Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(O)=O)=CC=1.C([O:29][C:30](=[O:46])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][C:32]=1[F:45])C1C=CC=CC=1>>[CH2:38]([O:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]([OH:46])=[O:29])=[C:32]([F:45])[CH:33]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1F
Agent: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting 4-Benzyloxy-2-fluoro-benzoic acid benzyl ester provided the title compound. MS: (M+H m/z=247.1).
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16](=[O:21])[N:17]([O:19][CH3:20])[CH3:18])[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:15][C@H:14]3[C:16](=[O:21])[N:17]([O:19][CH3:20])[CH3:18])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CON(C)C(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: CON(C)C(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(N-methoxy-N-methylcarbamoyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 37; 420 mg 0.69 mmol), 10% palladium on charcoal (375 mg, 0.35 mmol) ethanol (25 ml) was stirred under hydrogen atmosphere (1 atm) at +60° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][CH2:14][C:15]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH:13][CH2:14][C:15]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)=[O:5]
Reactant: CN1CCCCC1C1(CN)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-3,6-difluorobenzoyl chloride (0.38 ml, 2.7 mmol) was added to tert-butyl 3-(aminomethyl)-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.55 g, 1.9 mmol) in dichloromethane (6 ml) and triethylamine (0.54 ml, 3.9 mmol) at 0° C. The reaction was stirred at 0° C. for 15 mins, before warming to room temperature. After 30 mins, lc-ms showed complete consumption of starting material. The reaction was quenched and the resulting mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on silica gel eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-8%) led to tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate as a white solid. m/z (M++H) 458.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[C:8]=2[CH:17]=1.Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1>>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:12]([C:9]2[C:8]3[CH:17]=[C:4]([CH:3]([O:2][CH3:1])[O:20][CH3:21])[C:5]([F:19])=[C:6]([F:18])[C:7]=3[O:11][N:10]=2)=[O:14])[CH2:25]1
Reactant: CCOC(=O)c1noc2c(F)c(F)c(C(OC)OC)cc12
Reactant: FC1(F)CNC1
Agent: Cl
Product: COC(OC)c1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F

Procedure:
Starting materials: ethyl 5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazole-3-carboxylate (Intermediate 206) and 3,3-difluoroazetidine hydrochloride.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:14][CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:16]1=[O:17]>CCCCCC>[Br:14][CH:15]([CH2:20][C:19]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:21])[C:16]([OH:18])=[O:17]
Reactant: O=C1CC(Br)C(=O)O1
Reactant: CCCCCCCCCCCCN
Solvent: CCCCCC
Product: CCCCCCCCCCCCNC(=O)CC(Br)C(=O)O
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 9.3 g. (0.05 mole) of dodecylamine in 30 ml. of hexane is added dropwise to a stirred mixture of 9.0 g. (0.05 mole) of 2-bromosuccinic anhydride in 70 ml. of hexane at 5°-10° C. over a period of 15 minutes. Reaction is exothermic and the mixture is stirred for an additional 15 minutes while still in cooling bath. As a result, the temperature rises to 15° C. and the reaction takes the appearance of a white emulsion. Hexane (100 ml.) is added and stirring is continued at ambient temperature for 24 hours. The white insoluble solid is filtered off, washed several times with hexane then dried at about 50° C. and reduced pressure to obtain 16.1 g. (89% yield) of a white slightly waxy solid product of this example; m. p. 62°-70° C. (opaque).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11](F)=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4]([F:21])[C:3]=1[F:22].[CH2:23]([O:30][C:31]([C:33]1[CH:39]=[CH:38][C:36]([O-:37])=[CH:35][CH:34]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[K+].[K]>CN(C)C=O>[CH2:23]([O:30][C:31]([C:33]1[CH:34]=[CH:35][C:36]([O:37][C:11]2[C:10]([F:17])=[C:9]([F:18])[C:8]([C:7]3[C:2]([F:1])=[C:3]([F:22])[C:4]([F:21])=[C:5]([F:20])[C:6]=3[F:19])=[C:13]([F:14])[C:12]=2[F:15])=[CH:38][CH:39]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2F)cc1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
37.6 g of decafluorobiphenyl (0.112 mol) are dissolved in 700 ml of dimethylformamide, and the solution is cooled to -10° C. by means of a cryostat, and a solution of 15 g of potassium 4-benzyloxycarbonylphenoxide (0.056 mol) in 300 ml of dimethylformamide is then added drop wise over the course of 2 hours. After 48 hours at -10° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, and the residue is taken up in a little tetrahydrofuran and filtered via a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off via a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [O:1]=[C:2]1[C:18]2[C:17]([N+]([O-])=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[C:3]1=[O:22].O.NN.N([O-])=O.[Na+].[BrH:30]>C(O)C.ClCCl.[Pd].[Cu]Br.O>[Br:30][C:17]1[C:18]2[C:2](=[O:1])[C:3](=[O:22])[C:4]3[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6][C:5]=3[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Br
Reactant: O=C1C(=O)c2c(nc3ccccn23)-c2cccc([N+](=O)[O-])c21
Agent: [Cu]Br
Agent: [Pd]
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C1C(=O)c2c(nc3ccccn23)-c2cccc(Br)c21
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A catalytic quantity of palladium on 10% carbon is added to an orange suspension of 110 mg (0.37 mmol, 1 eq) of 5,6-dihydro-5,6-dioxo-4-nitro-naphtho[1',2':4,5]imidazo[1,2-a]pyridine in ethanol under argon and the mixture is brought to reflux. 36.3 μL of hydrazine monohydrate (0.37 mmol, 1 eq) are then added. The reaction mixture immediately becomes violet. After 30 min, 36.3 μL of hydrazine monohydrate (0.37 mmol, 1 eq) are added. After 1 h of reaction, the reaction mixture is allowed to return to ambient temperature and the brown-violet precipitate is filtered through dried cotton and solubilized in 15 mL of conc. hydrobromic acid. This solution is cooled to -15° C., then a solution consisting of 64 mg (0.93 mm mmol, 2.5 eq) of sodium nitrite and 5 mL of distilled water is added dropwise. The medium is left under agitation at this temperature for 1.5 h. The reaction medium is added dropwise to a solution cooled to -5° C., consisting of 21 mg (0.15 mmol, 0.4 eq) of copper(I) bromide and 5 mL of conc. hydrobromic acid. A violet solution is obtained and its agitation is continued for 2.5 h. The reaction medium is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate, then with distilled water. The organic phase is extracted, dried on sodium sulfate and evaporated to dryness. The raw product is purified on preparation plates (support silica, eluant: dichloromethane/methanol, 95/5) to produce 30 mg of 4-bromo-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a] pyridine in the form of yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](N(OC)C)=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([Mg]Br)=[CH2:26]>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[CH:25]=[CH2:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Solvent: C1CCOC1
Product: C=CC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 15 g (45.7 mmol) of benzyl (3-{2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)carbamate (from Step C) in 1000 mL anhydrous THF under nitrogen atmosphere cooled to 0° C. via ice/water bath was added dropwise via cannula a 1.0 M solution of vinyl magnesium bromide (100 mL in THF, 100 mmol) and the resulting solution stirred for 1 h at 0° C. The reaction was quenched by a slow addition of 500 mL 1 M HCl keeping the temperature below 5° C. and stirred for 30 min. The mixture was then extracted with ethyl acetate and the combined organics washed with water followed by brine. The organics were then dried over sodium sulfate, filtered, and concentrate under vacuum. The residue was purified by Biotage 75M flash eluting with 30% ethyl acetate in hexane to afford the title compound (11 g, 78%) as a light yellow solid. LC-MS: m/z (ES) 310 (MH)+, 332 (MNa)+. 1HNMR (500 MHz, CDCl3) δ:7.44-7.36 (m, 7H), 7.18 (d, J=8.4 Hz, 2H), 6.70 (br s, 1H), 6.44 (dd, J=10.5, 17.6 Hz, 1H), 6.32 (dd, J=1.1, 17.6 Hz, 1H), 5.85 (dd, J=1.1, 10.5 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 2H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13]4)[CH:7]=2)[O:2]1.C1OC2C=CC(B(O)O)=CC=2O1.[Br-:37].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:37][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13]3)[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)OCO4)ccc2c1
Reactant: [Br-]
Agent: OB(O)c1ccc2c(c1)OCO2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3cc(Br)c4c(c3)OCO4)ccc2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of ethyl 6-[4,5-methylenedioxyphenyl]-2-naphthoate (19.61 g, 56.50 mmol, prepared in a similar manner via a Suzuki coupling of 3,4-methylenedioxyphenyl boronic acid and 6-carboethoxynaphthyl-2-trifluoromethanesulfonate, 84% yield) in CH2Cl2 (900 mL) was pyridinium tribromide (19.91 g, 62.26 mmol) at RT. The resulting mixture was allowed to stir overnight. After 24 hours, additional amount of pyridinium tribromide (9.05 g, 28.3 mmol) was added and the mixture stirred overnight. The mixture was washed with H2O, brine and dried over magnesium sulfate. After filtering, the solvent was removed and purified on silica gel (CH2Cl2) to give ethyl 6-[3-bromo-4,5-methylenedioxyphenyl]-2-naphthoate (100%) as a white solid. 1H NMR (300 MHz; CDCl3): δ 1.47 (t, J=7.2 Hz, 3H), 4.46 (q, J=7.2 Hz, 2H), 6.05 (s, 2H), 6.90 (s, 1H), 7.15 (s, 1H), 7.57 (dd, J1=9.0 Hz, J2=1.5 Hz, 1H), 7.84 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:14])=[O:13]
Reactant: Sc1cccs1
Reactant: O=C1CCCCCO1
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with ε-caprolactone to obtain 6-(2-thienylsulfanyl)hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>>[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][N:1]1[CH2:9][CH2:8][N:7]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCNCCN1
Reactant: O=Cc1ccc[nH]1
Product: c1c[nH]c(CN2CCN(Cc3ccc[nH]3)CCN(Cc3ccc[nH]3)CC2)c1

Procedure:
1,4,7-tris(pyrrole-2ylmethyl)-1,4,7-triazacyclononane was prepared according to procedure B using TACN and pyrrole-2-carboxaldehyde as starting material.
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]([N:45]2[C:53]3[C:48](=[C:49]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][CH:52]=3)[CH:47]=[CH:46]2)([CH2:43][CH3:44])[C:31]([NH:33][CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][OH:36])=O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.II>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([N:45]2[C:53]3[C:48](=[C:49]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:58])([CH3:60])[CH3:59])[CH:50]=[CH:51][CH:52]=3)[CH:47]=[CH:46]2)([C:31]2[O:36][CH:35]=[C:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:33]=2)[CH2:43][CH3:44])=[CH:28][CH:29]=1
Reactant: CCC(C(=O)NC(CO)c1ccccc1)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1ccc(Cl)cc1)(c1nc(-c2ccccc2)co1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (46 mg, 0.109 mmol) was added to a stirred solution of 9b (40 mg, 0.073 mmol) in DCM (0.73 mL) at 0° C. After 2 h, the reaction was quenched by addition of saturated aqueous sodium thiosulfate and extracted with DCM. The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude residue that was dissolved in DCM (1 mL) and added dropwise to a stirred solution in which triphenylphosphine (172 mg, 0.657 mmol), followed by triethylamine (31 μL, 0.220 mmol), had been added to iodine (28 mg, 0.110 mmol) in DCM (1 mL) at 0° C. The resulting mixture was warmed to rt, and after 1 h, quenched with saturated aqueous sodium thiosulfate. The mixture was extracted with ethyl acetate, and the combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude residue that was purified by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford the title compound 9c. m/z (ES) 528 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1)c1ccc(F)cc1
Yield: 77.5 %

Procedure:
To a solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.3 mmol) at room temperature was stirred with pyridine (2.49 mL, 30.8 mmol) and 4-fluoroaniline (1.95 mL, 20.6 mmol) for 2 hrs. The reaction was quenched with 1 M HCl aqueous and then extracted with DCM, filtered through a phase separator and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give 4-fluoro-N-(4-fluoro-phenyl)-benzenesulfonamide (2.15 g, 78%). LCMS (m/z, Method A) ES+ 270 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH2:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]>C(O)C>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([N:12]([CH2:10][CH3:11])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][N:5]=1
Reactant: CCNc1ccccc1
Reactant: Clc1ncnc(Cl)c1Cl
Solvent: CCO
Product: CCN(c1ccccc1)c1ncnc(Cl)c1Cl
Temperature: 25 °C
Yield: 114 %

Procedure:
To 2 ml of ethanol were added 0.3 g of 4,5,6-trichloropyrimidine and 0.5 g of N-ethylaniline, followed by heating under reflux for 8 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was added water and extracted three times with t-butyl methyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.5 g of 4,5-dichloro-6-(N-ethyl-N-phenylamino)pyrimidine.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17](O)([CH3:19])[CH3:18])[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]([F:7])([CH3:19])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: CC(C)(O)c1cc(Cl)ncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of DAST (0.153 mL, 1.159 mmol) in DCM (5 mL) was added 2-(6-chloro-4-pyrimidinyl)-2-propanol (Intermediate 28, 100 mg, 0.579 mmol) dissolved in DCM (5 mL) dropwise, and the resulting mixture stirred under argon at −78° C. for 4 hrs. The reaction mixture was quenched with excess saturated sodium bicarbonate solution (50 mL) and extracted with DCM (2×20 mL). The organic layers were collected and solvent was removed gently in vacuo. Crude product in DCM was taken into the next reaction without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[C:12]2=[N:13][C:14]([Cl:18])=[C:15]([Br:17])[N:16]=[C:11]2[CH:10]=[CH:9]1)=[O:7])(C)(C)C.[CH2:19]=[O:20].[OH-].[Na+].Cl>O1CCOCC1.O>[Br:17][C:15]1[N:16]=[C:11]2[C:10]([CH2:19][OH:20])=[CH:9][N:8]([CH2:6][OH:7])[C:12]2=[N:13][C:14]=1[Cl:18]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)n1ccc2nc(Br)c(Cl)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn(CO)c2nc(Cl)c(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromo-3-chloro-pyrrolo[2,3-b]pyrazine-5-carboxylic acid tert-butyl ester (6.0 g, 18.0 mmol) in 1,4-dioxane (100 mL) was added methanal (5.4 g, 180.4 mmol) and 1 M NaOH solution (54 mL) and the reaction mixture was stirred at room temperature for 16 h. 1.2 N HCl was added into the reaction mixture until the mixture reached pH 7. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with water (50 mL) and extracted with ethyl acetate (150 mL×3). The organic layers were combined and concentrated in vacuo to give (2-bromo-3-chloro-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (4.4 g, 83%) as yellow solid. LC-MS: 292.2 (M−H). This was used directly without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@@:25]1([O:33][C:2]([NH:1][C:4]3[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=3)=[N:23][CH2:24]1)[CH2:26]2
Reactant: Cc1cc(N=C=S)nc(C)c1C#N
Reactant: NCC1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc(C)c1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.09 g, 0.48 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.17 mL, 1.19 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.11 g, 0.49 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.22 mL, 1.43 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile (0.10 g, 0.32 mmol, 66% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.08 (s, 1H), 6.60 (s, 1H), 3.88 (d, J=10.38 Hz, 1H), 3.61 (d, J=10.38 Hz, 1H), 2.98 (s, 2H), 2.70-2.79 (m, 2H), 2.63-2.69 (m, 2H), 2.55-2.60 (m, 4H), 2.31-2.39 (m, 4H), 1.99 (s, 1H), 1.89 (s, 1H), 1.54-1.62 (m, 2H), 1.41-1.49 (m, 1H). MS (LC/MS) R.T.=0.78; [M+H]+=312.1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
2-Bromo-1,3-thiazole-4-carboxylic acid (0.8 g, 3.85 mmol) was initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (0.94 g, 5.77 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.55 g, 5.77 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 g, 5.77 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. The aqueous phase was extracted with dichloromethane; the organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. This gave a total of 1.0 g (89% of theory) of 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:13]([O:20][C:21](=[O:25])[CH:22]([C:23]#[N:24])[C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: N#CCC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A suspension of 1,4-difluoro-2-methyl-5-nitrobenzene (1.00 g), cyanoacetic acid benzyl ester (1.01 g) and potassium carbonate (1.76 g) in N,N-dimethylformamide (20.0 mL) was stirred at 60° C. for 1 day. To this reaction mixture was added 1 mol/L hydrochloric acid (25.4 mL), and this mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. This residue was washed with ethanol to give the title compound (1.54 g).