Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=O.C([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)C.[N+](C1C=CC=CC=1)([O-])=O>>[N+:8]([C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[N:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1)[O-:10]
Reactant: CCc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: [O-][N+](=Nc1ccccc1)c1ccccc1

Procedure:
The reduction reaction was carried out in the same manner as set forth in Example 6 except for using a mixture of 1.0 mmol of o-methyl nitrobenzene and 1.0 mmol of o-ethyl nitrobenzene instead of using nitrobenzene alone, and using 19.5 mg (the amount required for swelling of the reactant in 100%) of Polymer supported reagent-2, and thereby an azoxybenzene derivative of a symmetrical structure and an azoxybenzene derivative of an asymmetrical structure were obtained as a main product, respectively.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC([NH:37][C:38]1([C:41]([OH:43])=O)[CH2:40][CH2:39]1)=O)(C)(C)C.[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:64])([F:63])[F:62])[CH:47]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH:56][C:41]([C:38]3([NH2:37])[CH2:39][CH2:40]3)=[O:43])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:62])([F:63])[F:64])[CH:47]=1
Reactant: COc1ccc(Oc2ccc(CN)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
540 μL (3.85 mmol) of triethylamine and 864 mg (2.69 mmol) of TBTU were added to a solution of 541.5 mg (2.69 mmol) of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid in 45 mL DMF and the mixture was stirred for 5 min at RT. Then 800 mg (2.69 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamine (from 84a) was added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down. 20 ml dichloromethane/trifluoroacetic acid/water=50/45/5 were added to the residue and the mixture was stirred for 1 h at RT. The reaction mixture was evaporated down, the residue was dissolved in dichloromethane and extracted with 10 mL of 1 M sodium hydroxide solution. The dichloromethane phase was separated off and evaporated down.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[CH:28]=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:31].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[CH:28]=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:31])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1cc2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.053 g (2.2 mmol) of 60% oily sodium hydride in 15 ml of N,N-dimethylformamide, 0.33 g (2.2 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 0.61 g (2.0 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.33 g (2.2 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 0.442 g (52.6%, light green powder) of the desired product.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:41])[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=4)[N:33]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[CH3:42][N:43]1[C:47]([CH2:48][CH2:49]OC2C=CC(C3CCN(C4CCC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)=[CH:46][CH:45]=[N:44]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:42][N:43]1[C:47]([CH2:48][CH2:49][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([OH:41])[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]5[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=5)[N:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[CH:46][CH:45]=[N:44]1
Reactant: Cn1nccc1CCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
DIAD (0.311 mL, 1.58 mmol) was added dropwise to 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (500 mg, 1.32 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (obtained as described in Example 15, preparation of starting materials) (249 mg, 1.98 mmol) and triphenylphosphine (519 mg, 1.98 mmol) in THF (10 mL) under nitrogen. The resulting suspension was stirred at ambient temperature for 16 hours then the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with EtOAc then a gradient of 3 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to give a solid which was triturated with ether, filtered and dried to give 4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (464 mg, 72.2%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([Mg]Cl)[CH3:13].Cl>C1COCC1.Cl[Ni]Cl.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC[Mg]Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(C(=O)O)cc1Cl
Temperature: 55 °C

Procedure:
To solution of 5,6-dichloronicotinic acid (21.46 g, 112 mmol) and 1,2-bis(diphenylphosphino)ethane dichloronickel(II) ((Ni(dppe)Cl2) (2.00 g, 3.6 mmol) in THF (60 mL, 1.9 M) is cooled to 0° C. and treated with ethyl magnesium chloride (2.8 M, 107 mL, 300 mmol) slowly via syringe with stirring under nitrogen. The reaction mixture is warmed to 55° C. for 3 h, cooled to 0° C. and acidified to pH 5 with 2 M HCl (100 mL). After concentrating in vacuo, the solution is reconstituted and extracted with ethyl acetate (2×200 mL), dried over Na2SO4, filtered and concentrated. The solvent removed in vacuo to provide crude 5-chloro-6-ethyl-nicotinic acid as a light brown glass (ESI-LCMS m/z calcd for C8H8ClNO2: 185.0; found 186.0 (M+1)+, which is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:41][CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCN3CCCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), [2-(1-pyrrolidinyl)ethyl]amine (121 mg, 1.056 mmol) in 1,4-dioxane (2 mL)), the title compound was obtained as a white foam (30 mg, 22%). 1H NMR (400 MHz, DMSO-d6) ppm 1.58-1.87 (m, 6H), 2.01 (dd, J=12.88, 2.02 Hz, 2H), 2.54-2.88 (m, 6H), 3.12-3.43 (m, 3H), 3.47 (td, J=11.62, 2.02 Hz, 2H), 3.93 (dt, J=9.47, 2.21 Hz, 2H), 5.77 (s, 1H), 5.91-6.31 (m, 1H), 6.56 (d, J=1.26 Hz, 1H), 6.92 (br. s., 1H), 7.07 (t, J=7.71 Hz, 1H), 7.18 (br. s., 1H), 7.41 (td, J=8.02, 1.64 Hz, 1H), 7.70 (t, J=1.77 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=5.05 Hz, 1H); MS (ESI): 599.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.7 %

Procedure:
4-Iodobenzenesulfonyl chloride (1.8 g, 6.0 mmol, 1.0 equiv) was added portion-wise to a 0° C. solution of 2-aminothiazole (654 mg, 6.53 mmol, 1.1 equiv) in 4.91 mL of anhydrous pyridine. After addition was complete, the reaction mixture was warmed to ambient temperature. After 3 d, the reaction mixture was concentrated in vacuo. The residue was treated with MeOH and ether to precipitate the product. The solid was collected by filtration, washing with ether, to afford the product as a light brown solid (1.18 g, 49%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[CH2:1]([O:3][C:4]([C@@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([OH:36])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.11 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 64, and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.095 g of 3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([N+:11]([O-])=O)=[CH:5][CH:4]=1.Cl[Sn]Cl.[OH-].[Na+]>COCCOCCOC.Cl>[NH2:11][C:6]1[C:7]([C:9]#[N:10])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(C#N)n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1ccc(N)c(C#N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 6-methoxy-3-nitropicolinonitrile (Piersanti, G. et al. Org. Biommolecular Chem. 2007, 5, 2567-2571.) (2.0 g, 11.1 mmol) in diglyme (52 mL) was added dropwise a solution of SnCl2 (6.35 g, 33.5 mmol) in concentrated HCl solution (26 mL) at 0° C. The solution was stirred at 0° C. for 1 hr, then the reaction mixture was neutralized with concentrated NaOH solution, and extracted with EtOAc (2×). The combined organic layers were washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel (50% EtOAc in hexanes) to give 3-amino-6-methoxypicolinonitrile (966 mg, 58%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 4.10 (bs, 2H), 6.81 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H). MS 150 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2([CH2:8][NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: ClCCCCBr
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Yield: 63.3 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (220 mg, 0.775 mmol), 1-bromo-4-chlorobutane (146 mg, 0.852 mmol) and potassium carbonate (118 mg, 0.852 mmol) were stirred in DMF (1 ml) at 60° C. for 24 hours until complete. Reaction was partitioned between ethyl acetate (50 ml) and water (75 ml). The organic layer was separated and washed further with water (2×30 ml), then dried over sodium sulphate, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 98:2:0.2 by volume) to give the title compound (184 mg, 63%) as a yellow solid. LRMS APCI+ m/z 375 [MH]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:42]1[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=1)(=[O:21])=[O:20])(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccncc3)c2c1
Yield: 15.8 %

Procedure:
2-Methylsulfonyl-N-(3-pyridin-4-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 47 from 1 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, of 380 mg 4-pyridylboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous sodium hydrogencarbonate solution and 42.7 mg of tetrakis(triphenylphosphine)palladium[0]. 100 mg of 2-methylsulfonyl-N-(3-pyridin-4-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 265° C. (analysis C19H16N4O4S2 % calculated C, 53.26; H, 3.76; N, 13.08; O, 14.94; S, 14.97. % found C, 52.59; H, 3.30; N, 12.89; S, 15.14).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[C:4](=[O:14])[C:3]=1[C:15]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]([Cl:28])[C:16]=1[C:17](OC)=[O:18]>[OH-].[Na+]>[Cl:28][C:21]1[C:16]2[C:17](=[O:18])[O:1][C:2]3[C:11](=[O:12])[C:10]4[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=4[C:4](=[O:14])[C:3]=3[C:15]=2[C:24]([O:25][CH3:26])=[CH:23][C:22]=1[CH3:27]
Reactant: COC(=O)c1c(Cl)c(C)cc(OC)c1C1=C(O)C(=O)c2c(O)cccc2C1=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)c(Cl)c2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O

Procedure:
In 20% aqueous sodium hydroxide was dissolved methyl 2-(3,5-dihydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methyl-6-chlorobenzoate as obtained in (1) and the solution was refluxed for 3 hours. The reaction mixture was allowed to cool, acidified, and extracted with ethyl acetate. The solvent layer was washed with water and dried. The solvent was then distilled off and the residue was dissolved in tetrahydrofuran (2 ml). After addition of acetic ahydride (2 ml), the crystals that separated out were recovered by filtration, washed with diethyl ether and dried to give crystals (70 mg) of 4-chloro-8-hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:16](=[O:18])[NH2:17])=[N:9][C:8]=2[N:7]=[C:6]1[N:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[C:2]#[C:3][CH3:4]>FC(F)(F)C(O)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:16]([NH2:17])=[O:18])=[N:9][C:8]=2[N:7]=[C:6]1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C(N)=O)n(C)c(=O)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2nc(C(N)=O)n(C)c(=O)c21
Yield: 83 %

Procedure:
77 mg of t-butyl 4-[7-(2-butynyl)-2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 1 ml of trifluoroacetic acid, and the solution was concentrated. The residue was purified by chromatography using NH-silica gel. Thus, 49 mg of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (5:1)
Reaction SMILES: [Na].CO.[CH3:4][O:5][C:6](=[O:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][C:12](OC)=[O:13]>C1(C)C=CC=CC=1>[O:13]=[C:12]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:6]([O:5][CH3:4])=[O:16]
Reactant: COC(=O)CCCSCC(=O)OC
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1SCCCC1=O
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a suspension of sodium (3.5 g, 0.15 mol) in dry toluene (300 mL) was added an excess of methanol (30 mL). After sodium was disappeared, the excess methanol was removed as the methanol-toluene azeotrope. When the distillation temperature had reached 105° C., Methyl 4-{[2-(methyloxy)-2-oxoethyl]thio}butanoate (28.3 g, 0.14 mol) in toluene (90 mL) was added over a period of ten mins. The methanol-toluene azeotrope was removed by distillation, after the distillation temperature rose to 106° C., the reaction mixture was cooled to room temperature. The reaction mixture was poured into a mixture of ice (100 g) and 12N HCl (20 mL). The organic layer was removed and the aqueous layer was extracted with three 60 mL portions of ether and the combined organic layers were dried over Na2SO4. After removing the solvent, 23.4 g of crude product was obtained (Yield: 96%).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH:5]([C:10]1[CH:11]=[C:12]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[C:4]([OH:44])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC(F)(F)F)cc3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC(F)(F)F)cc3)C2)c1
Temperature: 78 °C

Procedure:
To compound 47a, 4-Methyl-2-{5-[1-(4-trifluoromethoxy-benzyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester (67.3 mg, 0.10 mmol) in EtOH (5.2 ml) was added 2M KOH (0.52 ml, 1.04 mmol). The reaction was heated to 78° C. for 1.5 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (41 mg, 63%). 1H NMR (300 MHz, MeOD) δ ppm 0.90-0.96 (m, 6 H) 1.50 (tt, J=13.38, 6.78 Hz, 1 H) 1.67 (dt, J=13.66, 6.92 Hz, 1 H) 1.88-2.03 (m, 3 H) 2.08 (d, J=17.33 Hz, 2 H) 3.03-3.14 (m, 1 H) 3.14-3.25 (m, 1 H) 3.49-3.62 (m, 2 H) 3.76 (t, J=7.72 Hz, 1 H) 4.34-4.47 (m, 2 H) 7.32 (s, 1 H) 7.42 (d, J=8.29 Hz, 2 H) 7.50 (s, 1 H) 7.57 (s, 1 H) 7.66 (d, J=8.67 Hz, 2 H) 7.78 (q, J=8.41 Hz, 4 H), Calcd for C32H33F6NO3 (M+H) 593.60, Found 594.3.
Reaction SMILES: [ClH:1].[N:2]1([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1([C:27]2C=CC(CC(O)=O)=C[CH:28]=2)C=NN=N1.C12CCC(NC1)CN2C(OC(C)(C)C)=O>>[ClH:1].[CH:3]12[CH2:28][CH2:27][CH:6]([NH:5][CH2:4]1)[CH2:7][N:2]2[C:8](=[O:21])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Agent: CC(C)(C)OC(=O)N1CC2CCC1CN2
Agent: Cl
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC1CN2

Procedure:
1-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from [4-(1H-tetrazol-1-yl)phenyl]acetic acid and commercially available tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate. LC/MS: [(M+1)]+=299
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Br:1])[CH:3]=[C:4]([Br:11])[C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Brc1cc(Br)c2nccn2n1
Solvent: CC(=O)O
Product: Brc1cc(Br)c2ncc(Br)n2n1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 100.00 g (361.1 mmol) 6,8-dibromoimidazo[1,2-b]pyridazine, which was prepared according to intermediate example 96d, in 1.6 L acetic acid were added 69.2 g (433.3 mmol) bromine at it and the mixture was stirred for 1 h. The precipitate was filtered, washed with water and dissolved in 10 L DCM. The organic üphase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated to give 81.99 g (64%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:25])([F:1])[F:26])[CH:4]=1)=[N:30][CH2:27][CH2:28][CH3:29])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CCCN
Product: CCCN=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 28 %

Procedure:
N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and n-propylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (90 mg, 28%) as white crystals. Mp 142.5-143.5° C.; 1H-NMR (CDCl3): δ 0.95 (t, 3H), 1.65 (sextet, 2H), 3.35 (q, 2H), 5.45 (br, 1H), 7.68 (br s, 1H), 7.80 (br s, 2H), 8.35 ppm (br, 1H); MA calc for C13H12F6N4 : C, 46.16%; H, 3.58%; N, 16.56%. Found: C, 46.31%; H, 3.65%; N, 16.23%.