Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:23]2[CH2:24][CH2:25][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ncoc1-c1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 3-Phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1377.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([S:31]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]2[O:20][C:16]([CH3:15])=[CH:17][CH:18]=2)=[N:9]3)(=[O:32])=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1ccc(CN)o1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(F)c(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=420.3 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3,4-difluorobenzenesulfonylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:28][C:13]2=[CH:14][C:15]3[C:16](=[O:27])[N:17]([CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2=[CH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[C:16](=[O:27])[C:15]=3[CH:14]=[C:13]2[N:28]=1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C[C@@H](O)CO)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C(=O)N1C[C@@H](O)CO

Procedure:
To a solution of (R)-2-(4-chloro-2-methoxypyridin-3-yl)-6-(2,3-dihydroxypropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (380 mg, 0.95 mmol) in 50 mL of dioxane was added 1 mL of conc. HCl. The mixture was heated to reflux and maintained for 3 h. The solvent was removed by rotary evaporation and the solid residue was triturated with n-butanol three times to give a white solid which was used directly in the next step. APCI MS: m/z 389.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-:10].[K+].O.[CH3:13]O>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([O:10][CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)cccc1Cl
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1cccc(Cl)c1C

Procedure:
8.1 g (0.05 mol) of 2,6-dichlorotoluene and 9.9 g (0.15 mol) of potassium hydroxide (85%) are heated in 40 ml of methanol in an autoclave at 160° C. for 20 hours, and the pressure rises to about 12 bar. After cooling, the reaction mixture is poured into about 250 ml of water and extracted three times with about 70 ml of dichloromethane. The united organic phases are dried over sodium sulphate and evaporated under reduced pressure. 3-Chloro-2-methylanisole is obtained as an oil (2.5 g, GC analysis: 37.1%, 12% of theory).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15][CH2:14]2>C(N(CC)CC)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C(C)C)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 9 described in example 116 from isobutyryl chloride, triethylamine and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=390.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([F:18])([F:17])[C:14](O)=[O:15].C(OCC)(=O)C>C1COCC1.O>[F:18][C:13]([F:17])([CH2:14][OH:15])[CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CO
Reaction time: 8 h

Procedure:
Under argon atmosphere 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2,2-difluoro-propionic acid, A2 (13.74 g, 53.85 mmol), dissolved in THF (200 mL) was treated with borane-methylsulfide complex (6.3 mL, 5.04 g, 66.6 mmol). After stirring overnight an additional portion of borane-methylsulfide complex (6.0 mL, 4.80 g, 63.43 mmol) was added. When the reaction was complete it was cautiously diluted with water and extracted with ethyl acetate (2×). An ethyl acetate solution prepared from the residue obtained by evaporation of the initial ethyl acetate extractions at 30° C. in vacuo was washed with water, brine (2×), dried (Na2SO4), filtered, and evaporated in vacuo at 30° C. Crude A3 was sonicated in ethyl acetate, and filtered to give pure 2-(2,2-Difluoro-3-hydroxy-propyl)-isoindole-1,3-dione, A3 (7.45 g). Flash chromatography of the liquor residue (Yamazen, 5 L silica gel cartridge, ethyl acetate/hexane gradient) afforded additional pure 2-(2,2-Difluoro-3-hydroxy-propyl)-isoindole-1,3-dione, A3 (1.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[CH2:20]([O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH2:20][CH3:21])[CH:28]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Product: CCOc1cccc(-c2c(C(=O)OC)c(C(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 31 step A, 200 mg, 0.67 mmol) and 3-ethoxyphenylboronic acid (72 mg, 0.54 mmol). Sticky liquid (105 mg, 41%). LC-MS: 384 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([O:3][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])[C:17]([CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[N:15]=1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: Cc1cc(O)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
At 0° C., NaH (60%, 125 mg, 3.06 mmol, 1.0 eq.) was added to 3-hydroxy-5-methyl-benzonitrile (408 mg, 3.06 mmol) in 10 mL of DMF solution. The reaction mixture was stirred at 0° C. for 5 minutes. 2,4,6-Trichloro-5-isopropyl-pyrimidine (691 mg, 3.06 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAc/hexane) to give a white solid (868 mg, 88%). LC-MS shows 322.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 3.60 (m, 1H), 2.42 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6].[ClH:1]
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Reactant: [Cl-]
Reactant: CCC(C)c1ccc(N)cc1
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(NC(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 2 h
Yield: 47 %

Procedure:
Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution of N-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) in chlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenyl amine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butyl aniline and 1.0 M HCl-ether) was added and continued reflux. After 2 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.45 g, 65%) as a syrup. TLC: Rf=0.22 (CH2Cl2:CH3OH; 10:1); 1H NMR (CD3OD): δ 7.27 (d, 4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, —NCH3), 2.69-2.58 (m, 2H, 2×-CH), 1.68-1.57 (m, 4H, 2×-CH2), 1.25 (d, 6H, 2×-CH3), 0.85 (t, 6H, 2×-CH3); HRMS: 337.2484 (337.2528 Calcd. for C22H31N3); HPLC: (CH3CN:H2O; 50:50 with 0.1% TFA): 98% pure.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:16])[N:12]([O:14][CH3:15])[CH3:13])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([N:12]([O:14][CH3:15])[CH3:13])=[O:16]
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)C(C)(C)N
Reaction time: 0.33 h
Yield: 176 %

Procedure:
The Boc-protected Weinreb amide, [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester, (1.1 g, 4.47 mmol), was taken up in TFA/CH2Cl2 (1:1, 50 mL) and stirred for 20 min. Removal of the solvent left 2-amino-N-methoxy-2,N-dimethyl-propionamide (1.15 g, 99%, quantitative yield) as its TFA salt. 1H NMR (200 MHz, CD3OD) δ (ppm): 1.63 (s, 6H), 3.25 (s, 3H), 3.78 (s, 3H). MS (ESI, positive ion): m/z 147.3 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[OH:14])[CH:7]=[CH:6]2.N1CCC(C(C2C=CC3C(=CC=C(Cl)C=3)C=2)=O)CC1.Cl[CH2:41][CH2:42][CH2:43][CH:44]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[OH:45].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH:44]([OH:45])[CH2:43][CH2:42][CH2:41][N:18]2[CH2:19][CH2:20][CH:15]([CH:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)[OH:14])[CH2:16][CH2:17]2)=[CH:51][CH:50]=1
Reactant: OC(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Reactant: OC(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Product: OC(CCCN1CCC(C(O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1

Procedure:
When in the procedure of Example 25, α-(6-chloro-2-naphthyl)-4-piperidinemethanol hydrochloride is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone and 4-chloro-1-(4-fluorophenyl)butanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, α-(4-fluorophenyl)-4-[(6-chloro-2-naphthyl)hydroxymethyl]-1-piperidinebutanol is produced.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[N-:15]=[N+:16]=[N-:17].[Na+].C(OC)=O>O>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][N:15]=[N+:16]=[N-:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COCc1ccccc1
Yield: 91.8 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 4.92 g of benzyloxymethyloxirane (prepared as described in Preparation 46), 160 ml of an 8:1 by volume mixture of methanol and water, 9.75 g of sodium azide and 40 ml of methyl formate were used, to give 5.7 g of the title compound having an Rf value of 0.22 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent) as a pale yellow oil.
Reaction SMILES: [Cl:1]CCl.[CH2:4]([O:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:15])=[CH:12][CH2:11][N:10]1C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH3:5].ClC(OC(Cl)C)=O>[Pd].CO>[ClH:1].[CH2:4]([O:6][C:7]([CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10]1)=[O:8])[CH3:5]
Reactant: ClCCl
Reactant: CCOC(=O)C1CC(C)=CCN1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: CCOC(=O)C1CC(C)CCN1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane (50 mL) solution of 1-benzhydryl-4-methyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid ethyl ester *(5.0 g, 14.9 mmol), 1-chloroethyl chloroformate (2.13 g, 14.9 mmol) was added at room temperature under argon. The reaction mixture was stirred overnight. After the reaction mixture was mixed with methanol (50 mL) and refluxed for an hour, cooled down to room temperature and 10% Pd/C (2 g) was added to reaction mixture and stirred under hydrogen overnight. The reaction mixture was filtered through celite and 1 M HCl in ether (15 mL) was added. After concentration, the residue was triturated with acetone, filtered to 2.03 g (65.5%) of 4-methyl-piperidine-2-carboxylic acid ethyl ester hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[NH2:37][CH:38]1[C:44](=[O:45])[NH:43][C:42]2[CH:46]=[CH:47][C:48]3[C:53]([C:41]=2[CH2:40][CH2:39]1)=[CH:52][CH:51]=[CH:50][CH:49]=3>CN(C=O)C.C(OCC)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](=[O:13])[NH:37][CH:38]1[C:44](=[O:45])[NH:43][C:42]2[CH:46]=[CH:47][C:48]3[C:53]([C:41]=2[CH2:40][CH2:39]1)=[CH:52][CH:51]=[CH:50][CH:49]=3)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2c(ccc3ccccc23)NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)NC1CCc2c(ccc3ccccc23)NC1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
A solution of 3-tert-butyloxycarbonylamino-3-methylbutanoic acid (2.43 g, 11.2 mmol) and 1-hydroxybenzotriazole (1.52 g, 11.3 mmol) in DMF (30 ml) was placed under an atmosphere of nitrogen. EDAC (2.19 g, 11.4 mmol) was added and the reaction mixture was stirred for 10 minutes at room temperature. Unresolved 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]- azepine (2.3 g, 10.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (200 ml) and the solution was extracted with dichloromethane (2×250 ml). The combined organic extracts were washed with 10% sodium bicarbonate (2×150 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give a solid residue which was suspended in diethyl ether. Filtration and drying afforded 4.5 g of (1,1-dimethyl -2-(4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepin-3-ylcarbamoyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2NC)=[C:4](CC)[N:3]=1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].CO>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:17]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCc1nc(N)nc2c1ncn2NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 168 h
Yield: 42 %

Procedure:
2-Amino-6-ethylmethylamino-9H-purine (0.5 g, 2.6 mmoles) and 2',3'-dide-oxy-3'-fluorouridine (0.5 g, 2.2 mmoles) were suspended in potassium phosphate buffer (50 ml, 10 mM), pH 7.0, containing potassium azide 0.04%. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphory-lase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 7 days, MeOH (170 ml) was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8). Product containing fractions were again pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:meth-anol (95:5). Solvent was removed and lyophilization yielded 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofura-nosyl)-9H-purine (0.22 g, 32%): mp 89°-9° C.;
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6](O)[CH2:7][CH3:8])[CH3:5].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:22]=[C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([C:29]3[C:34]([F:35])=[CH:33][C:32](F)=[CH:31][C:30]=3[F:37])=[C:19]([Cl:38])[N:18]=2)=[N:15][CH:16]=1.C(OCC)(=[O:41])C>CSC>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:22]=[C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([C:29]3[C:34]([F:35])=[CH:33][C:32]([O:41][CH2:8][CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[CH:31][C:30]=3[F:37])=[C:19]([Cl:38])[N:18]=2)=[N:15][CH:16]=1
Reactant: CCC(O)N(C)C
Reactant: CCOC(C)=O
Reactant: Nc1ccc(-c2nc(Cl)c(-c3c(F)cc(F)cc3F)c(NCC(F)(F)F)n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CSC
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(-c3ccc(N)cn3)nc2NCC(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of sodium hydride (33.6 mg, 0.84 mmol) in 2 mL of dimethylsulfide is added N,N-Dimethylaminopropan-1-ol (99 μL, 0.84 mmol) slowly. After 30 minutes, 2-(5-aminopyridin-2-yl)-6-chloro-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (100 mg, from Step A) is added and the resulting reaction mixture is heated at 60° C. for 4 h. The reaction mixture is cooled to room temperature, and diluted with ethyl acetate. The organic layer is washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered, concentrated and dried under reduced pressure to yield 2-(5-aminopyridin-2-yl)-6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine as a yellow semi-solid (60 mg). MS: m/z 517.3 (M+H). This product was used in the next step without further purification.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[NH2:17])C=CC=CC=1.[Cl:30][CH2:31][CH2:32][O:33][CH2:34]Cl>C(Cl)Cl>[Cl:30][CH2:31][CH2:32][O:33][CH2:34][N:15]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[N:8]=[CH:16]1
Reactant: Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCOCCl
Solvent: ClCCl
Product: Nc1ncnc2ncn(COCCCl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 11 (1.79 g, 4.74 mmol) in CH2Cl2 (70 mL) was added (2-chloroethoxy)methyl chloride (0.65 g, 5.0 mmol). The reaction mixture was stirred at 25° C. for 8.0 h to afford a solid. Filteration and crystallization from MeOH gave 12 (1.66 g, 4.27 mmol) in 90% yield: mp 184-186° C.; Rf (hexanes/EtOAc=1:2) 0.28; UV (EtOH) λmax 267 (ε 14,600); 1H NMR (DMSO-d6) δ 3.73 (t, J=4.5 Hz, 2 H, CH2Cl), 3.86 (t, J=4.5 Hz, 2 H, OCH2), 5.76 (s, 2 H, H2C1′), 8.49 (s, 1 H, HC2), 8.74 (s, 1 H, HC8), 9.32, 10.05 (2 br, 2 H, NH2); 13C NMR (DMSO-d6) δ 43.13 (CH2Cl), 68.82 OCH2 78.10 (C1′), 118.20 (C5), 143.53 (C2), 146.50 (C8), 149.39 (C4), 151.60 (C6); MS m/z 227 (M+, Cl-cluster). Anal. (C8H10ClN5O) C, H, N, Cl; calcd (%): 42.20, 4.43, 30.76, 15.59; found (%): 42.32, 4.50, 30.69, 15.62.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[CH:4][CH:3]=1.[CH3:26]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(Cl)cc1
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 28 h
Yield: 13.3 %

Procedure:
3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol), trimethyboroxine (0.076 mL, 0.54 mmol), Pd(PPh3)4 (0.063 g, 0.05 mmol), and K2CO3 (0.224 g, 1.62 mmol) were combined in dioxane (10 mL) and heated at reflux under nitrogen for 5 hours. Additional Pd(PPh3)4 (50 mg) and trimethylboroxine (0.200 mL) were added and reflux was continued for 28 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, with THF washings, concentrated, and purified by flash chromatography on silica gel, eluting with 40% ethyl acetate/heptane to 100% ethyl acetate. Further purification by reverse-phase HPLC, eluting with 10% to 90% CH3CN in water with 0.1% TFA, afforded the title compound as a white solid (0.025 g, 13%). 1H-NMR (300 MHz, DMSO-6): δ 8.46 (d, J=2.0 Hz, 1H), 8.21 (d, J=7.0 Hz, 1H), 7.90-7.95 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.60-7.65 (m, 2H), 7.42-7.46 (m, 4H), 7.16 (d, J=8.1 Hz, 1H), 2.41 (s, 3H). MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH:5]([Cl:7])[Cl:6])[Cl:3].[CH2:8]([Cl:11])[CH:9]=[CH2:10]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:11][CH2:8][CH2:9][CH2:10][Si:2]([CH2:4][Si:5]([Cl:7])([Cl:6])[CH2:10][CH2:9][CH2:8][Cl:11])([Cl:3])[Cl:1]
Reactant: C=CCCl
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: ClCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)CCCCl
Yield: 35 %

Procedure:
To a 100 ml, three neck, round bottomed flask equipped with a dropping funnel and a reflux condenser, 6 g(0.03 mole) of bisdichlorosilylmethane, 6.5 g(0.08 mole) of allyl chloride, and 60 μl of 1% chloroplatinic acid solution in isopropanol, at reflux using a 80° C. oil bath for 3 hours under the dry nitrogen atmosphere. Gas chromatography analysis showed that no bisdichlorosilylmethane was left. Vacuum distillation of the reaction products gave 3.85 g(110°-112° C./0.05 mmHg) of bis{(3-chloropropyl)dichlorosilyl]methane in 35.6% yield. Besides this product, 4.10 g of (trichlorosilyl){(3-chloropropyl)silyl}methane was also obtained in 38.0% yield and (propyldichlorosilyl){(3-chloropropyl)dichlorosilyl}methane.