Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:38][C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[O:38][C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:35]=2)[CH2:20][CH2:21]1)=[O:13]
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Reactant: CCOC(=O)c1ccc(CCl)o1
Product: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)o1

Procedure:
Ethyl 5-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-2-carboxylate 23 was prepared, according to the procedure described for compound 7, starting from ethyl 5-(chloromethyl)furan-2-carboxylate. Yield: 290 mg, 71%.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32]>CN(C=O)C>[OH:32][CH2:31][CH2:30][CH2:29][C:28]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:34])[CH3:33]
Reactant: CC(C)(N)CCCO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CCCO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). Mukaiyama Reagent (CAN 878-23-9, 233.8 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and 4-amino-4-methyl-pentan-1-ol (CAN 85054-53-1, 101.33 mg, 0.64 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19×250 mm/acetonitrile/10 mM ammonium acetate in water) to give the desired product (100 mg, 70.26%) as colorless sticky liquid; LC-MS (UV peak area, ESI) 96.12%, 334.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[F:19].C([O-])=[O:21].[Na+].C(O)C>O>[F:19][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[C:3]=1[CH2:2][OH:21]
Reactant: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CO)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1-bromomethyl-2-fluoro-6-methoxy-5-(trifluoromethyl)naphthalene (11.16 g, 35 mmol), sodium formate (5.85 g, 86 mmol), ethanol (134 mL) and water (34 mL) was heated to reflux with stirring. Dissolution occurred within 20 minutes. After 1.5 hours the heating source was removed, 2.5N NaOH (14 mL) was added, and the reaction mixture was cooled to room temperature. The ethanol was removed, water (100 mL) was added and the solid was filtered. The white solid was washed with water and dried in vacuo to give the product in quantitative yield. A small portion was recrystallized from petroleum ether:ethyl acetate, m.p. 113°-114° C.
Reaction SMILES: [N+]([CH:4](NS(C1C=CC=CC=1)(=O)=O)CCOCCC(NS(C1C=CC=CC=1)(=O)=O)[N+]([O-])=O)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:40][S:41]([O:44][CH2:45][CH2:46][CH:47]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][N:63]([S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[N+:80]([O-:82])=[O:81])(=[O:73])=[O:72])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=2)=[CH:58][CH:57]=1)[CH2:48][CH2:49][O:50][S:51]([CH3:54])(=[O:53])=[O:52])(=[O:43])=[O:42]>CN(C=O)C.C(OCC)(=O)C>[CH3:54][S:51]([O:50][C:49]1[CH:48]=[C:47]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][N:63]([S:71]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=3[N+:80]([O-:82])=[O:81])(=[O:73])=[O:72])[CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=3)=[CH:58][CH:57]=2)[CH:46]=[C:45]([O:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH:4]=1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)Cc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=[N+]([O-])C(CCOCCC(NS(=O)(=O)c1ccccc1)[N+](=O)[O-])NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1cc(Cc2ccc(CN(Cc3ccccn3)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)cc(OS(C)(=O)=O)c1
Reaction time: 30 h
Yield: 80.7 %

Procedure:
A solution of bis(3-nitrobenzenesulfonylaminopropyl)ether (190 mg, 0.38 mmol) and finely ground, freshly oven-dried cesium carbonate (320 mg, 1.14 mmol) in anhydrous DMF (60 mL) was heated to 80° C. Methanesulfonic acid, 5-methanesulfonyloxy-3-(4-{[(2-nitro-benzenesulfonyl)-pyridin-2-ylmethyl-amino]-methyl}-benzyl)-pentyl ester (250 mg, 0.38 mmol) in DMF (20 mL) was then added to the reaction over a 30 hour period via syringe pump. After complete addition, the reaction was stirred another 30 hours. The mixture was then cooled, diluted with 300 mL ethyl acetate and extracted repeatedly with water. The organic phase was then dried and concentrated, and the residue was purified by column chromatography on silica gel using 25% ethyl acetate in dichloromethane as eluant to afford the desired product (203 mg, 51%). 1H NMR (CDCl3) δ 1.47–1.71 (m, 9H), 2.42 (d, 2H, J=6.1 Hz), 3.15–3.32 (m, 12H), 4.53 (s, 2H), 4.55 (s, 2H), 6.94 (d, 2H, J=6.4 Hz), 7.03 (d, 2H, J=6.4 Hz), 7.05 (d, 1H, J=5.8 Hz), 7.52 (m, 4 H), 7.64 (m, 6 H), 7.91 (m, 5H), 8.44 (d, 1H, J=5.4 Hz).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[S:7].Br[C:9]1[CH:10]=[C:11]([O:17][C:18]2[C:19]([CH3:25])=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.CN(C=O)C.[H-].[Na+]>O>[CH3:25][C:19]1[C:18]([O:17][C:11]2[C:12]([C:15]#[N:16])=[N:13][CH:14]=[C:9]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:10]=2)=[C:23]([CH3:24])[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Br)cnc1C#N
Reactant: S=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Pyridine-2(1H)-thione (0.768 g, 6.90 mmol) and 5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.58 mmol) were added to DMF (12 mL) and cooled to 0° C. 95% Sodium hydride (0.174 g, 6.90 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was poured into water (100 mL) and stirred for 30 minutes. A cloudy milky solution that was not filterable resulted. The reaction was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and brine, dried, and concentrated. The residue was purified over silica gel (2:3 to 0:1 hexane:ethyl acetate) to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol, 92.3% yield) as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)[C:3]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][C:5]=2[O:9]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)Cc2cc(Br)c(-c3cccnc3)cc2O1
Product: COc1ccc(N2CCN(c3cc4c(cc3-c3cccnc3)OC(C)(C)C4)CC2)cc1
Yield: 45.8 %

Procedure:
By using 3-(5-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)pyridine (160 mg, 0.526 mmol) synthesized in Reference example 11 and 1-(4-methoxyphenyl)piperazine (303 mg, 1.58 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 100 mg (yield 46%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15](OC)=[O:16])[CH:11]=2)=[N:6][CH:7]=1.[NH3:26]>>[Br:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15](=[O:16])[NH2:26])[CH:11]=2)=[N:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Product: Cc1cc(Nc2nc(NCc3cc(C(N)=O)no3)ncc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
5-Bromo-2-[3-(methoxycarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 104; 50 mg, 0.11 mmol) was suspended in 7N methanolic ammonia (5 ml) and stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was triturated with DCM/diethyl ether (50:50) and the product collected by filtration to give the title compound (35 mg, 76%). NMR (DMSO): 2.18 (s, 3H), 4.57 (d, 2H), 6.28 (br s, 1H), 6.50 (s, 1H), 7.72 (s, 2H), 8.01 (s, 1H), 8.05 (s, 1H), 12.06 (s, 1H); m/z 393 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[CH:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([O:10][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[C:8]([F:11])[CH:7]=1)=[O:6]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Yield: 69.1 %

Procedure:
Using a method similar to Example 710, Step 2, using 3,5-difluoro-4-hydroxy-benzaldehyde (Journal of Medicinal Chemistry (1989), 32(2), 450-5.) (2.50 g, 15.8 mmol), 6-chloronicotinonitrile (2.19 g, 15.8 mmol) and K2CO3 (3.27 g, 23.7 mmol) gives 6-(4-formyl-2,6-difluoro-phenoxy)-nicotinonitrile (2.84 g) as a white solid. 1HNMR (CDCl3): 9.95 (s, 1H), 8.39 (s, 1H), 8.02 (d, 1H), 7.58 (d, 2H), 7.25 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28].[I:29]Cl.OS([O-])=O.[Na+].C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([I:29])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(I)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 96.1 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,2-difluoro-7-(trimethylsilyl)benzo[d][1,3]dioxol-4-yl)-5-fluoropicolinate (400 mg, 0.92 mmol) in 1,2-dichloroethane (5 mL) was treated with iodine monochloride (900 mg, 5.5 mmol) and stirred for 20 h at 20° C. The mixture was combined with 10 wt % NaHSO3 solution (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL), and the combined organic phases were washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (430 mg, 96%): mp 156-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 5.02 (s, 2H), 3.99 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.22, −137.49; ESIMS m/z 487 ([M+H]+), 485 ([M−H]−).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)cc1
Yield: 27.7 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 4-methylbenzene boronic acid (8 mg, 0.06 mmol) giving 5.5 mg (28%) of the title compound. MS (ESI+) calcd for C18H15N5O2S2 397.066716, found 397.066596.
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[OH:20])=[CH2:2].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CCOCC.C(=O)(O)[O-].[Na+]>[CH:1]([CH:3]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH2:2]
Reactant: C=CC1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CC1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 1-vinyl-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (0.462 g, 1.64 mmoL) from Step A in DMF (8 mL) was added imidazole (0.335 mg, 4.92 mmol) and then tert-butyldimethylsilyl chloride (0.370 g, 2.4 mmol). The reaction was stirred at room temperature for 20 h and then diluted with ether and sodium bicarbonate solution. The mixture was extracted twice with ether. The combined ether layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the title compound (0.56 g) as a mixture of isomers.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([N:4]1[CH2:9][CH:8]([O:10][CH2:17][CH2:16][O:18][CH2:19][CH3:20])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCN1CC(O)c2ccsc2S1(=O)=O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN1CC(OCCOCC)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
The product from Step A (4.2 g, 17.1 mmol) was dissolved in tetrahydrofuran (75 mL) and cooled to 0° C. at which point p-toluenesulfonic acid (163 mg, 0.6 mmol) was added followed by ethylvinyl ether (3.3 mL, 34.3 mmol). This mixture was stirred at 0° C. for 2 h, diluted with cold ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (70 mL) and brine (70 mL). The organic layer was dried (MgSO4) and evaporated to provide 5.2 g of crude product which was used in the next step without further purification.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][O:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1.[O-]CC.[Na+].C(O)C.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)=[O:33]>O>[CH:46]1([CH2:45][O:44][C:36]2[CH:35]=[C:34]([C:32](=[O:33])[CH2:31][CH:14]([C:13](=[O:20])[CH2:12][O:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:39]=[CH:38][C:37]=2[O:40][CH:41]([F:43])[F:42])[CH2:48][CH2:47]1
Reactant: CCOC(=O)CC(=O)COCc1ccc(OC)cc1
Reactant: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1)C(=O)COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To 460 ml of an ethanol solution containing 13.5 g (50.7 mmol) of ethyl 4-(4-methoxybenzyloxy)-3-oxobutyrate (see WO 2004060890) was added 18.9 ml (50.6 mmol) of 21% sodium ethoxide-ethanol solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Then, to the above mixture was added dropwise 300 ml of ethanol solution containing 16.5 g (42.3 mmol) of 2-bromo-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone obtained in Reference example 45-(a) under ice-cooling, and the mixture was further stirred at 10° C. or lower for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 14.0 g of the title compound as a pale yellowish oil. (Yield: 63%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[Na+].Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc(Cl)cc1

Procedure:
100 ml of 95% 4-chlorobenzylamine and 51.53 g of sodium cyanate in 1 liter of water were treated below 25° C. with 194 ml of 4N HCl. Further sodium cyanate (5.15 g) was added and the pH adjusted to 7.3. After 3 days the solid was collected, washed with water and dried to give the title compound (131.1 g) as a white solid mp 186-9° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[C:16]([C:22](=[O:38])[NH:23][CH:24]3[CH:31]4[CH2:32][CH:27]5[CH2:28][C:29]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:33][CH:25]3[CH2:26]5)[CH2:30]4)[CH:15]=[N:14]2)=[CH:9][CH:8]=1.O>CO>[CH3:37][S:34]([C:29]12[CH2:33][CH:25]3[CH2:26][CH:27]([CH2:32][CH:31]([CH:24]3[NH:23][C:22]([C:16]3[CH:15]=[N:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:39])=[O:5])=[CH:12][CH:11]=4)[C:17]=3[S:18][CH2:19][CH2:20][CH3:21])=[O:38])[CH2:30]1)[CH2:28]2)(=[O:35])=[O:36]
Reactant: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
Lithium hydroxide monohydrate (27.5 mg, 0.65 mmol) was added to a suspension of 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid methyl ester (Intermediate#105) (116 mg, 0.22 mmol) in methanol (4 mL)/water (2 mL) at ambient temperature. The resulting suspension was stirred at ambient temperature for 18 hours. The bulk of the organic solvent was removed in vacuo and the resulting solution was diluted with water (10 mL) and washed with ether (10 mL). The aqueous layer was acidified to ˜pH4 with 2M HCl then extracted with EtOAc (3×25 ml). The EtOAc layers were combined, washed sequentially with water (5 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid (113 mg, 100%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]2[CH2:21][CH2:22][CH2:23][C:15]=12.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:20][C:19]2[N:14]=[C:15]3[CH2:23][CH2:22][CH2:21][C:16]3=[CH:17][CH:18]=2)[CH:7]=1
Reactant: Nc1ccc2c(n1)CCC2
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A heavy walled resealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (1.5 g, 6.79 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine (1.09 g, 8.14 mmol), acetonitrile (10 mL) and Hunig's base (877 mg, 1.19 mL, 6.79 mmol). The mixture was heated at 80° C. with stirring for 3d, after cooling to room temperature, the solvents were distilled off and the crude residue obtained was purified by chromatography (80 g column, 50 μM from Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 26%) as a light brown solid. 1H NMR (CHLOROFORM-d) δ: 10.51 (s, 1H), 8.94 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.92 (t, J=7.7 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 1.87-2.24 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); LC-MS 319.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:9]([C:15]2[N:19]([CH2:20][CH3:21])[N:18]=[N:17][N:16]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:9]([C:15]2[N:19]([CH2:20][CH3:21])[N:18]=[N:17][N:16]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 101.1 %

Procedure:
To a solution of ethyl 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate (1.0 g, 2.6 mmoles) at -78° in CH2Cl2 was rapidly added 7.8 mL (7.8 mmoles) of diisobutylaluminum hydride solution (1.0 Molar in methylene chloride). After stirring for 45 minutes, the mixture was quenched with 1N HCl solution. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residual oil was triturated with hexane to give 0.9 g (100%) of the title compound; m.p. =103°-111° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1>>[F:9][C:7]1[CH:8]=[C:2]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH3:11])[CH:3]=[C:4]([F:10])[C:5]=1[NH2:6]
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Nc1c(F)cc(Br)cc1F
Product: Cc1c[nH]c2ccc(-c3cc(F)c(N)c(F)c3)cc12
Yield: 54.9 %

Procedure:
The title compound (68 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (160 mg, 0.62 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.71 (s, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 2H), 7.28-7.21 (m, 2H), 7.09 (s, 1H), 5.12 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]>CO.[Pd]>[NH2:1][C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D9, 850 mg, 2.07 mmol) in methanol (10 ml) was added Pd/C 10% wt (85 mg, 10 wt %) and the mixture was stirred under hydrogen (1 atmosphere) for 5 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (D10, 623 mg, 94%); Rt (HPLC): 4.00 min; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 9.16 (s, 1H), 7.28-7.42 (m, 1H), 7.16-7.26 (m, 2H), 7.02-7.14 (m, 1H), 6.59-6.68 (m, 2H), 4.56-4.85 (m, 1H), 2.07-2.41 (m, 2H), 1.52-1.77 (m, 2H), 1.51 (s, 3H), 1.31 and 1.05 (s, s, 9 H).