Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH3:19])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 18 h
Yield: 68 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (1.00 g, 4.13 mmol), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (Japan Tobacco Inc WO 9518125) (0.84 g, 4.13 mmol), and triphenylphosphine (1.41 g, 5.37 mmol) in THF (17 mL) was treated dropwise at ambient temperature with diisopropyl azodicarboxylate (0.96 mL, 5.0 mmol). After 18 h, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine (40 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using 10-15% ethyl acetate in hexanes to give the product (1.2 g, 68%). 1H. NMR (400 MHz, CDCl3) δ 7.98 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.30 (m, 8H), 6.78-6.69 (m, 3H), 4.99 (s, 2H), 4.19 (t, J=6.6 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.53 (q, J=7 Hz, 2H), 0.88 (t, J=7 Hz, 3H); MS (FIA) m/e 428 (M+1).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]#[N:22])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:25][NH:24][C:21]([C:17]1[C:18]2[CH:19]=[CH:20][C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[N:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[NH:22]
Reactant: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Yield: 78.5 %

Procedure:
A stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile (example 29, step A) (571 mg, 2.0 mmol), hydroxylamine hydrochloride (514 mg, 7.4 mmol), sodium carbonate (424 mg, 4.0 mmol) in ethanol (7.5 ml) and water (7.5 ml) was heated under reflux conditions for 24 h, water (40 ml) was added, and the mixture was extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated to yield the crude product as solid which was further purified by crystallization (dichloromethane/methanol) to yield N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-5-carboxamidine as white solid (500 mg, 79%). MS: m/e=319.2 (M+H+); m.p. 200.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCNC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 250 mg (0.88 mmol) of [(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid, 177 mg (1.31 mmol) of HOBt, 252 mg (1.31 mmol) of EDC and 72 mg (0.96 mmol) of 2-methoxyethanamine in 6.3 ml of DMF was stirred at RT for 2 h. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 269 mg (90% of theory) of the title compound.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CCO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: C1CNCCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: Clc1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M+, C12H17N2Cl).10% CH3OH—CH2Cl2); RPLC tR=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH++H, C31H35N3O3).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][S:16]2(=[O:22])=[O:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(O)C>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][S:16]3(=[O:21])=[O:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 83.9 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.00 g, 3.02 mmol) and 4-fluorobenzylamine (1.31 g, 10.5 mmol) in a mixture of anhydrous ethyl alcohol (40 ml) and N,N-dimethylformamide (10 ml) was heated under reflux for 10 h. The solvent was then evaporated in vacuo and the residue was diluted with dichloromethane (500 ml). The organic phase was washed with 5% aqueous acetic acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the white solid obtained from dichloromethane and ethanol gave 1.04 g (84% yield) of the title amide as white crystals; mp 227–228° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 and 2.07 (2×1H, m, CH2), 2.28–2.43 (2H, m, CH2), 3.19–3.31 (2H, m, CH2), 3.64 (3H, s, NCH3), 3.6–3.8 (2H, m, CH2), 4.59 (2H, AB part of ABX system, JAB=14.9 Hz, Δν=36.1 Hz, JAX=6.6 Hz, JBX=5.8 Hz, NCH2), 7.06 (2H, m, aromatics), 7.31 (2H, m, aromatics), 7.52 (1H, broad NH). Anal. Calcd for C17H19FN4O5S: C 49.75, H 4.67, N 13.65. Found: C 49.67, H 4.63, N 13.77.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].Cl[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([CH:13]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[O:4][CH2:5][C:6]#[N:7])[C:14]#[N:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC(Cl)c1ccccc1
Reactant: N#CCOc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccccc1OC(C#N)c1ccccc1

Procedure:
A mixture of 2-(2-hydroxyphenoxy)acetonitrile (14.9 g., 0.1 mole), 2-chloro-2-phenylacetonitrile (15.2 g., 0.1 mole), finely powdered potassium carbonate (13.8 g., 0.1 mole) and 80 ml. of acetone is refluxed 3 hours. The mixture is then treated with 2-chloro-2-phenylacetonitrile (7.6 g., 0.05 mole) and potassium carbonate (6.9 g., 0.5 mole) and refluxed six hours. The mixture is filtered, the solids washed with acetone and the combined filtrate evaporated in vacuo to give an oil. Crystallization of the oil affords 2-phenyl-2-(2-cyanomethoxyphenoxy)acetonitrile.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 g of N-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: [O:1]([CH:8]([P:13](=[O:16])([OH:15])[OH:14])[P:9](=[O:12])([OH:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[C:17]([O:23][CH2:24]I)(=[O:22])[C:18](C)(C)C>>[CH2:2]([O:1][CH:8]([P:13](=[O:16])([O:14][CH2:24][O:23][C:17](=[O:22])[CH3:18])[O:15][CH2:24][O:23][C:17](=[O:22])[CH3:18])[P:9](=[O:12])([O:10][CH2:24][O:23][C:17](=[O:22])[CH3:18])[O:11][CH2:24][O:23][C:17](=[O:22])[CH3:18])[CH2:7][CH2:6][CH3:5]
Reactant: CC(C)(C)C(=O)OCI
Reactant: O=P(O)(O)C(Oc1ccccc1)P(=O)(O)O
Product: CCCCOC(P(=O)(OCOC(C)=O)OCOC(C)=O)P(=O)(OCOC(C)=O)OCOC(C)=O

Procedure:
This compound was prepared as described in Example 51 by substituting (n-butoxymethylene)-bisphosphonic acid for (phenoxymethylene)-bisphosphonic acid and by substituting iodomethyl acetate for iodomethyl pivalate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH3:16][C:14]1[N:1]=[C:2]2[N:6]([C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][S:3]2
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2sccn12
Yield: 30 %

Procedure:
A mixture of 2-aminothiazole (5.0 g. 49.931 mmol) and ethyl 2-chloroacetoacetate (11.5 g, 69.965 mmol) in absolute ethanol (50 mL) was refluxed for 24 h under stirring. The solvent was evaporated under vacuum and the residue was triturated with water (150 mL). The resulting solid was filtered, and dried to give crude product which was further purified by column chromatography to give 3.15 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.41 (t, J=6.9 Hz, 3H), 2.61 (s, 3H), 4.38 (q, J=6.6 Hz, 2H), 7.41 (d, J=4.2 Hz, 1H), 8.05 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 211.30 (MH)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
(+,−) Trans-2-phenyl-cyclopentylamine (5.95 g, 37.0 mmol, preparation 3) was dissolved in dry methylene chloride and cooled to 0° C. under a nitrogen atmosphere. 6.1 mL (40.7 mmol) of DBU was added followed by dropwise addition of 2-propanesulfonyl chloride (4.6 mL, 40.7 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was judged incomplete by TLC and an additional 20% of DBU and 2-propanesulfonyl chloride were added. Stirring at room temperature was continued for 3 days. The reaction was diluted with methylene chloride and washed (1×100 mL) with 1N HCl. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to 9.3 g. The product was purified on silica by Chromatotron® eluting with 99:1 methylene chloride:ethyl acetate to yield 5.7 g (31%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>C(#N)C>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:22][CH2:23]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(C)n1cc(C(=O)C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1cc(C(=O)C(=O)NC2CCN(CCNC(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 65 °C
Reaction time: 72 h

Procedure:
The title compound was prepared according to general procedure C described in Scheme 2. 2-(1-Isopropyl-1H-indol-3-yl)-2-oxo-N-(piperidin-4-yl)acetamide hydrochloride (200 mg, 0.64 mmol) was treated with acetonitrile (3 mL), K2CO3 (265 mg, 1.91 mmol), and tert-butyl 2-bromoethylcarbamate (266 mg, 1.28 mmol). The reaction mixture was stirred at 65° C. for 72 h and was then concentrated under reduced pressure. The crude material was purified by silica chromatography (Biotage, 0-5% MeOH/DCM, 30 min.) to provide the title compound as a brown oil. The material was further purified using reverse phase HPLC to provide the desired product as a pink solid TFA salt (132 mg, 45%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccncc1
Yield: 39 %

Procedure:
Prepared in 39% yield from 2-chloro-3-cyanopyridine and 4-(tributylstannyl)pyridine according to the procedure described for Example 164A. MS (ESI+) m/z 181.9 (M+H)+; 1H NMR (CDCl3) δ 7.50 (dd, J=8.1, 4.7 Hz, 1H), 7.88 (d, J=6.4 Hz, 2H), 8.14 (dd, J=8.0, 1.9 Hz, 1H), 8.83 (d, J=4.4 Hz, 2H), 8.94 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=1>CN(C=O)C.C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:15]2[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: Cc1cc(Cl)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc(C)c3ccc(Br)cc32)nc(N)n1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-3-methyl-1H-indazole (500 mg, 2.37 mmol) in dry DMF (5 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (684 mg of a 60% dispersion in mineral oil, 7.11 mmol). After warming to RT for 30 minutes, 4-chloro-6-methylpyrimidin-2-amine (510 mg, 3.55 mmol) was added and the solution warmed to 65° C. for 18 hr. The reaction mixture was cooled to RT, quenched by dropwise addition of water (5 mL) and extracted with 2:1 chloroform/isopropanol (3×10 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a yellow semi-solid which was slurried in acetonitrile (3 mL). The precipitate was collected by filtration to furnish the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta 2.29 (3H, s), 2.56 (3H, s), 6.79-6.93 (2H, m), 6.93-6.95 (1H, m), 7.48 (1H, dd, J=8.43, 1.66 Hz), 7.78 (1H, d, J=8.35 Hz), 9.07 (1H, d, J=1.42 Hz); LC-MS: m/z=+317.95/319.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>CN(C=O)C.O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (0.78 g, 2.5 mmol) in 8 mL of DMF was added maleic anhydride (0.266 g, 2.7 mmol), and the mixture was heated with stirring in a 70° C. oil bath for 2.5 hours. The resulting suspension was cooled to room temperature and then diluted with water. The solid was collected, washed sequentially with a mixture of toluene/DMF (1:1), water, and IPA. The solid was dried in vacuo at 60° C. for 16 hours to afford 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.87 g, 86%) as a pale yellow powder, mp 224-225° C. (decomposition with gas evolution).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)n1
Yield: 38.7 %

Procedure:
A suspension of 1.11 g (0.0028 mol) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 80 ml of tetrahydrofuran was treated with 7.6 ml (0.056 mol) of dipropylamine. After stirring at reflux for 24 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.50 g (39%) of 7-chloro-3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 123-125°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].[NH:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:12]([C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[NH:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:12]([C:22]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an aqueous solution containing 6.80 g of H-Gly-OH and 9.20 g of sodium hydrogen carbonate, under ice-cooling condition, was added 120 ml of THF solution containing 27.5 g of Boc-Ser(Bzl)-OSu, and the mixture was stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To a stirred solution of the 1-benzyl-2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (109.0 g, 251 mmol) in CH2Cl2 (1000 mL) under N2 at −78° C. was added BBr3 (1M in CH2Cl2, 302 mL), dropwise, over 1.5 h. After the addition, the reaction was warmed to 0° C. and stirred for 2.5 h then warmed to rt. After a total of 5 h the reaction mixture was cooled to 0° C. and quenched with water (250 mL). The mixture was stirred overnight then rotovap'd to a residue. The residue was partitioned between EtOAc (1500 mL) and H2O (500 mL). The layers were shaken, separated, and the organic layer was washed with H2O (2×250 mL), brine (2×250 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give a viscous black goo (114 g). The residue was dissolved in CHCl3 and flashed on silica (2000 g). The column was eluted with hexane and 8% EtOAc/Hexane. The product was collected, filtered, rotovap'd and the residue triturated with hexane then dried to give the product as an off-white solid (89.2 g, 213 mmol, 85%) with mp 96-100° C. 400mg of the crude solid was recrystallized from hexane to give desired product as an off-white solid (311 mg) with mp 97-100° C.; 1H NMR (DMSO-d6) δ 0.73 (t, J=6.7 Hz, 3H), 1.10-1.20 (m, 4H), 1.51-1.60 (m, 2H), 2.67 (t, J=7.3 Hz, 3H), 5.29 (s, 2H), 6.82 (d, J=7.2 Hz, 2H), 7.04-7.20 (m, 7H), 7.30-7.35 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.73-7.78 (m, 3H); IR (solid) 3380, 2920, 1610, 1200, 740 cm−1; mass spectrum [ES], m/z 420 (M+H)+;
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>CO>[CH:1]([N:14]1[CH2:17][CH:16]([NH:24][CH3:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN
Solvent: CO
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 67.9 %

Procedure:
1-Benzhydryl-3-(methylamino)azetidine was prepared under the conditions of Example 9, but starting with 50 g of 1-benzhydryl-3-(methanesulphonyloxy)-azetidine and 48.9 g of methylamine in 250 cm3 of methanol. 27 g of 1-benzhydryl-3-(methylamino)azetidine are obtained in the form of a colorless solid, melting point 75° C.