Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 6-chloro-9H-purin-2-amine (5.0 g, 29.6 mmol) and NaH (1.43 g, 32.5 mmol) in DMF (30 mL) was stirred at room temperature for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (SEMCl, CAS Reg. No. 76513-69-4, 4.91 g, 29.6 mmol) was added and the resulting mixture was stirred at room temperature for 1.0 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 117a (5.1 g, 58%) as a yellow solid. MS-ESI: [M+H]+ 300.1
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:8]([CH3:16])=[CH:7][C:6]=1[CH:17](C)[CH:18]=C)(=O)C.CC(C)=O.[C:25](=[O:27])=[O:26].O=[O+][O-].CSC.[OH-].[K+]>C(Cl)Cl.O.[N+]([O-])([O-])=O.[Ag+]>[OH:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15]2)[C:8]([CH3:16])=[CH:7][C:6]=1[CH:17]([CH3:18])[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: C=CC(C)c1cc(C)c(-n2cccc2)cc1OC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: O=[O+][O-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(C(C)C(=O)O)c(O)cc1-n1cccc1
Reaction time: 2 h

Procedure:
A solution of 2.7 g (10 mmoles) of 3-[2-acetoxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-1-butene in 40 ml of absolute methylene chloride is cooled to -78° with acetone/dry ice and ozone is blown through until the blue colour no longer disappears. Then, 2 ml of dimethyl sulphide are added and the cooling bath is removed. The reaction mixture is carefully concentrated in a vacuum rotary evaporator, the residue is dissolved in 50 ml of ethanol, and a solution of 3.7 g (23 mmoles) of silver nitrate in 5 ml of water is added. A solution of 75 ml of a 1 N potassium hydroxide solution is added dropwise to this mixture in the course of approximately 15 minutes. The heterogeneous mixture is further stirred for another 2 hours. The reaction mixture is filtered and the residue is washed with ethanol. The alkaline filtrate is left to stand overnight at room temperature and extracted with methylene chloride. The alkaline solution is cautiously acidified with 6 N hydrochloric acid while cooling and repeatedly extracted with methylene chloride. The organic phases are again washed twice with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Recrystallisation from diisopropyl ether/petroleum ether yields 2-[2-hydroxy-5-methyl-4-(pyrrol-1-yl)phenyl]-propionic acid having a melting point of 73°-74°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[N:34][N:33]3[C:36](=[O:46])[N:37]([CH2:39][CH:40]([OH:45])[CH2:41][O:42][CH2:43][CH3:44])[N:38]=[C:32]3[C:31]=2[C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[N:34][N:33]3[C:36](=[O:46])[N:37]([CH2:39][C:40](=[O:45])[CH2:41][O:42][CH2:43][CH3:44])[N:38]=[C:32]3[C:31]=2[C:47]2[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=2)=[CH:28][CH:29]=1
Reactant: CCOCC(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOCC(=O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Reaction time: 2 h
Yield: 95 %

Procedure:
The Dess-Martin reagent (56 mg, 0.131 mmol) was added to a solution of 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-hydroxypropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 29, (50 mg, 0.109 mmol) in 1 mL of CH2Cl2. The reaction was stirred for 2 h., filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-oxopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (47 mg, 95% yield) as a yellow solid. MS [M+H]+: found 457.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([N:12](C(OCC2C=CC=CC=2)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:7]1)(=[O:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-].[C]>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:9][N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)OCC1CC(NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
tert-Butyl 3-[(acetyloxy)methyl]-5-{[(benzyloxy)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (5.0 g) and palladium(II) hydroxide-carbon (500 mg) were suspended in methanol (100 ml), and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 8 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (3.50 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[Cl:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([Cl:28])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cc1Cl
Reactant: C=CCCC(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccc(Cl)c(Cl)c1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-pent-4-en-1-ol and 1,2-dichloro-4-iodo-benzene.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:49][C:50]1[CH:76]=[C:75]([F:77])[CH:74]=[CH:73][C:51]=1[O:52][CH:53]1[CH2:58][CH2:57][N:56]([C:59]2[N:60]=[C:61]3[CH2:72][CH2:71][NH:70][CH2:69][C:62]3=[N:63][C:64]=2[NH:65][CH:66]([CH3:68])[CH3:67])[CH2:55][CH2:54]1>CC(N(C)C)=O>[F:49][C:50]1[CH:76]=[C:75]([F:77])[CH:74]=[CH:73][C:51]=1[O:52][CH:53]1[CH2:54][CH2:55][N:56]([C:59]2[N:60]=[C:61]3[CH2:72][CH2:71][N:70]([C:6]([CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[O:8])[CH2:69][C:62]3=[N:63][C:64]=2[NH:65][CH:66]([CH3:68])[CH3:67])[CH2:57][CH2:58]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(O)C1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C1CCCO1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrahydrofuran-2-carboxylic acid (10.9 μL, 0.113 mmol) in DMA (0.35 mL) at room temperature was added DIPEA (39.5 μL, 0.226 mmol), followed by HATU (43.0 mg, 0.113 mmol). After stirring for 5 min, the reaction mixture was treated with a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DMA (0.4 mL). The reaction mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (16.0 mg, 34.5%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (m, 6H), 1.97 (m, 4H), 2.16 (m, 4H) 2.82 (m, 2H), 3.10 (m, 2H), 3.45 (m, 2H), 3.89 (m, 4H), 4.14 (m, 1H), 4.44-4.87 (m, 4H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 502.6.
Reaction SMILES: C([N:8]1[C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[C:17]=2[OH:28])=[O:14])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[C:23]([C:18]1[C:17]([OH:28])=[C:16]([CH:21]=[C:20]([CH3:22])[CH:19]=1)[NH:15][C:13]([C:12]1[NH:11][N:10]=[N:9][N:8]=1)=[O:14])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: ClCCl
Product: CCCC(=O)c1cc(C)cc(NC(=O)c2nnn[nH]2)c1O

Procedure:
A stirred solution of 1-benzyl-3'-butyryl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide in dichloromethane (75 ml), heated at reflux, was treated with anhydrous aluminium chloride (2.2 g) over a period of 15 minutes. After heating and stirring for a further hour, the mixture was cooled and treated with aqueous hydrochloric acid (2 N; 50 ml). The resulting suspension was heated at reflux with stirring for 15 minutes and then cooled. The precipitated solid was filtered off and combined with a residue which was subsequently obtained by evaporation of the dichloromethane layer of the filtrate. This combined solid was digested in aqueous sodium carbonate solution (2 N) at 90° C., then filtered to remove insoluble material and acidified by treatment with concentrated hydrochloric acid. Recrystallisation from a mixture of dimethylformamide and water gave 3'-butyryl-2'-hydroxy-5'-methyltetrazole-5-carboxanilide (0.78 g), m.p. 231°-233° C. (with decomposition).
Reaction SMILES: CN.[CH3:3]NC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([S:19](=[O:22])(=[O:21])[NH2:20])=[C:16](C)[N:17]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][CH:16]=[C:15]([S:19](=[O:22])(=[O:21])[NH:20][CH3:3])[N:14]=2)=[CH:9][CH:8]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)[nH]c1S(N)(=O)=O
Reactant: CNC
Agent: CN
Product: CNS(=O)(=O)c1c[nH]c(-c2ccc(Cl)cc2)n1
Yield: 4.4 %

Procedure:
Substituting aqueous methylamine for the dimethylamine in Example 3 2-(4-chlorophenyl)-4-methyl-sulfamoylimidazole, melting at 246°-248°, was obtained (4.4% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32](OC)=[O:33])(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][CH2:32][OH:33])(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CCO)s2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
Prepared using General Procedure 17: To a stirred solution of (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (13 mg, 0.02 mmol) in THF (0.5 mL) was added sodium borohydride (2.3 mg, 0.06 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.03 mL, 0.7 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. Purification of the crude material by preparative HPLC gave 6 mg (60%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 46. LCMS-ESI (m/z) calculated for C23H24N4O4S2: 484.1; found 485.1 [M+H]+, tR=3.26 min. 1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J=8.9, 2.3 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.19-4.96 (m, 1H), 4.87-4.63 (m, 3H), 4.17 (dd, J=8.2, 4.4 Hz, 2H), 3.53 (ddd, J=17.2, 8.8, 3.5 Hz, 1H), 3.46-3.34 (m, 2H), 3.32-3.11 (m, 1H), 2.86-2.59 (m, 1H), 2.19-1.97 (m, 1H), 1.48 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.83, 165.72, 161.71, 144.11, 141.85, 133.47, 133.26, 129.53, 127.99, 126.92, 126.58, 122.64, 115.51, 113.87, 103.79, 72.54, 58.86, 57.43, 55.67, 34.69, 31.27, 21.73. Chiral HPLC: (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide was eluted in MeOH, 96.2% ee, tR=12.58 min (Chiral Method 2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:15]([O:17]CC3C=CC=CC=3)[CH2:14]2)[CH2:10][C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH2:10][C:9]1=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Reaction time: 1 h

Procedure:
A 4.86 g (10.8 mmol) portion of 1-benzyl-4-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-2-pyrrolidone (Isomer B) was dissolved in 140 ml of ethanol, and the solution was mixed with 1 g of palladium hydroxide on carbon catalyst and subjected to 1 hour of catalytic reduction under a hydrogen pressure of 3 atmospheres and under irradiation of light. After removal of the catalyst by filtration, the solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 4.01 g (quantitative) of the title compound. Thereafter, optical resolution of Isomers B1 and B2 as enantiomers originated from the pyrrolidine 4 position asymmetric carbon atom of the thus obtained compound was carried out by HPLC under the following conditions.
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][N:12]=1.N>C1COCC1>[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COCOc1ccc(Br)nc1
Agent: N#C[Cu]
Agent: N
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(C)C)nc1
Reaction time: 0.67 h

Procedure:
6.69 g (74.7 mmol) copper(I)cyanide in 15 ml dry THF was cooled to −75° C., where 149 ml (149 mmol) of a 1M tert-butylmagnesium chloride solution was added drop-wise. Stirring was continued for 40 min. After that, 4.07 g (18.67 mmol) 2-bromo-5-methoxymethoxy-pyridine (Zhong, W. et al. WO2008147547) dissolved in 30 ml dry THF were added drop-wise. The reaction mixture was stirred at −75° C. for 1 h and then allowed to reach room temperature, where stirring was continued for another 6 h. Then 30 ml of 25% aqueous ammonia was added to the reaction mixture. The mixture was filtered and extracted twice with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield 2.64 g of the pure title compound as an oil. LCMS: tR=0.55 min, M+H=196 (method K).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](OCC)=[O:18]>S(=O)(=O)(O)O>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17](=[O:18])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Oc1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(O)cc(O)c2c2c1CCCC2
Temperature: 0 °C

Procedure:
Phloroglucinol (1 g) and ethyl 2-oxocyclohexane carboxylate (1.32 g) were stirred in 75% sulfuric acid (10 ml) overnight, the mixture poured into ice water and filtered. Yield: 1.55 g.
Reaction SMILES: Cl[CH:2]([CH3:28])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:27])[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:28][CH:2]1[C:3]2=[N:5][C:6]3[C:11]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=3[C:16]([OH:27])=[C:17]2[C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[O:19]1
Reactant: CC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
1.60 g of 4-dimethylamino-pyridine were added to a suspension of 4.5 g of the product of Step A in 90 ml of tetrahydrofuran and the mixture was refluxed for four hours and was evaporated to dryness under reduced pressure. The residue was added to 90 ml of water and the mixture was stirred for 30 minutes and was vacuum filtered. The product was washed with water and dried under reduced pressure at 70° C. to obtain 4.50 g of 1,3-dihydro-3-methyl-1-[(2-pyridinyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol which was crystallized from absolute ethanol.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]S(C3C=CC=CC=3)(=O)=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)C>O.O1CCOCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccc(Br)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
One example of a way of carrying out this Step is by a standard method using sodium hydroxide to hydrolyse commercially available 4'-bromo-4-benzene-sulphonyloxybiphenyl in a mixture of water and dioxan as solvent. The colourless crystals obtained by crystallisation of the product from ethanol have a melting point of 166° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23](=[O:33])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[O:35][C:36](=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])/[C:24](/[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:36](\[OH:35])/[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: COC(=O)COCc1ccccc1
Reactant: COC(=O)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
Lithium diisopropylamide was generated by addition of n-butyl lithium (17 mL, 1.9M in hexane, 33.33 mmol), di-isopropyl amine (4.66 mL, 33.33 mmol) in tetrahydrofuran (15 mL) at 0° C. and stirred for 10 min. In a separate flask, a mixture of benzyloxy-acetic acid methyl ester (3) (4 g, 22.22 mmol) and oxalic acid tert-butyl ester methyl ester (2) (5.33 g, 33.33 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and then lithium diisopropylamide was added at −78° C. The mixture was stirred at −78° C. for 1 h. After 1 h, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 1 h. After completion of the reaction, the reaction was quenched with 1N HCl, and extracted with ethyl acetate. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure, passed over a normal silica column using 25% ethyl acetate in hexane to get (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (2.4 g, 35%) as ketoenol tautomers and ketone hydrate as a thick light yellow coloured oil. These were immediately used for next step.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(Cl)Cl>N1CCCCC1.O>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)C1=C(O)C(C(=O)C=Cc2ccccc2)C(=O)OC1=O

Procedure:
A mixture of 4.24 g. of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 2.12 g. of benzaldehyde, 20 drops of piperidine and 75 ml. of chloroform is refluxed for eight hours. The water liberated during the reaction is removed by a receiver. The reaction mixture is concentrated and triturated with ethanol to afford 5-acetyl-3-cinnamoyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 154°-155° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([N:12]=[C:13](Cl)[CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([N:19]([CH2:20][CH3:21])[C:13](=[N:12][S:9]([C:5]1[CH:6]=[C:7]([Br:8])[C:2]([NH2:1])=[C:3]([Br:16])[CH:4]=1)(=[O:11])=[O:10])[CH3:14])[CH3:18]
Reactant: CCNCC
Reactant: CC(Cl)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(C)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
100 Mg. of crude N-(4-amino-3,5-dibromophenylsulfonyl) acetimidoyl chloride is stirred in 10 ml. of methylene chloride with 1 ml. of diethylamine at room temperature overnight. Volumes of water and methylene chloride equal to the volume of the reaction mixture are added, agitated and the layers separated. The organic layer is dried over magnesium sulfate and evaporated to dryness, in vacuo. The residue is taken up in 1 ml. of ethyl acetate and the dropwise addition of petroleum ether affords N,N-diethyl-N'-(4-amino-3,5-dibromophenylsulfonyl) acetamidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1.[CH2:20]([CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(OCCO)C.[OH-].[Na+]>[ClH:1].[CH2:20]([CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:10]=3)[N:5]=[C:4]([CH3:19])[CH:3]=2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Cl)c2cc(Oc3ccccc3)ccc2n1
Reactant: c1ccc(CC2CCNC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCO
Product: Cc1cc(N2CCC(Cc3ccccc3)C2)c2cc(Oc3ccccc3)ccc2n1

Procedure:
4-Chloro-2-methyl-6-phenoxyquinoline (0.2 g; see Preparation 3 above) and 3-benzyl-pyrrolidine (0.3 g) in 2-ethoxyethanol (4 mL) were heated in a microwave to 200° C. for 20 minutes. The mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC, the relevant fractions combined and evaporated to give a clear oil which was acidified with concentrated hydrochloric acid and then evaporated. Trituration with ether gave the title compound as a white powder.