Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=O)[CH2:18][C:17]2=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Product: CCCCN1CCCN(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting butyl bromide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-butyl 8-chloro 1,2,4,5-tetrahydro 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = C4H9, R4 = C6H5) melting at 159°-161° C., upon recrystallisation in 50% ethanol.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].C([NH:32][OH:33])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:11]4=[O:26])[CH2:27][O:28][C:4]3=[CH:3][C:2]=2[O:33][N:32]=1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Reactant: CC(=O)NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.40 g, 2.7 mol) and acetohydroxamic acid (0.60 g, 8.0 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (2.60 g, 8.0 mmol). The reaction mixture was stirred at ambient temperature for 18 h and water was added. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with (ethyl acetate/hexanes (2/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.05 g, 5%): mp 190-192° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.54-8.52 (m, 1H), 7.79-7.73 (m, 1H), 7.35-7.20 (m, 5H), 7.08-6.96 (m, 3H), 6.15 (s, 2H), 5.09-4.85 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 164.2, 163.3, 158.7, 155.6, 149.9, 143.5, 137.6, 131.7, 129.4, 126.4, 124.5, 123.6, 123.1, 121.9, 116.8, 111.5, 109.9, 91.4, 81.0, 56.8, 45.3; MS (ES+) m/z 384.9 (M+1).
Reaction SMILES: [CH2:1](I)[CH3:2].CC(C)=O.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([N:13]1[CH2:2][CH2:1][N:10]([N:8]=[O:9])[CH2:11][CH2:12]1)[CH3:15]
Reactant: O=NN1CCNCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCN(N=O)CC1
Yield: 103.5 %

Procedure:
Ethyl iodide (8.13 g, 0.052 mole) was added to acetone (80 ml) containing N-nitroso piperazine (6.0 g, 0.052 mole) (prepared as described in U.S. Pat. No. 2,907,767) and anhydrous potassium carbonate (7.3 g, 0.052 mole). The mixture was heated under reflux for 24 hours, cooled, treated with water (50 ml) evaporated to 1/2 volume and extracted with ether (3×150 ml). The combined extracts were dried (K2CO3) filtered and evaporated in vacuo to yield N-ethyl-N'-nitrosopiperazine (7.71 g, 98%), as a straw coloured oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:35]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and cyclohexanecarbonyl chloride in the same manner as in Example 32.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1cccc(CCC(=O)Cl)c1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,3-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.016 mg (4.6%); MS m/z; 351.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06-3.10 (m, 2H); 3.17-3.21 (m, 2H); 3.73 (s, 3H); 3.79 (s, 3H); 6.82-6.84 (m, 1H); 6.90-6.92 (m, 1H); 6.95-6.99 (m, 1H); 7.75-7.77 (m, 1H); 7.80-7.82 (m, 1H); 8.14 (br s, 1H); 8.41 (s, 1H); HPLC (METHOD [A]): rt 11.49 min (94.5%)
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: COC(=O)C(C)(Br)c1cnccn1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1cnccn1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A DMF (15 mL) solution of sodium hydride (0.38 g, 9.4 mmol, 60%) was added to malononitrile (0.62 g, 9.4 mmol) in DMF (3 mL) at 0° C. After 10 minutes the intermediate from Step C (2.1 g, 8.6 mmol) was added. After stirring for 2 hours at room temperature the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate and the organic layer concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 8.85 (1H, s), 8.65 (1H, d, J=2.6 Hz), 8.58 (1H, s), 5.12 (1H, s), 3.81 (3H, s), 2.09 (3H, s). m/z=231.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(ccn2Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68.8 %

Procedure:
Indole-5-carboaldehyde (1.0 g) was dissolved in DMF (14 mL), and potassium hydroxide (460 mg) and 4-fluorobenzyl bromide (1.4 g) were sequentially added thereto under ice cooling. The mixture was stirred for 65 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (20% to 50% ethyl acetate/hexane), and the title compound (1.2 g) was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:1][C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Product: CCOC(=O)c1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-phenylthiazole-5-carboxylate and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (47.2 mg) with purity >90%. LCMS (pos) m/z 437.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 22.4 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and isopropylamine (44 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (48 mg, 0.13 mmol, yield 22%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CN(C)C=O.[CH2:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>O>[CH:1]([NH:4][CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])([CH3:3])[CH3:2]
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCC(C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of isopropylamine (5.65 g) and dimethylformamide (DMF, 5 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 25° C. for 15 h. The reaction mixture was poured into water (100 mL) and the bottom layer separated, washed with water (10 mL) and dried over sodium sulfate to provide N-isopropyl N-(2-trifluoromethyl-3,3,3-trifluoropropyl)amine (15 g): MS (m/e) 223 (M+, 1.2%), 208 (100%), 72 (7.8%); 1H NMR (CDCl3) 1.06 (d, J=6 Hz, 6H), 1.12 (m, 1H), 2.81 (m, 1H), 3.07 (m, 3H) ppm; 19F NMR −67.0 (d, J=9 Hz) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32]>>[CH3:26][C:4]1[N:3]=[C:2]([NH:32][C:28]2[O:27][CH:31]=[CH:30][N:29]=2)[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Reactant: Nc1ncco1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 2-chloro-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (25 mg, 0.06 mmol, Step-1, single enantiomer) and oxazol-2-amine (16 mg, 0.19 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CO.[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[CH:12][CH:13]=[CH2:14]>C(O)C>[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21]1[C:22]([NH2:23])=[N:4][C:3]([NH2:5])=[N:2][CH:24]=1)=[CH:12][CH:13]=[CH2:14]
Reactant: C=CC=Cc1cc(OC(C#N)=CNc2ccccc2)c(I)cc1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C=CC=Cc1cc(Oc2cnc(N)nc2N)c(I)cc1C

Procedure:
To a suspension of guanidine hydrochloride (3.10 g, 32.5 mmol) in 10 mL ethanol was added a solution of 25% NaOMe in methanol (7.0 mL, 32.5 mmol). The resulting solution was added to the crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-phenylamino-acrylonitrile of step 4, and the mixture was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (10% MeOH/methylene chloride+0.1% NH4OH), and recrystallized from EtOAc to give 2.1 g of 5-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-pyrimidine-2,4-diamine, MP=195-197° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[C:17]#[C:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)[CH3:23]
Reactant: C#Cc1ccc(Br)cc1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
LDA solution (2M) in THF (20.71 mL, 41.436 mmol) was added to a stirred solution of 1-bromo-4-ethynyl-benzene (3 g, 16.57 mmol) in dry THF (40 mL) at −70° C. and stirred for 30 min. Ethyl chloroformate (11.81 mL, 74.58 mmol) was added and the mixture was allowed to warm to ambient temperature. Stirring was continued for 2 h. The mixture was cooled, and quenched with saturated NH4Cl solution. THF was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified over normal silica gel column chromatography using EtOAc-hexane as eluting solvent to get (4-bromo-phenyl)-propynoic acid ethyl ester (2.9 g, 69.13% yield) as a light yellow liquid. GC-MS: 253 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.0 Hz, 3H). 4.28 (q, J=7.0 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: C[Mg]Br
Reactant: O=Cc1nc2ccc(F)cn2c(=O)c1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 9 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.3555 g, 8.691 mmol) in THF (86.91 mL) was added methyl-magnesium bromide 3 M in Et2O (4.345 mL, 13.04 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 1.5 h. After 1.5 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-7-fluoro-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92-8.97 (1 H, m), 8.14 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83-7.90 (1 H, m), 5.26 (1 H, d, J=6.7 Hz), 5.09 (1 H, qd, J=6.5, 6.3 Hz), 1.38 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=286.9 [M+1 (79Br)] and 289.0 [M+1 (81Br)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cncc(Br)c1
Product: CCOc1ccc(NC(=O)c2cncc(Br)c2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 5-bromonicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.11 (s, 1H), 9.11 (d, J=2.1, 1H), 8.88 (d, J=1.8, 1H), 8.80 (d, J=9.3, 1H), 8.42 (t, J=2.1, 1H), 7.75 (d, J=2.7, 1H), 7.34-7.30 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [CH2:1]([O:4][P:5]([CH2:11][C:12]([OH:14])=O)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[CH2:8]([O:7][P:5]([CH2:11][C:12]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:32]([O:31][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:38])=[O:14])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(CC(=O)O)OCC=C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: C=CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)OCC=C
Reaction time: 0.75 h

Procedure:
[Bis(2-propenyloxy)phosphinyl]acetic acid (7.0 g., 0.032 mol.) is dissolved in 200 ml. of acetonitrile and stirred in an ice bath under a drying tube. 1,1'-Carbonyldiimidazole (5.5 g., 0.032 mol.) is then added and the mixture is stirred for 45 minutes. L-Proline t-butyl ester (5.5 g., 0.032 mol.) is then added, the ice bath removed, and the mixture stirred overnight. The solution is then evaporated in vacuo and the residue taken up in ethyl acetate and washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, then dried (MgSO4) and evaporated to a viscous liquid (10.7 g., 89%). The product [Bis(2-propenyloxy)phosphinyl]acetyl-L-proline, tert-butyl ester is substantially pure by tlc (Rf =0.35, silica gel, ethyl acetate; several trace impurities).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(S(C)(=O)=O)C3)CC1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.070 g, 0.18 mmol) and triethylamine (0.052 ml, 0.37 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (0.015 ml, 0.19 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.004 g, 5%) as yellow solid. MS m/e: 439 (M+H+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH3:9])(C)(C)C.[ClH:14]>O1CCOCC1>[ClH:14].[CH2:10]([NH:7][CH2:8][CH3:9])[CH:11]=[CH2:12].[CH2:10]([NH:7][CH2:8][CH3:9])[CH:11]=[CH2:12]
Reactant: C=CCN(CC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCNCC
Temperature: 25 °C

Procedure:
At 10° C. 28.9 g allyl-ethyl-carbamic acid tert-butyl ester (156 mmol) are dissolved in 200 ml 4N HCl in dioxane and slowly warmed to room temperature. When the development of gas has ceased the mixture is warmed at 30° C. for 1 h. The mixture is concentrated under reduced pressure and crystallized from EtOH/TBME to yield the hydrochloric acid salt of allyl ethyl amine as white plates.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4].C([N:18]=[C:19]=[N:20]C1C=NC=CC=1)(C)(C)C>>[CH2:1]([NH:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:20][C:19]#[N:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCCCNC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-n-Butyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 96.0°-97.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[C:26]([CH:31]=O)=[N:27][CH:28]=[CH:29][CH:30]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:31][C:26]1[C:25]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)([CH3:24])[CH3:23])=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CCCCNCc1ncccc1C(C)(C)c1ccc(Cl)cc1)C(=O)OC(C)(C)C

Procedure:
Using General Procedure B, (4-amino-butyl)-methyl-carbamic acid tert-butyl ester, 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 were reacted to give [4-({3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-butyl]-methyl-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.24-1.32 (m, 2H), 1.33-1.42 (m, 11H), 1.65 (s, 6H), 2.20-2.24 (m, 2H), 2.79 (s, 3H), 3.08-3.12 (m, 2H), 3.26 (s, 2H), 7.05-7.08 (m, 2H), 7.21-7.26 (m, 3H), 7.84-7.87 (m, 1H), 8.46-8.48 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:35][CH2:36][OH:37]>>[CH3:33][N:2]([CH3:1])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:35][CH2:36][OH:37])[C@@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[C@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1
Reactant: OCCBr
Product: C[C@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1CCO
Yield: 40.6 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-((S)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (74 mg, 0.17 mmol) and 2-bromo ethanol (23 mg, 0.18 mmol) gave 7-cyclopentyl-2-{5-[(S)-4-(2-hydroxy-ethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 42%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)sc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)sc2cc(N)ccc21

Procedure:
A mixture of 6-nitro-3-methyl-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069-1076, 4.85 g, 23.1 mmol) and 10% palladium-on-carbon (491 mg, 0.461 mmol) in a mixture of MeOH (45 mL) and tetrahydrofuran (45 mL) is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 17 h. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and triturated with ethyl acetate/hexanes. Filtration then provides the title compound, mp 188-190° C.; MS (ESI+) for C8H8N2OS m/z 181 (M+H)+.