Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][C:8](=[O:20])[N:7]([CH:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[N:7]2[C:8](=[O:20])[CH2:9][C@@H:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=3[F:19])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H]1CN(C(c2ccc(OC)cc2)c2ccc(OC)cc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)cc2)N2C[C@@H](C(=O)O)[C@H](c3cc(F)c(F)cc3F)CC2=O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5.9 g (11.5 mmol) of the product from Step D in 100 mL of 3:1 tetrahydrofuran/methanol was added 30 mL (30 mmol) of a 1N aqueous lithium hydroxide solution and the resulting mixture was stirred at 60° C. for 2 h. The solution was concentrated and acidified with 100 mL of 1N aqueous hydrochloric acid. The resulting mixture was then extracted with three 250-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid and saturated aqueous brine (100 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title acid as a colorless foamy solid that was used without further purification. LC/MS 522.2 (M+23).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[N:19]/[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)/N=C/c1ccccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CS(C)(=O)=O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 1 g (10.6 mmol) of (methylsulphonyl)methane in 30 ml of THF was cooled to −78° C. and admixed slowly with 6.65 ml of n-butyllithium solution (1.6M in hexane, 10.6 mmol). After 30 min at −78° C., the suspension obtained was added to a solution, cooled to −78° C. beforehand, of 850 mg (3.55 mmol) of the compound from Example 111A in 20 ml of THF. The reaction mixture was stirred at −78° C. for a further 30 min and then slowly warmed to RT. After 30 min, it was cooled to −20° C. again and the reaction was halted by addition of 20 ml of 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate. The organic phase was separated and washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was stirred with 10 ml of methanol/water 10:1 and the solid was filtered off with suction. The slightly yellowish solid was stirred with 20 ml of pentane/isopropanol 5:1, then filtered off with suction again. Drying in an HV gave 800 mg (55% of theory) of the title compound (82% purity according to LC/MS).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].CCN(CC)CC.[CH3:24][O:25][CH2:26][C:27]#[CH:28]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:28]#[C:27][CH2:26][O:25][CH3:24])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: C#CCOC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCC#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 55 °C
Yield: 77.7 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (3.0 g, 8.69 mmol) and Et3N (22 mL) in dry dioxane (22 mL) was purged with argon during 15 min. (Ph3P)2PdCl2 (305 mg, 0.435 mmol), CuI (166 mg) and 3-methoxy-propyne (2.20 mL, 26.08 mmol) were added and the mixture was heated to 55° C. for 100 min. After cooling, the reaction mixture was filtered and the filtrate diluted with EtOAc, washed with water and brine and dried (Na2SO4). Evaporation of the volatiles gave a residue which was purified by MPLC (silica gel, cyclohexane/EtOAc 4:1) to yield the title compound (1.94 g, 78%) as a beige solid, m.p. 107-111° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(CC(=O)c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
A stirred solution of 3-(4-bromo-phenyl)-1-(4-methoxy-phenyl)-3-o-tolyl-propan-1-one (214 mg) in dichloromethane (5.1 ml) under argon was cooled to −78° C. A solution of BBr3 (2.09 ml, 1 M in dichloromethane) was added dropwise. The mixture was stirred at −78° C. for 45 min, at 0° C. for 4 h and at room temperature for 30 min. Since the reaction was not complete, the mixture was again cooled to −78° C. and a solution of BBr3 (1 ml, 1 M in dichloromethane) was added. The mixture was stirred at −78° C. for 30 min and at 0° C. for 4.5 h. Water and a saturated aqueous NaHCO3 solution were added and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 7:3) to give the title compound (21 mg) as a light brown solid, MS (ESI+): m/z=394.8 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([C:20](=[O:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].O>O1CCCC1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([CH:20]([OH:22])[CH3:21])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(C(C)=O)C(=O)OC(C)(C)C)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)O)o1
Yield: 72.5 %

Procedure:
To 2.26 g of tert-butyl 2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-oxobutanoate in 50 ml of tetrahydrofuran, 7.7 ml of 1M lithium tri-sec-butylborohydride in tetrahydrofuran solution was added at -78° C. under stirring, and the resulting reaction solution was stirred at the same temperature for 2 hours. After addition of water, the reaction solution was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=12/1→4/1] to give 1.65 g of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][NH:20][C:19](=[O:22])[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH3:36]>C1COCC1>[CH2:35]([N:20]1[C:19](=[O:22])[CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:14]2([CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:31])[CH:7]=3)[CH2:12][CH2:13]2)[CH2:21]1)[CH3:36]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (65 mg, 0.15 mmol) in THF (1 mL) at 0° C. was added NaH (6 mg, 0.15 mmol) and the reaction mixture was stirred for 30 minutes. Bromoethane (34 mg, 23 μL, 0.31 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give 2-ethyl-9-(4-isopropoxy-3-methyl-benzoyl)-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 2H), 7.39-7.29 (m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 4.56 (dt, J=12.1, 6.0 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.59-3.19 (m, 5H), 3.09 (d, J=12.4 Hz, 1H), 2.92 (d, J=28.7 Hz, 1H), 2.22 (s, 1H), 2.23-2.16 (m, 3H), 1.59 (s, 3H), 1.35 (d, J=6.0 Hz, 6H), 1.14 (t, J=7.2 Hz, 3H). ESI-MS m/z calc. 450.3. Found 451.1 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31][C:32]([F:37])([F:36])[CH2:33]NN>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][C:32]([F:37])([F:36])[F:31])[C:4]=2[C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: NNCC(F)(F)F
Product: FC(F)(F)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2,2,2-trifluoro-ethyl)-hydrazine provided the title compound. MS: (M+H m/z=461.2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[CH:4][NH:5][CH:6]=1.[C:15](N1C=CN=C1)(=[O:17])[CH3:16]>>[C:15]([N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[CH:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)n1ccnc1
Reactant: Clc1c[nH]cc1-c1cccc(Cl)c1Cl
Product: CC(=O)n1cc(Cl)c(-c2cccc(Cl)c2Cl)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
The mixture of 0.3 g of 4-chloro-3-(2,3-dichlorophenyl)pyrol and 0.6 g of N-acetylimidazole was fused for one hour at 140° C. in a stream of argon. The resulting reaction mixture was purified by thin-layer chromatography to obtain 0.2 g of the desired product (colorless or slightly colored crystal, m.p. 97° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[C:30](O)(=[O:32])[CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]([CH3:29])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([Br:1])[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:24][CH2:25]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CC(=O)N1CCC(N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
The 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(piperidine-4-yl)amino)benzamide (0.2 g, 0.447 mmol) dissolved in DMSO (2 mL) and acetic acid (0.054 g, 0.896 mmol) were added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.342 g, 0.672 mmol) was added to it and stirring was continued for overnight. After completion, reaction mass was poured into ice, and extracted using 10% MeOH/DCM. Combined organic layers were dried, concentrated to provide crude material, which then purified with column chromatography using silica (100-200 mesh size) to afford the desired compound (0.15 g, 17%). LCMS: 503.20 (M+1)+; HPLC: 96.06% (@ 254 nm) (Rt; 5.143; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 8.21 (t, 1H, J=4.8 Hz), 7.23 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 5.85 (s, 1H), 4.32 (d, 1H, J=12.4 Hz), 4.23 (d, 2H, J=4.8 Hz), 3.77 (d, 1H, J=13.2 Hz), 2.98 (t, 2H, J=11.2 Hz), 2.54 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.97 (s, 3H), 1.53-1.60 (m, 4H), 1.38-1.41 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)([O-:3])=[O:2].Br.C(O)(=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(Oc2ccc(O)cc2)c1

Procedure:
m-nitrophenol and 4-bromoanisole yield p-(m-nitrophenoxy)anisole of m.p. 69°-71° C. and reaction with hydrobromic acid/acetic acid yields p-(m-nitrophenoxy)phenol which distils in the bulb-tube at 95°-97° C./0.04 Torr;
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:38])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[C:26]=1[CH3:37])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([C@H:10]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:34])([F:36])[F:35])[C:26]=3[CH3:37])[C@H:9]([OH:8])[CH3:38])=[N:15][N:14]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O)ccc(C#N)c1C(F)(F)F
Temperature: -55 °C
Yield: 68.7 %

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methyl-2-(trifluoromethyl)benzonitrile (500 mg, 0.92 mmol) was dissolved in THF and cooled to −55° C. under N2 atmosphere. TBAF (11.0M solution in THF, 1.10 mL, 1.11 mmol) was added to the precooled solution slowly and the temperature was allowed to rise. The progress of the reaction was monitored by TLC. After the reaction was complete, it was quenched with a saturated solution of NH4Cl and extracted with EtOAc. Purification with column chromatography provided the desired product (270 mg, 68%). 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.17 (d, J=9 Hz, 2H), 7.96 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 6.01 (d, J=9 Hz, 1H), 5.13 (m, 1H), 4.69 (d, J=6 Hz, 1H), 4.53 (m, 1H), 2.35 (m, 3H), 1.39 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[OH:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][C:24]4[CH:23]=[C:22]([OH:21])[CH:27]=[CH:26][CH:25]=4)[N:30]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Reactant: N=C(N)Nc1cccc(O)c1
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2ccnc(Cl)c21

Procedure:
Prepared by treatment of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one with 1-(3-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.46 (m, 3H, CH3), 4.49 (m, 2H, CH2), 6.39 (m, 1H, Ph-H), 7.07 (m, 1H, Ph-H), 7.20 (m, 2H, Ph-H and Ar—H), 7.77 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.18 (d, 1H, J=5.6 Hz, Ar—H), 8.37 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.41 (s, 1H, Ar—H), 9.23 (s, 1H, OH), 9.32 (s, 1H, NH). MS (ESI+) m/z 362.1670 (M+H)+
Reaction SMILES: CS(O)(=O)=O.[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7]1.[C-:25]#[N:26].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15][C:25]#[N:26])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reactant: [C-]#N
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCC1(Cc2ccccc2)CCC2(CC1)OCCO2

Procedure:
A mixture of 18.6 g. (0.055 M) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2) (prepared as in Preparation 30) and 18 g. of potassium cyanide in 180 ml. of hexamethylphosphoramide is heated for about 17 hours in an oil bath at about 145° C. The resulting gel is allowed to cool, diluted to 800 ml. with water and extracted with benzene. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on 1 l. of silica gel and eluted with 25% ethyl acetate in Skellysolve B and the fractions found similar by TLC pooled to give 4-benzyl-4-(cyanomethyl)cyclohexan-1-one ethylene ketal (3).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6](C(OC)=O)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(=O)c2ccccc21
Reaction time: 16 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and THF (10 mL) was added sodiumhydroxide 9 mL (1M solution). The solution was stirred for 16 h and thereafter acidified with 10% HCl. The mixture was extracted with ethyl acetate, the combined organic layer was washed with water and brine, and dried over MgSO4. The solvent was distilled off under reduced pressure to afford the title compound as a white solid. 1H NMR (Acetone-D6): δ 1.44 (s, 6H), 2.07 (t, J=6.7 Hz, 2H), 2.73 (t, J=6.7 Hz, 2H), 7.70 (d, J=8.2 Hz, 1H), 8.19 (dd, J=1.9, 8.2 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:15])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 4.9 parts of (4-fluorophenyl)(4-piperidinyl)-methanone hydrochloride, 5 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reaction mixture is cooled, washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of ethanol and 1,1'-oxybisethane, yielding 3 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.Cl.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1CC(=O)Nc2cc(N)ccc2C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C)C3)ncc1Cl
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 8-amino-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide (22 mg, 0.08 mmol), and camphorsulfonic acid (17.4 mg, 0.08 mmol) were heated in IPA (3 mL) at 120° C. for 16 hours. The mixture was heated for another 2.5 hours at 120° C. after the addition of 10 drops of 4 N HCl/dioxane. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:8) followed by semi-preparative HPLC gave 5 mg of 2-[5-chloro-2-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (16% yield): 1H NMR (300 MHz, CD3OD) δ 8.7 (d, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.67 (m, 3H), 7.4 (m, 1H), 7.2 (m, 1H), 3.95 (s, 1H), 3.7 (s, 1H), 3.6 (s, 2H), 2.95 (s, 3H), 2.53 (s, 3H); MS (m/e): 452.2 (M+1).
Reaction SMILES: [CH2:1]([Sn:5]([Cl:11])(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[NH4+].[Cl-].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.[Zn]>[CH2:15]([Sn:5]([Cl:11])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](Cl)(CCCC)Cc1ccccc1

Procedure:
In a round-bottom two-necked flask equipped with a condenser and a dropping funnel, 31.25 mmol (9.5 g) of dibutyltindichloride were dissolved in 25 ml of tetrahydrofurane (THF). Then 125.1 mmol (8.18 g) of zinc (zinc granules: −30+100 mesh, Sigma-Aldrich) and 50 ml of water saturated with NH4Cl were added. With vigorous stirring 125.1 mmol (21.4 g) of benzylbromide (in 1:1 stoichometric ratio with respect to zinc) were added drop wise at a rate sufficient to keep temperature below 27° C. The reaction flask was cooled down with ice. First a brown benzyldibutyltin chloride was formed as an intermediate. The addition took about 30 min. The resulting heterogeneous colorless mixture was stirred for a further 60-120 min to complete disappearance of Zn powder. The organic layer was separated, washed with saturated aqueous NaCl and dried over MgSO4. Solvent was removed by distillation under reduced pressure up to 45° C. for 5 hours. An oil like liquid remained, which was distilled under vacuum to afford the pure compound.