3:44])(=[N:35][C:36]([CH:38]3[CH2:43][CH2:42][N:41]([CH2:45][CH3:46])[CH2:40][CH2:39]3)=[O:37])=[O:34])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CCI
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Product: CCN1CCC(C(=O)N=S(C)(=O)c2ccccc2-c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 77 %

Procedure:
Product of Example 26 was ethylated using standard N-alkylating procedure with ethyl iodide to give titled compound in 77% yield.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[OH-].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of 2.66 g of (R)-(-)-thiazolidine-4-carboxylic acid in 10 ml of a 2N-aqueous sodium hydroxide solution were added 4.1 g of benzyloxycarbonyl chloride and 15 ml of a 2N-aqueous sodium hydroxide solution with stirring under ice-cooling at the same time, and then the mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with diethyl ether. The reaction mixture was then acidified by adding hydrochloric acid under ice-cooling. The mixture was allowed to stand for 30 minutes, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 4.14 g of (R)-(-)-3-benzyloxycarbonylthiazolidine-4-carboxylic acid as a colorless clear viscous oil. The oily substance was allowed to stand under cooling to form a solid, and the solid was recrystallized from diethyl ether-petroleum ether to obtain a pure (R)-(-)-3-benzyloxycarbonylthiazolidine-4-carboxylic acid.
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:35])C>>[C:19]([SiH2:18][O:17][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([CH2:6][C:5]([NH2:1])=[O:4])=[C:8]([CH3:35])[N:9]=2)[CH:12]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: N
Reactant: CCOC(=O)Cc1c(C)nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Product: Cc1nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1CC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
At −78° C., ammonia (25 ml) is added to [6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester (950 mg, 1.85 mmol) in a glass autoclave. The reaction mixture is stirred at room temperature for 48 hours. After removal of volatiles, the residue is recrystallized from diethylether to afford the title compound (800 mg, 90%). MS (ES+): 458 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:14])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3]
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: COCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 135.2 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 97 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 42 mg, 0.20 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 5% methanol/ethyl acetate) to afford (R)-2-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (121 mg, 90%) as a colorless gum: [α]30589=−53.5° (c=0.17, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1900; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.75-2.30 (m, 8H, 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, OCH3), 3.19 (s, 3H, SO2CH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=1)=O)CCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:17]1([CH:13]([C:10]2[S:9][C:8]([CH2:6][OH:5])=[CH:12][CH:11]=2)[CH2:14][CH2:15][CH3:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCCCOC(=O)c1ccc(C(CCC)n2ccnc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(c1ccc(CO)s1)n1ccnc1
Yield: 129.7 %

Procedure:
0.2 g of the butyl ester of example 7 is reduced in 3 ml of tetrahydrofuran with 0.2 g of lithium aluminum hydride and worked up in the usual way. 0.2 g of the title compound is obtained as oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.C[N+]([O-:29])(C)C.[Cl-].[Na+]>COCCOCCOC.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][OH:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Reactant: C[N+](C)(C)[O-]
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCCCCCN1CCC(C)(c2cccc(CCO)c2)C(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a stirred solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)-piperidine (Preparation 8, 50 mg, 0.16 mmol) in bis(2-methoxyethyl)ether (1.5 mL) at 0° C. under nitrogen was added dropwise borane (1.0 M in tetrahydrofuran, 0.35 mL, 0.35 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then for 2 hours at room temperature. Trimethylamine N-oxide (48 mg, 0.64 mmol) was subsequently added and the reaction mixture heated at reflux under a nitrogen atmosphere for 2 hours. To the cooled reaction was then added diethyl ether (10 mL) and saturated aqueous sodium chloride solution (10 mL). The phases were separated and the aqueous layer was further extracted with diethyl ether (10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5 g) eluted with ethyl acetate:hexane (50:50) to give the title compound as an oil (30 mg).