Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[C:18]([F:24])[CH:17]=1>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)=[C:18]([F:24])[CH:17]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccc(Br)cc2F)c2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In an oven dried 20 mL scintillation vial, indole-3-carboxylic acid (500 mg, 3.10 mmol) was massed. The vial was charged with a stir bar and DMF (10 mL), and then capped under an atmosphere of nitrogen. The solution was cooled to 0° C., followed by addition of NaH (60% dispersion in mineral oil, 375 mg, 9.38 mmol). The reaction was allowed to stir for 5 min. 4-Bromo-2-fluorobenzyl bromide (1.00 g, 3.73 mmol) was added in one portion, and the reaction was allowed to stir 15 min at 0° C. then warmed to 25° C. over 30 min. Reaction was monitored by LCMS, and upon completion was quenched cautiously with H2O. The reaction mixture was diluted with dichloromethane (20 mL) and the organic layer was acidified to pH 1 with 1M HCl. The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with hexanes/ethyl acetate (0 to 100%) to afford 1-(4-bromo-2-fluorobenzyl)-1H-indole-3-carboxylic acid as a solid (LCMS: RT=0.795 min, (M+H)+ m/z=348).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N)c(S(=O)(=O)O)c1
Product: CC(=O)Nc1ccc(N)c(S(=O)(=O)O)c1

Procedure:
That is, 2,5-diaminobenzenesulfonic acid is acetylated with acetic anhydride to obtain 2-amino-5-acetylaminobenzenesulfonic acid, which is then diazotized in an ordinary manner and coupled with 1,7-Cleve's acid to thereby obtain the compound [A] shown below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:18]
Reactant: CN=C=O
Reactant: NCCSCc1nc2ccccc2[nH]1
Product: CNC(=O)NCCSCc1nc2ccccc2[nH]1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]benzimidazole is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:19][N:20]=[C:21]3[C:26]=2[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[N:24][N:23]=[CH:22]3)[N:9]=[N:8]1.C(#N)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[NH2:20][C:21]1[C:26]([C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[O:19])=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:24]=[N:23][CH:22]=1
Reactant: FC(F)(F)c1cc(Cn2nnc(-c3onc4cnnc(-c5ccccc5Cl)c34)c2-c2ccncc2)cc(C(F)(F)F)c1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CC#N
Solvent: O
Product: Nc1cnnc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
To 3-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-phenyl)-isoxazolo[3,4-d]pyridazine (100 mg, 0.166 mmol), add 8.0 ml of acetonitrile, and 170 μL of water, followed by molybdenum hexacarbonyl (22 mg, 0.083 mmol). Heat the mixture to 80° C. for 4 h., then cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate and purify the residue by chromatography (silica gel, hexanes/EtOAc gradient) to provide 42 mg of a yellow solid. Exact Mass 603.1: MS (aspci): m/z=603.9 (M+1), m/z=601.9 (M−1); 1H NMR (300 MHz, CDCl3) δ 8.65–8.80 (m, 3H), 7.79 (s, 1H), 7.65 (br d, J=7.4 Hz, 1H), 7.31 (s, 2H), 7.15–7.00 (m, 2H), 6.96 (d, J=7.4 Hz, 1H), 6.87 (br t, J=7.4 Hz, 1H), 6.12 (br s, 2H), 5.21 (ABq, J=22.5, 7.5 Hz, 2H).
Reaction SMILES: [CH:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.Cl.[Pd]>[CH:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CC(=O)C2CCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(CC(=O)C2CCCCC2)cc1

Procedure:
Bubble nitrogen for 10 min into a solution of 4-(2-cyclohexyl-2-oxo-ethyl)-benzonitrile (478 mg, 2.10 mmol) in methanol (80 mL) with concentrated HCl (5 drops). Add 10% Pd/C (Degussa type E101, 96 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the catalyst through Celite® and concentrate in vacuo to obtain the hydrochloride salt of the title compound. Wash with diethyl ether/hexane (1:1) and filter the white solid. Add saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (145 mg, 30%). MS (ES+) m/z: 232 (M+H)+.
Reaction SMILES: O[C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:45])[CH3:46])([CH:38]([CH3:39])[CH3:40])[CH:41]([CH3:42])[CH3:43])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 70 °C
Reaction time: 72 h
Yield: 104.6 %

Procedure:
N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (177 mg, 0.262 mmol) synthesized in Example (35b) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (70.0 mg, 0.402 mmol) and triethylamine (0.22 mL, 1.58 mmol) were added, followed by stirring at 70° C. for 3 days under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (180 mg, yield ˜100%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8](C3CCCC3)[C:9]=2[CH:10]=1.C1C[N:22]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NCC1C(=O)NC(C)=CC=1CO[Si](C(C)(C)C)(C)C.O>CS(C)=O>[NH:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:16]([NH2:22])=[O:18])[C:5]=2[CH:6]=[N:7]1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.8 %

Procedure:
To a solution of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (2.3 g, 7.5 mmol) in DMSO (30 mL), PyBOP (5.82 g, 11.20 mmol) was added and reaction stirred at room temperature for 15 min. 3-(Aminomethyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2(1H)-one (2.52 g, 8.96 mmol) was then added and reaction mixture stirred overnight. On completion, water was added and the resulting precipitate filtered and washed with water. This solid was then stirred with acetonitrile for 10 min and filtered again to obtain 6-bromo-1-cyclopentyl-N-44-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.4 g, 40.9%).
Reaction SMILES: S([C@@:5]1(O)[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(C)(=O)=O.CC1C(=O)N=C2N([C@@H]3O[C@H](CO)[C@@H](O2)C3)C=1.[FH:38].[K].[F-].[NH4+]>C(O)CO>[F:38][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1
Reactant: Cc1cn([C@H]2C[C@@](O)(S(C)(=O)=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: F
Agent: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Agent: [F-]
Agent: [K]
Solvent: OCCO
Product: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 10 %

Procedure:
3'-Mesylthymidine or 2,3'-anhydrothymidine is allowed to react with potassium hydrogen fluoride or ammonium fluoride in ethylene glycol at 191° C. for 10 to 90 minutes, thus giving 3'-deoxy-3'-fluorothymidine (yield: 10 to 14%) [Japanese Patent Publication No. 10472 (1973)].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:33][CH2:34]2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 79.9 %

Procedure:
Pulverized potassium carbonate (0.76 g, 5.5 mmole) and potassium iodide (0.97 g, 5.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-ylmethyl)piperidine (1.16 g, 5.0 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (1.27 g, 5.0 mmole) in 25 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 5 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (1.8 g, 80%). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(Cl)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-Chloro-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][C@@:4]1([OH:12])[CH:9]2[CH2:10][CH2:11][NH+:6]([CH2:7][CH2:8]2)[CH2:5]1.[Cl-].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([N:36]=[C:37]=[S:38])=[CH:27]2>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([NH:36][C:37]([NH:2][CH2:3][C@@:4]1([OH:12])[CH:9]3[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]3)[CH2:5]1)=[S:38])=[CH:27]2
Reactant: [NH3+]C[C@]1(O)C[NH+]2CCC1CC2
Reactant: COc1cc2cnc(N=C=S)cc2cc1Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2cnc(NC(=S)NC[C@]3(O)CN4CCC3CC4)cc2cc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirring suspension of (S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride (111 mg, 0.484 mmol) in DMF (3 mL) was added Hunig's Base (0.5 mL, 2.86 mmol) and the resulting mixture was stirred at room temperature for 35 minutes. Then was added a suspension of 6-chloro-3-isothiocyanato-7-methoxyisoquinoline (106 mg, 0.423 mmol) in DMF (3 mL) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated in vacuo and the residue subjected to a silica gel column in 1% NH4OH/9% MeOH/90% CHCl3 to give 140.3 mg (82%) as a white solid, (S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea. LCMS RT 1.28 min, MH+=407.1, 409.0, 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.85 (1H, t, J=5.2 Hz), 9.15 (1H, br. s.), 8.63 (1H, s), 7.76 (1H, s), 6.92 (1H, s), 6.89 (1H, s), 4.14 (1H, dd, J=13.9, 5.6 Hz), 3.99 (2H, s), 3.90 (1H, dd, J=14.0, 5.2 Hz), 3.46 (3H, s), 2.89-3.01 (2H, m), 2.75-2.88 (3H, m), 2.03-2.15 (1H, m), 1.89-1.96 (1H, m), 1.77-1.88 (1H, m), 1.63 (1H, ddd, J=13.4, 6.1, 3.4 Hz), 1.32-1.45 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.[CH3:37][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:34])[CH3:37])=[CH:35][CH:36]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18 mmol) was dissolved in 0.885 mL of dry THF. A solution of 3 M of methylmagnesium bromide in ether (71 μL, 0.213 mmol) was added. The solution was allowed to stir at ambient temperature for 2 hours when TLC indicated complete consumption of starting materials. The reaction mixture was diluted with EtOAc and washed with water and saturated aqueous NH4Cl. The organic layer was reduced in vacuo to 1 mL and cooled to get the product 16 to crystallize from the solvent (92 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 1.16 (d, 18H, J=8 Hz), 1.55 (septet, 3H, J=8 Hz), 1.78 (s, 3H), 2.29 (s, 1H), 4.04 (s, 3H), 4.72 (ABqt, 2H, J=13 Hz), 6.99 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=6,9 Hz), 7.52 (dd, 1H, J=4, 9 Hz), 8.42 (dd, 1H, J=2, 8 Hz), 8.87 (dd, 1H, J=2, 4 Hz); 19F NMR (282.6 MHz, CDCl3) δ 60.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.S(Cl)([Cl:25])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([Cl:25])=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A 5.85 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid in 30 ml of thionyl chloride was refluxed on a steam bath for one hour, then evaporated to dryness. The residue was boiled with dimethoxyethane, then cooled and the solid recovered and washed with ether, giving 6.90 g of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride.
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C)C=O>[O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:26])=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: -15 °C
Yield: 66 %

Procedure:
A slurry of 2.30 (7.52 mmol) g 4-(4-phenoxyphenoxy)benzoic acid, 30 ml of thionyl chloride and 2 drops of N,N-dimethylformamide is refluxed under nitrogen atmosphere for 16 hours. Excess thionyl chloride is distilled to yield an oil, and 200 ml of anhydrous n-hexane is added. The solution is cooled to -15° C., and the resulting precipitate is filtered and dried under nitrogen atmosphere. The precipitate is dissolved in a minimum volume of hot n-hexane, the solution is filtered and the filtrate is cooled to -15° C. to yield 1.82 g (66 percent yield) of 4-(4-phenoxyphenoxy)benzoyl chloride having a melting point of 85° C. to 89° C. by DSC measurement.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2([CH3:19])[O:15][CH2:16][CH2:17][O:18]2)[CH2:9]1)=[O:22])[CH:25]=[CH2:26]
Reactant: CC1(C2=CCCN(Cc3ccccc3)C2)OCCO1
Reactant: C=CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC=C(C2(C)OCCO2)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (7.8 g) in toluene (70 ml) was added allyl chloroformate (3.9 ml) and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was then concentrated and the residue was purified by column chromatography to give 2-(1-allyloxycarbonyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (6.95 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:36]>O1CCOCC1>[ClH:36].[CH3:12][CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:35]=3)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1C#N
Yield: 73.2 %

Procedure:
1,1-Dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 76) (0.410 g, 0.860 mmol) was dissolved in 1,4-dioxane (1 ml). Added HCl (1 ml, 4.00 mmol) in dioxane (4M) and stirred at R.T. for 2 hours. Added ether, filtered and dried in the oven under vacuum at R.T. to give 0.26 g of white solid. 50 mg was purified by MDAP to give the title compound (13 mg) as a cream solid. δH (MeOD, 400 MHz): 1.44 (6H, d), 3.63 (2H, m), 4.33 (2H, m), 4.52 (2H, s), 4.92 (1H, m), 7.30 (1H, d), 7.43 (1H, d), 8.15 (1H, dd), 8.21 (1H, d), 8.38 (1H, dd), 8.45 (1H, d); MS (ES): C21H20N4O3 requires 376; found 377 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12](OC)=[O:13])[CH:5]=1>CO>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([CH2:12][OH:13])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Cl)c(Cl)c(Cl)n1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 80.3 %

Procedure:
Sodium borohydride (173 mg, 4.60 mmol) was added to a mixture of methyl 4,5,6-trichloropyridine-2-carboxylate (1.0 g, 4.16 mmol) in methanol (25 mL) at room temperature. After 40 min, the reaction was warmed to 50° C., and additional sodium borohydride (307 mg, 8 mmol) was added in 2 batches over the following 3 hours. The methanol was removed by rotary evaporation and the residue was diluted with 10% citric acid, aq. (50 mL) and stirred vigorously. The precipitate was collected, washed with water and dried to provide (4,5,6-trichloropyridin-2-yl)methanol (713 mg, 3.34 mmol), mp 82-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([CH:17]=[CH2:18])=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:14][CH:15]=[C:17]2[CH3:18]
Reactant: Nc1ccc(Br)cc1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2ccc(Br)cc12

Procedure:
Stir a solution of 4-bromo-phenylamine (1 eq), in 1,4-dioxane and cool to approximately 12° C. Slowly add sulfuric acid (2 eq) and heat at reflux. Add methylvinyl ketone (1.5 eq) dropwise into the refluxing solution. Heat the solution for 1 hour after addition is complete. Evaporate the reaction solution to dryness and dissolve in methylene chloride. Adjust the solution to pH 8 with 1 M sodium carbonate and extract three times with water. Chromatograph the residue on SiO2 (70/30 hexane/ethyl acetate) to obtain the desired subtitled intermediate. MS ES+m/e=158.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:7]=2[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: COc1ncc2nc(N=C(SC)SC)sc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of dimethyl 5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (100 mg, 0.349 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (80 mg, 0.349 mmol) and cesium carbonate (228 mg, 0.698 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids were collected by filtration to afford (R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (78 mg, 64% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (br. s., 1H) 8.63 (s, 1H) 3.95-4.18 (m, 4H) 3.71 (d, J=9.77 Hz, 1H) 3.41 (d, J=15.26 Hz, 1H) 2.74-3.10 (m, 5H) 2.11-2.27 (m, 2H) 1.71-1.86 (m, 1H) 1.50-1.70 (m, 2H). MS (LC/MS) R.T.=1.66; [M+H]+=347.0.