Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=O)C.CCOC(C)=O>C1COCC1>[CH2:1]([NH:13][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of dodecyl amine (3.22 g, 17.64 mmol) in 50 mL anhydrous THF was added n-BuLi (7.05 mL, 17.64 mmol) dropwise. When the addition was complete, the mixture was stirred for 10 min at 0° C. then at room temperature for 30 min. This lithiated amine was added dropwise to a cooled (0° C.) solution. of 5-bromo-3′-chloro-6-(2-hydroxy-ethoxy)-biphenyl-3-carboxylic acid ethyl ester (2.5 g, 5.78 mmol) in 40 mL anhydrous THF via cannula. The reaction was stirred for 10 min at 0° C. when the addition was complete then at room temperature overnight. Then the reaction mixture was heated to 35° C. for 1 hour then more n-BuLi was added (0.7 mL, 1.75 mmol). The reaction. was then worked up as in Step 2 of Example 135. There yielded 2.5 g, 80% of a yellow oil as desired product after flash chromatography (25% EtOAc:75% Hexanes) on silica gel.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: NCC1CC1
Solvent: CO
Solvent: CC#N
Product: FC(F)(F)COCc1cc(NCC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cyclopropylmethanamine (91 mg, 1.28 mmol) a in MeOH (2 mL) was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (111 mg, 0.43 mmol) in acetonitrile (2 mL). The mixture was stirred at ambient temperature overnight. The solution was concentrated and purified by preparative HPLC to give the title compound as a solid, 72 mg (58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[C:24]([C:18](=[CH:17][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:25]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccc(-c2ccccc2)cn1
Product: CCOC(=O)C(C#N)=CNc1ccc(-c2ccccc2)cn1
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
A mixture of 2-amino-5-phenylpyridine (1.19 g., 6.99 mmoles) and ethyl ethoxymethylenecyanoacetate (1.18 g., 6.99 mmoles) was fused at an oil bath temperature of 100° for 15 minutes. The product was recrystallized from toluene to give the title compound (1.3 g.), m.p. 126°-134°. An additional crop of product (0.3 g.), m.p. 119°-126° was obtained from the mother liquors. Total yield of product, 1.6 g. (78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:15]2)[CH:6]=[C:7]([NH2:13])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][OH:40]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[O:15]2)[CH:6]=[C:7]([NH:13][CH2:38][CH2:39][OH:40])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCI
Reactant: CCCOc1c(N)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-2-(3-methoxy-4-propoxy-5-aminophenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (20 mg. 0.048 mmol), potassium carbonate (0.4 g), and 2-iodoethanol (82.47 mg, 0.48 mmol) was suspended in 2 mL of DMF. The reaction mixture was stirred at room temperature for 20 hours, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to an oil which was purified by column using 3:1 hexane/ethyl acetate as solvent (12.8 mg, 57.9%). 1H NMR (CDCl3): 1.02 (t, 3H), 1.79 (m, 2H), 1.99 (m, 2H), 2.43 (m, 2H), 3.33 (m, 2H), 3.81 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 3.88 (s, 6H), 3.90 (t, 2H), 5.18 (m, 2H), 6.40 (d, 2 H), 6.61 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]([OH:24])[CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[C:28](OCC)(=O)C.CCCCCC>>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]([O:24][CH3:28])[CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Product: CCCCC(OC)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from (±)-2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypentyl)pyridine (Example 95) according to the procedures described in Example 98. 1H NMR (300 MHz, CDCl3): δ 7.10 (m, 4 H), 4.32 (m, 2 H), 3.92 (m, 1 H), 3.76 (septet, J=7.0 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 3.12 (s, 3 H), 1.87 (m, 1 H), 1.52 (m, 2 H), 1.19 (m, 16 H), 0.821 (t, J=7.4 Hz, 3 H). FAB-MS: calcd for (C24H34NFO2) 387, found 388 (M+H). Anal. Calcd for C24H34NO2F: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.38; H, 8.82; N, 3.45; F, 4.90. mp 121-123° C. Rf=0.5 (20% ethyl acetate/hexane).
Reaction SMILES: [Na].Br[C:3]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]2[C:9](=[O:20])[N:8]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:7](=[O:32])[N:6]([CH3:33])[C:5]=2[N:4]=1.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1>O>[Si:25]([O:24][CH2:23][CH2:22][CH2:21][N:8]1[C:9](=[O:20])[C:10]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:3]([O:42][CH2:41][CH2:40][N:37]3[CH2:38][CH2:39][O:34][CH2:35][CH2:36]3)=[N:4][C:5]=2[N:6]([CH3:33])[C:7]1=[O:32])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: OCCN1CCOCC1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OCCN1CCOCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Step 1 Sodium (0.053 g, 2.31 mmol) was dissolved in 2-morpholinoethanol (5 mL) and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was added. The reaction was stirred at room temperature for 24 h. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione (0.27 g, 100% yield) as a clear oil. LCMS retention time=2.990 min and 96% purity, LCMS MH+ 592.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (2S,3S)-N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1B) (4.90 g, 20.0 mmol) in DMF (20 mL) at rt was added imidazole (3.41 g, 50.1 mmol), and then tert-butydimethylsilyl chloride (3.91 g, 25.9 mmol). After stirring at rt overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 0-20% EtOAc/hexane to yield (2S,3S)-3-(tert-butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (6.86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccc(C(=O)OC)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 45 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 196°-197° C., was prepared from 2-chloro-8-chloromethyl5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and methyl 4-hydroxybenzoate. The yield was 45% of theory.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.CI>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH3:1])[S:13][C:12]=2[CH:16]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2ccsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50 mmole) was added under argon to a solution of 6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) at −75°. After stirring at −75° for a further 30 minutes, the cooling bath was exchanged and the reaction warmed to −10° C. prior to addition of CH3I (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at 0° C. for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated NaHCO3 (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.2 g of an amber oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.639 (91%) of a colourless oil. 1H NMR (DMSO-d6) δ 7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4 Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for C10H10OS: C, 67.38; H, 5.66; S, 17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=[N:12][OH:13])[NH2:11])=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16](Cl)=O>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]1[O:13][N:12]=[C:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:11]=1
Reactant: NC(CSc1ccc(Cl)cc1)=NO
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: ClCc1nc(CSc2ccc(Cl)cc2)no1

Procedure:
2-(4-Chlorophenylthio)acetamidoxime (21.7 g, 0.1 mol) was stirred in toluene (150 ml) whilst a solution of chloroacetyl chloride (11.3 g, 0.1 mol) in toluene (50 ml) was added dropwise over 20 minutes. The thick suspension was refluxed for 1 hour to give a black mixture which was cooled and then extracted with water and ether. The ether extracts were evaporated to give a brown oil which was chromatographed on silica gel (200 g) and eluted with ether/hexane (2:3) to give 5-chloromethyl-3-(4-chlorophenylthiomethyl)-1,2,4-oxadiazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=C1Cc2cc(O)ccc2N1
Product: O=C1Cc2cc(OCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 140 from 5-hydroxy-oxindole (J. Chem. Soc. 1961, 2723) and 4-phenylmercapto- butyl bromide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=CC=C([C:31]([F:34])([F:33])[F:32])C=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reactant: FC(F)(F)c1cccc(Br)c1
Product: Cn1c(=O)c2c(-c3cccc(C(F)(F)F)c3)n(CCN)cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 1-bromo-3-(trifluoromethyl)benzene;
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[BrH:15]>[Cu]Br>[Br:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCC2
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
5-Aminoindane was treated with concentrated hydrobromic acid. The suspension was cooled to −5° C., and 5M sodium nitrite solution was added at a temperature between 0° C. to 5° C. in period of 30 minutes through an addition funnel. Stirring was continued for 20 minutes at 0° C. to 5° C. The reaction mixture was now very dark fluid slurry. In a second reaction vessel, a solution of copper (I) bromide in concentrated hydrobromic acid had been prepared and preheated to 40° C. When the diazonium salt slurry was added in portions, a very slow gas evolution was observed which became vehement when heating to 60° C. After stirring at 60° C. for 40 min, the gas evolution ceased. The mixture was poured onto water. The product was extracted twice with ethyl acetate. Some of the precipitated copper bromide was removed by filtration to facilitate phase separation. The organic extracts were washed twice with water and one time with brine. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. After flash chromatography, the title compound was obtained as pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:12]>O.[Cu]Cl>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:12])[CH:3]=[N:4][CH:5]=1
Reactant: N
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: Cl[Cu]
Solvent: O
Product: Nc1cncc(C(F)(F)F)c1
Temperature: 170 °C
Reaction time: 48 h

Procedure:
Prepared according to the method of Barlin et al., Aust. J Chem., 1990, 43, 1175: 3-Chloro-5-(trifluoromethyl)pyridine (3.0 g, 16.52 mmol) is suspended in water (67.5 ml) and treated with copper(I)chloride (8.18 g, 82.62 mmol). Aqueous ammonia solution (25%, 67.5 ml) is added, and the reaction is stirred for 48 hours at 170° C. in the autoclave. The reaction mixture is cooled to room temperature and extracted three times with dichloromethane. The combined organic phases are washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo to yield analytically pure product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].CO.Cl.[H][H]>[Pd].CC(O)C>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:16]
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc2n(c(=O)c1CCCl)C(C)CCC2
Yield: 86 %

Procedure:
A mixture of 9.5 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]-pyrimidin-4-one, 160 parts of methanol and 40 parts of 2-propanol saturated with hydrogen chloride was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 9.5 parts (86%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (intermediate 175).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Br:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Br)cn3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (16 mg, 0.046 mmol, prepared as described for Example 8) and N-bromosuccinimide (8.2 mg, 0.046 mmol) were dissolved in DMF (0.2 ml) and the solution stirred overnight at 50 C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 20% acetone:hexanes to yield the title compound.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].CN(C=[O:25])C>>[CH2:1]([C:8]([OH:25])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Temperature: 40 °C

Procedure:
A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40° C. with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (1 L×3). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.22-7.26 (m, 5H), 4.23 (q, J=7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)[CH3:2].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+].O>CO>[CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:19])=[CH:9][CH:10]=2)[O:5]1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOC1CCc2ccc(O)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC1CCc2ccc(OC)cc2O1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
The above-obtained 2-ethoxy-7-hydroxychroman (10.9 g) was dissolved in 60 ml of methanol, and 10.6 g of dimethyl sulfate and 13.5 g of a 25% sodium hydroxide aqueous solution were added thereto at room temperature. The mixture was stirred at this temperature for 1 hour. After 30 ml of water was added thereto, the methanol was removed by distillation in vacuo, and the residue was extracted twice with 50 ml of toluene. The toluene layer was washed with water, and the toluene was removed by distillation in vacuo. The resulting residue was purified by distillation to obtain 11.0 g of a desired colorless liquid (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[CH:12][CH:13]=1.[Cl:14][CH2:15][CH:16]1[O:18][CH2:17]1>FC(F)(F)CO>[Cl:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[CH:12][CH:13]=1
Reactant: ClCC1CO1
Reactant: CN1C(=O)c2ccc(N)cc2C1=O
Solvent: OCC(F)(F)F
Product: CN1C(=O)c2ccc(NCC(O)CCl)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.3 %

Procedure:
Twenty-five grams (g) (0.142 mole) 4-amino-N-methylphthalimide [Flitsch, Chem. Ber. 94:2494(1961)] and 20.7 g (0.21 mole) 1-chloro-2,3-epoxypropane were added to 150 ml 2,2,2-trifluoroethanol and the reaction mixture was heated to reflux with stirring for 48 hours. Seventy to eighty ml of 2,2,2-trifluoroethanol was removed by distillation and a heavy yellow precipitate formed when the remaining solution cooled to room temperature. This precipitate was triturated with ethyl acetate, collected by filtration and dried to give 29.5 g (77% yield) of the desired phthalimide intermediate m.p. 136°-138.5° C.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[OH-].[NH4+:17]>C(#N)C>[NH2:17][C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1cnc(N)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (2.15 g, 9.34 mmol) was dissolved in acetonitrile (11.7 ml), and, with stirring at room temperature, aqueous 32% ammonium hydroxide (11.36 ml, 93 mmol) was added drop wise. A white suspension was obtained after few seconds. Acetonitrile was evaporated and the aqueous suspension was filtered on a buckner funnel. The obtained solid was washed with water (20 ml) and dried affording ethyl 2-aminopyrimidine-5-carboxylate as a white solid (1.192 g, 7.13 mmol, 76% yield, MS/ESI+ 168.1 [MH]+).
Reaction SMILES: [CH:1]([N:6]1[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:7]12)=[CH:2][C:3](=[CH2:5])[CH3:4].[H-].[Na+].C(OCC)(=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[OH:11][C:9]1[C:8]2[C:7](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]([CH:1]=[CH:2][C:3](=[CH2:5])[CH3:4])[C:12](=[O:13])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=C(C)C=Cn1c(=O)oc(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 18 (1.3 mmols, 0.3 g); Sodium hydride (1.3 mmols, 0.065 g); Diethyl malonate (6.5 mmols, 1.0 g). Yield: 0.08 g (21%), white solid, m.p.=123° C.-124° C.