Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]([CH2:22][N:23]([C@@H:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11]2)=[C:5]([F:43])[CH:4]=1)#[N:2].[N-:44]=[N+:45]=[N-:46].[Na+].Cl.C(N(CC)CC)C.CN(C=O)C>O>[F:9][C:7]1[CH:8]=[C:3]([C:1]2[NH:46][N:45]=[N:44][N:2]=2)[CH:4]=[C:5]([F:43])[C:6]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]([CH2:22][N:23]([C@@H:31]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C#N)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(-c3nnn[nH]3)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 185 mg of tert-butyl {[1-(4-cyano-2,6-difluorophenyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 414 mg of sodium azide, 876 mg of triethylamine hydrochloride, and 4.0 mL of DMF was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, and water added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl ({1-[2,6-difluoro-4-(1H-tetrazol-5-yl)phenyl]-4-phenylpiperidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product (beige foamy substance, 208 mg). ESI+: 625
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.Cl.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[C:18]1([NH:24][N:25]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCC(C(=NNc2ccccc2)c2ccccc2F)CC1
Yield: 82.7 %

Procedure:
A mixture of 14.6 g of 4-(2-fluorobenzoyl)-1-methylpiperidine, 12.0 g of phenylhydrazine hydrochloride and 16.0 g of sodium acetate in 280 ml of n-butanol was heated under reflux for 3.5 hrs. The reaction mixture was cooled, filtered and concentrated. The residue was washed with ether to yield 17 g (83% ) of 4-(2-fluorobenzoyl)-1-methylpiperidine phenylhydrazone, mp 131°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16]C(=O)C)[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23](C(OCC3C=CC=CC=3)=O)[CH3:24])[C:12]3[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:11]=3[S:10]2)=[CH:5][CH:4]=1>Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][NH:23][CH3:24])[C:12]3[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Solvent: CO
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.5 %

Procedure:
1.42 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in a mixture of 15 ml of conc. HCl and 15 ml of methanol. The solutin is saturated with gaseous hydrogen chloride, and the saturated solution is stirred at room temperature for 19 hours. The mixture is evaporated under reduced pressure at a temperature below 35° C. to remove solvent. The residue is dissolved in 10% HCl. The solution is washed with ether, alkalized with potassium carbonate and then extracted with chloroform. The extract is washed with water, dried and then evaporated to remove solvent. A mixture of ethanol and ethyl acetate is added to the residue, and crystalline precipitates are collected by filtration. 770 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Br[CH:11]([CH2:14][CH2:15]Cl)[CH:12]=[O:13]>O>[CH:12]([C:11]1([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:15][CH2:14]1)=[O:13]
Reactant: CC(C)(C)S
Reactant: O=CC(Br)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SC1(C=O)CC1
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen and while cooling with ice, 112 ml of tert-butyl mercaptan are added dropwise over 10 minutes to a solution, cooled to 5° C., of 80 g of sodium hydroxide in 750 ml of water. Then 50 ml of methanol are added. After 1 hour, 151 g of 2-bromo-4-chlorobutanal (89.5%) are added dropwise over 15 minutes with efficient stirring and cooling, whereupon the temperature of the reaction mixture rises from 5° to 20° C. After 30 minutes, the mixture is extracted 4 times with diethyl ether. The combined organic phases are washed twice with a saturated solution of sodium chloride and dried over magnesium sulfate. The residue obtained after concentrating the residue on a rotary evaporator is fractionated over a 30 cm packed column, affording 89 g of 1-formyl-1-tert-butylthiocyclopropane in 89% purity. Boiling point: 112°-114° C./8 400 Pa.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>Cl>[C:10]1([NH:9][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: BrCC1CCCCO1
Agent: Cl
Product: c1ccc(NCC2CCCCO2)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A mixture of 2-(bromomethyl)tetrahydro-2H-pyran (100 g, 0.558 mol) and aniline (155.96 g, 1.67 mol) was heated at 100° C. under nitrogen overnight and cooled to room temperature. A 3N hydrochloric acid solution (400 mL) was added and the aqueous layer was washed three times with isopropyl ether. The aqueous layer was made basic with 50% sodium hydroxide solution, and the product was extracted three times into isopropyl ether. The combined organic extracts were washed once with water and evaporated under reduced pressure. The resulting oil was poured into water (1400 mL) and stirred. The water was decanted and water (1500 mL) was again added. The aqueous layer was again decanted and the oil was triturated again in water (1500 mL) to give a solid, which was recrystallized from methanol/water and dried under high vacuum to give 78.5 g of product containing one mole of water (67% yield). A 2.0 g portion was recrystallized from methanol/water and dried under high vacuum to give 0.71 g, mp 55°-58° C.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([OH:13])=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:19]([O:13][C:8]1[C:7]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]2[C:10]([CH:9]=1)=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=2)[CH3:20]
Reactant: C[Si](C)(C)c1cc2ccc(F)c(F)c2cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc2c(F)c(F)ccc2cc1[Si](C)(C)C

Procedure:
54.7 g (about 0.12 mol) of 7,8-difluoro-3-trimethylsilanylnaphthalen-2-ol are stirred at 80° C. for 19 h together with 19.5 ml (0.26 mol) of bromoethane and 34.5 g (0.25 mol) of potassium carbonate in 400 ml of ethyl methyl ketone. The batch is filtered, and the residue is washed with ethyl methyl ketone. The filtrate is concentrated, and the residue is taken up in MTBE. The solution is washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The residue remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=9:1), giving (3-ethoxy-5,6-difluoronaphthalen-2-yl)trimethylsilane as a dark-brown solid.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.[CH2:22]([O:26][C:27]([CH2:29][NH:30][C:31]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38](C(O)=O)[NH:39]2)=[CH:35][CH:34]=1)=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:27]([CH2:29][NH:30][C:31]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([C:6]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=4)[CH:10]([CH2:20][Cl:21])[CH2:9]3)=[O:7])[NH:39]2)=[CH:35][CH:34]=1)=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Reactant: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)O)[nH]c2c1
Product: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 69 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with N-[(butoxycarbonyl)methyl]-2-carboxyindole-6-carboxamide by the method described above and the product recrystallised from EtOAc to give with N-[(butoxycarbonyl)methyl]-2-[[3-(chloromethyl)-6-nitroindolin-1-yl)carbonyl]indole-6-carboxamide as a yellow solid (69%), mp 286° C. (dec.). 1H NMR [(CD3)2SO] δ12.20 (d, J=1.5 Hz, 1H, indole NH), 8.99 (d, J=2.2 Hz, 1H, H-7), 8.50 (t, J=6.0 Hz, 1H, amide NH), 8.06 (s, 1H, H-3' or H-7'), 8.05 (dd, J=8.2, 2.2 Hz, 1H, H-5), 7.78 (d, J=8.5 Hz, 1H, H-4'), 7.75 (d, J=8.2 Hz, 1H, H-4), 7.60 (dd, J=8.5, 1.4 Hz, 1H, H-5'), 7.30 (d, J=1.6 Hz, 1H, H-3' or H-7'), 4.87 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.2 Hz, 1H, H-2), 4.19-4.08 (m, 3H, H-3 and CH2Cl), 3.92 (d, J=5.9 Hz, 2H, CONHCH2), 1.44 (s, 9H, t-Bu); 13C NMR δ169.1 (CO2 tBu), 167.1 (CONH), 160.4 (CON), 147.6, 144.6, 140.0, 135.7, 132.0, 130.0, 129.2 (C-6,8,9,2',6',8',9'), 125.5, 121.7, 119.4, 118.9, 112.2, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 80.5 (OCMe3), 54.0 (C-2), 47.0 (CH2Cl), 42.0 (C-3), 41.9 (CH2CO2 tBu), 27.7 (t-Bu). Anal. (C25H25ClN4O6) C, H, N.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30](O)=[O:31])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:33]=1.ON1C2C=CC=CC=2N=N1.[CH2:44]([N:46]=[C:47]=NCCCN(C)C)C.CNC.C1COCC1>ClCCl.C(Cl)(Cl)Cl>[CH3:44][N:46]([CH3:47])[C:30](=[O:31])[CH2:29][N:25]1[N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:33]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:27][C:26]1=[O:28]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(=O)O)c(=O)o3)c1)C2=O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(=O)N(C)C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(S)-2-{5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-2-oxo-1,3,4-oxadiazol-3(2H)-yl}acetic acid (229 mg, 0.49 mmol) obtained in Step 2 was suspended in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours after adding 1-hydroxybenzotriazole (133 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (188 mg, 0.98 mmol), and a 2.0 mol/L dimethylamine/THF solution (2.45 mL, 4.88 mmol). After diluting the mixture with chloroform, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)—N,N-dimethyl 2-{5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-2-oxo-1,3,4-oxadiazol-3(2H)-yl}acetamide (142 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1>C(#N)C.C(N)(C)C.C(N(CC)CC)C>[C:19]([NH:18][C:10]([NH:9][CH:5]([CH3:6])[CH3:4])=[N:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)#[N:20]
Reactant: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)N
Product: CC(C)NC(=Nc1cccc(C(F)(F)F)c1)NC#N
Temperature: 25 °C
Reaction time: 42 h
Yield: 158.6 %

Procedure:
To a solution of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 286 mg) in dry acetonitrile (2 ml), isopropylamine (0.184 ml) and triethylamine (0.150 ml) were added. The mixture was stirred for 42 h at room temperature under nitrogen. After concentration the residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (210 mg, 79%) as a syrup. Crystallization from ethyl acetate / heptane 1:3 gave white crystals (165 mg, 62%). Mp 109-111° C.; 1H-NMR (CDCl3): δ 1.20 (d, 6H), 4.05 (m,1H), 4.67 (br d, 1H), 7.42 (m, 1H), 7.50 (s,1H), 7.55 (m, 2H), 7.68 ppm (br, 1H); MA calc for C12H13F3N4 : C, 53.33%; H, 4.85%; N, 20.73%. Found: C, 53.61%; H, 4.92%; N, 20.67%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH2:13][CH2:12]OC1=O>N1C=CN=C1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][OH:9])=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Product: OCCOc1ccc(Br)cc1
Temperature: 140 °C
Yield: 103.3 %

Procedure:
4-Bromophenol (100 g, 0.58 mol) was dissolved in in xylenes (220 mL). [1,3]Dioxolan-2-one (53.7 g, 0.61 mol) and imidazole (592 mg, 8.70 mmol) were added. The mixture was heated to 140° C. for 3 days. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (130 g, quantitative). LC-MS: tR=0.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[CH:21]=[O:22].NS(O)(=O)=[O:25].Cl[O-].[Na+]>O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:25])=[O:22]
Reactant: COc1cccc(-c2ccc3c(C=O)c(OC)ccc3c2)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Reaction time: 0.5 h

Procedure:
200 mg of the compound 2-methoxy-6-(3-methoxyphenyl)-1-naphthaldehyde (0.68 mmol, 1 eq) is dissolved in a mixture of 8 ml of water and 17 ml of acetone. To the cooled reaction mixture, amidosulfonic acid (H2NSO3H) (1.51 mmol, 2.21 eq) and sodium hypochlorite (0.78 mmol, 1.14 eq) are added. After stirring for 30 min, the acetone is removed in vacuum on a rotary evaporator, and dichloromethane is added. The organic and aqueous phases are separated, and the organic phase is washed three times with saturated sodium chloride solution. After drying and concentrating the organic phase on a rotary evaporator, the desired product was obtained as a yellow solid in quantitative yield (209 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:34])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate [(Example 1, Step 6) 580 mg, 1.49 mmol] was suspended in toluene (5 mL) and dioxane (5 mL), placed into an oil bath preheated to 110° C. and treated in one portion with Lawesson's Reagent (603 mg, 1.49 mmol, 1 equiv). After stirring for 30 minutes, the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[F:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:16][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:11]=1
Reactant: COc1ccc(C(O)c2cc(F)ccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2cc(F)ccc2O)cc1
Reaction time: 15 h
Yield: 81.7 %

Procedure:
To a solution of (2-benzyloxy-5-fluorophenyl)-(4-methoxyphenyl)-methanol (0.98 g, 2.90 mmol) in methanol (18.6 mL), a 20% palladium hydroxide catalyst (98 mg) was added and furthermore 2N—HCl (1 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 15 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:6)] to obtain the title compound (0.55 g, 82%).
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:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[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]=[CH:20][C:21]([C:22]([N:42]4[CH2:43][CH2:44][N:39]([C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[O:38])[CH2:40][CH2:41]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=613.98 (M+H+); retention time=0.72 minutes.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:7]([OH:9])=[O:8].[CH3:23]O>>[OH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:7]([O:9][CH3:23])=[O:8]
Reactant: CO
Reactant: CCCCCCCCCCCCCC(O)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCC(O)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To methanol (10 ml), cooled in an ice-brine bath, was added thionyl chloride (0.87 ml) dropwise. After stirring at 0° C. for 10 minutes, 2-hydroxypentadecanoic acid (1.54 g) was added. The mixture was stirred at room temperature for 3 hours, and concentrated under vacuum. The residue was dissolved in ethyl acetate (60 ml), and washed with water (40 ml×2), saturated aqueous sodium bicarbonate (30 ml), and brine (30 ml). The organic phase was dried, concentrated to dryness, and triturated in diisopropyl ether to give methyl 2-hydroxypentadecanoate (0.77 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[C:7]([CH3:9])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:24]C)([O:22][CH3:23])[O:20][CH3:21]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:9])/[CH2:8][P:19]([O:22][CH3:23])([O:20][CH3:21])=[O:24])[CH3:2]
Reactant: COP(OC)OC
Reactant: C=C(C)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OC)OC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1, E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:20]C(=O)OC(C)(C)C)[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][NH:15][N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:20])[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][NH:15][N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(C2(N)CCc3n[nH]cc3C2)c1
Reaction time: 4 h
Yield: 96.2 %

Procedure:
Tert-butyl 5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamate (499 mg, 1.35 mmol) was taken up in 2 mL of dioxane followed by the addition of HCl (3.38 mL of a 4N solution in dioxane). The reaction was stirred for 4 h and then concentrated to yield 350 mg (96% yield) of a white solid. 1H-NMR (CD3OD) δ8.17 (d, J=2.7 Hz, 1H), 7.60 (s, 1H), 7.52-7.45 (m, 1H), 7.44-7.32 (m, 2H), 3.77 (d, J=14.8 Hz, 1H), 3.21 (d, J=14.8 Hz, 1H), 3.10-2.94 (m, 1H), 2.82-2.66 (m, 1H), 2.59-2.42 (m, 2H), 1.30 (s, 9H); retention time (min)=1.70 (method [8]); MS (ESI) 253.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH:36]=O)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH2:36][N:15]1[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][NH:10][C:11]3=[O:18])[CH2:17][CH2:16]1)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(CN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.056 g, 0.22 mmol) and 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde (0.067 g, 0.22 mmol) were dissolved in dry 1,2-dichloroethane (5 mL). To the reaction mixture was added crashed 4A Molecular Sieve (0.028 g), a catalytic amount of glacial acetic acid. The reaction mixture was stirred at room temperature for 1 hr and it was then added at room temperature sodium triacetoxyborohydride (0.071 g, 0.33 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with water and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via semi-preparative HPLC (aqueous 0.5% TFA/acetonitrile) to yield crude 8-[8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalen-1-ylmethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one which was directly used to the next step.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][N:3]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cnc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)C1=O
Yield: 44 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 232 and 1-acetylimidazolidin-2-one (64 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (93 mg) was obtained.