Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]4[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]4)=[CH:22][CH:21]=3)=[C:16]([O:38]C)[CH:15]=2)[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH2:8][C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]4[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]4)=[CH:22][CH:21]=3)=[C:16]([OH:38])[CH:15]=2)[CH:13]=1
Reactant: COc1cc(-n2cc(N)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-n3cc(N)cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 190 °C

Procedure:
As described in GENERAL METHOD 3-1, thiophenol (0.02 mL, 0.23 mmol) was added to a microwave vial containing 6-(4-(4-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (100 mg, 0.23 mmol) and K2CO3 (31.7 mg, 0.23 mmol) and NMP (2 mL). The microwave vial was evacuated and filled with N2 (2×). The reaction mixture was heated in a microwave reactor at 190° C. for 20 min, then filtered through celite (pre-packed filter funnel) with methanol. The filtrate was acidified to pH 3 using 1 M HCl aqueous solution and then adsorbed onto a methanol conditioned SCX column. The column was washed several times with methanol then eluted with 2 N ammonia in methanol solution. The eluent was collected, concentrated in vacuo, then purified by preparative HPLC under basic conditions to give 5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (50 mg, MS: 422.26 [M+H+]; LCMS Rt=0.43 min (LCMS method Q); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (d, J=10.11 Hz, 1H), 7.49 (d, J=8.59 Hz, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.18 (dd, J=8.59, 2.53 Hz, 1H), 7.12 (d, J=2.02 Hz, 1H), 6.89 (d, J=9.60 Hz, 1H), 4.77-4.93 (m, 1H), 2.92 (s, 3H), 1.61 (dd, J=12.38, 3.28 Hz, 2H), 1.33 (t, J=12.38 Hz, 2H), 1.27 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:46])=[C:20]([C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[C:28]3[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClCCl.Cl.[N:58]1[CH:63]=[CH:62][C:61]([CH2:64][C:65](Cl)=[O:66])=[CH:60][CH:59]=1>O>[Cl:46][C:19]1[C:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[N:7][C:2]([NH:1][C:65](=[O:66])[CH2:64][C:61]3[CH:62]=[CH:63][N:58]=[CH:59][CH:60]=3)=[CH:3][CH:4]=2)=[CH:44][CH:43]=[C:42]([Cl:45])[C:20]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([CH3:33])[CH:29]=[C:28]2[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: O=C(Cl)Cc1ccncc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(=O)Cc5ccncc5)nc4)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
To a mixture of 8-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (90 mg), triethylamine (56 mg) and dichloromethane (2 ml) was added 4-pyridylacetyl chloride hydrochloride (53 mg) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature and allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(4-pyridylacetamido)pyridin-3-yl]acryloylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (10 mg) as an amorphous powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[N:6][CH:7]=1.[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:35].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9]([NH:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:16]([CH3:15])[C:17](=[O:35])[CH2:18][CH2:19]3)[CH:3]=1)=[O:14]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)C(=O)Nc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(-c3cncc(NC(=O)C(C)(C)C)c3)ccc21
Temperature: 120 °C
Yield: 74.3 %

Procedure:
A microwave vial was charged with N-(5-bromopyridin-3-yl)pivalamide (0.2 g, 0.778 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) (0.246 g, 0.856 mmol) and DMF (4 mL). The reaction mixture was purged with Argon; then, bis(triphenylphosphine)palladium(II)chloride (0.055 g, 0.078 mmol), followed by 1N aqueous Na2CO3 solution (2.33 mL, 2.33 mmol) were added and the reaction was heated in the microwave at 120° C. for 5 min. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2×20 mL). The resulting filtrate was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.195 g, 74%) as a white solid. MS: 338.2 (M+H+).
Reaction SMILES: CCCCCC.[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([S:29]([N:20]2[C:17]3=[N:18][CH:19]=[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=4)[CH:15]=[C:16]3[CH:22]=[CH:21]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(F)c3)cnc21
Yield: 92.4 %

Procedure:
2.5 M solution of n-Bui in hexane (2.47 mL, 6.18 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of azaindole 7 (1.088 g, 5.13 mmol) in THF (5.5 mL). After the mixture was stirred for 20 min at −78° C., neat PhSO2Cl (0.785 mL, 6.2 mmol) was added dropwise. The mixture turned brown. Stirring at −78° C. was continued for 0.5 b. Cooling bath was removed, the mixture was stirred at r.t. overnight, and separated between AcOEt:saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (2×5 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated, and separated by means of SGC with hexane:AcOEt as eluent in gradient to afford 12 (1.6705 g, 92%) as white solid. 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=4.0 Hz, 1H), 7.08 (dddd, J=8.4, 8.0, 2.5, 1.1 Hz, 1H), 7.25 (ddd, J=9.9, 2.5, 1.7 Hz, 1H), 7.33 (ddd, J=7.8, 1.7, 1.1 Hz, 1H), 7.43 (ddd, J=8.0, 7.8, 6.0 Hz, 1H), 7.47-7.53 (m, 2H), 7.57-7.62 (m, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 8.21-8.26 (m, 2H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]C)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>CO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate (3.84 g, 14.53 mmol) and NaOH (0.87 g, 21.79 mmol) in 15 mL of MeOH and 5 mL of water was stirred at room temperature for 3 hours. The volatiles were removed in vacuo to give 1-(4-nitrophenyl)piperidine-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2N)CC1
Yield: 99.3 %

Procedure:
To a solution of 4,6-dichloro-5-aminopyrimidine (1 g, 6.1 mmol) in TEA (2 mL) and toluene (10 mL) was added 1-Boc-piperazine (2.3 g, 12.3 mmol). The mixture was refluxed for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product 4-(5-amino-6-chloropyrimidin-4-yl)-piperazin-1-carboxylic acid tert-butyl ester (1.9 g, 99%). 1H NMR (CDCl3, 400 Hz) δ 8.16 (s, 1H), 3.87 (s, 2H), 3.56 (m, 4H), 3.29 (m, 4H), 1.49 (s, 9H). MS (ESI+) [M+H]+ 314.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl-].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.[CH3:35][N:36]([CH2:38][CH:39]1[CH2:44][CH2:43][C:42](=O)[CH:41]=[C:40]1[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=1)[CH3:37]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[C:42]2/[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH:39]([CH2:38][N:36]([CH3:37])[CH3:35])[CH2:44][CH2:43]/2)=[CH:33][CH:34]=1
Reactant: COc1cccc(C2=CC(=O)CCC2CN(C)C)c1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(C2=C/C(=C/c3ccc(Cl)cc3)CCC2CN(C)C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
21.6 g potassium tert-butylate and 65 g 4-chlorobenzyltriphenylphosphonium chloride were suspended in 800 ml analytical grade toluene under a nitrogen atmosphere at room temperature and the suspension was then stirred at 70° C. for one hour. 11.5 g 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone in 100 ml analytical grade toluene were added at this temperature and the mixture was stirred at 70° C. for 3 days. The mixture was quenched with 500 ml water. The phases were separated and the aqueous phase was washed 3 times with 200 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from the solvent in vacuo. The solid which had precipitated out was filtered off and washed with diiso-ether. The combined organic phases were freed from the solvent in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/methanol=9/1. 5.2 g E-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine base were obtained as the first product fraction. To prepare the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 4.7 g (27.6% of theory) of the title compound 46 were obtained in this way in the form of white crystals. 3.5 g Z-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine base were obtained as the second product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 3 g (17.6% of theory) of the title compound 41 were obtained in this way in the form of white crystals.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH-].[Na+]>ClCCl.O>[N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH:20][C:27]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][N:21]=5)=[O:28])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 101A (59 mg, 0.206 mmole) was dissolved in anhydrous dichloromethane (2.0 mL). To the solution was added 2-pyrazine carboxylic acid (51 mg, 0.412 mmole), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (79 mg, 0.412 mmole) and 1-hydroxybenzotriazole hydrate (28 mg, 0.206 mmole). The mixture was stirred at room temperature overnight then diluted with water. The pH of the mixture was was adjusted to pH 9 with 1 N NaOH and extracted three times with dichloromethane. The combined organic layers were concentrated to give the crude product. The crude product was purified by column chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 9.81 (s, 1H) 9.54 (d, J=1.53 Hz, 1H) 8.83 (d, J=2.44 Hz, 1H) 8.66 (d, J=2.14 Hz, 1H) 8.58-8.63 (m, 1H) 7.94 (d, J=8.85 Hz, 1H) 7.52 (dd, J=8.85, 2.14 Hz, 1H) 3.52-3.62 (m, 1H) 2.74-2.84 (m, 1H) 2.61-2.72 (m, 2H) 2.24-2.41 (m, 6H) 1.55-1.64 (m, 4H) 1.40-1.52 (m, 2H). MS: (M+H)+=394.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH2:21]CC)[CH2:15][CH2:16][C:17](OC)=[O:18].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].N>CCOCC.CO>[CH3:25][Si:2]([CH3:1])([CH3:24])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[O:18]
Reactant: CCC[C@H](CCC(=O)OC)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CC(C)C[Al+]CC(C)C
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: C[C@H](CCC=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -95 °C
Yield: 92 %

Procedure:
A 3.79 g amount of the compound (4-6), methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-heptanoate was taken in a 300 ml eggplant-shaped flask, 100 ml of hexane was added, and the solution was stirred and cooled to -95° C. Thereafter 12.3 ml of a hexane solution (0.93 mol/liter) of diisobutylaluminum hydride was added and the solution stirred for 1 hour. A 100 ml amount of methanol was used to break down the excess reducing agent, then 30 ml of a saturated aqueous solution of ammonia chloride and 50 ml of ether were added and the solution was stirred at room temperature for 1 hour. The insolubles were removed by filtration by Celite, then the solution was separated and the aqueous layer was extracted by ether. The organic layer was washed two times by saturated saline in an amount of 50 ml, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 4.07 g. This was purified by a silica gel column (Merck gel: 300 g, hexane/ethyl acetate=50/1) to obtain the desired product (4-7), (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-pentanal in an amount of 3.17 g (yield 92%).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][Cl:7].C(OCC)(=O)C.O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1([S:36][CH3:37])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[S:25]1>CN(C)C=O>[Cl:7][CH2:6][CH2:5][CH2:4][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1([S:36][CH3:37])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[S:25]1
Reactant: ClCCCBr
Reactant: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCl)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.5 g) in dimethylformamide (10 ml), 3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-2-methylthio-3-oxo-2H-1,4-benzothiazine (3.5 g, compound No. 8) dissolved in dimethylformamide (5 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 10 minutes at room temperature. 1-Bromo-3-chloropropane (1.9 g) is added to the reaction mixture, and the mixture is stirred for 1 hour at 50°-60° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 4.0 g (93.4%) of the titled compound.
Reaction SMILES: Br.C1C2(CCN=C(N)N2)CCC1.[OH:13][C@@H:14]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:15][N:16]1[C:21]2([CH2:25][CH2:24]CC2)[CH2:20][CH2:19][N:18]2[C:26](=[O:36])[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[N:29]=[C:17]12>>[O:13]=[C:14]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:15][N:16]1[C:21]2([CH2:24][CH2:25]2)[CH2:20][CH2:19][N:18]2[C:26](=[O:36])[CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:29]=[C:17]12
Reactant: O=c1cc(-c2ccncc2)nc2n1CCC1(CCCC1)N2C[C@@H](O)c1ccccc1
Agent: Br
Agent: NC1=NCCC2(CCCC2)N1
Product: O=C(CN1c2nc(-c3ccncc3)cc(=O)n2CCC12CC2)c1ccccc1

Procedure:
A solution of 15.91 g (0.15 mol) of cyclopentylideneacetonitrile in 170 ml of an aqueous ammonia solution (29%) and 57 ml of methanol was heated at 100° C. in a sealed tube for 24 h. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 90/10 to afford 12.15 g of the product as a colorless oil. 3.2 Tert-butyl 1-(cyanomethyl)cyclopentylcarbamate The product was obtained by analogy with the method described in step 1.2 and using (1-aminocyclopentyl)acetonitrile. The compound was used as such in the next step. 3.3 Tert-butyl 1-(2-aminoethyl)cyclopentylcarbamate To a suspension of 8.48 g (223.63 mmol) of lithium aluminum hydride in 687 ml of diethyl ether at 0° C. was added dropwise 16.7 g (74.54 mmol) of tert-butyl 1-(cyanomethyl)cyclopentylcarbamate dissolved in 344 ml of diethyl ether. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 1 h. The reaction mixture was diluted with 100 ml of diethyl ether at 0° C. and treated with excess of a saturated aqueous solution of sodium sulfate. Further solid sodium sulfate was added and the organic phase was filtered to remove salts. The solvent was evaporated to dryness to give 13.83 g of product as an oil. 3.4 1-(2-Aminoethyl)cyclopentanamine hydrobromide (1:2) The product was obtained by analogy with the method described in step 1.6 and using tert-butyl 1-(2-aminoethyl)cyclopentylcarbamate. The compound was used as such in the next step. Mp: 194-196° C. 3.5 6,8-Diazaspiro[4.5]dec-7-en-7amine hydrobromide (1:1) The product was obtained by analogy with the method described in step 1.7 and using 1-(2-aminoethyl)cyclopentanamine hydrobromide (1:2). The compound was used as such in the next step. 3.6 8′-Pyridinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one The product was obtained by analogy with the method described in step 1.8 and using 6,8-diazaspiro[4.5]dec-7-en-7amine hydrobromide (1:1). The compound was used as such in the next step. Mp: 241-243° C. 3.7 1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(1:1) (hydrochloride) The product was obtained by analogy with the method described in step 1.9 and using 8′-pyridinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]-pyrimidin]-6′(1′H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:13])[CH:11]=[CH2:12].N12CCN(CC1)CC2>[OH-].[Na+]>[O:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:11]([C:10]#[N:13])[CH2:12]1
Reactant: C=CC#N
Reactant: O=Cc1ccccc1O
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: N#CC1=Cc2ccccc2OC1
Temperature: 90 °C

Procedure:
A microwave vessel was charged with 2-hydroxybenzaldehyde (Aldrich, 3.0 mL, 28.6 mmol), acrylonitrile (9.4 mL, 143 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.80 g, 7.2 mmol), and heated in a microwave Personal Chemistry at 90° C. for 13 hours. Sodium hydroxide (1N, 200 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL), and the combined organic layer washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-20% ethyl acetate in hexane providing the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.88 (d, J=1.36 Hz, 2H), 6.90 (d, J=8.14 Hz, 1H), 7.01 (td, J=7.46, 1.01 Hz, 1H), 7.30 (m, 2H), 7.58 (s, 1H). MS (DCI) m/z 175.05 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]([OH:16])=O)[CH3:2].Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:14]([C:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:7][C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: CCc1onc(-c2ccccc2)c1C(=O)O
Reactant: NCCCCl
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCCl
Yield: 80.2 %

Procedure:
A solution of 3.1 g of 5-ethyl-3-phenylisoxazole-4-carboxylic acid (prepared as described in J. Org. Chem. 1985, 50, 5660-5666), 2.94 g of 3-chloropropylamine hydrochloride, 2.62 mL of 92% diethyl cyanoposphonate and 4.38 mL of triethylamine in 50 mL of anhydrous dimethylformamide was stirred at room temperature for 3 hours, poured into 500 mL of water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography (ethyl acetate-petroleum ether 3:7) to give 3.35 g (73%) of the title compound. M.p. 75-76° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of trans-4-aminocyclohexanol (7.90 g., 68.5 mmol) in acetonitrile (150 mL), was added cesium carbonate (51.4 g., 157.5 mmol) and benzyl bromide (18.2 g., 143.8 mmol). The solution was stirred at ambient temperature for 16 hours. The solution was complete by LC-MS and the mixture filtered through a frit, washed with additional acetonitrile, and condensed under reduced pressure. The solid was partitioned between water and dichloromethane (500 mL) and dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (17.14 g, 85%). ES-MS (m/z) 296.5 [M+1]+.