Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([NH2:40])(=[O:39])[CH2:36][CH2:37][CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[C:35]([NH:40][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(N)=O
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)ccn1
Yield: 44.5 %

Procedure:
100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 25 hours to a bath temperature of 90° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel first with hexane, then with hexane:ethyl acetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide with a melting point of 173° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([CH3:13])[O:15][CH3:16])=[O:6]
Reactant: CNOC
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-bromo-2-methyl benzoic acid (430 mg, 2.00 mmol) in anhydrous DCM, under nitrogen at ambient temperature was added N,O-dimethylhydroxylamine hydrochloride (215 mg, 2.20 mmol), pyridine (0.18 mL, 2.23 mmol) and CBr4 (662 mg, 2.00 mmol). Triphenyl phosphine (576 mg, 2.20 mmol) was added portion-wise over 10 min and the resulting mixture stirred at ambient temperature for 2.5 h. The reaction mixture then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (310 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)(=O)[CH3:30]>>[CH2:1]([N:3]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([O:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:29][CH3:30])[CH2:33][CH2:34]2)=[CH:40][CH:41]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN1CCC(Oc2ccc(CN(CC)c3cc(OC)ccc3[C@@H]3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 34.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(1-acetylpiperidin-4-yloxy)benzaldehyde (57 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (9.2 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl.[N:13]1([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[N:30][N:29]=[N:28]3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([N:13]3[CH2:14][CH2:15][N:16]([CH2:2][CH2:3][C:4]4[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=4)[CH2:17][CH2:18]3)=[O:32])=[CH:22][CH:23]=2)[CH:31]=[N:30][N:29]=[N:28]1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: N#Cc1ccc(CCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC2)cc1

Procedure:
Combined 4-(2-bromoethyl)benzonitrile (68 mg, 0.32 mmol) with 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (100 mg, 0.324 mmol), tetrabutyl ammonium iodide (120 mg, 0.324 mmol) and potassium carbonate (179 mg, 1.30 mmol) in DMF (2 mL) and stirred at 80° C. overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. After initial purification by HPLC, repurification by preparative TLC eluting with 5% of 1:9 NH4OH/methanol in DCM afforded the title compound. LC/MS: [(M+1)]+=402.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH:32]([CH3:35])[CH2:33]Cl)[CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH:32]([CH3:35])[CH2:33][O:1][C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:18])[C:3]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:27][CH2:26]1
Reactant: CC(CCl)CN1CCOCC1
Reactant: O=c1oc2c(-c3ccccc3)cccc2c(O)c1-c1ccccc1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(-c3ccccc3)cccc12)CN1CCOCC1
Yield: 69.1 %

Procedure:
Prepared according to the method of Example 8, by alkylation of 4-hydroxy-3,8-diphenyl-coumarin with 3-morpholino-2-methyl-1-chloropropane. After recrystallisation from ethanol, a solid melting at 120°-121° C. is obtained. Yield 69.1%.
Reaction SMILES: COC1C(OC)=CC=C2C=1CCC2=O.C(ON=O)CCC.[ClH:22].[CH3:23][O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[N:37]O)[C:29]2=O>CO>[ClH:22].[CH3:23][O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH:28]([NH2:37])[CH2:29]2
Reactant: COc1ccc2c(c1OC)CC(=NO)C2=O
Agent: CCCCON=O
Agent: COc1ccc2c(c1OC)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC(N)C2

Procedure:
In a procedure described by Cannon, J. G. et al. in J. Med. Chem., V.25, p. 1442 (1982), 4, 5-dimethoxy-1-indanone is reacted with n-butylnitrite in methanol and upon acidification with HCl, 4,5-dimethoxy-2-oximino-1-indanone is recovered as a precipitate. This is added to a major amount of glacial acetic acid and a minor amount of concentrated sulfuric acid and hydrogenated over a palladium on carbon catalyst to produce 4,5-dimethoxy-2-aminoindan hydrochloride, which is then recovered.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]CC)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br.O>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(O)cc2s1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
A solution of 2-amino-6-ethoxybenzothiazole (5 g, 25.74 mmol) and of 48% hydrobromic acid in water (130 ml, 1.141 mol) in 65 ml of acetic acid is distributed in ten 20 ml microwave tubes, and then heated at 150° C. by microwave for 200 seconds. The reaction medium is concentrated. The residue is taken up in 200 ml of water, basified to pH 8 by addition of 75 ml of saturated NaHCO3 solution and extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness to give 3.4 g of 2-aminobenzothiazol-6-ol (gray powder).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:9][CH2:10][CH3:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:14][NH:15][CH2:16]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2F)CNC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 104 mg (0.3 mmol) of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine in 3 ml of dichloromethane at 0° C. After stirring for 30 minutes, the reaction medium is evaporated off under a stream of nitrogen. 126 mg of 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate are obtained in the form of a pale yellow oil with a yield of 100%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]=1>S(=O)(=O)(O)O>[OH:9][C:4]1[CH:5]=[C:6]2[C:7]([CH:4]=[CH:5][C:6](=[O:8])[O:8]2)=[CH:2][CH:3]=1
Reactant: Oc1cc(O)cc(F)c1
Agent: O=S(=O)(O)O
Product: O=c1ccc2ccc(O)cc2o1
Temperature: 0 °C
Reaction time: 24 h
Yield: 146.9 %

Procedure:
1-Fluoro-3,5-dihydroxybenzene (1.0 g, 7.8 mmol) and ethyl 2-benzyl acetoacetate (1.72 g, 7.8 mmol) are suspended in 20 mL of 70% sulfuric acid at room temperature. The reaction mixture is stirred for 24 hours and poured into ice water. The solid is filtered and washed with water. The yellowish crude product is re-crystallized from hot ethanol to afford the 7-hydroxy coumarin intermediate (929 mg, 42%).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([CH2:24][NH2:25])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:25]([CH2:24][C:22]2[CH:23]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=2[S:26]([CH3:29])(=[O:28])=[O:27])[CH:10]=1
Reactant: COc1ccc(S(C)(=O)=O)c(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(S(C)(=O)=O)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Yield: 84.4 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.33 g), 1-[5-methoxy-2-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (3.0 g) and potassium carbonate (4.12 g) were stirred in ethanol (30 ml) at 85° C. for 16 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (4 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.7 g).
Reaction SMILES: [C:1]([OH:8])(=O)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].ClC(OCC(C)C)=O.CN1CCOCC1.[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:42])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:42][C:1](=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC=CC=CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC=CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
A solution of 0.67 g of 2,4-hexadienoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.79 ml portion of isobutyl chloroformate followed by a 0.66 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. The solvents were removed at reduced pressure and the solid was recrystallized to give 1.0 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2,4-hexadienamide: mp=258-260° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH3:1][N:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Under nitrogen, 96.7 g (1.1 mol) of N-methyl-N-tertbutylamine and 111 g (1.1 mol) of triethylamine was dissolved in 1050 mL of anhydrous tetrahydrofuran (THF). The solution was cooled to 0° C. and treated with 140.6 g (1.0 mol) of benzoyl chloride. The reaction was allowed to slowly warm to ambient temperature and stir overnight. Filtration and subsequent concentration in vacuo of the filtrate gave the crude product which was purified by sublimation (65°, 0.2 torr) to give 184 g (96%) of colorless N-methyl-N-tertbutybenzamide: mp 80.5°-82.0° C.; NMR (CDCl3) δ1.52 (s, 9H), 2.87 (s, 3H), 7.34-7.40 (m, 3H), 7.40-7.46 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7]([O:9]C(C)(C)C)=O.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([O:16][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH3:15])[CH2:7][OH:9]
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)C(CO)Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 76.3 %

Procedure:
1.14 g of tert-butyl (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-hydroxybutanoate obtained in Example 123 was dissolved in 10 ml of dimethylformamide, and 0.65 g of tert-butyldimethylchlorosilane and 0.37 g of imidazole were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of toluene, and then a 1M toluene solution of diisobutylaluminum hydride was added thereto with stirring under cooling to -78° C. The mixture was stirred at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution with stirring under cooling to -78° C., and the temperature was raised to room temperature. Then, 1N hydrochloric acid and ethyl acetate were added thereto for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.99 g (yield: 76%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-(tert-butyldimethylsilyloxy)butanol.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]12[CH2:21][CH2:20][C:17]([CH2:22][CH:23]=[O:24])([CH2:18][CH2:19]1)[CH2:16][O:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]12[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][OH:24])([CH2:18][CH2:19]1)[CH2:16][O:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCC12CCC(c3ccccc3Oc3ccccc3)(CC1)OC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCCC12CCC(c3ccccc3Oc3ccccc3)(CC1)OC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a −78° C. solution of 2-(1-(2-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetaldehyde (150 mg, 0.465 mmol) in DCM (5 mL) under N2 was added dropwise DIBAL-H (0.558 mL of a 1 M solution in DCM, 0.558 mmol). The reaction mixture was stirred at −78° C. for 2 h, after which CELITE® (3500 mg) was added. The reaction was then quenched at −78° C. with sat. aq. NH4Cl (2 mL). The mixture was stirred at rt for 30 min, after which MgSO4 (1000 mg) was added. Stirring was continued at rt for 1 h, after which the mixture was filtered. The solid was washed with DCM (4×). The combined filtrates were concentrated in vacuo to give a crude oil, which was purified by flash chromatography (SiO2) using a gradient from 0% to 50% EtOAc/hexane (10 min) to give the title compound (135 mg, 0.416 mmol, 89% yield) as a clear oil. 1H NMR (CDCl3) δ: 7.78-7.73 (dd, J=7.9, 1.9 Hz, 1H), 7.38-7.32 (m, 2H), 7.20-7.07 (m, 3H), 7.01-6.95 (m, 2H), 6.83-6.78 (dd, J=8.0, 1.4 Hz, 1H), 3.96-3.84 (s, 2H), 3.75-3.66 (t, J=7.4 Hz, 2H), 2.61-2.50 (m, 2H), 1.98-1.88 (m, 2H), 1.75-1.61 (m, 4H), 1.51-1.42 (t, J=7.4 Hz, 2H), 1.33 (s, 1H).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].O=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][C:13]#[N:14]>CCO>[C:2]([N:6]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CCC(=O)c1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a slurry of tert-butylhydrazine hydrochloride (12.8 g, 102.9 mmol) in 350 mL of EtOH was added sodium hydroxide (3.5 g, 88.2 mmol). After 1 hr of stirring, a solution of 3-oxo-3-phenyl-propionitrile (10.6 g, 73.5 mmol, in 50 mL of EtOH) was added and the resulting slurry was heated to reflux. After 12 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting solid was washed with hexanes and dried under reduced pressure to give the title compound (13.1 g, 83% yield) as yellow-colored solid, which was used without further purification. LRMS m/z /(APCl) 216 (M+1); 500 MHz 1H NMR (CD3OD) δ 7.67 (d, J=7.5 Hz, 2H), 7.35-7.29 (m, 2H), 7.25-7.20 (m, 1H), 5.86 (s, 1H), 1.65 (S, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[CH:44]1([CH:50]=O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH:44]1([CH2:50][NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH:12]3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]4[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=4[CH:43]=3)=[CH:9][CH:10]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: O=CC1CCCCC1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNCC4CCCCC4)cc3)cc21
Reaction time: 2 h

Procedure:
A solution of 0.346 g of benzyl 4-[4-(2-aminoethoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 184b) and 0.068 ml of cyclohexanecarbaldehyde in 2 ml of methanol is stirred at room temperature over 3.5 hours, admixed in portions with 0.037 g of sodium borohydride and subsequently stirred for a further 2 hours. The reaction mixture is admixed with 2 ml of 1N NaOH, stirred for 30 minutes and then partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.48 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.97.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:13]2[O:17]C[CH2:15][O:14]2)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8]>CO.O1CCCC1.C(N(CC)CC)C.[C].[Pd]>[CH:7]([C:6]1[C:5]([OH:12])=[C:4]([CH:3]=[CH:2][CH:11]=1)[C:13]([O:14][CH3:15])=[O:17])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(C2OCCO2)c1O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C=O)c1O
Yield: 85.3 %

Procedure:
86 g of methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate are dissolved in a mixture of 700 ml of methanol and 50 ml of tetrahydrofuran, and 70 ml of triethylamine and 7 g of 10% palladium-carbon are added to the solution. The mixture is subjected to catalytic hydrogenation under atmospheric pressure. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. 10% hydrochloric acid is added to the residue and the mixture is concentrated. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. The resultant crystals are collected, washed with cold ethanol and dried to give 51.1 g of methyl 3-formyl-2-hydroxybenzoate as colorless needles.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22].CCOC(C)=O>>[ClH:22].[C:1]1([C:7]#[C:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C(#CC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4 M hydrogen chloride/EtOAc solution (70 ml) was added to tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (7.0 g), followed by stirring at room temperature for 30 minutes. The solvent was evaporated to obtain 4-(phenylethynyl)piperidine hydrochloride (5.4 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.C1COCC1.[CH2:19]([N:21](CC)CC)C.Cl.CN>O>[Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5]([NH:21][CH3:19])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(-c2cccs2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNc1ncc(Br)c(-c2cccs2)n1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A 16 by 100 mm vial was charged with 5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine (1.00 g, 3.6 mmol), THF (4 mL), triethylamine (1.5 ml, 11 mmol), and methylamine hydrochloride (0.49 g, 7.3 mmol), and water (0.4 mL). The vial was capped and heated to 85° C. with stirring for 20 hours. The reaction was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0 to 4% methanol in dichloromethane) to afford 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine. MS m/z=271 [M+H]+. Calc'd for C9H8BrN3S: 270.