Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Br[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>O1CCOCC1.[Cu]I.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Brc1cccc(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Yield: 76.3 %

Procedure:
A mixture of 3-bromobenzoyl chloride (10.0 g, 45.6 mmol), 2-bromoaniline (7.91 g, 46 mmol), Cs2CO3 (30 g, 92 mmol), CuI (0.437 g, 2.3 mmol) and 1,10-phenanthroline (0.829 g, 4.6 mmol) in anhydrous 1,4-dioxane (110 ml) was heated at 120° C. for 8 h. After cooling to RT, the mixture was poured into ethyl acetate (300 ml), worked up with water (250 ml). The aqueous solution was extracted with dichloromethane (300 ml). The organic phase was collected, combined, and dried over Na2SO4. Purification by a short silica gel column (hexanes/ethyl acetate 3:1) gave a solid which was washed with hexanes to give a light yellow solid 1 (9.54 g, 76% yield).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1>O1CCCC1>[CH:16]1[CH:17]=[C:18]2[C:13](=[C:14]([S:19]([N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7]3)(=[O:21])=[O:20])[CH:15]=1)[CH:12]=[CH:11][N:10]=[CH:9]2
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: C1CNCCNC1
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2cnccc12)N1CCCNCC1
Temperature: -5 °C
Yield: 41.1 %

Procedure:
Homopiperazine (3.413 g) was dissolved in tetrahydrofuran (57 ml) with stirring. After cooling the solution to −5° C., 5-isoquinolinesulfonyl chloride hydrochloride (3.00 g) was added while maintaining the internal temperature at 10° C. or less. The mixture was stirred at 5° C. or less for four hours. The reaction mixture was allowed to stand to reach room temperature and filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure, followed by the addition of ethyl acetate (57 ml), water (17 ml), and 3 N hydrochloric acid aqueous solution (6.4 ml). The mixture was separated into layers to obtain a water layer. After washing the water layer with ethyl acetate (7 ml), water (6 ml), ethyl acetate (57 ml), and 6 N sodium hydroxide aqueous solution (3 ml) were added to separate the mixture into layers and obtain an organic layer. The organic layer was concentrated under reduced pressure and the residue was dried under reduced pressure to obtain fasudil (1.36 g). The yield was 41%. The fasudil is processed by the method described in JP-A-9-71582 to obtain fasudil hydrochloride.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C@H:15]1[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][N:16]1[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:16]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C@@H:15]3[CH3:14])=[CH:28][CH:27]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: C[C@H]1CN(C)CCN1c1ccc(N)cc1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)C[C@@H]3C)cc2)nc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (420 mg), 4-[(2S)-2,4-dimethylpiperazin-1-yl]aniline (392 mg), diisopropylethylamine (665 μL), and dioxane (8.4 mL) was stirred at 110° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=95:5) to obtain 5-chloro-3-({4-[(2S)-2,4-dimethylpiperazin-1-yl]phenyl}amino)-6-ethylpyrazine-2-carboxamide (560 mg) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)N4CCOCC4)cc3)nc2c1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 239 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-morpholinylcarbonylbenzaldehyde. [M+H]+ calcd for C29H29N5O3: 496.24; found: 496.25.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[F:30][C:29]([F:32])([F:31])[C:26]1[N:27]=[CH:28][C:23]([O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH:5]=[C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)nc3)c2)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (0.200 g), 5-bromo-2-(trifluoromethyl)pyridine (0.156 g, 1.00 equiv), cesium carbonate (0.450 g, 2.00 equiv), and tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.019 g, 0.074 equiv) in toluene (3 mL, 0.2 M) was heated to reflux for 12 h. Additional catalyst (0.02 g) and 5-bromo-2-(trifluoromethyl)pyridine (0.200 g) was added and the mixture was refluxed for an additional 6 h. The reaction was allowed to cool to room temperature and filtered through Celite washing with ethyl acetate. Water was added and the mixture was extracted with ethyl acetate (2×). The combined organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/dichloromethane) to give the title compound as a white solid (0.141 g, 47% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (9H, s), 2.32 (2H, t, J=5.6 Hz), 2.44 (2H, t, J=5.6 Hz), 3.41 (2H, t, J=5.8 Hz), 3.50 (2H, t, J=5.8 Hz), 6.32 (1H, s), 6.87-6.96 (2H, m), 7.06 (1H, d, J=7.6 Hz), 7.32-7.39 (2H, m), 7.62 (1H, d, J=8.6 Hz), 8.46 (1H, d, J=2.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2[N:10]=N[CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CC(C)=NC=1Cl)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[N:10][C:16]([CH3:17])=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1ccc(C)nc1Cl
Product: CCOC(=O)c1oc2nc(C)ccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH3:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1)CCN2Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Into a 200 mλ pressure resistant reactor (autoclave) equipped with a stirrer, 20 g (0.084 mol) of 1-benzyl-5-formylindoline and 100 mλ of ethanol were charged, and the interior of the reactor was flushed with nitrogen. 2 g of 10% Pd/C was introduced, and the reactor was closed, whereupon hydrogen was introduced from a hydrogen supply pipe and reacted at 80° C. for 6 hours while adjusting the initial pressure of hydrogen in the reactor to be 6 2 kg/cm. Upon confirming the ceasing of absorption of hydrogen, the reaction was terminated. Then, the reaction solution was cooled to room temperature, and the hydrogen was released, and the palladium catalyst (10% Pd/C) was collected by filtration, and ethanol was distilled off under reduced pressure to obtain a colorless liquid as the residue. The obtained liquid was subjected to vacuum distillation to obtain 9.5 g of 5-methylindoline having a boiling point of from 56 to 57° C./0.3 mmHg. The yield was 85% (based on 1-benzyl-5-formylindoline).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH:7](=[N:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)CCN
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: CN(C)CCN=Cc1ccccc1

Procedure:
A solution of 88.0 g of N,N-dimethylethylenediamine in 150 ml. of benzene is treated with a solution of 106 g of freshly distilled benzaldehyde in 150 ml. of benzene. This mixture is stirred and refluxed for 2 hours while collecting 22 ml. of an aqueous layer in a Dean-Stark tube. The solvent is then distilled and the residue fractionated to give 156 g of distillate, boiling point 98°-100° C. at 4 mm. of Hg.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)[CH:9]=[CH:8]2>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:15][CH2:16][C:17]([CH3:1])([OH:20])[CH2:18][CH2:19]1)[CH:9]=[CH:8]2
Reactant: C[Mg]Br
Reactant: O=C1CCC(n2ccc3cc(Br)ccc32)CC1
Solvent: C1CCOC1
Product: CC1(O)CCC(n2ccc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methylmagnesium bromide (1.4 M solution in toluene/THF) (3.667 ml, 5.134 mmol) was added dropwise to a cooled solution (at 0° C.) of intermediate D30 (0.5 g, 1.711 mmol) in THF (20 ml) under a N2 atmosphere. The resulting reaction mixture was warmed to room temperature and further stirred for 4 h. After cooling in an ice bath, the mixture was carefully quenched with NH4Cl (aqueous sat. solution), and was subsequently extracted with DCM. The organic layer was separated, dried (Na2SO4), and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-30% EtOAc/heptane as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield cis-D33 (0.096 g, 18.2%) and trans-D33 (0.12 g, 22.7%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25](OCC)=[O:26])[C:4]1=[O:30])[CH3:2].[NH3:31]>CO>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6][CH:5]([CH2:24][C:25]([NH2:31])=[O:26])[C:4]1=[O:30])[CH3:2]
Reactant: CCOC(=O)CC1N=C(c2ccccc2)c2cc(OC)c(OC)cc2N(CC)C1=O
Reactant: N
Solvent: CO
Product: CCN1C(=O)C(CC(N)=O)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 0 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
Stir at 0° C. under an inert atmosphere for 48 hours, 70 mg (0.17 mmol) of ethyl (1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)acetate (IIbv) and 1.5 ml of methanol at 35% molar saturation with NH3. Evaporate to dryness. Purify by silica chromatography (dichloromethane 9/methanol 1). Recrystallize in ether. One obtains 12 mg of the abovenamed product as a white powder. Yield: 17%. M: 105–107° C. 1H-NMR (CDCl3, 300 MHz): d 1.10 (t, 3H, CH3), 3.02–3.09 (m, 1H —CH2), 3.22–3.29 (m, 1H —CH2), 3.75 (s, 1H, OCH3), 3.98 (s, 1H, OCH3), 4.01 (AB system, ? d=0.67, JAB=13.9, 2H, —NCH2), 4.13 (t, 1H, CH), 5.52 (s, 1H exchangeable NH2), 6.43 (s, 1H exchangeable NH2), 6.67 (s, 1H Ar), 6.85 (s, 1H Ar), 7.38–7.47 (m, 3H Ar), 7.59–7.62 (m, 2H Ar).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:29]=2)=[CH:33][CH:32]=1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1ccc(S)cc1
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SCc2ccncc2)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 4-(bromo-methyl)pyridine hydrobromide (62.5 mg, 0.25 mmol), N,N,N-tributyl-1-butan-aminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Si:29]([N:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:32])[CH3:31]
Reactant: C1=C(c2cnc3[nH]ccc3c2)CCC(N2CCCOCC2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C3=CCC(N4CCCOCC4)CC3)cnc21
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a stirred solution of azaindole (XXVa-101) (12.65 g, 42.5 mmol) in DMF (120 mL) was added 60% NaH dispersion in mineral oil (2.04 g, 51.0 mmol) portionwise over 3 min. After 15 min, tert-butyldimethylchlorosilane (8.33 g, 55.3 mmol) was added and the mixture stirred for a further 66 h. The mixture was diluted with EtOAc (150 mL) and saturated NaHCO3 solution (100 mL) and partitioned. The aqueous layer was extracted with EtOAc (4×150 mL) and CH2Cl2 (100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to yield a honey coloured viscous oil. This was purified by means of SGC using hexane:CH2Cl2 (gradient elution from 100:0 to 0:100, v/v) followed by CH2Cl2:MeOH (gradient elution from 100:0 to 90:10, v/v) to afford the silylated azaindole (XXVIIa-101) (15.37 g, 87%). 1H NMR (400 MHz, CDCl3) δ 0.62 (s, 6H), 0.92 (s, 9H), 1.68 (m, 1H), 1.87-1.93 (m, 2H), 2.05-2.10 (m, 1H), 2.18-2.26 (m, 1H), 2.36-2.43 (m, 1H), 2.57-2.63 (m, 2H), 2.83-2.86 (m, 5H), 3.75 (t, J=4.7 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 6.02-6.05 (m, 1H), 6.49 (d, J=3.5 Hz, 1H), 7.21 (d, J=3.5 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H).
Reaction SMILES: O([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1.[BrH:16]>C(Cl)(Cl)Cl>[BrH:16].[Br:16][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: c1ccc(OCCN2CCCCC2)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: BrCCN1CCCCC1
Yield: 79 %

Procedure:
15 g of the 1-(2-phenoxyethyl)piperidine thus obtained was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled, added with 20 ml of chloroform and then the chloroform layer was separated. The hydrobromic acid layer was condensed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 15.1 g of 1-(2-bromoethyl)piperidine hydrobromide having a melting point of 89° C. to 91° C. in a yield of 79%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][C@@H:20]([CH2:22][NH2:23])[CH2:19][O:18]1.C(O)C>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][C@H:20]3[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CN)O1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)OC[C@H](CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)O1
Yield: 96.1 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (11.00 g, 38.26 mmol) was reacted with (S)-2,2-dimethyl-[1,3]dioxolane-4-methanamine (5.81 g, 57.4 mmol) according to the method described in Part A of Examples 125–135. When the reaction was complete, it was concentrated under reduced pressure, and the residue was stirred with water (100 mL). The resulting solid was isolated by filtration, mixed twice with ethanol and concentrated under reduced pressure. The solid was then triturated with diethyl ether, isolated by filtration, and dissolved in dichloromethane. An insoluble impurity was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 14.05 g of (S)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13](OS(C(F)(F)F)(=O)=O)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1.[Cl:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:35]([CH3:42])=[C:36]2[C:41]=1[O:40][CH2:39][CH2:38][CH2:37]2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([C:13]2[C:6]3[C:7]4[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=4[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5]=3[N:16]=[C:15]([CH3:17])[C:14]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:35]([CH3:42])=[C:36]2[C:41]=1[O:40][CH2:39][CH2:38][CH2:37]2
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(Cl)c2c1CCCO2
Reactant: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1-c1cc(Cl)c2c(c1C)CCCO2
Temperature: 90 °C
Yield: 95.2 %

Procedure:
A mixture of ethyl 9-cyclopropyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (500 mg, 1.120 mmol), 2-(8-chloro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.415 g, 1.344 mmol), and Na2CO3 (0.356 g, 3.36 mmol) in 1,4-dioxane (8.8 ml) and water (2.2 ml) was degassed with N2 for 5 min, treated with Pd(Ph3P)4 (0.129 g, 0.112 mmol), degassed with N2 for 5 min, and then heated to 90° C. for 2 hours. The reaction was cooled to rt, diluted with water, extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-40% EtOAc/Hexane) gave ethyl 4-(8-chloro-5-methylchroman-6-yl)-9-cyclopropyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (510.8 mg, 1.066 mmol, 95% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00 (s, 1 H), 4.33-4.23 (m, 2 H), 4.03 (q, J=7.1 Hz, 2 H), 3.17-3.06 (m, 1 H), 2.80 (t, J=5.9 Hz, 2 H), 2.74-2.61 (m, 5 H), 2.17-2.06 (m, 2 H), 1.91-1.70 (m, 7 H), 1.65-1.57 (m, 2 H), 1.20-1.06 (m, 4 H), 0.98 (t, J=7.1 Hz, 3 H); LCMS (m/z) ES+=479 (M+1).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].C(N(CC)CC)C.O>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
1-benzoyl-5-amino-1H-indole (25 mg, 0.106 mmol) was dissolved in dichloromethane (1.0 ml) at room temperature and mesyl chloride (0.01 ml. 0.116 mmol) and triethylamine (0.016 ml, 0.115 mmol) were added. The solution was stirred at room temperature for 30 minutes to complete the reducing reaction. After pouring water (2 ml), dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate and then, purified through flash column chromatography (an eluent:ethyl acetate/n-hexane=1/2, v/v). As a result, the present compound (20 mg, productive yield 60%) was obtained.
Reaction SMILES: C(S([C:8]1[N:9]=[CH:10][C:11]2[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[C:15](=[O:21])[NH:14][C:12]=2[N:13]=1)(=O)=O)CCC.[CH3:22][O:23][CH2:24][CH2:25][CH:26]([NH2:31])[CH2:27][CH2:28][O:29][CH3:30].C(Cl)Cl.C(Cl)Cl.CO.CC(C)=O>ClCCCl>[CH2:19]([O:18][C:16]1[C:15](=[O:21])[NH:14][CH:12]2[N:13]=[C:8]([NH:31][CH:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])[N:9]=[CH:10][CH:11]2[CH:17]=1)[CH3:20]
Reactant: COCCC(N)CCOC
Reactant: CCCCS(=O)(=O)c1ncc2cc(OCC)c(=O)[nH]c2n1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CO
Product: CCOC1=CC2C=NC(NC(CCOC)CCOC)=NC2NC1=O
Yield: 44.3 %

Procedure:
A solution of compound 3B (50 mg, 0.16 mmol) and 3-methoxy-1-(2-methoxy-ethyl)-propylamine (140 mg, 0.96 mmol) in 1 ml DCE was heated to 85° C. for 72 hours. The reaction mixture was chromographed directly on a Supelco™ 2 g/12 ml silica column with gradient solvent of CH2Cl2 to a final solvent mixture of CH2Cl2:MeOH:acetone (94:3:3). Two additional chromatographies were required to provide 24 mg of 6-Ethoxy-2[3-methoxy-1 (2-methoxy-ethyl)-propylamino]-8,8a-dihydro-4aH-pyrido[2,3-d]pyrimidin-7-one (Example 1) at 86% purity as judged by MS/HPLC. M++337.