Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.ClCCCl.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:20]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5 g) was suspended to 1,2-dichloroethane (50 ml) and acetyl chloride was added (2.2 g). To this reaction system was added portionwise aluminum chloride (15 g) under ice-cooling and the mixture was stirred at room temperature for 10 minutes. The reaction system was poured into ice. Chloroform was added and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration to give 2-acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5.2 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C(OCC)C>[CH3:8][C:7]1[C:2]([B:14]([OH:19])[OH:15])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccnc1Br
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: Cc1cccnc1B(O)O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A 100-mL, 3-necked round-bottom flask was charged with 2-bromo-3-methylpyridine (1.00 g, 5.81 mmol) and diethyl ether (30 mL). A solution of isopropylmagnesium chloride (2 M in THF, 8.0 mL, 16.0 mmol) was added dropwise with stirring at 0° C., and the resulting solution stirred for 3 h at 0° C. Triisopropyl borate (2.6 g, 13.8 mmol) was added, and the solution stirred for 1 h at room temperature. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 3-methylpyridin-2-ylboronic acid (0.730 g, 92%) as light yellow oil. MS (ESI, pos. ion) m/z 138 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][N:64]([CH:66]([CH3:68])[CH3:67])[CH3:65])C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][N:64]([CH:66]([CH3:68])[CH3:67])[CH3:65])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCN(C)C(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCN(C)C(C)C)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-methyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OCC)(OCC)(OCC)[CH3:15]>>[C:9]([C:6]1[C:7]2[O:8][C:14]([CH3:15])=[N:1][C:2]=2[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=1)#[N:10]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Yield: 62.4 %

Procedure:
Compound 477B (0.360 g, 2.01 mmol) and triethyl orthoacetate (1.30 g, 8.04 mmol) were combined and heated at reflux under nitrogen for 1 h. The solvent was removed in vacuo and the resulting residue purified by flash chromatography eluting with 5% ether/CH2Cl2 to give 0.255 g (63%) of compound 477C as a brown solid. HPLC: 98.4% at 1.80 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 204.28 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:13][CH2:14][C:15]#[N:16].Cl>O1CCOCC1>[Cl:13][CH2:14][C:15]1[NH:16][C:4](=[O:6])[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([CH3:12])[CH:8]=2)[N:1]=1
Reactant: N#CCCl
Reactant: COC(=O)c1cc(C)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2nc(CCl)[nH]c(=O)c2c1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
1. 91.4 g of methyl 2-amino-5-methylbenzoate and 23.4 ml of chloroacetonitrile are dissolved in 1.01 of absolute dioxan and the solution is cooled to 10° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 15° C. After 4 h., a further 23.4 ml of chloroacetonitrile are added thereto. The mixture is stirred at room temperature for a further 18 h. The suspension is subsequently evaporated in a vacuum. The crystalline residue is suspended with 2.51 of ice/water, adjusted to pH 8 to 9 with about 100 ml of 25% ammonia, stirred at 5° C. for 1 h. and then filtered. The crystals are washed with water and dried in a vacuum. There are obtained 114.1 g of 2-chloromethyl-6-methyl-3H-quinazolin-4-one of m.p. 263°-265° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:15]=1)=[O:13])C>CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([N:16]2[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:14]([C:12]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]3[CH2:5][C:4]([OH:33])=[O:3])=[O:13])=[N:15]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC1CCCCN1C(=O)c1cc(-c2ccccc2)n(-c2ccc(OC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3CC(=O)O)cc2-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperidin-2-ylacetic acid ethyl ester (330 mg) obtained in Example 52 in methanol (4 mL), 1M aqueous sodium hydroxide (1.84 mL) was added, and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified with 1M aqueous hydrochloric acid (2 mL), followed by extraction with ethyl acetate. The thus-obtained organic layer was washed with water and saturated brine and dried over sodium sulfate anhydrate. The resultant mixture was subjected to filtration, and the solvent was removed under reduced pressure, to thereby give the title compound as an amorphous product (311 mg, 98%).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2 Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H) 6.15 (m, 1, 1'H), 8.6 (br s , 1, NH), and aromatic protons. Anal. Calcd. for C24H31 N3O7Si: C, 57.46;H, 6.23; N, 8.37. found: C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1>C(Cl)Cl>[CH:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[CH2:21][CH2:22][OH:23])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: Brc1cccc2cc3ccccc3cc12
Agent: [Li]CCCC
Solvent: ClCCl
Product: OCCc1c2ccccc2cc2ccccc12

Procedure:
A solution in methylene chloride (20 ml) of 2-(9-anthryl)ethanol (3.5 g; 15.7 mmoles), which had been obtained by reaction between bromoanthracene and n-butyllithium and subsequent reaction with ethylene oxide was slowly added to an ice-cold solution of phosgene (20 ml; 38.4 mmoles; 20% in toluene). The reaction mixture was kept for 3 hours in an ice-bath and was then allowed to stand at room temperature during the night. Work up by vacuum evaporation of the solvent gave a crystalline residue, which was recrystallized from methylene chloride solution by precipitation with hexane to give 3.36 g (75%) of AEOC as practically colourless crystals, mp 85°-87° C. 270 MHz 1H-NMR in CDCl3 : 4.10 (t, J=8 Hz, 2 H); 4.66 (t, J=8 Hz, 2 H); 7.46-7.61 (m, 4 H); 8.03 (d, J=8 Hz, 2 H); 8.27 (d, J=8.6 Hz, 2 H); 8.43 (s, 1 H, H-10).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1>>[ClH:2].[C:11]1([CH3:15])[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:10]=1
Reactant: Cc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: Cc1cccc(-c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)c1
Yield: 70.5 %

Procedure:
Following General Procedure A2, 4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.048 g, 0.32 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.075 g, 99%) as a tan solid. MW=393.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.93 (s, 1H), 9.79 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.39-7.33 (m, 4H), 6.96 (s, 1H), 6.91 (s, 1H), 3.42 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 2.24 (quin, J=7.6 Hz, 2H); APCI MS m/z 358 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH:8][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:6]([F:12])[CH:5]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Nc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Under argon, sodium hydride (60%, 372 mg, 9.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67 g, 8.08 mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.3 g, 4.04 mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130 ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%) (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50° C. to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.4 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Cc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Yield: 107 %

Procedure:
The 4-bromo-6-methyl-1H-indazole (950 mg, 4.5 mmol), the {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (2.2 g, 9 mmol), copper (II) acetate (1.22 g, 6.75 mmol) and pyridine (0.73 mL, 9 mmol) in DCM (80 mL) were stirred in the presence of molecular sieves (4 A, 2 g) in air. After 40 hours the mixture was filtered through a pad of celite and concentrated to afford 3.3 g of crude material. This was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc 0 to 30% in hexane to afford 1.98 g of desired compound (D12) slightly impure but carried forward.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1.[Cl-].[Na+]>[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 22 mmol) in THF (34 mL) at 0° C. under nitrogen was added n-BuLi (8.8 mL, 22 mmol, 2.5M in hexanes). A solution of ethyl 2,3,4,8-tetra-methyl-2-azabicyclo[2.2.2]octane-6-carboxylate (4.8 g, 20 mmol) in THF (46 mL) was added to the mixture and the reaction was stirred at 0° C. for 1 hour. Ethyl chloroformate (2.3 mL, 24 mmol) in THF (3 mL) was then added and the mixture was stirred for 15 minutes. The reaction mixture was diluted with saturated sodium chloride and partitioned between water and ether. The aqueous layer was extracted with ether (2X) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether/hexanes (15/85) to afford 3.9 g (63%) of diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18]O)=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=S(Cl)[Cl:23]>>[Cl:20][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:17]([CH2:18][Cl:23])=[CH:16]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Product: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure C using (2-(2-chlorophenyl)-8-chloroquinolin-3-yl)methanol (0.675 g, 2.22 mmol) and SOCl2 (0.81 mL). 8-Chloro-3-(chloro-methyl)-2-(2-chlorophenyl)quinoline was obtained as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, s), 7.88 (1H, dd, J=8.2, 1.2 Hz), 7.81 (1H, dd, J=7.4, 1.2 Hz), 7.48 (1H, d, J=7.4 Hz), 7.42-7.46 (1H, m), 7.27-7.41 (3H, m), 4.63 (1H, d, J=9.8 Hz), 4.33-4.45 (1H, m) Mass Spectrum (ESI) m/e=322.0 and 324.0 (M+1)
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[C:2](=[O:1])[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2Nc2ccccc2N1CCCCl
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (12.1 g, 0.058 mol, prepared as described in Synthesis, 1985, 550) in dry N,N-dimethylformamide (150 ml) kept under an atmosphere of nitrogen, sodium hydride (2.8 g, 0.069 mol, 60% dispersion in oil) was added and the reaction mixture was stirred for 1 hour. 1-Bromo-3-chloropropane (10.9 g, 0.069 mol) was slowly added and the mixture was stirred overnight. The reaction mixture was quenched with water (200 ml) and extracted with diethyl ether (2×250 ml). The combined organic extracts were washed with water (3×300 ml), dried (MgSO4) and the solvent was evaporated in vacuo. The solid was washed with heptane (100 ml), filtered off and dried, affording 11.1 g (67%) of 10-(3-chloropropyl)-5, 10-dihydro-dibenzo[b,e][1,4]diazepin-11-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([Cl:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-chlorobenzoate (2.8 g, 10.6 mmol) and cyclopentanone (4.47 g, 53.2 mmol) in methanol (20 mL) was added acetic acid (1.3 mL, 21.2 mmol) and the reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.7 g, 26.6 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 5-bromo-2-chloro-3-(cyclopentylamino)benzoate (0.5 g, 14.2%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(O)CN
Reactant: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(C(C)C)ccc1C2
Reaction time: 0.75 h
Yield: 54.9 %

Procedure:
A solution of 2.16 g of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone and 80 mg of p-toluenesulfonic acid in 60 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.4 g (55%) of (RS)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(CCBr)cc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-4-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH:11]([CH2:10]/[CH:9]=[CH:8]/[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0 °C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9]C(OC(C)(C)C)=O)[C:7](=[O:17])[NH:6]1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:9][C@H:8]1[C:7](=[O:17])[NH:6][C@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CN=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1N

Procedure:
cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine (ca. 1 g) is dissolved in 2 ml of methylene chloride and the solution is cooled to 0° and treated with 0.5 ml of trifluoroacetic acid for 30 minutes at 0°. The solution is washed with 5% aqueous sodium bicarbonate and extracted with dilute hydrochloric acid. The aqueous phase is neutralized and extracted with ethyl acetate. Evaporation of the solvent gives the title compound.