Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCCl)cn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (1.00 g, 8.4 mmol) in dry dichloromethane (10 mL) was added triethylamine (1.27 g, 12.6 mmol) and the reaction mixture was stirred at 0° C. To the reaction mixture 3-chloropropionyl chloride (1.42 g, 12.6 mmol) was added drop wise over a period of 15 minutes, and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified over silica gel using methanol/chloroform as eluent. The pure fraction was concentrated to obtain 3-chloro-N-(6-cyanopyridin-3-yl)propionamide. To a solution of potassium hydroxide (0.1 g, 1.5 mmol) in dry methanol (20 mL) was added hydroxylamine hydrochloride (0.105 g, 1.5 mmol) and the mixture was stirred for 30 minutes. White precipitate of potassium chloride obtained was filtered and to the filtrate was added 3-chloro-N-(6-cyanopyridin-3-yl)propionamide (0.209 g, 1.0 mmol) as obtained herein above, and the reaction mixture was stirred at reflux temperature for 4 hours. The reaction mixture was then concentrated and the crude product obtained was triturated with diethyl ether to obtain a solid which was crystallized from ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45]O)[CH2:31]1)[CH3:29].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31]1)[CH3:29]
Reactant: CCN1CC[C@H](N2CCc3ccccc32)[C@H](CO)C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC[C@H](N2CCc3ccccc32)[C@H](COc2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 24.5 %

Procedure:
Under a nitrogen gas stream, 4-fluorophenol (168 mg) and triphenyiphosphine (420 mg) were added to a solution of cis-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (300 mg) in tetrahydrofuran (4 ml). After cooling the resultant mixture to −10° C., diethyl azodicarboxylate (278 mg) was gradually added dropwise thereinto. Then the resultant mixture was gradually warmed to room temperature and stirred at the same temperature overnight. After adding water (40 ml), the reaction mixture was extracted with ether (40 ml) for three times. The organic phase was washed successively with a saturated aqueous solution (40 ml) of sodium bicarbonate and a 1 N aqueous solution (40 ml) of sodium hydroxide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd. NH-DM2035, hexane/ethyl acetate system) to give the title compound (100 mg) as a colorless oil (yield: 25%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:12][CH3:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([NH:15][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:12][CH3:13])=[NH:11])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCc1cccc(N(C#N)CC)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(CC)C(=N)Nc2cccc3ccccc23)c1
Temperature: 160 °C
Yield: 67.2 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-ethylcyanamide (500 mg, 2.86 mmol) and 1-aminonaphthalene hydrochloride (520 mg, 2.86 mmol) was heated in a pre-heated oil bath at 160° C. for 2 hours and then allowed to cool to room temperature. The resulting solid was taken in dichloromethane and washed with 10% NaOH solution. The organic layer was concentrated and the resulting residue was flash chromatographed on silica gel to give N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine (610 mg, 67%) as a light brown liquid.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
3-Bromo-2-ethyl-6-nitropyridine (2.6 g, 11.3 mmol) and 2-chloro-4-hydroxypyridine (2.9 g, 22.5 mmol) were dissolved in DMA (20 mL). The solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.7 g, 33.8 mmol) was added and the reaction mixture was stirred at 110° C. for 12 h. EtOAc (80 mL) was added and the suspension was washed with 10% K2CO3 (aq) (2×50 mL), 5% LiCl (aq) (2×50 mL), and brine (2×50 mL). The solution was dried (Na2SO4), concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.3 g, 37.2%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.16 (dd, J=5.7, 2.3 Hz, 1H), 2.79 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[CH2:29](Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl-].C[Zn+]>CN(C)C=O.O1CCCC1>[CH3:26][C:21]([C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)([CH3:25])[C:22](=[O:23])[CH3:29]
Reactant: ClCCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Agent: C[Zn+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)C(C)(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 65.7 %

Procedure:
N,N-Dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (0.800 g, 0.00194 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 2.42 ml, 0.00484 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. The resultant solution is added dropwise to a mixture of methyl zinc chloride (2.0 M, 0.970 ml, 0.00194 mol) in tetrahydrofuran, followed by addition of palladium tetrakistriphenylphosphine (0.220 g, 0.000190 mol). The resultant mixture is stirred overnight at room temperature, quenched with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an orange solid. The solid is chromatographed on silica gel to afford the title compound as an off-white solid (0.270 g, 65.7%, mp 195-196° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[F:54][C:55]1[CH:56]=[C:57]2[C:61](=[CH:62][CH:63]=1)[CH2:60][NH:59][CH2:58]2>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:59]1[CH2:58][C:57]2[C:61](=[CH:62][CH:63]=[C:55]([F:54])[CH:56]=2)[CH2:60]1)=[O:6]
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Reactant: Fc1ccc2c(c1)CNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl)N1Cc2ccc(F)cc2C1
Reaction time: 16 h
Yield: 109.7 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.8 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline hydrochloride (D8) (0.10 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E65) as a white solid (0.14 g). MS electrospray (+ion) 430/432 (MH+). 1H NMR δ (DMSO-d6): 10.48 (1H, s), 7.46-7.06 (6H, m), 4.88-4.60 (3H, m), 4.51 (2H, m), 3.80-3.55 (1H, m), 3.46-3.18 (2H, m), 2.88 (2H, m), 2.38-1.64 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH2:26][CH2:25][O:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: OCCOC1CCCCO1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(OCCOC2CCCCO2)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a suspension of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol (0.150 g, 0.547 mmol), 2-(Tetrahydro-pyran-2-yloxy)-ethanol (0.0960 g, 0.657 mmol), and Triphenylphosphine (0.230 g, 0.876 mmol) in Methylene chloride (6 mL) cooled to 0° C. on an ice bath was slowly added Di-tert-butyl azodicarboxylate (0.202 g, 0.876 mmol), at which time a solution formed. The reaction mixture was stirred at rt overnight. The reaction did not go to completion so equal amounts of 2-(Tetrahydro-pyran-2-yloxy)-ethanol, Triphenylphosphine, Methylene chloride, and Di-tert-butyl azodicarboxylate were added as were at the start of the reaction and stirred. The reaction mixture was then concentrated and dissolved in minimal amounts of DCM. It was then purified by silica gel chromatography (ISCO, 0-30% EtOAc) to give (2,5-Dichloro-pyrimidin-4-yl)-{2-fluoro-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-amine as a clear oil (98 mg, 44%). 1H-NMR (CDCl3): 8.17 (s, 1H), 7.22 (m, 1H), 6.93 (s, 1H), 6.82 (m, 2H), 4.63 (s, 1H), 4.22 (m, 2H), 3.98 (m, 1H), 3.74 (m, 2H), 3.47 (m, 1H), 1.67 (m, 2H), 1.55 (m, 2H) 1.49 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To the suspension of 4-(3-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.55 g, 95%) as a tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:27])=[N:16][O:17][C:18]=2/[CH:19]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[O:7])=[CH:4][CH:3]=1.[Cl-].[C:31]([O:35][C:36](=[O:39])[CH2:37][Zn+])([CH3:34])([CH3:33])[CH3:32]>C1COCC1.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:27])=[N:16][O:17][C:18]=2[C@@H:19]([NH:20][S@@:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:7])=[CH:28][CH:29]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:27])=[N:16][O:17][C:18]=2[C@H:19]([NH:20][S@@:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:7])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1noc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1noc([C@@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Cc1noc([C@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a round bottomed flask was added (R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (0.083 g, 0.194 mmol) in THF (0.5 mL). This solution was cooled to 0° C. before addition of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.464 mL, 0.232 mmol) and stirring at 0° C. for 1 h before addition of another more zinc reagent (0.388 mL, 0.194 mmol). After stirring 3 h at 0° C. the solution was quenched with aqueous ammonium chloride solution and EtOAc added. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (3S)-tert-butyl 3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (Rf (1:1 EtOAc:hex)=˜0.3, Mass: 0.043 g, LC/MS m/z 545 [M+H]+) and (3R)-tert-butyl 3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (Rf (1:1 EtOAc:hex)=˜0.15, Mass: 0.045 g, LC/MS m/z 545 [M+H]+).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[NH:23][C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32]([O:34][CH2:35]Cl)[CH3:33]>O1CCCC1.C(OCC)C>[C:26]1([CH2:25][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[N:23]([CH2:35][O:34][CH2:32][CH3:33])[C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (0.064 g, 2 mmole) in tetrahydrofuran (15 mL) was cooled in an ice bath. N,N-bis(phenylmethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.32 mmole) was added and the reaction mixture was allowed to warm to room temperature for 20 minutes. Chloromethyl ethyl ether was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with diethyl ether, washed twice with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methylene chloride) to provide 0.43 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH:15][C:26](=[O:27])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)N=C=O
Reactant: C=CCNc1nc(N)c2cc([N+](=O)[O-])ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCNc1nc(NC(=O)NC(C)(C)C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To 5 ml of a solution of 165 mg (0.67 mmol) of 2-allylamino-4-amino-6-nitroquinazoline in THF was added 17 mg (10.7 mmol) of sodium hydride. After the mixture was stirred under ice cooling for 0.5 hour, 76 mg (0.77 mmol) of t-butylisocyanate was added, followed by stirring for 1.5 hours at room temperature. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 79 mg (yield: 34.2%) of the title compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]5[CH2:53][CH2:52]5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:54][OH:55])[CH2:11][O:12]2)C1C=CC=CC=1.C1COCC1.ClC1C=CC=CC=1Cl>[Pd].CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:54][OH:55])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]2[CH2:53][CH2:52]2)=[CH:43][CH:42]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 3 h
Yield: 97.9 %

Procedure:
[(1S,2S,3S,4R,55)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1g (220.3 mg, 0.29 mmol) was dissolved in 10 mL mixed solution (THF and MeOH, v:v=1:1), followed by addition of 1,2-dichlorobenzene (0.34 mL, 3 mmol) and Palladium/carbon (90 mg, 10%). The mixture was exchanged with H2 three times and stirred for 3 hours, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 1 (140 mg, white solid), yield: 100%. MS m/z (ESI): 510.2 [M+18]. 1H NMR (400 MHz, CD3OD): δ 7.45 (d, 1H), 7.36 (m, 2H), 7.10 (d, 2H), 6.82 (m, 2H), 4.14 (d, 1H), 4.05 (m, 4H), 3.83 (m, 3H), 3.78 (m, 1H), 3.66 (m, 2H), 3.57 (m, 2H), 3.40 (m, 1H), 0.56 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:9][S:8][C:6]1[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:7]=1
Reactant: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Reactant: C1COCCN1
Product: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CCOCC2)n1

Procedure:
The above-prepared [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130° C. for 15 hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by filtration to give [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[N+:8]([O-:11])([O-])=[O:9].[K+].[CH2:13]([O:15][P:16]([O-:20])[O:17][CH2:18][CH3:19])[CH3:14]>S(=O)(=O)(O)O>[N+:8]([C:4]1[CH:3]=[C:2]([CH:6]([P:16](=[O:20])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[OH:7])[S:1][CH:5]=1)([O-:11])=[O:9]
Reactant: O=Cc1cccs1
Reactant: CCOP([O-])OCC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOP(=O)(OCC)C(O)c1cc([N+](=O)[O-])cs1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Thiophene-2-carboxaldehyde (3.20 mL, 34.0 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0° C. Potassium nitrate (4.05 g, 44.0 mmol) was added and the resultant mixture was stirred for 30 minutes and was poured onto ice. The product was extracted with ether, washed with aqueous sodium bicarbonate, dried with anhyrous magnesium sulfate and evaporated to give an oil which was immediately mixed with diethylphosphite (4.40 mL, 34.0 mmol) and adsorbed onto excess basic alumina. After 18 hours, the product was extracted with methylene chloride, concentrated in vacuo to an oil and purified by column chromatography (silica gel) with ethyl acetate-hexane 1:1 to give 1.01 g (10.0%) as an oil. 1H NMR (DMSO-D6): d, 8.64 (s,1H) 7.62 (s,1H) 6.95 (dd,1H,OH), 5.36 (dd,1H,PCH), 4.05 (m,4H,CH2), 1.22 (t,6H,CH3). MS (DCl): 296 (MH+), 278 (M-OH). C9H14NO6PS.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[CH3:20]O>>[Cl-:3].[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][C@@H:6]([NH3+:5])[C:17]([O:19][CH3:20])=[O:18])=[CH:9]1
Reactant: CO
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H]([NH3+])Cc1c[nH]c2ccccc12
Product: [Cl-]
Reaction time: 24 h
Yield: 86 %

Procedure:
Thionyl chloride (9.87 mmol, 0.72 mL) was added dropwise to a solution of D-tryptophan (1.000 g, 4.89 mmol) in methanol (33 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and residual methanol traces removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (1.070 g, 86%).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:20]([CH3:19])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CC(C(=O)O)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 2 (Method B) from 2-benzoyl-6-chloroindole (step 3 of Example 2, Method B) and diethyl methylmalonate.