Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCC(C)(C)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a stirred solution of N-[4-(1,1-dimethylpropyl)phenyl]acetamide (Preparation 99, 12 g, 0.058 mol) in acetic anhydride (50 mL) at −5° C. was added HNO3 slowly. The reaction was maintained at 0° C. for 1 hour and then room temperature for 18 hours. The reaction was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (15 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(=S)=S>[OH:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1cc(-c2nc3ccccc3s2)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1cc(-c2nc3ccccc3s2)cc(OC)c1O
Yield: 78.7 %

Procedure:
A solution of 2-(3,4,5-trimethoxyphenyl)benzothiazole (4.0 g), aluminium trichloride (4.0 g) and carbon disulphide (75 cm3) was stirred at room temperature overnight. The reaction mixture was poured onto 20% hydrochloric acid (500 cm3) and extracted with ethyl acetate (3×50 cm3). The combined organic extracts were washed with water (2×250 cm3), dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethyl acetate to give 3.0 g (75.0%) of the desired product.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1>CS(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33][C:1]4[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=4)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN1c2ncc(Cc3cccc(O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 56.1 %

Procedure:
Resorcinol (0.082 g, 0.74 mmol) in dimethyl sulfoxide (1 mL) was treated with potassium tert-butoxide (1.0M in tetrahydrofuran, 0.15 mL, 0.15 mmol). The resulting stirred solution was treated with 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.050 g, 0.14 mmol) in dimethyl sulfoxide (1 mL) and the mixture was stirred an additional 16 hours. The mixture was diluted with ethyl acetate (50 mL) washed with brine, water, and brine (15 mL each). The organics were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) followed by crystallization from hexanes to give the title compound (0.031 g, 51%), m.p. 219°-220° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=[O:2].O=S(Cl)Cl.[CH3:17]O>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([O:8][CH3:17])=[O:7])=[O:2]
Reactant: O=Cc1cc(C(=O)O)ccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 7.599999904632568 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
3-formyl-4-hydroxybenzoic acid (Aldrich 633488, 20 g; 120.39 mmol; 1 eq.) was dissolved in MeOH (400 mL). The solution was cooled down to 0°. SOCl2 (26.20 mL; 361.16 mmol; 3 eq.) was added dropwise (addition took 60 min and the temperature of the reaction mixture increased to 7.6° C.). The reaction mixture was stirred at RT for 24 hours. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (500 mL) and washed with a saturated aqueous solution of NaHCO3 (300 mL), HCl 1N (300 mL) and brine (300 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (19.86 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 8.25-8.24 (d, J=2.33 Hz, 1H), 8.08-8.03 (dd, J=8.79 Hz, 2.33 Hz, 1H), 7.12-7.09 (d, J=8.75 Hz, 1H), 3.83 (s, 3H). LC/MS (Method B): 179.1 (M−H)−. HPLC (Method A) Rt 3.04 min (Purity: 91.6%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[C:15](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:13][C:14]1[C:15]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]3[S:9][CH:10]=[CH:11][N:12]=3)[CH2:6][CH2:5]2)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: c1csc(CN2CCNCC2)n1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
The resulting 2-(piperazin-1-ylmethyl)thiazole (supposedly 0.580 g, 3.18 mmol, 1 eq) was suspended in iPrOH (3.1 mL) and DIPEA (2.2 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.800 g, 3.18 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.750 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 2.65 (br s, 4H, piperazine N(CH2)2), 3.09 (m, 4H, piperazine N(CH2)2), 3.90 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.66 (d, J=3.0 Hz, 1H, thiazole 5-H), 7.72 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.90 mins-399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])/[C:10](=[CH:22]/[N:23]([CH3:25])[CH3:24])/[CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCOc2cc(Br)ccc21
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
8-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.0 g, 20.7 mmol) in dimethylformamide dimethylacetal (15 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (20 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (5.32 g, 86%). 1H NMR δ (ppm)(CDCl3): 7.73 (1 H, s), 7.61 (1 H, d, J=8.29 Hz), 7.29 (1 H, dd, J=8.29, 1.94 Hz), 7.18 (1 H, d, J=1.91 Hz), 4.28-4.21 (2 H, m), 3.14 (6 H, s), 2.77-2.70 (2 H, m).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[C:10]([OH:12])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:51])([CH3:50])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@@H:61]([NH2:68])[CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:50])([CH3:51])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@H:61]([CH:62]1[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1)[NH:68][C:10]([C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH:1]([CH3:2])[CH3:3])=[O:12])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40]
Reactant: CC(C)N1CCCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](N)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCCN1C(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-1-isopropyl-piperidine-2-carboxylic acid (0.497 g; 2.90 mmol) and HATU (1.65 g; 4.35 mmol) in DCM (100 mL) was cooled to 0° C. and (5R,8S)-7-[(S)-2-((S)-2-Amino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (1.65 g; 2.90 mmol) and DIPEA (2.98 mL; 17.4 mmol) were added. The reaction mixture was stirred for 3 h at room temperature quenched with saturated aqueous bicarbonate. The aq. phase was extracted twice with DCM, the combined organic phases dried with Na2SO4, filtered and the solvent was removed in vacuo. The product was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=1.62 min; M/z=629 [M+]; HPLC (method A3): Rt=5.01 min
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=CC=3)=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:16][CH:27]=[CH:26][C:19]=3[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccccc1N1CCN(c2ccncc2)CC1
Temperature: 4 °C
Reaction time: 2 h

Procedure:
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml) was treated with a M sodium hydroxide solution (1.65 ml) and stirring continued for a further 2 hours. The mixture was diluted with water (10 ml) and the resulting solution concentrated in vacuo. Water (20 ml) was added and then a M hydrochloric acid solution (1.65 ml). On cooling to 4° C., a solid precipitated. This mixture was concentrated in vacuo, the solid collected and washed with ice-water, then dried to give the title compound, 320 mg, as a solid: m.p. 294°-296° C.; NMR (d6DMSO+TFA) δ 8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)+ ; calculated for C19H21N3O4 : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 195 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.307 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 6′-(cyclohexyloxy)-5-fluoro-3,3′-bipyridin-2-amine (280 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (81.1 mg) as colorless crystals.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][O:21][C:20]3([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]3)[O:19]2)(=O)=O)=CC=1>CC(C)=O>[C:1]([S:3][CH2:17][CH:18]1[CH2:22][O:21][C:20]2([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)[O:19]1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC2(C1)OCC(COS(=O)(=O)c1ccc(C)cc1)O2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC2(C1)OCC(CSC(C)=O)O2

Procedure:
A stirred slurry of potassium thioacetate (1.14 g, 10 mmol) in a solution of the tosylate of Example L (4.14 g, 10 mmol) in acetone (30 ml) is refluxed under nitrogen for 5 hrs. The reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent is filtered, the solvent is removed using the rotary evaporator and the residue is chromatrographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.C[O:13][C:14](=O)[CH2:15][N:16]=[C:17]=[S:18]>N1C=CC=CC=1>[SH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]3[C:14](=[O:13])[CH2:15][NH:16][C:17]3=[S:18])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: COC(=O)CN=C=S
Solvent: c1ccncc1
Product: O=C1CNC(=S)N1c1ccc2nc(S)sc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Into a 13×100 mm screw cap Pyrex® vial were added 6-amino-1,3-benzothiazole-2-thiol (108 mg, 0.59 mmol), methyl-2-isothiocyanatoacetate (94.8 mg, 0.72 mmol), and pyridine (2 ml). The vial was purged with Ar, capped, and shaken in an oven at 60° C. for 8 h. The solution was concentrated, and the residue was triturated with Et2O to give a rusty brown powder (59 mg, 35%). 1H NMR (DMSO-d6) δ=4.27 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.61 (s, 1H), 10.40 (s, 1H), 13.86 (br s, 1H); ESIMS: m/z 280 (M−H); mp>266° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH:11]1[CH2:13][CH2:12]1)=[N+:2]=[N-:3].O=[C:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].C[O-].[Na+]>CO.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:15]([CH3:21])=[C:16]([C:17]([OH:19])=[O:18])[N:3]=[N:2]2)=[C:5]([CH:11]2[CH2:13][CH2:12]2)[CH:6]=1
Reactant: COC(=O)CC(C)=O
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-azido-4-chloro-2-cyclopropylbenzene (204 mg, 1.054 mmol) and methyl 3-oxobutanoate (0.341 ml, 3.16 mmol) in MeOH (2 ml) was added sodium methoxide (5M in MeOH) (1.264 ml, 6.32 mmol) dropwise and the mixture was stirred at RT for 2.5 h. The mixture was heated at 50° C. for 5 hrs and then left to stir at RT for 16 hrs. The resulting mixture was diluted with water, extracted with diethylether (×2) and the organic extracts were discarded. To the aqueous layer was added 6M HCl (aq) until acidic and this was extracted with diethyl ether. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an orange oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:6][OH:7].[OH-].[Na+:13]>O>[OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]([O-:11])=[O:10])[CH2:5][CH2:6][OH:7].[Na+:13]
Reactant: O=C(O)CN(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CN(CCO)CCO

Procedure:
N,N-Bis-(2-hydroxyethyl)aminoacetic acid (364.933 grams, 2.2144 moles) (this material is 99% pure; it contains 1% or 3.613 grams of H2O) is added with stirring to a cooled solution of pure sodium hydroxide (88.57 grams, 2.2144 moles) in pyrogen-free distilled water (400 ml.). The mixture is stirred until solution is effected. After reaching room temperature, the solution is stirred while enough pyrogen-free distilled water is added to make the total volume 1,000 ml. The solution is sterilized by filtration. This solution is 41% or 2.2144 molar in sodium N,N-bis-(2-hydroxyethyl)aminoacetate.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Brc1ncccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1ncccn1

Procedure:
Reaction of 2-bromopyrimidine with 1,3-diaminopropane in ethanol containing sodium ethoxide gives 2-(3-aminopropylamino)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[CH2:9][CH2:10][N:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: Nc1ccccc1N1CCN(C=O)CC1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=CN1CCN(c2ccccc2-n2cccc2)CC1
Yield: 71 %

Procedure:
A mixture of 4-(2-aminophenyl)piperazine-1-carbaldehyde (1.27 g, 6.2 mmol), 2,5-dimethoxytetrahydrofuran (1.13 g, 8.6 mmol) and concentrated acetic acid (4 mL) was heated 1.75 hours at reflux. The reaction mixture then was cooled in an ice-bath, diluted with water/ice and extracted with methylene chloride. The methylene chloride extract was washed with aqueous sodium hydroxide and then water, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (97.5/2.5) to give 4-(2-pyrrol-1-ylphenyl)piperazine-1-carbaldehyde (1.12 g, 4.4 mmol) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].Cl[C:33]1[C:42]2C(=CC=C(S(N[C@H]3CC[C@H](C(OCC)=O)CC3)(=O)=O)C=2)C(Cl)=CN=1>COCCOC.CC(N(C)C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:33][CH3:42])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@H](C(=O)O)CC3)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Temperature: 60 °C

Procedure:
trans-4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR59## Guanidine hydrochloride (273 mg, 2.86 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.82 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of ethyl trans-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (370 mg, 0.78 mmol) in DMA (10 mL) was added and the mixture heated at 90° C. for 3 h. The solvents were evaporated in vacuo, the residue was partitioned between Et2O (100 mL), aqueous NH4Cl (10 mL), and water (150 mL). The separated aqueous phase was extracted with Et2O (3×100 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using toluene-i-PrOH-0.880NH3 (100:0:0 to 90:10:0.05) as eluant to give ethyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (70 mg, 0.15 mmol).
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(Cl)Cl>[CH:1]1([C@@H:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 75 °C
Reaction time: 19 h

Procedure:
A solution of (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 116 mg) in methylene chloride (CH2Cl2, 4.0 mL) in a pressure glass tube was treated with the catalyst [Ru(p-cymene)(S—C3-TunePhos)Cl]Cl (8.5 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 60 bar pressure. The reaction mixture was stirred at 75° C. under this hydrogen pressure for 19 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 34.1% ee (67.05% of the first peak, (S)-20; 32.95% of the second peak, (R)-20) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with methylene chloride (CH2Cl2, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (107 mg) was analyzed by chiral HPLC analysis and result showed a 34.1% of enantiomeric excess favoring the first peak (67.05% of the first peak, (S)-20; 32.95% of the second peak, (R)-20).
Reaction SMILES: Cl[Si:2]([CH3:20])([CH3:19])[CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18].[CH3:21][C:22]1[CH-:26][C:25]([CH3:27])=[C:24]([CH3:28])[C:23]=1[CH3:29].[Na+]>O1CCCC1>[CH3:19][Si:2]([CH3:20])([CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18])[C:26]1[CH:25]([CH3:27])[C:24]([CH3:28])=[C:23]([CH3:29])[C:22]=1[CH3:21]
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reactant: Cc1[cH-]c(C)c(C)c1C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1=C(C)C(C)=C(C)C1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a light yellow solution of chlorodimethyl(2-methyl-4-phenyl-1H-indenyl)silane (9.40 g, 31.4 mmol, 1.00 eq.) in tetrahydrofuran (40 mL) at −30° C. was added sodium (tetramethylcyclopentadienide) (4.76 g, 33.0 mmol, 1.05 equiv.) in portions to give a cloudy orange solution. The reaction was allowed to warm to room temperature and stirred for 23 hours. The mixture was evaporated under vacuum leaving an orange residue. The residue was extracted with pentane (50 mL) and the extract was filtered to give a bright yellow solution and yellow solid. The solution was evaporated under vacuum to yield thick, orange oil. Yield 10.16 g (84%). 1H NMR (C6D6): δ 7.61 (d, 2H), 7.41 (m, IH), 7.31 (m, 4H), 7.19 (m, IH), 6.85 (s, IH), 3.60, (s, IH), 3.16 (br s, IH), 2.00 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H), 1.82 (s, 6H), −0.23 (s, 3H), −0.24 (s, 3H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1>>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=1
Reactant: Clc1ccncn1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Product: CCOC(=O)C1CCN(c2ccncn2)CC1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 32, 4-chloropyrimidine hydrochloride was reacted with ethyl piperidine-4-carboxylate to give ethyl 1-(4-pyrimidinyl)piperidine-4-carboxylate in 46% yield.