Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][NH:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](O)(=[O:33])[CH3:32].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:8]1[C:9]2[CH2:30][N:29]([CH2:32][CH2:31][OH:33])[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)cc1
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(CCO)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol) was dissolved in methanol (2 mL). Acetic acid (10.83 μL, 0.19 mmol) was added followed by glycoaldehyde (11.36 mg, 0.19 mmol) and sodium cyanoborohydride (11.89 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by preparative HPLC yielding 2-(4-benzyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (18.10 mg, 19.7%). MS (ES+) (M+H)+=441.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cccc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 25.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (200 mg, 0.31 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (123.15 mg, 0.37 mmol) in sodiumcarbonate (98.57 mg, 0.93 mmol), Pd(PPh3)2Cl2 (10.8 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 60 mg (25.4% yield) of titled compound. MS: m/z=760.1 (M+1).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[C:29]([F:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:31][C:27]1[CH:28]=[C:29]([F:30])[C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:32])[CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3c(F)cc(Cl)cc3F)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.30 g (4.57 mmol) of potassium cyanide was added to 1.05 g (2.28 mmol) of the compound from Example 111A in 21 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.74 g (83% of theory) of the target compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([CH3:31])[CH:23]=1.Cl>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:30])=[C:24]([CH3:31])[CH:23]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(Cl)ccc1N=C=O
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Cl)ccc1NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH—H), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CH—H), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CuI), 4.27-4.51 (m, 4H, CH2, CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([OH:46])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[OH:46][CH:37]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)COc1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in 80% purity by HPLC. MS(ESI+): m/z=502.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH2:32]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.CN>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Agent: CN
Product: CNCCn1cc(-c2ccc(F)c(C)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=435, obsd.=435).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[S:7][CH:6]=1)=[CH2:4]>[Pd].C(O)C>[F:23][C:2]([F:1])([F:22])[CH:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:9][C:8]=2[S:7][CH:6]=1)[CH3:4]
Reactant: C=C(c1csc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(c1csc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A mixture of tert-butyl 8-[1-(trifluoromethyl)vinyl]-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (140 mg), 10% palladium on carbon (50 mg) and ethanol (10 ml) was stirred for 12 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg, 99.3%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:32].[O:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:21][CH2:20]2)=[N:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-{4-[2-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.3 g, 3.03 mmol) was dissolved in 3 ml dichloromethane and 4N HCl in dioxane (15.2 ml, 60.7 mmol) was added. The white suspension was stirred for 4 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar, to get the desired salt as a white solid (1.2 g, quant.) [MS: m/e=329.2 (M+H+)].
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5]C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:32]1([C:38]2[N:39]=[C:40]3[N:45]=[C:44]([NH:46][C:47]([C:49]4[N:53]=[N:52][NH:51][C:50]=4[C:54]([OH:56])=O)=[O:48])[CH:43]=[CH:42][N:41]3[CH:57]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCC1>CN(C=O)C.O.CC#N>[C:32]1([C:38]2[N:39]=[C:40]3[N:45]=[C:44]([NH:46][C:47]([C:49]4[N:53]=[N:52][NH:51][C:50]=4[C:54]([N:4]4[CH2:5][CH2:9][CH2:7]4)=[O:56])=[O:48])[CH:43]=[CH:42][N:41]3[CH:57]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Diisopropylethylamine (89 mg, 0.69 mmol) and TBTU (88 mg, 0.27 mmol) were added to a solution of 5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-3H-[1,2,3]triazole-4-carboxylic acid (80 mg, 0.23 mmol) in DMF (1 ml), and the dark brown solution was stirred for 30 min at RT. Azetidine (39 mg, 0.68 mmol) was added, and the mixture was stirred at RT overnight. The title compound (25 mg, 28%) was obtained from the reaction mixture by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN). MS (m/e)=389.3 [M+H+].
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16]([C:17]1[CH:23]=[N:2][O:19][C:18]=1[CH:20]1[CH2:22][CH2:21]1)=[O:27]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(NS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.53 g) was added to a stirred solution of 1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.8 g) in ethanol. Sodium acetate (0.63 g) was then added portionwise over a period of ten minutes. The mixture was then stirred at room temperature for 0.5 hours. Further quantities of hydroxylamine hydrochloride (0.2 g) and sodium acetate (0.24 g) were added and stirring was continued for 0.5 hours. Water was added, the mixture was extracted with dichloromethane and the combined organic extracts were washed with water, dried and the solvent evaporated. The crude product was purified by column chromatography to yield 4-[2-chloro-4-(methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (compound 1) as a white solid, 1.66 g, m.p. 122.8-124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[OH-:18].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:18])=[O:14])=[N:11][CH:12]=1
Reactant: O=Cc1ccc(NCc2cccc(Cl)c2)cn1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(NCc2cccc(Cl)c2)cn1

Procedure:
4.93 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxaldehyde are added in small portions to the cold stirring solution consisting of 70.4 g of silver nitrate in 150 ml of water and 33.1 g of sodium hydroxide in 150 ml of water. The mixture is stirred 10 minutes after the last of the aldehyde is added and filtered. The yellow filtrate is cooled and 12 N hydrochloric acid is added until the pH is 5. A solid precipitates which is collected by filtration and crystallized from methanol, to yield the 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid melting at 170°-174°.
Reaction SMILES: [NH2:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=O.O=[C:28]([CH3:39])[CH2:29][CH:30]([CH2:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl[Si](C)(C)C>CN(C=O)C>[CH2:10]([N:7]1[CH2:6][C:5]2[S:17][C:2]3[N:1]=[C:28]([CH3:39])[C:29]([CH:30]([CH2:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:3]=3[C:4]=2[CH2:9][CH2:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(CC(C)=O)C(=O)OCC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCN(Cc2ccccc2)C3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Temperature: 100 °C

Procedure:
To a solution of (2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol) in dry DMF (4 mL) under nitrogen atmosphere was added chlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. An extra volume of chlorotrimethylsilane was added (0.100 mL) and the reaction mixture was stirred at 100° C. for 48 h. After cooling, the volatiles were removed under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane furnished the title compound as a dark oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].N1C=CN=C1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:4][CH2:5][C:6]([NH:21][C:20]1[C:15]([NH2:14])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cccnc1N
Temperature: -78 °C
Yield: 19 %

Procedure:
Acetoxyacetyl chloride (2.73 g, 20 mmol) was added dropwise to a stirred solution of imidazole (2.72 g, 40 mmol) in dry tetrahydrofuran (20 ml) under nitrogen at 0° C. After the addition was complete, the thick white suspension was cooled to --78° C. and a solution of 2,3-diaminopyridine (2.18 g, 20 mmol) in dry tetrahydrofuran (60 ml) was added over 10 minutes. The mixture was allowed to warm to room temperature overnight and then saturated aqueous sodium bicarbonate (100 ml) was added. The mixture was extracted with dichloromethane (3×80 ml), the extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown solid. Recrystallisation from ethyl acetate gave 3-(acetoxyacetyl)amino-2-aminopyridine (795 mg, 38%) as white flakes.
Reaction SMILES: C1(S(N2C3C(=CC=CC=3)C(Br)=C2)(=O)=O)C=CC=CC=1.COC1C=C(B(O)O)C=CC=1OC.[CH3:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][C:38]=2[S:44](Cl)(=[O:46])=[O:45].C1(S([N:57]2[C:65]3[C:60](=[CH:61][C:62]([Cl:66])=[CH:63][CH:64]=3)[C:59](Br)=[CH:58]2)(=O)=O)C=CC=CC=1.[CH:68]1([O:73][C:74]2[CH:75]=[C:76](B(O)O)[CH:77]=[CH:78][C:79]=2[O:80][CH3:81])[CH2:72][CH2:71][CH2:70][CH2:69]1>>[Cl:66][C:62]1[CH:61]=[C:60]2[C:65](=[CH:64][CH:63]=1)[N:57]([S:44]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]3[C:37]=1[N:36]=[CH:35][C:34]([CH3:33])=[CH:43]3)(=[O:46])=[O:45])[CH:58]=[C:59]2[C:76]1[CH:77]=[CH:78][C:79]([O:80][CH3:81])=[C:74]([O:73][CH:68]2[CH2:69][CH2:70][CH2:71][CH2:72]2)[CH:75]=1
Reactant: COc1ccc(B(O)O)cc1OC1CCCC1
Reactant: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cc(Cl)ccc21
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Product: COc1ccc(-c2cn(S(=O)(=O)c3cccc4cc(C)cnc34)c3ccc(Cl)cc23)cc1OC1CCCC1

Procedure:
8-[5-Chloro-3-(3-cyclopentyloxy-4-methoxy-phenyl)-indole-1-sulfonyl]-3-methyl-quinoline 95 was prepared using the same protocol as described in Examples 21 and 22, substituting 8-quinoline-sulfonyl chloride, 1-Benzenesulfonyl-3-bromoindole and 3,4-dimethoxyphenyl boronic acid with 3-methyl-quinoline-8-sulfonyl chloride, 1-Benzenesulfonyl-3-bromo-5-chloro-indole and 3-cyclopentyloxy-4-methoxy-phenylboronic acid respectively. MS(ESI) [M+H+]+=547.10.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([OH:24])[C:19]([OH:23])=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1>>[ClH:9].[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([O:24][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]([O:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Agent: Cl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(OC(=O)c1ccccc1)c2OC(=O)c1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methylacetyl chloride with benzoyl chloride and 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride with the compound of Example 15, the title compound was prepared. m.p. 173°-182° C.; 1H NMR (CD3OD) δ: 2.88 (t, 1H), 3.05 (dd, 1H), 3.65-3.8 (m, 2H), 4.0-4.1 (br s, 1H+CH3OH), 6.35 (d, 1H), 7.05-7.35 (m, 10H), 7.35-7.55 (m, 3H), 7.9-8.0 (m, 4H), 8.5-8.65 (br s, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:24]2[CH2:23][S:22][CH2:21][C@@H:20]([C:25]([O:27][CH3:28])=[O:26])[NH:19][C:18](=[O:29])[C@@H:17]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:16][O:15][C:14](=[O:38])[C:13]=2[C:12]([CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:42](O)C>C(OCC)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Si:1]([O:8][C:9]1[C:24]2[CH2:23][S:22][CH2:21][C@@H:20]([C:25]([O:27][CH2:28][CH3:42])=[O:26])[NH:19][C:18](=[O:29])[C@@H:17]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:16][O:15][C:14](=[O:38])[C:13]=2[C:12]([CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1

Procedure:
A solution of 61 mg of tert-butyl (4R, 7S)-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-12-methoxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate and 11.4 mg of tetraisopropyl orthotitanate in 2 ml of ethanol was heated at reflux for 40 hours. The solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent to yield tert-butyl (4R, 7S)-14-(tert-butyldimethylsilyloxy)-4-ethoxycarbonyl-1,3,4,5,6,7,8,10-octahydro-12-methoxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, tert-butyl (4R, 7S)-4-ethoxycarbonyl-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.