Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:31]2[CH2:32][CH2:33][CH:28]([CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:26][CH2:25]3)[CH2:29][CH2:30]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of 4-bromophenylsulphonyl chloride (411 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine trihydrochloride (545 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-bromophenylsulphonyl)-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (410 mg), mp 163-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=2[O-])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.NCCO>C(#N)C>[NH2:22][C:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: NCCO
Product: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (29.8 g, 104 mmol) was dissolved in a mixture of acetonitrile (662 mL) and pyridine (33.8 mL, 418 mmol) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (pTsCl, 25.9 g, 136 mmol) was added and the reaction mixture was heated at 75° C. for 5 hours. 2-Aminoethanol (166 mL, 2.75 mol) was added after allowing the reaction mixture to cool to room temperature. After one hour, the acetonitrile was evaporated and the crude product was partitioned between ethyl acetate and a saturated aqueous solution of sodium chloride. The layers were separated and the organic layer was evaporated to dryness and then purified on 1.5 kg of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (15.2 g, 51%) as a white solid. ESI-MS m/z calc. 284.1, found 285.2 (M+1)+. Retention time 1.16 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.99-7.98 (m, 1H), 7.90-7.87 (m, 1H) 7.72-7.7.69 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 6.42 (d, J=8.3 Hz, 1H), 5.83 (s, 2H), 2.11 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([N:10]=C=O)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.C1COCC1>[N:1]1[CH:6]=[C:5]([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1
Reactant: CC(C)(N=C=O)c1cncnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(N)c1cncnc1

Procedure:
The crude 2-(5-pyrimidinyl)-2-propylisocyanate was treated with a mixture of 1.0N sodium hydroxide (26 mL), water (20 mL) and THF (100 mL) at 0° C. for 30 min, then the mixture was poured into ethyl acetate (200 mL) and water (100 mL). The aqueous layer was acidified to pH 5 with 10% citric acid, extracted twice with ethyl acetate, and then adjusted to pH 11, saturated with sodium chloride, and extracted with methylene chloride (3×250 mL). The combined methylene chloride extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(5-pyrimidinyl)-2-propylamine (950 mg) as a colorless oil.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:7](CC)CC)C.[C:12]1(C)C=[CH:16][CH:15]=[CH:14][CH:13]=1>[O-2].[O-2].[Mn+4]>[C:3]1([C:5]#[N:7])[CH:2]=[CH:1][N:4]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1
Reactant: C=CC#N
Agent: [Mn+4]
Agent: [O-2]
Product: N#Cc1ccn2ccccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of pyridine (4.0 g) in ethyl acetate (10 mL) was added chloroacetic acid (4.7 g) at room temperature, and the mixture was heated under reflux overnight. After the reaction mixture was cooled to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give 1-carboxymethyl pyridinium chloride (5.7 g). To a solution of the obtained compound (5.7 g) in toluene (300 mL) were added acrylonitrile (8.7 g), manganese dioxide (16.4 g) and triethylamine (4.0 g), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30]C(OCC1C=CC=CC=1)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1

Procedure:
A solution of 10.432 g (18.36 mmol) of compound 6 in 500 ml THF and 500 ml ethyl alcohol was stirred with 1.043 g of 10% palladium on carbon at room temperature. for 18h over 1 atmosphere hydrogen pressure. The mixture was filtered through celite pad and the filtrate was concentrated to provide 6.06 g yield) of compound 7. The oil was triturated with diethyl ether and the white solid was filtered and washed to provide pure 7 (M. P. 92-94).
Reaction SMILES: CC1NC(=O)C(=CC=1C(=O)CC)C#N.C(C1C=C(C#N)C(=O)NC=1CC)(=O)C.[CH3:29][C:30](=[O:36])[CH2:31][C:32](=[O:35])[CH2:33][CH3:34].CO[CH:39](OC)[N:40]([CH3:42])[CH3:41]>CN(C)C=O>[CH3:39][N:40]([CH:42]=[C:31]([C:32](=[O:35])[CH2:33][CH3:34])[C:30](=[O:36])[CH3:29])[CH3:41]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(C)=O
Agent: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: CCc1[nH]c(=O)c(C#N)cc1C(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)C(C)=O
Reaction time: 8 h

Procedure:
A-4. 1,2-Dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile--A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 265°-268° C. with decomposition the acidic mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful; however, the two compounds should be separable.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([O:28][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC(O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (50.68 g) in pyridine (380 ml) was stirred at 15° C. under an atmosphere of nitrogen during the dropwise addition of methanesulfonyl chloride (18.4 ml). The reaction mixture was then allowed to warm to ambient temperature and stirred for a further 2 hours and evaporated. The residue was dissolved in diethyl ether, washed sequentially with 2M aqueous hydrochloric acid (500 ml and 250 ml), water, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to afford 4-benzyl-5-(3-ethoxycarbonyl-2-methanesulfonyloxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (64 g) as a pale yellow gum Mass spectrum 500 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3OC(C)(C)[O:36][C@@H:35]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]3[CH2:34][C@@H:35]([OH:36])[CH2:41][C:42](=[O:43])[O:44]3)[C:10]([CH:28]([CH3:29])[CH3:30])=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
(4R-cis)-1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 mL of tetrahydrofuran and 15 mL of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro -4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two crops.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.1 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.12 mmol) and potassium carbonate (640 mg, 4.37 mmol) in dimethylformamide (20 mL) was added methyl 3-phenylpropiolate (506 μL, 3.43 mmol) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→40/60) to give the title compound (166 mg, yield 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:19][C@@H:20]1[C:28](=[O:29])[N:27]2[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]3[C:32]4[CH:39]=[CH:38][N:37]([S:40]([C:43]5[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=5)(=[O:42])=[O:41])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:26]2)[CH2:21]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C@@H:20]2[C:28](=[O:29])[N:27]3[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]4[C:32]5[CH:39]=[CH:38][N:37]([S:40]([C:43]6[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=6)(=[O:42])=[O:41])[C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:26]3)[CH2:21]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](N)C(=O)N5C4)ncnc32)cc1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](Nc6cc(F)cc(Cl)c6)C(=O)N5C4)ncnc32)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
A mixture of 3-chloro-5-fluorophenylboronic acid (44 mg, 0.25 mmole) 127.b, powdered 4 Å molecular sieves (0.3 g), cupric acetate (83 mg, 0.45 mmole), triethylamine (69 μL (0.68 mmole), and anhydrous THF (3 mL) was stirred under a N2 atmosphere for 5 min. A solution of (2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one (0.1 g) 127.5 in anhydrous THF (1.5 mL) was added and the reaction mixture was stirred at room temperature for 24 hr and then heated at 60° C. for 48 hr. The mixture was diluted with EtOAc and filtered through a celite plug. The filtrate was concentrated in vacuo, absorbing onto 3 g silica gel. Purification by flash column chromatography (ISCO 24 g SiO2, 40% EtOAc/hex then gradient to 100% EtOAc) afforded 19.4 mg of (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one 127.6 as a white solid. LCMS (ESI) m/z: 569.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:5](=NC#N)[NH:4][CH2:3]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.CN(C=[O:37])C>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:4]2[CH2:3][CH:2]([CH3:1])[N:6]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[C:5]2=[O:37])=[CH:27][CH:28]=1
Reactant: Fc1ccc(OCCCCCCBr)cc1
Reactant: CN(C)C=O
Reactant: CC1CNC(=NC#N)N1c1ccncc1
Agent: [H-]
Agent: [Na+]
Product: CC1CN(CCCCCCOc2ccc(F)cc2)C(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [5-methyl-1-(4-pyridyl)tetrahydro-1H-2-imidazolyliden]amino methanenitrile (60 mg, 0.30 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (19 mg, 0.60 mmol, 75% in mineral oil) in one portion. The mixture was stirred at room temperature for 20 min followed by addition of 1-[(6-bromohexyl)oxy]-4-fluorobenzene (123 mg, 0.45 mmol) dissolved in DMF (3 ml) drop by drop. The resulting mixture was heated to 80° C. and stirred overnight (16 hours). The solvent was removed under reduced pressure and the crude residue was purified by column chromatography eluting with 15% methanol in ethyl acetate to afford the product (i.e., Compound 13) as a white solid (44 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Agent: BrB(Br)Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)nc(SCc2c(O)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In a 250 mL round bottom flask, 2-{[(2-chloro-6-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (200 mg, 0.67 mmol) was dissolved in DCM (10 mL). BBr3 (1.42 mL, 1.42 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. Water (5 mL) was added, followed by Na2SO4 (20 g) and DCM (100 mL) after 5 minutes. The solution was filtered and evaporated. The crude product was purified by column chromatography to provide the title compound as a white solid (180 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.06 (s, 3H), 4.48 (s, 2H), 6.02 (br, 1H), 6.83 (d, 1H), 6.93 (d, 1H), 7.15 (t, 1H), 10.44 (br, 1H); M+283.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[Cl:18][C:17]1[C:12]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)C(F)(F)COc1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2,2,3,3-Tetrafluoropropan-1-ol (60.0 g, 0.45 mol) was added to a slurry of NaH (60% dispersion in oil, 15.20 g, 0.63 mol) in anhydrous THF (450 mL) at 0° C. and the reaction mixture allowed to warm up to room temperature, then stirred for 1 hour. 2,3-dichloropyridine (45.0 g, 0.30 mol) was added and the reaction heated to a gentle reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between EtOAc (300 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a yellow oil (71 g, 96%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][N:16]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]2[CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][O:1][C:2]3([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH2:3]3)[CH2:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.0 g, 2.13 mmol) in THF (10 mL) was added DIEA (1.1 mL, 6.38 mmol) followed by an addition of a solution of methylsulfonyl methanesulfonate (1.1 g, 6.38 mmol) in THF (2 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was warmed to room temperature and then heated at 40° C. for 16 hours. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM. The organic layer was washed with a sat. solution of NaHCO3, followed by washing with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 100% DCM in hexanes as eluent to obtain tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.5 g, 51%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)+; Retention time: 1.62 minutes (3 min run).
Reaction SMILES: OC1C=CC(C2C3C=C(N(C)C)C=CC=3S(=O)(=O)CCC2)=CC=1.[O:24]=[S:25](=[O:37])([CH3:36])[O:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(=O)(C)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[S:25]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:37])(=[O:24])[CH3:36]
Reactant: CS(=O)(=O)OCCCCOS(C)(=O)=O
Agent: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOS(C)(=O)=O
Yield: 61.6 %

Procedure:
A mixture of 1.00 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H)