Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+].ClCCl>[Br:10][CH2:11][C:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)=[O:13]
Reactant: O=C(Cl)CBr
Reactant: Cc1cc(N)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(NC(=O)CBr)ccc1Br
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
4-Bromo-3-methylaniline (10.08 g, 54.18 mmol) in 2N sodium hydroxide (200 mL) was treated with bromoacetyl chloride (5.00 mL, 60.8 mmol) as a solution in dichloromethane (200 mL) dropwise. After 15 minutes, the layers were separated. The organic phase was washed with 1N hydrochloric acid, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide 11.75 g (71%) of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 3H), 4.01 (s, 2H), 7.23 (m, 1H), 7.44 (d, 1H, J=2.4 Hz), 7.49 (d, 1H, J=8.8 Hz), 8.07 (br s, 1H); MS (DCI/NH3) m/e 306 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH3:27])[C:10]1=[O:28])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:26]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:28])[CH3:27]
Reactant: [H][H]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 99.2 %

Procedure:
Five percent Pd/BaSO4 (60 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example E, 0.21 g, 0.55 mmol) in 16 mL of THF. The mixture was shaken under 50 PSI of hydrogen for 31 hours, filtered, and concentrated to afford 0.16 g of a solid. This solid was dissolved in 1N sodium hydroxide and washed with chloroform. The chloroform layer was back extracted with sodium hydroxide, and the combined basic extracts were acidified to pH 3. The aqueous layer was extracted with chloroform, dried over magnesium sulfate, and concentrated to give 0.11 g of the title compound as a solid, mp 170-171 ° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoethanol (6.37 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 18 min, product retention=17.9 min (20 mL/min, 220 nM) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.047 mmol, 68.2% yield): LCMS=475.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.25 (1 H, t, J=5.94 Hz), 8.09-8.19 (2 H, m), 7.58-7.84 (7 H, m), 5.14 (1 H, s), 3.60-3.67 (2 H, m), 3.34-3.44 (2 H, m); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([NH2:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH2:16][NH2:17])[CH2:14][NH2:15].C(N(CC)CC)C>C(O)CCC>[NH2:15][CH2:14][C:13]([CH3:18])([CH3:12])[CH2:16][NH:17][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)(CN)CN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(CN)CNc1nc(Cl)nc2[nH]ccc12
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.904 mmol) in solid form in a round-bottom flask, a solution of 2,2-dimethyl-1,3-propanediamine (0.325 mL, 2.71 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was added. The mixture was heated at 70° C. for 3 h. It was then purified by HPLC to give N-(3-amino-2,2-dimethylpropyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (212 mg).
Reaction SMILES: [Zn](C)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@@H:20]([OH:21])[CH3:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Zn]C
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: C[C@H](O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 13 prepared according to Example 11, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15 (0.162 g, 51%). HLPC analysis of the product presented in the Figures. 1H NMR (CDCl3, 300 MHz) 7.43-7.31 (5H, broad s), 5.16 (2H, s), 4.30-3.60 (2H, broad m), 3.63 (1H, dq, J=6.4, 6.4 Hz), 3.30-2.70 (2H, broad s), 2.15-1.90 (1H, broad s), 1.84-1.72 (1H, m), 1.76-1.56 (1H, m), 1.58-1.36 (2H, m), 1.23 (3H, d, J=6.4 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.81, 137.04, 128.61, 128.08, 127.93, 68.35, 67.19, 46.61, 45.02, 43.25, 27.08, 24.37, 20.95 ppm. LRMS m/z 263.68 (M+, C15H21NO3, requires 263.15.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Al+3].[Cl-:16].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:16][C:2]1[CH:11]=[CH:6][C:5]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(O)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Temperature: 25 °C
Yield: 158.3 %

Procedure:
Over a 30 minute period, 3-bromo-adamantane-1-carboxylic acid (2) (16.0 g, 61.7 mmol) in 50 ml of dry chlorobenzene at −10° C. was added to 100 ml dry chlorobenzene and 9.3 g, 70 mmol AlCl3. The mixture was then warmed to room temperature for 1 hour and then heated to 90° C. for 10 hours. The mixture was then poured onto 200 g of crushed ice, and the filtered to provide 14.2 g (yield=79.3%) of 3-(4-chloro-phenyl)-adamantane-1-carboxylic acid (3).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15]([O:19][C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][C:3]=2[F:14])[CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Product: COc1ccc2ncc(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c2n1
Yield: 48 %

Procedure:
According to procedure F and starting from 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine and (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine the title intermediate was isolated as a yellow oil (304 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[CH3:22])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[CH3:22])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)C(CC(C)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
222 mg (purity 85%, 0.50 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoic acid (mixture of racemic diastereomers) and 91 mg (0.55 mmol, 1.1 eq.) of ethyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 180 mg (purity 91%, 63% of theory)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)=[C:8]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([S:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (2 g, 4.2 mmol) is added tetrabutylammonium fluoride solution (1M in THF, 21 ml, 21 mmol). The mixture is first stirred at room temperature for 5 hours and to it is added dichloromethane followed by water. The layers are separated and the organic layer is washed with water and dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 10.85 g (65.0 mmol) of carbazole, 2.60 g (65.0 mmol) of sodium hydroxide and 6.1 mL (72.0 mmol) of allylbromide in 100 mL dimethylsulfoxide was heated to 60° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then concentrated. The crude product was purified using column chromatography (silica, 1:4 dichloromethane:hexane). Yield: 9.85 g (73%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2nocc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2nocc12
Yield: 103.8 %

Procedure:
To a solution of 5.99 g (45.0 mmoles) (1) in 135 ml carbon tetrachloride was added 8.81 g (49.5 mmoles) N-bromosuccinimide and 100 mg benzoyl peroxide. The mixture was refluxed while illuminated by a 250 watt sunlamp for 18 hours. The mixture was cooled and filtered, and the filtrate concentrated to give 9.9 g of a dark red oil. The oil was extracted with 500 ml hot hexane. The hexane solution was evaporated to 150 ml and cooled to give 6.60 g (69%) of crystalline (2), m.p. 51.0°-52.5°; nmr (deuteriochloroform): 4.6 (s, 2H), 7.2 (m, 3H), 9.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C@@H:33]1[CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][C@@H:33]([F:32])[CH2:34][C@H:35]5[C:38]([OH:40])=[O:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2C[C@@H](F)C[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-(S)-fluoro-L-proline was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-(S)-Fluoro-pyrrolidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CN)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CNS(C)(=O)=O)c1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
Methanesulfonyl chloride (4.170 g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine (5.000 g, 36.4 mmol) and triethylamine (3.946 g, 39.0 mmol) in THF (100 mL) at room temperature. The mixture was stirred for 18 h and the insolubles were removed by filtration. The organic solution was concentrated to a yellow oil which was purified by flash chromatography (6:4 hexanes:EtOAc to 1:1 hexanes:EtOAc) to yield N-(3-methoxy-benzyl)-methanesulfonamide (7.431 g). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 6.92–6.82 (m, 3H), 4.62 (m, 1H), 4.28 (d, 2H), 3.80 (s, 3H), 2.87 (s, 3H); MS 214 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>[NH4+].[Cl-]>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
tert-Butyl 3-amino-4-methoxybenzyl(methyl)carbamate (265.3 mg, 0.996 mmol) was dissolved in pyridine (3000 μl, 37.1 mmol) and cooled to 0° C. MsCl (93 μl, 1.195 mmol) was added dropwise, and the reaction was stirred at RT for 1 hour. The solution was diluted with NH4Cl sat. sol. and extracted twice with DCM. The organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give tert-butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)-carbamate (249.5 mg, 0.724 mmol, 72.7% yield, MS/ESI+ 367.2 [MNa]+) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([CH:19]=O)[CH:11]=2)[CH:9]=1)[CH3:2].[NH2:22][CH:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12](/[CH:19]=[N:22]/[CH:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CN1CCC(N)C1=O
Reactant: CCOc1ccc(F)c(-c2cc(C=O)nc(C(C)C)c2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(/C=N/C3CCN(C)C3=O)nc(C(C)C)c2)c1
Reaction time: 8 h

Procedure:
A solution of 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 116) (570 mg, 1.98 mmol) in DCM (10 mL) was treated with 3-amino-1-methyl-pyrrolidin-2-one (226.45 mg, 1.98 mmol) and magnesium sulphate (1193.7 mg, 9.92 mmol). The mixture was stirred overnight and then filtered and concentrated to give 3-[(E)-[4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-2-pyridyl]methylene-amino]-1-methyl-pyrrolidin-2-one as an oil. To a stirred solution of this material (759.25 mg, 1.98 mmol) in anhydrous THF (10 mL) under nitrogen at room temperature, was added phenyl vinyl sulfone (0.34 g, 2.02 mmol) and silver acetate (0.04 g, 0.01 mL, 0.2200 mmol). The resulting mixture was left to stir at room temperature for 2 h. The reaction mixture was filtered through Celite and the celite was washed with THF (approx. 20 mL). The filtrate was stirred under nitrogen in an ice bath and treated with potassium t-butoxide (2.33 mL, 3.96 mmol) over 5 minutes. After completion of the addition, the mixture was stirred at room temperature for 1 hr. Acetic acid (0.23 mL, 3.96 mmol) was added and the mixture was stirred for 5 minutes and then filtered through Celite and concentrated. The material was purified by chromatography using a Biotage Si—NH column, and eluting with 10-100% ethyl acetate in isohexane to give racemic 2-[4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one as a yellow gum (734.8 mg);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1N.N([O-])=O.[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: Nc1ccccc1Br
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccccc1-c1ccccn1
Temperature: 80 °C

Procedure:
2-Bromobenzenamine (18.77 g) in 50 ml of conc HCl and 50 ml of water, was cooled in an ice bath and treated dropwise with stirring with a solution of sodium nitrite (8.28 g) in water (35 ml). After the addition was complete, the mixture was stirred in the ice bath for a further 30 minutes and then added portionwise (over 5 minutes) to pyridine (275 ml) stirred in an oil bath at 80° C. The mixture was heated (at 80° C.) for a further 1 hour, when the excess of pyridine was distilled off under reduced pressure. The residue was basified (aqueous sodium hydrogen carbonate) and extracted with ethyl acetate (3×). The extracts were washed with water (2×), dried (sodium sulphate) and evaporated to give a dark oil, which was flash chromatographed on silica using methylene chloride/ethyl acetate (20/1) as eluant. Pure sub-title compound (6.56 g) was obtained as a dark brown oil. m/z 235/233 (MW), 154 (Base Peak).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[CH2:25](O)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(F)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(OC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethoxy)benzoic acid (1.00 g, 4.46 mmol) in ethanol (10 ml) was added thionyl chloride (1.33 g, 11.2 mmol) at 0° C. The reaction solution was slowly warmed to room temperature, and stirred at the same temperature overnight. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→9:1) to give ethyl 3-fluoro-4-(trifluoromethoxy)benzoate (0.72 g, 64%) as a colorless and clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O.[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC1=C(C)C(=O)C(CCCCCC(=O)O)=C(C)C1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Reaction time: 12 h

Procedure:
To a well stirred solution of 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the free form) (0.21 part) in ethanol (10 volume parts) was added 3 drops of concentrated sulfuric acid under cooling in ice bath and kept standing for 12 hours. After addition of water, the reaction mixture was extracted with diethyl ether and the diethylether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with chloroform to give 2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of ethyl ester) (0.20 part) as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Na+:9].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>O.ClCCl>[Br:10][CH:11]([CH3:15])[C:12]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:13].[Na+:9]
Reactant: CC(Br)C(=O)Br
Reactant: NCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)NCCS(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
25.6 g of taurine (204 mmol) and 16.38 g of NaOH (409 mmol) were dissolved in 20 ml of deionized water. 2-Bromopropionyl bromide (44 g, 21.36 ml, 204 mmol) dissolved in 50 ml of dichloromethane was then added to the solution drop wise at 0° C. over 30 minutes. During the addition, a large amount of solid was produced. The reaction flask was manually agitated to thoroughly mix the compounds until no more exotherm was observed with additional agitation. The reaction mixture was then allowed to sit for 1 hour. The solid was filtered and washed with a small amount of absolute ethanol and then ethyl ether and then dried in vacuo. The compound can be used in this state or recrystallized from methanol.