Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.CC[O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:19]2[CH2:20][CH2:21][N:16]([C:14]([OH:15])=[O:13])[CH2:17][CH2:18]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CCl)c1
Reactant: CCOC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cccc(CN2CCN(C(=O)O)CC2)c1
Yield: 112.5 %

Procedure:
A mixture of 48.6 g (0.31 moles) of m-methoxybenzyl chloride, 49.0 g (0.31 moles) of ethyl N-piperazinocarboxylate, 250 ml of isopropyl alcohol and 35 ml of 10N sodium hydroxide was heated at reflux for 18 hours. The reaction mixture was evaporated in vacuo and gave an oil. The oil was Kugelrohr distilled bp 106° C./0.025 mm of mercury and gave 87.3 g of 4-[(3-methoxyphenyl)methyl]-1-piperazinecarboxylic acid, ethyl ether as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@H:30]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazole (180 mg, 0.262 mmol) synthesized in Example (35c) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.53 mL, 0.53 mmol) was added, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. Water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired compound (103 mg, yield 79%) as a white solid.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:26]3[CH:27]=[C:28]4[O:33][CH2:32][O:31][C:29]4=[CH:30][C:25]=3[CH2:24][CH:23]([CH3:34])[N:22]([C:35](=[O:38])[CH2:36]Cl)[N:21]=2)=[CH:16][CH:15]=1)([O-])=O>C(O)C>[NH2:11][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:26]3[CH:27]=[C:28]4[O:33][CH2:32][O:31][C:29]4=[CH:30][C:25]=3[CH2:24][CH:23]([CH3:34])[N:22]([C:35](=[O:38])[CH2:36][NH:6][CH3:4])[N:21]=2)=[CH:16][CH:15]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCl)OCO3
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNCC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Yield: 53.5 %

Procedure:
1.03 g (15.3 mmol) of methylamine hydrochloride and 2.64 ml (18.3 mmol) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 140 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was dissolved in 30 ml of chloroform, washed with 20 ml of 4% NaOH solution, then 2×20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the process of Example 16 and the product obtained was purified by column chromatography (adsorbent: Kieselgel 60, eluent: methanol--benzene 4:1). The crude product obtained was triturated with 5 ml of ethyl acetate at 25° C. to obtain 0.60 g (53.6%) of the aimed product, m.p. 198°-200° C. (weak decomp.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:41])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]3[C:22](=[O:40])[CH:23]([NH:24][C:25]([C:27]4[C:28]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[Cl:39])=[N:29][O:30][C:31]=4[CH3:32])=[O:26])[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1.[C:42](O)(=O)[CH3:43]>CN(C)C=O.[Zn]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:41])[CH:13]([C:14]([OH:16])=[O:15])[N:12]3[C:22](=[O:40])[CH:23]([NH:24][C:25]([C:27]4[C:28]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[Cl:39])=[N:29][O:30][C:31]=4[CH3:32])=[O:26])[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1.[CH2:28]([NH:29][CH2:42][CH2:43][NH:29][CH2:28][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CSc3nnnn3C)S[C@H]12
Reactant: CC(=O)O
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)O)C(C)(CSc3nnnn3C)S[C@H]12
Product: c1ccc(CNCCNCc2ccccc2)cc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
2,2,2-Trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (0.67 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.8 ml) and zinc powder (0.7 g) under cooling at -15° C. and the mixture was stirred for 2 hours at the same temperature. After the reaction, zinc powder was filtered off and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was dissolved in methanol (0.8 ml) and to this solution was added a solution of N,N'-dibenzylethylenediamine diacetate (0.18 g) in water (5 ml) and precipitates were collected by filtration, washed with water and dried to give N,N'-dibenzylethylenediamine 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (0.24 g), mp. 117° to 119° C. (dec.).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:37]=[C:36]([O:44][CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:35]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:37]=[C:36]([O:44][C@@H:45]2[CH2:50][CH2:49][C@H:48]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:47][CH2:46]2)[CH:35]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C1CCC(Oc2cc(CO)nc(C(F)(F)F)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.20 g, 2.49 mmol) (from WO 2009114512) and 4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexanone (0.900 g, 3.10 mmol) in dry 1,2-dichloroethane (30.00 mL, 380.8 mmol) were stirred for 5 minutes, and sodium triacetoxyborohydride (1.87 g, 8.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate. The mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH). Fractions containing the second peak were combined and stripped down to give {1-(cis-4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. 1H NMR (500 MHz, CDCl3) δ: 8.90 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.46 (d, 1H), 6.98 (s, 1H), 6.86 (d, 1H), 5.73 (s, 2H), 5.41 (m, 1H), 4.80 (s, 2H), 3.82 (d, 2H), 3.67 (d, 2H) 3.59 (m, 2H), 3.46 (s, 2H), 3.15 (m, 1H), 2.42 (m, 2H), 2.11 (m, 2H), 1.70-1.90 (m, 6H), 0.96 (m, 2H), −0.4 (s, 9H). MS (ES): 683 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]=[CH:10][CH:9]=[C:8]3[O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(C(F)(F)F)cc4)ccnc23)c1F
Yield: 11.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-46, 126 mg, 0.44 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 142 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) in CH2Cl2 (5 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 8.80-8.75 (m, 2H), 8.16 (t, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 6.96 (d, J=5.1 Hz, 1H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 574.26 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[Cl-].C[CH:16]=[N+:17]=[CH:18]C.[OH-].[Na+].[CH2:22](Cl)Cl>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:16][N:17]([CH3:18])[CH3:22])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: CC=[N+]=CC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CN(C)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Yield: 100 %

Procedure:
To a solution of 6-trifluoromethylindole (1.0 g, 5.4 mmol) in CH2Cl2 (10 mL) was added N,N-dimethylmethylene ammonium chloride (0.63 g, 6.75 mmol, 1.25 eq.) in one portion and the resultant mixture was stirred at rt for 2 h under N2. 1M NaOH (6.75 mL,) was added, and the reaction mixture was extracted into methylene chloride. The organic layer was washed with aqueous saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 1.3 g (100%) of title compound.
Reaction SMILES: NC1C(NC2C=CC=C(O)C=2)=NC(NC2C=CC=C(O)C=2)=NC=1C(OCC)=O.[CH2:29]([O:31][C:32]([C:34]1[N:39]=[C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:37]=[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:35]=1[N+:54]([O-])=O)=[O:33])[CH3:30].[H][H]>[Pd]>[NH2:54][C:35]1[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:37][C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:39][C:34]=1[C:32]([O:31][CH2:29][CH3:30])=[O:33]
Reactant: [H][H]
Reactant: CCOC(=O)CNc1nc(NCC(=O)OCC)c([N+](=O)[O-])c(C(=O)OCC)n1
Agent: [Pd]
Agent: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N
Product: CCOC(=O)CNc1nc(NCC(=O)OCC)c(N)c(C(=O)OCC)n1

Procedure:
In a manner similar to the preparation of 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 6-ethoxycarbonyl-N2,N4-bis(ethoxycarbonylmethyl)-5-nitro-2,4-pyrimidinediamine, hydrogen, and 10% Pd/C were reacted to yield 5-amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 6.25 (bs, 2H), 4.38 (q, 2H, J=6.9 Hz), 4.23–4.14 (m, 6H), 4.05 (bs, 2H), 1.39 (t, 3H, J=6.9 Hz), 1.30–1.22 (m, 6H); LCMS: ret. time: 17.67 min.; purity: 95%; MS (m/e): 370 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCCCCC.C([Li])CCC.Cl[Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][Si:24](Cl)([CH3:26])[CH3:25].[Cl-].[Na+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][Si:21]2([CH3:29])[CH3:28])=[N:6][CH:7]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Cl)cn1
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a tetrahydrofuran (350 ml) solution of 5-chloropyridin-2-ylamine (10.28 g, 80.0 mmol) was added a hexane solution (1.58M, 50.6 ml, 80.0 mmol) of n-butyl lithium at −78° C. The resulting mixture was stirred for 1 hour. At the same temperature, a tetrahydrofuran (50 ml) solution of 1,2-bis(chlorodimethylsilyl)ethane (17.22 g, 80.0 mmol) was added to the reaction mixture, followed by stirring for 1 hour. A hexane solution (1.58M, 50.6 ml, 80.0 mmol) of n-butyl lithium was added at the same temperature and the resulting mixture was stirred for 30 minutes. At room temperature, a saturated aqueous solution of sodium chloride was added to the reaction mixture. Diethyl ether was added to the resulting mixture to separate it into layers. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was distilled under reduced pressure (120° C./3.0 mmHg) to give the title compound (12.97 g, 47.9 mmol, 60%) as a colorless acicular substance.
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N:1]1([C:7]2([CH:11]([NH2:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCOCC2)CCC1
Product: NC(c1ccccc1)C1(N2CCOCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=247.3 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-morpholin-4-yl-cyclobutanecarbonitrile (intermediate T) and phenyllithium.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](S(C)(=O)=O)[C:10]=2F)[CH2:5][CH2:4]1)[CH3:2].[C-:20]#[N:21].[Na+].C1OCCOCCOCCOCCOCCOC1.C[N:42]([CH3:45])C=O>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:20]#[N:21])[C:10]=2[C:45]#[N:42])[CH2:5][CH2:4]1)[CH3:2]
Reactant: [C-]#N
Reactant: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Reactant: CN(C)C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Product: CCN1CCC(c2cccc(C#N)c2C#N)CC1

Procedure:
Preparation according to Example 31: 1-ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine (1.06 g, 3.72 mmol), N,N-dimethylformamide (30 ml), sodium cyanide (0.7 g, 14.0 mmol) and 18-crown-6-ether (5 mg). Yield: 0.35 g. MS m/z (relative intensity, 70 eV) 239 (M+, 3), 225 (17), 224 (bp), 154 (6), 71 (5).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[C:7](C(C)C)[CH:6]=[CH:5][C:4]=1[NH:12][C:13]([NH2:15])=[NH:14].[C:16](=O)([O-])[O-].[Na+].[Na+].CO[CH2:24][CH2:25]O>C(OCC)(=O)C>[NH:12]([C:13]1[N:14]=[CH:25][CH:24]=[CH:16][N:15]=1)[C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)c1ccc(NC(=N)N)c(Br)c1
Reactant: O=C([O-])[O-]
Reactant: COCCO
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc(Nc2ncccn2)cc1

Procedure:
Part B: A mixture of the product from part A (1.09 g), 2-bromo-4-isopropylphenylguanidine hydrochloride (1.17 g), and sodium carbonate (424 mg) in 2-methoxyethanol (30 mL) was refluxed for 19 hr. The cooled reaction mixture was diluted with ethyl acetate and washed with water (2×) and brine, dried and evaporated. The crude reaction product was chromatographed on silica gel using 50% petroleum ether in methylene chloride as eluent. The intermediate anilinopyrimidine was obtained as an oil (337 mg). CI Mass Spec. (M+H)+ =462.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1.[OH-].[NH4+]>O>[CH2:19]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(CCN)c1
Reactant: BrCCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CCNCCc2ccccc2)c1
Temperature: 165 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 1.51 g of β-(3-methoxyphenyl)-ethylamine and 1.85 g of β-phenethyl bromide was heated to 70°-80° C. on a bath and then was progressively heated to 165° C. over 10 minutes. The mixture was held at 165° C. for 5 minutes and was then cooled. 50 ml of water and then 4 ml of concentrated ammonium hydroxide were added thereto and the mixture was extracted 3 times with 40 ml of methylene chloride. The combined organic extracts were washed with 100 ml of aqueous sodium chloride solution and was dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness to obtain 3.4 g of raw product which was chromatographed over silica gel. Elution was with a 9-1 chloroform-ethanol mixture and the homogenous fraction with an Rf = 0.45 was taken to obtain 1.2 g of N-phenethyl-3-methoxyphenethylamine in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.O.[Br].[N:27]#[C:28]C#N>C(O)(=O)C>[NH2:27][C:28]1[NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:3][C:2]=2[N:1]=1
Reactant: N#CC#N
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c(N)c2)CC1
Agent: [Br]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A 100 mL flasked was charged of tert-butyl 4-(2-(3,4-diaminophenoxy)ethyl)piperazine-1-carboxylate (1.53 g, 4.54 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromine (0.526 g, 5 mmol) and continued to stir at 0° C. The reaction temperature was allowed to warm to room temperature and it was stirred over night. The reaction was completed as determined by LCMS. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in acetone, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.7 g of tert-butyl 4-(2-(2-amino-1H-benzo[d]imidazol-5-yloxy)ethyl)piperazine-1-carboxylate as a di-acetate salt as black foam. MS (EI): 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12](=[O:19])[C:13]3[C:18]([C:10]=2[C:9]2[C:4](=[CH:5][C:6]([F:20])=[CH:7][CH:8]=2)[N:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[ClH:1].[ClH:1].[CH3:21][N:22]([CH2:23][CH2:24][NH:25][C:2]1[C:11]2[C:12](=[O:19])[C:13]3[C:18]([C:10]=2[C:9]2[C:4](=[CH:5][C:6]([F:20])=[CH:7][CH:8]=2)[N:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:26]
Reactant: CN(C)CCN
Reactant: O=C1c2ccccc2-c2c1c(Cl)nc1cc(F)ccc21
Product: CN(C)CCNc1nc2cc(F)ccc2c2c1C(=O)c1ccccc1-2
Product: Cl
Temperature: 90 °C
Yield: 68.6 %

Procedure:
To a suspension of 6-chloro-3-fluoro-7H-indeno[2,1-c]quinoline-7-on (860 mg, 3.0 mmol) in pyrydine (10 ml) was added N,N-dimethylethylenediamine (800 mg, 9.0 mmol), and the mixture was stirred with heat at 90° C. for 12 hours. The reaction mixture was distilled to dryness. To the residue was added water and chloroform for extraction. The chloroform layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1(v/v)). The purified material was dissolved in 20 ml of tetrahydrofuran. To the the solotion was added 4N-hydrochloride/dioxane (2 ml) and the mixture was concentrated under reduced pressure. The residue obtained was crystallized from diethylether to give 420 mg (yield 34.3%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:42])[CH2:39][CH2:40][CH3:41]>>[CH2:38]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCCCO
Agent: [Li]CCCC
Product: CCCCOc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) with 2 equivalents each of n-butyl lithium and n-butanol by the procedure described in Reference Examples 6 and 7 to afford 2-(2-n-butyloxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=500 (M++1); Rt=4.34 min. 1H-NMR 500 MHz (CDCl3): δ 0.93 (t, 3H), 1.40-1.46 (m, 2H), 1.70-1.75 (m, 2H), 4.22-4.26 (t, 2H), 7.18-7.30 (m, 7H), 7.40-7.42 (m, 1H), 7.57-7.60 (m, 1H), 8.54-8.55 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:33]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-methoxy-benzoic acid.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[C:14]1([CH2:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[C:14]1([CH2:20][NH:21][CH:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCCC(NCc2ccccc2)CC1
Yield: 100 %

Procedure:
A mixture of 46 parts of ethyl hexahydro-4-oxo-1H-azepine-1-carboxylate, 26 parts of benzenemethanamine, 2 parts of a solution of thiophene in methanol 4% and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 69.1 parts (100%) of ethyl hexahydro-4-[(phenylmethyl)amino]-1H-azepine-1-carboxylate as a residue (interm. 27).