Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:18]1(=O)[C:30]2[C:22]([C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[CH:19]1.C([O:34]CC)C>C1COCC1>[CH2:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:29]1([OH:34])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:30]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nccn2Cc2ccccc2)c2ccccc2-c2ccccc21
Temperature: -20 °C

Procedure:
1.2 eq of n-butyllithium are added at −70° C. to N-benzylimidazole in THF. The mixture is allowed to warm to −20° C. in the course of one hour and is then again cooled to −70° C. After addition of 1 eq of fluorenone in THF, it is allowed to warm to RT in the course of 5 h. Aqueous work-up, extraction with EA, followed by subsequent drying of the organic phase over magnesium sulfate and evaporation of the solvents yields a solid, yellowish residue. Trituration with diethyl ether yields a solid, which is filtered off with suction.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C1CCN2C(=NCCC2)CC1>>[CH3:10][CH:8]([S:5]([NH:4][CH2:3][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:15][CH:16]=1)[CH3:1])(=[O:6])=[O:7])[CH3:9]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNS(=O)(=O)C(C)C)cc1
Yield: 72 %

Procedure:
Scheme Va, step C: {2-[4-(2-Aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.15 g, 0.53 mmol, prepared in example 12), isopropylsulfonyl chloride (0.1 mL, 0.58 mmol) and DBU (0.1 mL, 0.61 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the title compound, [(methylethyl)sulfonyl]{2-[4-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}amine, (0.149 g, 72%) as a white crystalline solid. Electron spray M.S. 391 (M*+H). Analysis for C17H30N2O4S2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C(#N)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]3[N:3]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(Cl)nc2c1I
Reactant: OC[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 85 %

Procedure:
5-Chloro-7-(3,4-difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (401 mg), DIPEA (0.35 mL) and (S)-2-pyrrolidinemethanol (401 mg) are stirred for 2.5 hours in an acetonitrile (60 mL) solvent at 90° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (395 mg). 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 1H), 7.67 (m, 1H), 7.29 (q, J=8.7 Hz, 1H), 6.11 (s, 1H), 4.45 (br, 1H), 3.85 (m, 1H), 3.77 (m, 1H), 3.57 (m, 2H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.70 (m, 1H).
Reaction SMILES: C(O)C.O[CH:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[C].[Pd].C(Cl)(Cl)Cl>[CH2:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(O)c1c[nH]c(C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Reaction time: 5.5 h
Yield: 83.8 %

Procedure:
To an ethanol solution (2.0 liters) of 258.0 g (0.73 mol) of methyl 4-(1-hydroxydodecyl)pyrrole-2-carboxylate prepared in Synthetic Example 11 was added 16 g of 10% palladium-carbon. A catalytic reduction with hydrogen was carried out at 50° C. under hydrogen atmosphere. After the reaction was completed within 5.5 hours, 1.5 liters of chloroform was added to the reaction mixture. The catalyst was filtered off, and the solvent was removed under a reduced pressure to give crystals. Recrystallization from 950 ml of ethanol afforded 179.6 g (83% yield) of methyl 4-dodecylpyrrole-2-carboxylate as white crystals, m.p. 68°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:16]#[N:17])=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Mg]Br.[CH3:29]I.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:16]#[N:17])([CH3:29])[CH:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(C#N)=Cc1cccc2ccccc12
Reactant: CI
Reactant: COc1ccccc1[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(C)(C#N)C(c1ccccc1OC)c1cccc2ccccc12
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a 5-liter, 4-neck flask equipped with a mechanical stirrer, a condenser fitted with nitrogen inlet, a cooling bath and thermal couple were added 882 g anhydrous THF and 250 g (1.05 mol) 2-cyano-3-naphthalen-1-yl-acrylic acid methyl ester 1. The mixture was cooled to 5° C. and 1098 g (1.09 mol) of a 1 M THF solution of 2-methoxyphenylmagnesium bromide 2 was slowly charged into the reaction mixture through an addition funnel while maintaining the temperature at 0-10° C. The mixture was stirred for an additional 30 min. Methyl iodide (598 g, 4.21 mol) then was added in one portion. The mixture was stirred at 40° C. for 28 hours and then cooled to 25° C. The mixture was treated with 943 g of 0.5 N HCl and the lower aqueous phase was separated and retained. The organic layer was concentrated by distillation until 871 g distillate was collected. The organic concentrate then was cooled to 35° C. and the aqueous layer was combined with the organic. To the mixture then was added 506 g methanol. The mixture was cooled to 0° C. and the product was filtered. The wet cake was washed with a mixture of 333 g of methanol and 666 g of water. The product 3 was dried in an oven at 55° C. under vacuum. Yield: 306 g, 81%. The diastereomeric excess was typically 100%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([O:29]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][N:14]([Si](C(C)C)(C(C)C)C(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:6][CH:7]=1.O.[CH:32]([NH2:34])=O>>[NH:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[CH:32][NH:34][C:27](=[O:29])[C:3]=4[N:4]=3)[CH:9]=[C:10]2[CH:16]=[CH:15]1
Reactant: NC=O
Reactant: COC(=O)c1nc(-c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)ccc1N
Solvent: O
Product: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Yield: 83 %

Procedure:
3.80 g of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylate in 60 ml of formamide are heated at 120° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 52 hours). The cooled reaction solution is added to about 50 ml of water, during which a precipitate precipitates out. This is filtered off with suction and dried, giving 2.00 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one as orange solid (yield 83%, content 98%); MS-FAB (M+H+)=264.1; Rf (polar method): 1.28 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH:22]1[CH2:23][CH2:24][CH2:25]1)=[O:20]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)OC1CCC1
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OC1CCC1

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 2-methyl-4-oxo-4H-chromene-8-carbaldehyde (2 g, 10.62 mmol) and cyclobutyl acetoacetate (1.66 g, 10.62 mmol). 3.4 g (98% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([CH:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:17].C1CCN2C(=NCCC2)CC1>C(#N)C.O>[C:13]([C:12]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][N:10]([C:19]2([CH2:18][C:16]#[N:17])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH:11]=1)(=[O:14])[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: NC(=O)c1c[nH]nc1Nc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 3-(phenylamino)-1H-pyrazole-4-carboxamide, Intermediate 31-1, (1.4 g, 6.9 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate, Intermediate 19-1 (3.1 g, 13.8 mmol) in acetonitrile (23 mL) was added DBU (1.0 mL, 6.9 mmol), and maintained at ambient temperature for 18 hours. The mixture was diluted with water, extracted with EtOAc, and the combined organics were washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was adsorbed onto silica gel in vacuo and then purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/DCM) to afford the title compound, Example #2-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][S:12](=[O:14])(=[O:13])[NH2:15])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and N—BOC-ethylenediamine (0.66 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 9/1) was performed to give N-[2-(tert-butoxycarbonylamino)ethyl]-sulfuric diamide (Compound GJ) (500 mg, yield: 50%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C)C=O>[Si:19]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide (403 mg, 2.00 mmol) in N,N-dimethylformamide (4 mL) was mixed with tert-butylchlorodiphenylsilane (514 μL, 2.00 mmol) and 1H-imidazole (136 mg, 2.00 mmol) under cooling with ice and stirred for one day while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1 (v/v)) to give the title compound as a colorless oil (536 mg, yield 61%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[H-].[Na+].CS(C)=O>CO>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:2]([CH3:1])([CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:3])=[CH:10][CH:11]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(Nc2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
First, 76.20 mmol of Bis-(4-(2,4,4-trimethylpentan-2-yl)phenyl)amine, 91.45 mmol of 4-Fluoronitrobenzene, 114.31 mmol of sodium hydride, 2.74 g of NaH, and 120 ml of dimethyl sulfoxide (DMSO) were added into a bottle. After stirring at 120° C. for 48 hrs, the reaction mixture was cooled and then poured into 1 L of methanol. The yellow precipitate was collected by filtration and dried under vacuum. The product was purified by silica gel column chromatography (dichloromethane:n-hexane=1:3) and recrystallized from ethyl acetate to afford 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline as a yellow crystal with a yield of 60%. The 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline had a melt point of 167° C. The synthesis pathway was as follows:
Reaction SMILES: [C:1]1([Sb:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([C:23]([O:22][CH3:21])=[O:34])=[CH:25][CH:26]=1.[C:14]1([Sb:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[Sb](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)c1ccc(C(=O)OC)cc1
Product: c1ccc([Sb](c2ccccc2)c2ccccc2)cc1

Procedure:
Triphenyl antimony oxide and dimethylterephthalate were reacted to yield triphenyl antimony dimethylterephthalate. ##SPC3##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1cccc(-c2nc(Cl)ncc2C)c1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)c1
Yield: 82 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-(3-(2-chloro-5-methylpyrimidin-4-yl)phenyl)acetamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 82% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.79 (s, 1H), 7.57 (d, 3H, J=8.2 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.35 (d, 1H, J=7.5 Hz), 7.22 (m, 2H), 3.44 (s, 2H), 2.42 (bs, 8H), 2.26 (s, 3H), 2.19 (s, 3H); (ESI): 431.3 [M+H]+, 216.3 [M+2H]2±.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[C:26]2[CH2:33][CH2:32][CH2:31][C:27]=2[N:28]=[CH:29][N:30]=1.Cl.C[O-].[Na+].CO>C(O)C.C(Cl)(Cl)Cl>[N:28]1[C:27]2[CH2:31][CH2:32][CH2:33][C:26]=2[C:25]([NH:21][C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[CH:14]=[C:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:23][CH:22]=2)=[N:30][CH:29]=1
Reactant: Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Reactant: Clc1ncnc2c1CCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(C=C1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
To a mixed solvent of 40 ml of chloroform and 20 ml of ethanol were added 2.33 g of 4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and 1.63 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and further 6 ml of an ethanol solution of hydrochloric acid (containing 0.4 g of hydrochloric acid) was added to the mixture and the mixture was stirred at 50° to 60° C. for 3.5 hours under heating. Then, under ice cooling, a 28% sodium methylate-methanol solution was added to the mixture to make it alkaline, and then the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.3 g of the title compound as yellowish white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=S)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To 3,5-dichloro-2-isothiocyanatopyridine (0.11 g, 0.55 mmol) in N,N-dimethylformamide (10 mL) was added Et3N (0.17 mL, 1.21 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.13 g, 0.56 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (10 mL) and N,N′-diisopropylcarbodiimide (0.26 mL, 1.65 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(3,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.08 g, 0.24 mmol, 44% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.91 (s, 1 H), 8.11-8.17 (m, 1 H), 7.97 (d, J=2.44 Hz, 1 H), 3.84 (d, J=9.77 Hz, 1 H), 3.59 (d, J=9.77 Hz, 1 H), 2.95-3.04 (m, 2 H), 2.72-2.81 (m, 2 H), 2.66 (t, J=7.63 Hz, 2 H), 2.01 (s, 1 H), 1.89 (s, 1 H), 1.54-1.62 (m, 2 H), 1.42-1.50 (m, 1 H). MS (LC/MS) R.T.=0.78; [M+]+=326.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16]O)=[CH:8][CH:7]=1>>[ClH:3].[Cl:3][CH2:16][CH2:15][CH2:14]/[CH:13]=[C:12](/[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)\[C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: OCCC/C=C(\c1ccc(F)cc1)c1cccnc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: Fc1ccc(/C(=C\CCCCl)c2cccnc2)cc1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
160 Parts of thionyl chloride were added dropwise to 10 parts of (E)-5-(4-fluorophenyl)-5-(3-pyridinyl)-4-penten-1-ol while stirring (exothermic reaction, the temperature rose to 45° C.). Upon complete addition, stirring was continued for 2 hours at room temperature. The reaction mixture was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again. The residue was solidified in 2,2'-oxybispropane. The product was filtered off and dried, yielding 11.5 parts (94.4%) of (E)-3-[5-chloro-1-(4-fluorophenyl)-1-pentenyl]pyridine hydrochloride (int. 60).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([CH:10]([CH2:12][CH3:13])[CH3:11])[CH:8]=[CH:7][N:6]1[CH:14]([CH2:16][CH3:17])[CH3:15]>CCCCCC>[CH:14]([N:6]1[CH:7]=[CH:8][N:9]([CH:10]([CH2:12][CH3:13])[CH3:11])[SiH:5]1[NH:3][CH2:1][CH3:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCN
Reactant: CCC(C)N1C=CN(C(C)CC)[SiH]1Cl
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)CC)C=CN1C(C)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
In an argon atmosphere, 3.30 g (73.2 mmol) of ethylamine was dissolved in 30 mL of hexane, and a solution obtained by dissolving 6.21 g (26.7 mmol) of Si(sBuNCHCHNsBu)(H)Cl in 5 mL of hexane was added thereto at −20° C. After stirring at room temperature for 2 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 92-96° C./4.0×102 Pa) to obtain 1,3-di-sec-butyl-2-ethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(sBuNCHCHNsBu)(H)NHEt) as a pale yellow liquid (yielded amount: 5.61 g, yield: 87%). This product was a mixture of a plurality of isomers differing in the steric configuration from each other.
Reaction SMILES: [Al](Cl)(CC)CC.[C:7](Cl)(=[O:9])[CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]([C:24]2[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[O:23])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>C(Cl)Cl>[C:7]([C:14]1[C:13]([O:12][CH3:11])=[CH:18][C:17]([O:19][CH3:20])=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=1)=[O:23])(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)c2nc(C(C)C)cs2)cc(OC)c1
Agent: CC[Al](Cl)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2nc(C(C)C)cs2)c(C(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of Et2AlCl (1.61 g, 12.04 mmol) in DCM at 0° C. was added acetyl chloride (630 mg, 8.02 mmol). The mixture was stirred at 0° C. for 30 min. Compound 41e (1.23 g, 4.01 mmol) was then added and the reaction mixture was stirred at 80° C. for 90 min. The reaction was poured in ice and DCM was added. The organic layers were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EtOAc/DCM) to yield compound 42e as a white solid in 82% yield.