Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C:5]#[N:6].[CH3:7][CH2:8][OH:9]>C(OCC)C>[ClH:1].[CH2:8]([O:9][C:5](=[NH:6])[CH2:4][O:3][CH3:2])[CH3:7]
Reactant: CCO
Reactant: COCC#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)COC
Temperature: -10 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Hydrochloric acid gas is bubbled through a solution of methoxyacetonitrile (26 g, 0.37 mol) in EtOH (22 mL) and diethyl ether (118 mL), which is chilled to −10° C. for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is cooled to −10° C. The solid that forms is collected by filtration, washed with diethyl ether and air dried to afford 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 87%) as a solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O1CCOCC1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Cc1c(O)cccc1O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of dioxane were added 600 g. of acetophenone and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated with stirring for 3 hours and then poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[C:16]([NH:2][C:1]3[C:3]4[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=4[N:10]=[CH:11][N:12]=3)[CH:21]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4nc(C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A solution of the product of Example 10B (28.4 mg, 0.151 mmol), and the product of Example 10E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum, and the resultant residue triturated with methanol to provide the title compound as a tan solid (26.5 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.92 (s, 1H), 9.63 (s, 1H), 8.70 (d, J=8.09 Hz, 1H), 8.55 (s, 1H), 7.52 (d, J=8.46 Hz, 1H), 7.38 (d, J=8.82 Hz, 2H), 7.27 (s, 1H), 7.06-7.18 (m, 3H), 6.94 (d, J=8.46 Hz, 3H), 6.61-6.72 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.66 (s, 3H); MS (ESI+) m/z 497.2 (M+H)+, (ESI−) m/z 495.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14](O)(=O)[CH2:15][CH3:16].Cl.C>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:14]([CH2:15][CH3:16])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: CCC(=O)O
Agent: Cl
Solvent: O
Product: CCc1nc2cc(Cl)ccc2n1CCCO

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 20 parts of propanoic acid and 200 parts of a hydrochloric acid solution 4 N is stirred and refluxed for 3 hours. The reaction mixture is cooled, water and crushed ice are added and the whole is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 5-chloro-2-ethyl-1H-benzimidazole-1-propanol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([O:15][CH3:16])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1NC(C)=O
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)cc([N+](=O)[O-])c1NC(C)=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of N-(4-bromo-2-methoxy-6-nitrophenyl)acetamide (2.89 g), morpholine (2.61 g), BINAP (1.21 g) and t-BuOK (1.53 g) in dioxane (50 mL) was degassed with N2 and the mixture was stirred at 110° C. in a sealed tube overnight. It was cooled to room temperature and filtered. The filtrate was concentrated in-vacuo. The residue was purified by silica gel chromatography eluted with MeOH/DCM=1/50 to afford the desired product (1.03 g, 35%) 1H NMR (300 MHz, CDCl3) δ ppm 2.15 (s, 1H), 3.18 (t, 4H, J=4.8 Hz), 3.85 (t, 4H, J=4.8 Hz), 3.88 (s, 3H), 6.63 (d, 1H, J=2.7 Hz), 6.96 (d, 1H, J=2.7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenylthiazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylthiazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 110-111° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:13]O>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:13])=[O:9])=[CH:5][CH:6]=1
Reactant: CO
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Tolylacetic acid (10 g) was dissolved in 30 ml of absolute methanol, followed by addition of 10% hydrogen chloride-methanol (10 ml), and stirred overnight at room temperature. The reaction solution was concentrated and dissolved in chloroform, followed by washing in saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvent. Methyl p-tolylacetate (11 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I.O>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To the solution of tert-butyl(6-chloro-4-iodopyridin-3-yl)carbamate (61 g, 0.172 mol) in 300 mL of anhydrous THF was added 60% NaH (7.6 g, 0.189 mol) at 0° C. under N2 atmosphere. After the addition was finished, the solution was stirred for 30 min, and then the solution of MeI (26.92 g, 0.189 mol) in 100 mL of dry THF was added. Then the solution was stirred at 0° C. for 3 hrs. TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to afford 63 g of crude tert-butyl(6-chloro-4-iodopyridin-3-yl)(methyl)carbamate used into the following de-protection without the further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1cc2ccccc2cn1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(c2cc3ccccc3cn2)CC1
Yield: 21.7 %

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 1 g (6.11 mmol) of 3-chloroisoquinoline and 0.869 g (6.72 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.34 g of pure product is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(CO)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (1.2 g) and sodium borohydride (0.21 g) in dioxane (15 ml) was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dilute hydrochloric acid, an aqueous solution of sodium bicarbonate, successively, dried and concentrated. The residue (1.2 g) was recrystallized from ethanol to give pale brown crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-methanol (0.55 g).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C(N)=O)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3][NH:2]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([N:5]1[CH2:6][CH2:7][S:1](=[O:9])(=[O:8])[NH:2][CH2:3][CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=S1(=O)CCNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNS(=O)(=O)CC1

Procedure:
To a solution of 1,2,5-thiadiazepane 1,1-dioxide (0.10 g, 0.67 mmol) in methylene chloride (2 mL) at −10 C was added methane sulfonyl chloride (0.06 mL, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol). After 72 hr the reaction was quenched with NaHCO3 (sat. aq.) and extracted into methylene chloride. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as a white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[CH:26][C:25]([N:28]([OH:29])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(N=O)cc1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)c1ccc(N(O)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), N,N-dimethyl-4-nitrosobenzenamine (150 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH2:9]O)[CH3:3].[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:9][C:8]1[S:7][CH:6]=[N:5][C:4]=1[CH:2]([CH3:3])[CH3:1]
Reactant: BrP(Br)Br
Reactant: CC(C)c1ncsc1CO
Solvent: ClCCl
Product: CC(C)c1ncsc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [4-(propan-2-yl)-1,3-thiazol-5-yl]methanol (800 mg, 5.1 mmol) in anhydrous dichloromethane (35 mL) was added tribromophosphane (520 μL, 5.5 mmol). The mixture was stirred at room temperature for 1.5 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole. The crude product was used without further purification.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:22]1[S:21][C@H:20]([CH2:19][OH:18])[CH2:24][O:23]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO)S1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.7 %

Procedure:
To a solution of cis and trans 4-(t-butyldiphenylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 42) (5.00 g, 10.07 mmol) in tetrahydrofurane (300 mL) was added tetrabutylammonium fluoride (15.0 mL, 15.0 mmol, 1.5 eq) at room temperature. The solution was stirred at room temperature for 45 min and acetic acid was added (850 μL) followed by evaporation under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate to give the pure compound (2.47 g) in 96% yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([Si:16]([CH3:28])([CH3:27])[O:17][CH:18]1[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21][CH2:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:27])[CH3:28])[CH2:19][CH2:20][CH2:21]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(N)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCC(NC(=O)OCc2ccccc2)CCC1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (4 mL, 28.02 mmol) was added to a stirred and cooled (0° C.) solution of the product of Example 5C (14.01 mmol) and diisopropylethyl amine (7.5 mL, 42.03 mmol) in dry dichloromethane (50 mL). After the addition, the solution was warmed to room temperature and stirred for another three hours. It was quenched with NaHCO3 solution. The phases were separated and the organic phase was washed with NaHSO4 solution brine, dried (Na2SO4), filtered, and evaporated. The crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester was isolated as an oil and was used without further purification. Tetrabutyl ammonium fluoride (42 mL, 1 M in tetrahydrofuran, 42.03 mmol) was added to a solution of crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester (about 14.01 mmol) in tetrahydrofuran (35 mL). The resulting solution was stirred for two hours at 23° C. before it was partitioned with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester as an oil. (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester (2.68 g, 9.66 mmol) was stirred in the presence of Pd(OH)2/C (0.5 g) in methanol under H2 (balloon) for two hours at 23° C. before it was filtered through a pad of Celite and the solvent was evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:14])[CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36](O)[CH:37]=1)[N:34]=[C:33]([C:39]1[N:43]3[CH:44]=[CH:45][C:46]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:47][C:42]3=[N:41][CH:40]=1)[CH:32]=[CH:31]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O.CCOC(C)=O>[F:1][C@H:2]1[C@H:7]([O:8][C:36]2[CH:37]=[C:28]([F:27])[CH:29]=[C:30]3[C:35]=2[N:34]=[C:33]([C:39]2[N:43]4[CH:44]=[CH:45][C:46]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:47][C:42]4=[N:41][CH:40]=2)[CH:32]=[CH:31]3)[CH2:6][CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:14])[CH2:3]1
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc3ccccc3c2)C[C@H]1F
Reactant: COCCOc1ccn2c(-c3ccc4cc(F)cc(O)c4n3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5F)c4n3)cnc2c1
Temperature: 90 °C
Yield: 97.7 %

Procedure:
(3R,4S)-naphthalen-2-ylmethyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (170 mg, 0.44 mmol) (Example 20, Step F, derived from Peak 2), 6-fluoro-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (173 mg, 0.49 mmol) and Cs2CO3 (290 mg, 0.89 mmol) were weighed into a flask and suspended in 10 mL of DMA. The reaction was then heated to 90° C. overnight. The reaction was then cooled to ambient temperature, followed by workup with water and EtOAc. The combined organic phase was concentrated in vacuo, followed by flash column chromatography (1-10% MeOH/DCM) affording the desired product as a brown semi-solid (270 mg, 0.43 mmol, 95%). MS APCI (+) m/z 639.2 and 640.1 (M+1/+3) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13]CC1C=CC=CC=1)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Nc1ccc(/C=C/C(=O)O)cn1
Yield: 60.9 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([N:18]1[CH2:17][CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:20][CH2:19]1)=[O:29]
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (1.00 mmol, 0.275 g) and pyridine (1.65 mmol, 0.130 g; 133 μL) in dry CH2Cl2 (10 mL) at 0° C. was added methyl chloroformate (1.10 mmol, 0.104 g; 85 μL) dropwise over 5 minutes. The resulting solution was warmed to room temperature and stirred for 1 hour. The reaction was diluted with CH2Cl2 (70 mL) and extracted with water (70 mL). The aqueous phase was extracted with CH2Cl2 (70 mL), the combined organics washed with water (70 mL), dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash chromatography (SiO2 : 1) CH2Cl2, 2) 5% EtOAc/CH2Cl2) to afford the title compound as a colorless oil (0.190 g, 57%).
Reaction SMILES: [F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH:22]=[O:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:46][O:45][CH2:44]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH2:22][OH:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:44][O:45][CH2:46]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
To a solution of 237a (131 mg, 0.197 mmol) in methanol (7 mL) was added sodium borohydride (59.8 mg, 1.57 mmol) at 0° C. The reaction was stirred at 0-25° C. for 1.5 h. It was then quenched with water (1.5 mL). The mixture was evaporated under reduced pressure and the residue was extracted with dichloromethane (3×30 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 237 (36 mg, 28%) as a white solid. MS-ESI: [M+H]+ 669.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=1.5 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.36-7.32 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 4.90-4.86 (m, 1H), 4.73-4.65 (m, 5H), 4.39-4.30 (m, 2H), 3.90-3.77 (m, 3H), 3.72 (s, 3H), 3.56-3.48 (m, 2H), 3.10-3.09 (m, 2H), 2.98-2.92 (m, 2H), 2.79-2.75 (m, 2H), 2.59-2.57 (m, 1H), 2.50-2.49 (m, 2H), 2.22-2.21 (s, 1H), 2.04-1.99 (m, 2H), 1.88-1.84 (m, 2H), 1.01 (d, J=6.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cc1
Yield: 47.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 4-Formylbenzonitrile (32.0 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 47.01 mg (47%) of the title compound. (300 MHz, DMSO-d6) 13.60 (s, 1H), 8.29 (d, J=8 Hz, 2H), 8.08 (s, 1H), 7.76 (s, 1H), 7.31 (m, 1H), 7.24 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.79 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=451 (M+H), HPLC: 2.43 min. (G Method)