Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:28])([CH3:27])[CH2:17][C:16]3([CH3:30])[CH3:29])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH:24]([O:23][C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:31])=[O:2])=[CH:10][CH:9]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:27])([CH3:28])[CH2:17][C:16]2([CH3:30])[CH3:29])([CH3:26])[CH3:25]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of [4-(8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 24, 0.02 g, 0.05 mmol) in methanol (1 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230–400 mesh) using 5% methanol in ethyl acetate as the eluent followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product (0.015 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6](OC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:13]=[C:12]([O:14][C:15]([F:16])([F:18])[F:17])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: COC(=O)COc1ccc(OC(F)(F)F)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCCOc1ccc(OC(F)(F)F)cc1Cl
Temperature: -78 °C

Procedure:
Methyl 2-[2-chloro-4(trifluoromethoxy)phenoxy]acetate (2.9 g, 10 mmol) was dissolved in dichloromethane (50 mL) and cooled to −78° C. A solution of diisobutylaluminum hydride in CH2Cl2 (1 M, 20 mL) was added and the reaction was warmed to 25° C. over 30 min. The reaction was quenched with methanol (2.0 mL) and poured into 0.5 N aqueous HCl. The aqueous phased was extracted with ethyl acetate and the combined organic layers were washed with brine and concetrated. The residue was chromatographed on silica gel eluting with 1:1 hexane:ethyl acetate gave 2-[2-chloro-4(trifluoromethoxy)phenoxy]ethanol.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.NC(C1C=[C:20]([CH:24]=[C:25]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31]C)=[O:28])C=1)[C:21]([OH:23])=O)=O.Cl.[NH2:37][C@@H:38]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:39]([OH:67])[CH2:40][N:41]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([I:66])[CH:61]=1)[C:42](=[O:58])[O:43][CH2:44][CH:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2.CN1CCOCC1>CN(C=O)C>[F:76][C:71]1[CH:70]=[C:69]([CH2:68][C@H:38]([NH:37][C:21](=[O:23])[CH2:20][CH2:24][CH2:25][C:27](=[O:28])[N:29]2[CH2:30][CH2:31][CH2:35][CH2:34][CH2:33]2)[C@H:39]([OH:67])[CH2:40][N:41]([CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([I:66])[CH:61]=2)[C:42](=[O:58])[O:43][CH2:44][CH:45]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]=3[C:52]3[C:57]2=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:74]=[C:73]([F:75])[CH:72]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN(Cc1cccc(I)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=C(CCCC(=O)N1CCCCC1)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN(Cc1cccc(I)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
HOBt (81 mg, 0.6 mmole) and EDC (105 mg, 0.55 mmole) are added to 1-carboxy-5-piperdinylglutaramide (IX, 100 mg, 0.5 mmole) in DMF (2 ml). The acid is activated 60 minutes then treated with 1-9H-fluoren-9-ylmethyl (2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbamate hydrochloride (XXXV, EXAMPLE 590, 300 mg, 0.43 mmole) and NMM (0.19 ml, 1.72 mmole). The reaction is stirred 3 hours then concentrated under reduced pressure. The residue is partitioned between ethyl acetate and saturated aqueous bicarbonate. The organic phases are washed with aqueous potassium bisulfate, saline, dried over sodium sulfate and finally concentrated under reduced pressure to give crude product. Purification via flash chromatography with ethyl acetate/hexane (50/50) then methanol/ethyl acetate (10/90) gives the title compound, M+H=838.
Reaction SMILES: [OH:1][C:2]1([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ncco2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ncco3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-hydroxy-4-oxazol-2-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.C[Mg+].[Br-].I[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1COCC1.C([O-])(O)=O.[Na+].[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: ICCN1CCOCC1
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: C[Mg+]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To 5-methoxy-2-methyl-1H-indole (5.00 g; 31.0 mmol) in 30 mL of dry THF at 0° C. was added dropwise MeMgBr (3.0M in Et2O; 11.4 mL; 34.2 mmol). The solution was stirred 30 min at r.t. after which ZnCl2 (0.5M in THF; 64 mL; 32 mmol) was added. The mixture was stirred at r.t., after 1 h, N-(2-iodoethyl)morpholine (14.41 g; 51.5 mmol) was added. The final mixture was stirred at r.t. overnight. The mixture was poored in saturated NaHCO3 (100 mL), extracted with EtOAc (2×100 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and flash chromatographed (Silica gel; EtOAc/Ace O to 10%) to yield 587 mg (7%) of the title compound.
Reaction SMILES: [C@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]1[CH:4]=[CH:3][CH2:2]2.N12CCCN=C1CCCCC2.[N+:27]([CH3:30])([O-:29])=[O:28]>Cl>[N+:27]([CH2:30][C@@:6]1([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@H:1]2[C@@H:5]1[CH:4]=[CH:3][CH2:2]2)([O-:29])=[O:28]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@H]12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl(±)-(1S,5R)bicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.73 g, 8.39 mmol) was dissolved in nitromethane (10 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then heated with stirring at 50 to 60° C. for 5 hours. The mixture was allowed to cool and then diluted with 1 N hydrochloric acid and saturated saline, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.98 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-methylbenzene. Yield: 21%. MS M+H calculated 380.1; found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 uM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]>C1COCC1>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:22]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1c2ccccc2C(=O)N1CCNc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCN(C(=O)n1ccnc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a 50 mL round-bottomed flask was added 2-(2-(4-fluorophenylamino)ethyl)-isoindoline-1,3-dione (204 mg, 718 μmol, from step 1), 1,1′-carbonyldiimidazole (175 mg, 1076 μmol, Aldrich), THF (2 mL). The reaction mixture was stirred at 80° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1H-imidazole-1-carboxamide. MS (ESI pos. ion) m/z: 379 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[O:11])[CH2:9][CH2:8]1>C(O)(C)C>[CH:7]1([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[OH:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1C(=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1[C@H](O)C1CC1
Reaction time: 36 h
Yield: 99.5 %

Procedure:
To a suspension of dichloro[(S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl][(S)-1,1′-bis(p-methoxyphenyl)-2-isopropylethane-1,2-diamine]ruthenium (II) (111 mg) and potassium-tert-butoxide (44.9 mg) in isopropanol (100 ml) was added (cyclopropyl)[2-(tert-butyldimethylsilyloxymethyl)phenyl]methanone (5.81 g) obtained in Step 2, and the mixture was subjected to medium pressure hydrogenation (5.0 kgf/cm2) at room temperature for 36 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (5.82 g).
Reaction SMILES: C(O[C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:9]([O:8][CH2:7][C:6](=[O:12])[C:5]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.3 %

Procedure:
One gram of 17α,21-diacetoxy-4-pregnene-3,20-dione is heated analogously to Example 1 in "Dowtherm" for 80 minutes to 285° C., worked up, separated, and combined. Recrystallization from hexane/ethyl acetate yields 700 mg of 21-acetoxy-4,16-pregnadiene-3,20-dione (83% of theory), m.p. 146°-148° C.
Reaction SMILES: [C:1]([C:4]1([NH:18][C:19]([CH3:21])=[O:20])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([O:16]C)[CH:8]=[CH:9][C:10]=2[O:14]C)[CH2:5]1)(=[O:3])[CH3:2].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>C(O)(=O)C(O)=O>[C:1]([C:4]1([NH:18][C:19]([CH3:21])=[O:20])[CH2:5][C:6]2[C:7]([OH:16])=[C:8]3[C:9]([C:22](=[O:27])[C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]3=[O:26])=[C:10]([OH:14])[C:11]=2[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(OC)c2c1CCC(NC(C)=O)(C(C)=O)C2
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)NC1(C(C)=O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 180 °C
Reaction time: 0.03 h

Procedure:
2-Acetyl-2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene (2.8 g), phthalic anhydride (3.4 g), aluminum chloride (40 g) and sodium chloride (8 g) were pulverized and mixed well and charged in a flask previously heated at 180° C. Heating was continued at 180° C. to melt the contents. After melting, heating was further continued for 2 minutes. Then, the temperature was quickly lowered to room temperature, followed by incorporation of a saturated oxalic acid solution (500 ml) cooled with ice water therein. The resultant mixture was stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration to give 9-acetyl-9-acetamino-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione. M.P., 295°-303° C. (decomp.).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)C.C(OO)(=[O:13])C.[ClH:16]>O>[ClH:16].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:13]
Reactant: CC(=O)Nc1ccccn1
Reactant: CC(=O)OO
Agent: Cl
Solvent: O
Product: Nc1cccc[n+]1[O-]
Temperature: 70 °C

Procedure:
The solution of 2-acetamidopyridine was chilled in an ice bath to 10°-15° C and treated with 118 g. of commercial 40% peracetic acid which was slowly added over a 40-minute period with ice-cooling and stirring. During the course of the addition the temperature was between 15°-25° C. After 1 hour stirring, with little cooling (temperature 20°-30° C), the turbid solution was heated for 3.5 hours at 70° C with stirring. To the clear hot solution were added 85 g. 37.5% hydrochloric acid and 37 g. water, and to the resulting cloudy solution was added 3.5 g. 37% formaldehyde solution to destroy any unreacted excess of peroxide compounds. The mixture was stirred and heated 2.5 hours at 80°-82° C. After cooling to room temperature, 40 g. xylene was added and the cloudy solution was evaporated, under vacuum, in a rotary evaporator, until the residue was solid. The resulting moist crystals were dried at 50°-60° C under vacuum, to give 116 g. of 2-aminopyridine-1-oxide hydrochloride, which on recrystallization from 1:1 ethanoltoluene mixture, weighed 98.8 g. The resulting colorless crystals gave a m.p. of 155°-156° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:36])[CH2:28][C:29](=[O:35])[N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)(=O)=O.[C-:37]#[N:38].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[CH3:36][N:27]([CH2:28][C:29](=[O:35])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:24]1[CH2:23][CH2:22][CH:21]([O:20][C:11]2[C:10]3[C:9]4[C@@H:8]([CH2:7][CH2:6][C:37]#[N:38])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:26][CH2:25]1
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCOS(C)(=O)=O)CC4)CC1
Reactant: [C-]#N
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC#N)CC4)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (107 mg, 0.20 mmol, 1.00 equiv) in DMSO (5 mL) were added NaCN (58.8 mg, 1.20 mmol, 6.00 equiv) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol, 0.10 equiv) at room temperature. The resulting solution was stirred for 2 h at 80° C. After cooling to room temperature, the reaction was then quenched by the addition of aqueous FeSO4 solution and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to give the desired 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (80 mg, 86%) as a yellow solid. MS (ES): m/z 468 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[N+:8]([C:7]1[C:2]([NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: NCC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.4 %

Procedure:
A mixture of 2-chloro-3-nitro-5-trifluoromethylpyridine (2.60 g), 2,2,2-trifluoroethylamine (0.79 g), N,N-diisopropylethylamine (1.04 g) and N-methyl-2-pyrrolidone (5 ml) was stirred at room temperature for 10 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give (3-nitro-5-trifluoromethylpyridin-2-yl)-(2,2,2-trifluoroethyl)amine (1.83 g).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: COc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-methoxyaniline (30 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-methoxyphenyl)benzamide as a white solid. Yield: 13 mg (13%). 1H-NMR: 10.41 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.43-7.41 (m, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.08 (m, 2H), 6.70 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nccc(-c4sc(C)nc4C)n3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Yield: 96.5 %

Procedure:
To a solution of 1-(4-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone (0.67 g, 1.64 mmol) in EtOH (3 mL) was added 2 M aq HCl (25 mL) in a steady stream. The mixture was heated at reflux for 1 h, cooled, and basified by addition of solid Na2CO3. The product was extracted with EtOAc. The combined organics were washed with brine, dried on Na2SO4, filtered, and evaporated to afford the title compound (580 mg) as a yellow solid. 1H-NMR (CDCl3) TM: 2.62 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.99 (m, 4H, CH2), 3.06 (m, 4H, CH2), 6.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.89 (m, 3H, Ph-H, NH), 7.44 (m, 2H, Ph-H), 8.31 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z 367 (C19H22N6S requires 366.5).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Li+].Cl>CO>[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:17])=[O:2])[CH2:8][CH2:9]1)(=[O:16])[CH3:15]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](NC(C)=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@H](C(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of trans-2-(4-acetylamino-cyclohexyl)-2-methyl-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is neutralised with 1M HCl and extracted with ethyl acetate (3×50 ml)—the combined organic phases are concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[BrH:12]>>[BrH:12].[NH2:11][C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[CH3:10]
Reactant: COc1ccc([C@H](C)N)cc1
Agent: Br
Product: C[C@H](N)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 11.0 g (72.7 mmol) (S)-1-(4-methoxy-phenyl)-ethylamine is added carefully 30 mL HBr (30% in HOAc). The mixture is stirred at 100° C. for 4 h. After cooling down to r.t., the solvent is removed in vacuo and the residue is dried in vacuo. The resulting product is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: Oc1ccc(Cl)nn1
Reactant: C1COCCN1
Product: Oc1ccc(N2CCOCC2)nn1
Yield: 74 %

Procedure:
6-Chloro-3-hydroxypyridazine (25.0 g, 0.191 mol) was dissolved in morpholine (120 mol), under reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 6-morpholino-3-hydroxypyridazine in white crystal (25.8 g as a yield of 74%).