Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:13]>>[C:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1
Product: O=C(Cl)Cc1ccccc1

Procedure:
Phenylacetic acid (PAA), 0.037 moles (5 g) was heated under reflux with an excess of SOCl2 for 60 minutes at a temperature of 75–80° C. After the reaction was completed, the excess SOCl2 was eliminated by vacuum evaporation, using a water pump (40–50° C.). This process was repeated two to three times, each time adding benzene to aid in elimination of SOCl2 and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of 2-hydrazino-2-imidazoline. HBr (3.5 g) was suspended in ether and shaken with 2N NaOH (2–5 equivalents) on an ice bath, until it was completely dissolved. The PAC was then added dropwise very slowly from a funnel with vigorous shaking. Excess NaOH was present to drive the reaction to completion. After the addition of PAC, the mixture was stirred at 0° C. for an additional 15–30 minutes. The ether layer was washed with water, then with saturated NaHCO3. It was then dried over Na2SO4, filtered and was brought to complete dryness. The solid residue from the ether layer was then crystallized from an ethanol-water mixture (70–80% ethanol). The yield, was approximately 55% without subjecting the residual amide to further separation from the aqueous layer.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:18][CH:17]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)(6-chloro-pyridin-3-yl)-amine and hydrazine monohydrate.
Reaction SMILES: C([O:3][C:4](=[O:34])/[C:5](/[F:33])=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C:9](/[F:31])=[C:10](\[C:13]1[C:22]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][C:20]2[C:19]([CH3:28])([CH3:27])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])C.[OH-].[Na+]>CCO>[F:33]/[C:5](=[C:6](/[CH3:32])\[CH:7]=[CH:8]\[C:9](\[F:31])=[C:10](/[C:13]1[C:22]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][C:20]2[C:19]([CH3:28])([CH3:27])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)\[CH2:11][CH3:12])/[C:4]([OH:34])=[O:3]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C(/F)C(=O)O)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure E and using (2Z,4E,6E)-2,6-difluoro-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-nona-2,4,6-trienoic acid ethyl ester (Compound 26, 80 mg, 0.17 mmol), 1M NaOH (0.51 mL), and EtOH (2 mL) at 40° C. for overnight followed by flash colulmn chromatography on silica gel (10%→50% EtOAc-hexane), the title compound was obtained as a yellow solid (54 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].[C:13]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])(=[O:17])[C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]([CH:4]([NH:5][CH:14]([C:13]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:16])[CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)=[O:12]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)C(Cc1c[nH]cn1)NC(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In a manner similar to Example 16, L-histidine methyl ester is condensed with pyruvoyl-L-proline in the presence of sodium cyano borohydride to yield N-[1-methoxycarbonyl-2-(1H-imidazol-4-yl)ethyl]-DL-alanyl-L-proline. The nmr spectrum in D2O shows the imidazole protons at 8.6 and 7.3; the protons adjacent to the imidazole and the methyl ester protons at 3.7 and the alanyl methyl at 1.1 to 1.38.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Yield: 91.8 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline-7-yloxy)methyl]pyrrolidine-1-carboxylate (170 mg, 0.33 mmol) was reacted with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product was eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (128 mg, 93%).
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:1][S:2]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)C(C)Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)S(C)(=O)=O
Temperature: 77 °C
Yield: 31.7 %

Procedure:
Sodium methanesulfinate (103 g, 937 mmol) was combined with ethyl 2-chloropropionate (109 g, 892 mmol) in ethanol (350 mL) in a 500 mL one neck round bottom flask. The reaction was heated to 77° C. for 20 h, and then allowed to cool to room temperature. The solids were removed by filtration through celite, and the filter pad was washed with ethanol. The combined filtrates were concentrated in vacuo. The crude product was suspended in diethyl ether (250 mL), and solids were removed by filtration. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil (51 g, 73%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.05 Hz, 3H) 1.67 (d, J=7.47 Hz, 3H) 3.05 (s, 3H) 3.83-3.92 (m, 1H) 4.18-4.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH3:36])=[CH:31][CH:30]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
To a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3, 80 mg, 0.2 mmol) and 4-methylamino-benzoic acid methylester (35 mg, 0.21 mmol) in dichloromethane (4 ml) were added N-ethyldiisopropylamine (29 mg, 0.22 mmol) and PyBroP (95 mg, 0.2 mmol). The mixture was stirred for 17 h at room temperature. The reaction solution was extracted with brine/water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5 g silica gel, heptane/AcOEt 8:2=>7:3) to give the title compound (37 mg) as a white solid. MS (m/e)=541.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(OC(C)C)(C)C>[CH2:16]([NH:20][C:21]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)OC(C)C
Product: CCCCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A solution of 6.5 g (0.03 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether was stirred under a blanket of nitrogen while 4 g (0.04 mole) of n-butyl isocyanate was added dropwise. The reaction was slightly exothermic and after 30 min, a solid separated. The solid was collected by filtration after 3 hr to give 3.85 g of crystalline product, m.p. 135°-136° C. After 24 hr, a second batch of crystals was obtained; 1.5 g; m.p. 132°-134° C. The two fractions were combined and recrystallized from cyclohexane to yield 3.6 g of product (38%), m.p. 136°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6]O.S(Cl)([Cl:27])=O>>[Cl:27][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 126.4 %

Procedure:
In substantially the same manner in Reference Example 94, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (6.00 g) was reacted with thionyl chloride (1.58 g) to obtain 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (5.77 g, yield 91%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])C(O)=O)=[CH:4][CH:3]=1.B.C1C[O:17][CH2:16]C1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:12][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Agent: B
Product: OCCCc1ccc(F)cc1

Procedure:
para-Fluorophenylpropionic acid (5.15 g, 31.0 mmol, 1 eq.) was dissolved in THF (150 mL). To this solution a 1.0 M solution of borane in THF was added dropwise (caution—exothermic) at 25° C. under N2. The mixture was refluxed overnight. The reaction was quenched with excess 1N HCl and extracted 3 times with EtOAc. The organic layers were dried (MgSO4), and stripped to yield 5.67 g of a pink oil. Evaporative distillation at 0.05 mmHg and 193-260° C. yielded 2.32 g of product as a clear colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:20]([CH:28]4[CH2:30][CH2:29]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](OC1N=CC(N)=CC=1)[C:37]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCC>C(#N)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([N:31]([CH2:36][CH3:37])[S:32]([CH3:35])(=[O:33])=[O:34])[C:20]([CH:28]4[CH2:29][CH2:30]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(OCc2ccccc2)nc1
Reactant: Nc1ccc(OCc2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCBr
Solvent: CC#N
Product: CCN(c1cc2nn(-c3ccc(OCc4ccccc4)nc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-(methanesulfonamido)-N-methyl-indazole-3-carboxamide (109) ESI-MS m/z calculated for [M+H]+: 492.1 was prepared according to procedure outlined in Method A using 6-benzyloxypyridin-3-amine instead of 4-bromoaniline. To a solution of compound (109) (120 mg, 0.24 mmol) in acetonitrile (10 mL) was added potassium carbonate (100 mg, 0.72 mmol) followed by bromoethane (0.09 mL, 1.2 mmol). The mixture was heated to 80° C. and stirred for 1.5 h. The mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (10 mL), washed with water (2 mL), brine (2 mL), dried (MgSO4) and concentrated in vacuo to afford 2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-indazole-3-carboxamide (i) (100 mg, 80%). This material was used without purification.
Reaction SMILES: [S:1]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[OH-].[K+]>CN(C=O)C>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: BrCCCCBr
Reactant: Cc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2cc3ccccc3n2CCCCBr)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-tosyl-1H-indole (199 mg, 0.73 mmol) in 3 mL DMF was added 1,4-dibromobutane (263 μL, 2.20 mmol) in 1 mL DMF and KOH (41 mg, 0.73 mmol), and the reaction stirred at room temperature 1.75 h. The reaction mixture was then partitioned between water and ether, and the aqueous layer extracted twice with ether. The combined organic extract was washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 15% ethyl acetate in hexanes to give a final yield of 178 mg (0.44 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.66-1.81 (m, 2H), 1.81-1.94 (m, 2H), 2.44 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 4.35 (t, J=7.6 Hz, 2H), 7.21 (t, J=7.0 Hz, 1H), 7.30-7.44 (m, 5H), 7.73 (d, J=7.9 Hz, 1H), 7.87 (d, J=8.1 Hz, 2H). 13C NMR (500 MHz, CDCl3, δ): 22.07, 29.04, 30.26, 33.26, 44.41, 111.08, 111.49, 121.67, 123.42, 125.83, 126.19, 128.09, 130.44, 135.22, 138.78, 139.12, 145.08. MS m/z 406.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Temperature: 110 °C
Yield: 60.4 %

Procedure:
A mixture of 3(R)-amino-piperidine-1-carboxylic acid tert-butyl ester (137 mg, 0.69 mmol) and 2-nitrofluorobenzene (102 mg, 0.72 mmol), K2CO3 (100 mg) was heated at 110° C. for 12 hr. The mixture was diluted with CH2Cl2, filtered and concentrated. The residue was purified by chromatography (5% EtOAc in hexane) to give a yellow oil (134 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.55 Hz, 1H, NH), 8.10 (d, J=7.20 Hz, 1H), 7.48 (t, 1H), 7.01 (d, J=8.30 Hz, 1H), 6.70 (t, 1H), 4.00 (broad, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 2.10 (m, 1H), 1.82-1.60 (m, 3H), 1.43 (s, 9H) ppm; IR (film) 3357, 2967, 2935, 2858, 1692, 1620, 1572, 15508, 1423, 1372, 1266, 1230, 1154 cm−1; LRMS (calculated for C16H23N2O4) 321. found 321.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.[Pd]>[CH2:13]([NH:20][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCc2ccccc2CC1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CNC2CCc3ccccc3CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5,6,8,9-Tetrahydro-benzocyclohepten-7-one (3.00 g) and benzylamine (2.00 g) are dissolved in ethanol (50 mL). A catalytic amount of 10% palladium on charcoal is added and the reaction mixture is placed under an atmosphere of hydrogen. The reaction mixture is stirred at r.t. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 1:2 Rf=0.50).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32]>CN(C)C(=O)C>[CH2:30]([N:33]([CH3:34])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH:31]=[CH2:32]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-(allyl-methyl-amino)-(E)-but-2-enyloxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow viscous oil, MS: 489 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([N:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[CH:31]=[N:30][C:29]=2[C:28]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:27]1)[CH:24]=[CH2:25]>C1COCC1>[CH2:23]([N:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[CH:31]=[N:30][C:29]=2[C:28]([C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:42])[C:38]([F:41])([F:39])[F:40])=[CH:27]1)[CH:24]=[CH2:25]
Reactant: C=CCn1cc(C(=O)C(F)(F)F)c2ncn(C)c(=O)c21
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (94 mg, 0.32 mmol, 1.1 equiv.) in 1.5 mL of THF was added n-BuLi (2.5 M in hexanes, 0.13 ml, 0.32 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 5-allyl-3-methyl-7-(2,2,2-trifluoro-acetyl)-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (83 mg, 0.29 mmol, 1 equiv.) in 1 mL of THF. After 15 minutes, the mixture was quenched with water, warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hex (0-60% gradient) to provide 44 mg (30%) of the title compound as a yellow foam. MS m/z 498.31 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N>C(N(CC)CC)C.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: N#CCc1ccc(Br)cc1
Agent: [Cu]I
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#CCc1ccc(C#Cc2ccccc2)cc1

Procedure:
A mixture of 49 g (0.25 mol) 4-bromobenzylcyanide, 30 g (0.3 mol) phenylacetylene, 0.1 g di(triphenylphosphine)-palladium(II-dichloride, 0.1 g copper(I)iodide and 0.2 g triphenylphosphine in 300 ml triethylamine are heated for 20 hours under a blanket of N2 and vigorously stirred. The mixture is then evaporated under water jet vacuum, the residue heated in hexane and the undissolved solid sucked off and dried. The thus obtained title compound is employed as such in the following reaction step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[S:9](Cl)([C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]>CN(C)C=O>[S:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])([C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCCCCN
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCCCN)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
Hexamethylenediamine (5.39 g, 45.9 mmol) was combined with dimethylformamide (15 ml), and a solution of dansyl chloride (2.40 g, 8.7 mmol) in dimethylformamide (10 ml) was dropwise added thereto, followed by stirring at room temperature for 4 hours. Insoluble materials were removed by filtration, and the filtrate was stirred at room temperature overnight. After concentration, water and ethyl acetate were added to thereto, and 1 N hydrochloric acid was added thereto to adjust the aqueous layer to pH 4. The aqueous layer was washed with ethyl acetate three times, adjusted to pH 11 with potassium carbonate and extracted with ethyl acetate twice. The extracts were collected, washed with water three times, dried over anhydrous sodium sulfate and concentrated to give Compound (4) (1.04 g) as an oil. Yield, 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 76 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3): δ 3.08-3.17 (m, 4H), 3.78-3.86 (m, 3H), 4.09-4.15 (m, 4H), 7.00-7.07 (m, 2H), 7.20-7.45 (m, 5H), 7.65-7.84 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:19][NH:1][C:2]2[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1n[nH]cc1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a suspension of 3-aminopyrazole-4-carboxylic acid (3.56 g, 0.023 mol) in 400 ml of methanol was added 3-cyclopentyloxy-4-methoxybenzaldehyde (5.06-g, 0.023 mole) and 95% sodium cyanoborohydride (1.85 g, 0.028 mol). The reaction mixture was stirred for 16 hours and then the methanol was evaporated under reduced pressure. The residue was treated with 100 ml of 15% aqueous NaOH and extracted twice with 100 ml portions of ether. The aqueous layer was acidified to pH 5 with 5N aqueous HCl and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate extracts were evaporated under reduced pressure and the residue was triturated with ether to give 3.7 g (49%) of the title compound, mp 134-136°, after recrystallization from methanol.