Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][CH2:36][C@H:37]([NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[C:38](O)=[O:39])=[O:34])=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:41]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:37]([C:38]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]([CH3:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:39])[CH2:36][CH2:35][C:33](=[O:34])[O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Reaction time: 6 h

Procedure:
25.7 g of H-Val-Thr(But)-OBut.HCl are reacted, in 250 ml of dimethylformamide, with 26.0 g of Z-Glu-(OBzl)-OH and 15 g of DCC in the presence of 9.5 g of HOBt. After stirring for 6 hours the mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the solution is washed as described under (A) and, after drying and evaporating off the solvent, 37.3 g of the title compound are obtained with a melting point of 140°-144° (decomposition). Elementary analysis correct (C, H and N).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CON
Reactant: O=C1CCCc2ccc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCCc2ccc(Cl)cc21
Temperature: 24 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred solution of 7-chloro-1-tetralone CAS: 26673-32-5 (5.0 g; 27.68 mmol) in methanol (55 ml) was added pyridine (2.87 ml; 34.05 mmol) followed by a portion wise addition of methoxyamine hydrochloride (2.84 g; 34.05 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 6.22 g (100% of theory) of crude 7-chloro-3,4-dihydro-2H-naphthalen-1-one-O-methyl-oxime as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[CH3:16][C:17]([O:19]C(C)=O)=[O:18]>>[O:8]([C:7]1[C:2]([CH2:1][O:19][C:17](=[O:18])[CH3:16])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ncccc1Oc1ccccc1
Yield: 28 %

Procedure:
A solution of 2-methyl-3-phenoxy-pyridine 1-oxide (0.690 g, 3.40 mmol) in Ac2O (3.4 mL) stirred at 80° C. for 3 h. The solution was concentrated and the resulting residue was diluted with CH2Cl2 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated. Purification by column chromatography on silica gel with hexanes/Et2O (1:1) afforded acetic acid 3-phenoxy-pyridin-2-ylmethyl ester as a clear oil (0.234 g, 28%). 1H NMR (CDCl3) δ 2.07 (s, 3H), 5.34 (s, 2H), 7.00 (d, 2H, J=8.0 Hz), 7.13-7.23 (m, 2H), 7.36 (m, 2H), 8.39 (dd, 1H, J=3.4, 2.1 Hz).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCC(OC2C=CC(C#N)=CC=2)C[CH2:24]1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=[O:5])[CH3:24]
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1

Procedure:
Synthesized from 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester (1.5 g) according to an analogous synthetic method to Example 215 described below, the total amount of 4-(piperidin-4-yloxy)benzonitrile crude product was dissolved in acetic anhydride (20 ml) and pyridine (20 ml), and the solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.1 g).
Reaction SMILES: C([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:16][C:13]([C:11]1[N:12]=[C:8]([NH:7][C:6](=[O:5])[OH:17])[S:9][CH:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(C)(C)O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1csc(NC(=O)O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
[4-(1-Hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (250 mg, 0.92 mmol) was taken into dry dichloromethane and cooled in an ice bath. To this was added trifluoroacetic acid and the mixture stirred at 0° C. for 4 hours. The mixture was evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated out and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel gradient eluted with 1:99 up to 3:97 methanol in dichloromethane gave [4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid (56 mg, 39%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 150 °C

Procedure:
To a solution of (rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoro-quinolin-6-yl)ethanol (Stage 174.1, 200 mg, 0.584 mmol) in acetic acid (3.2 mL) were added iodine (296 mg, 1.167 mmol) and H3PO2 (0.642 mL of a 50% aqueous solution, 5.84 mmol). The RM was heated at 150° C. for 30 min. After cooling down to rt the acetic acid was evaporated under reduced pressure, water was added and the solution was neutralized with a solution of 10% NaHCO3. The product which precipitated was extracted with DCM, the combined organic phase were dried over MgSO4, filtered, evaporated to dryness and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, hexane/EtOAc=50:50->0:100) to afford the title compound as a off white crystalline solid (tR 4.61 min (conditions 3), MH+=327.2, 1H-NMR in DMSO-d6: 8.85 (dd, 1H); 8.28 (dd, 1H); 8.20 (d, 1H); 7.85 (s, 1H); 7.78-7.68 (2H, m); 7.44 (dd, 1H); 7.29 (d, 1H); 4.95 (q, 1H); 1.79 (d, 3H)).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[O:19]1[C:24]2[C:25]([NH:29][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1
Reactant: Nc1cccc2c1OCCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1OCCN2
Yield: 26.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 166 mg of 3,4-dihydro-2H-1,4-benzoxazin-8-ylamine and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 100 mg of N-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:44][CH2:43][CH2:42][C:39]3[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:41][CH:40]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=629.94 (M+H+); retention time=0.77 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 0.150 g (0.629 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.180 g (0.629 mmol) of the above prepared (example 2A]) 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, dissolved in 5.4 ml of abs. acetonitrile, was added 0.226 g of Cs2CO3 (0.692 mmol). The reaction was stirred for 3.5 h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15) yielded 0.248 g of pure title compound as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[OH-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>O.ClCCCl>[CH2:19]([C:6]1[C:7]([OH:8])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[OH:14])[CH:18]=[CH2:17]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: C=CCc1c(O)c(C(C)=O)cc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
4,6-Diacetylresorcinol (19.4 g; 0.1 mole), sodium hydroxide (8.0 g; 0.2 mole) and allyl bromide (12.1 g; 9 ml; 0.1 mole) in water (160 ml) and 1,2-dichloroethane (150 ml) were stirred at reflux for 3 hours. The mixture was cooled to room temperature, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane (3×50 ml). The combined organic layers were dried (anhydrous sodium sulphate) and evaporated to give 2-allyl-4,6-diacetylresorcinol as a pink oil (9 g; 38%) which rapidly crystallised, m.p. 84°-86° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([Cl:12])=[N:6][C:7]([Cl:11])=[N:8][C:9]=1Cl)([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[Cl:11][C:7]1[N:6]=[C:5]([Cl:12])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:9]([O:21][C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)[N:8]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: -40 °C
Yield: 90.1 %

Procedure:
To a stirred mixture of 5-isopropyl-2,4,6-trichloropyrimidine (23.68 g, 0.105M), 3,5-dimethylphenol (12.2 g, 0.2M) in anhydrous DMF (200 ml) cooled in a dry ice-acetone bath (−40° C.) under nitrogen atmosphere, was portionwise added 60% sodium hydride (4.2 g, 0.105M). The reaction temperature was then slowly raised to room temperature during 3 hr. The reaction mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a pale yellow solid. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 28 g (90%) of a white solid. m.p. 107-108° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.35 (6H, s), 3.58 (1H, m), 6.72 (2H, s), 6.91 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C1C(=O)N([O:16][C:17]([C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([N:27]=[N+:28]=[N-:29])=[C:21]([F:30])[C:20]=2[F:31])=O)C(=O)C1.Cl>CS(C)=O>[N:27]([C:22]1[C:21]([F:30])=[C:20]([F:31])[C:19]([C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:16])=[C:24]([F:25])[C:23]=1[F:26])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)ON2C(=O)CCC2=O)c(F)c1F
Reactant: NCCCCC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)NCCCCC(=O)O)c(F)c1F
Reaction time: 8 h

Procedure:
To a solution of 5-aminovaleric acid (12 mg, 100 μmol) in dry DMSO (250 μL) was added N-succinimidyl 4-azido-2,3,5,6-tetrafluorobenzoate (25 mg, 75 μmol). The reaction was allowed to proceed overnight at 45° C. in the dark. The mixture was then acidified with 250 μL of 0.5 N hydrochloric acid and extracted with 400 μL of ethyl acetate three times. The combined extracts were concentrated in vacuo and purified by silica chromatography using 2:1 hexane-ethyl acetate to yield the desired product as a white powder. Yielded: 3 mg, 9 μmol, 12%. TLC: Rf=0.3 (1:1 hexane-ethyl acetate) 1H-NMR (300 MHz, (CD3)2SO): δ 12.03 (s, 1H), 8.89 (t, 1H, J=5.4), 3.23 (q, 2H, J=6.3), 2.22 (t, 2H, J=7.2), 1.497 (m, 4H). ESI-MS m/z: (neg) 333.07 [M−H]−. Calc. 334.23
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=1[Cl:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 88 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (0.60 g, 1.39 mmol) in toluene (30 mL) was added azidotrimethylsilane (0.55 mL, 4.17 mmol) and dibutyltin oxide (0.10 g, 0.42 mmol). The reaction mixture was heated and stirred under argon at reflux temperature for 40 h. The solution was cooled and the toluene removed under reduced pressure. Methanol was then added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.58 g, 87%). MS(ES) m/e 474.2 [M +H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][CH:22]3[CH2:30]C4C(=CC=CC=4)[CH2:23]3)=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41].[CH3:43]C(C(OC(C)(C)C)=O)(C)N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][C:22]([CH3:30])([CH3:23])[CH3:43])=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41]
Reactant: CC(C)(NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of Intermediate 2 (180 mg, 0.489 mmol) in THF (3 ml) was added tert-butyl 2-methylalaninate (Intermediate 8) (117 mg, 0.73 mmol), stirred for 30 minutes, and then NaBH(OAc)3 (310 mg, 1.467 mmol). The reaction was stirred for 24 hours, diluted with EtOAc and the organics washed with sat NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound (Intermediate 15) (120 mg, 48% yield).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[N:6][CH:7]=1.[C:13](=O)([O-])[O-:14].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.CO>[CH3:13][O:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC)cn1
Temperature: 90 °C
Yield: 47.1 %

Procedure:
100 mg of ethyl 5-fluoropyridine-2-carboxylate obtained from Reference Example 18 (step 2) was dissolved in 1 ml of dimethylformamide and 1 ml of methanol, and 163 mg of potassium carbonate was added to it and stirred under heat at 90° C. for 40 minutes. This was neutralized with aqueous 10% citric acid solution, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 46.5 mg of methyl 5-methoxypyridine-2-carboxylate as a white crystal.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])=[CH:6][CH:5]=1.[NH2:29][NH2:30]>CO.O>[CH3:27][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[S:16][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:29][NH2:30])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
To a suspension of 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzoic acid methyl ester (Example 6, 364 mg, 1 mmol) in methanol (10 mL) add anhydrous hydrazine (128 ml, 4 mmol). Warm the resulting mixture to 60° C. and stir at this temperature for 18 hrs. Cool the resulting solution to room temperature, and add 3 drops of water. Concentrate the solution under vacuum and purify the residue by flash chromatography (elute with 5% methanol in dichloromethane) to give the title compound (271 mg).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].I[CH3:30]>CN(C=O)C.O>[Cl:28][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([Cl:2])[C:8]=1[N:9]([CH3:30])[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)N(C)c3c(Cl)cncc3Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
5.2 mg (0.130 mmol, 1.05 equiv) sodium hybride, 60% oil dispersion, were added to a room temperature solution of 50 mg (0.124 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichlor-pyridin-4-yl)-amide in 3 mL anhydrous DMF. After 30 min. 7.7 μl (0.124 mmol, 1.0 equiv) iodomethane were added and the mixture stirred at room temperature for 4 h. The reaction mixture was diluted with 50 mL H2O and extracted 2×20 mL ethyl acetate. The ethyl acetate extracts were combined, washed 2×5 mL H2O, 1×5 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (25% ethylacetate/hexanes, flash) to give 27 mg (52%) of a white crystalline solid: mp 118-119° C.; HRMS calcd for C21H22N4OCl3+H: 417.12519. Found: 417.12270.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: O=S1(=O)COc2cc(F)ccc2N1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)COc2cc(F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.3 %

Procedure:
A mixture of the title compound of Step D (0.5 g, 2.46 mmol), K2 CO3 (1.02 g, 7.38 mmol), benzyl bromide (0.463 g, 2.71 mmol) and TBAB (79 mg) in DMF (5 mL) was stirred at room temperature for 48 h. After the reaction was complete, the reaction mixture was poured into an H2 O/ethyl acetate mixture (10/100 mL). The organic phase was separated, dried and concentrated to give the title compound of Step E as a brown solid (0.76 g). 1H NMR (CDCl3, 300 MHz): δ7.32 (m,6H, aromatic) 6.72 (d,1H, 11 Hz), 6.34 (d, 1H, 8 Hz), 4.82 (s,2H), 4.69 (s,2H).