Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O1C2C=CC(O)=CC=2OC1.[F:45][C:46]1[CH:47]=[C:48]([OH:53])[CH:49]=[CH:50][C:51]=1[F:52]>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([C:49]1[CH:50]=[C:51]([F:52])[C:46]([F:45])=[CH:47][C:48]=1[OH:53])([OH:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and 1,3-benzodioxol-5-ol with 3,4-difluorophenol, the title compound was obtained as a white solid (42%); MS (ES+) m/z 424 (M−17), 426 (M−17), 464 (M+23), 466 (M+23).
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[NH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[OH:26].C(Cl)(Cl)Cl.Cl>O>[O:12]=[C:4]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)[C:2](=[O:26])[C:6]2([CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[NH:5]1
Reactant: CO
Reactant: N#Cc1ccc(N2C(=N)C3(CCOCC3)NC2=O)cc1C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F

Procedure:
1.66 g of the product of Example 1 were introduced into 30 ml of methanol, 10 ml of chloroform and 10 ml of 2N hydrochloric acid, and the mixture was refluxed for 50 minutes. 100 ml of water were added and extraction was carried out 3 times with ethyl acetate. The organic phase was washed with salt water, dried and purified on silica with methylene chloride-acetone: 85-15 as eluant. The resultant product was dissolved in 100 ml of isopropanol at about 70° C. and filtration was carried out, followed by concentrating, ice-cooling for one hour, separating and drying to obtain 1,425 g of the expected product (white crystals) melting at 192°-193° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[NH:12][C:13]2[C:18]([C:19](=O)[N:20]=1)=[C:17](OC)[C:16](OC)=[C:15](OC)[CH:14]=2.Cl[C:29]1C=C[N:32]=[C:31](CNC)[CH:30]=1>CCO>[CH:19]1[C:18]2[C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]=3[CH:15]=[CH:14][C:13]=2[N:12]=[CH:11][N:20]=1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(OC)c1OC
Reactant: CNCc1cc(Cl)ccn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2ccc3ncncc3c2c1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of 2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (0.2 g, 0.78 mmol) and 4-chloro-2-methylaminomethylpyridine (0.13 g, 0.86 mmol) in EtOH (8 mL). The mixture was heated at 90° C. for 5 h. After cooling, the resulting white solid was filtered and washed with MeOH to provide quinazolino-pyridine compound.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].[CH2:10]=O.[BH4-].[Na+]>CO.ClCCl>[CH3:1][C@@H:2]1[N:7]([CH3:10])[C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9]
Reactant: C[C@@H]1N[C@@H](C)CNC1=O
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CNC(=O)[C@H](C)N1C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (3S,5S)-3,5-dimethyl-2-piperazinone in methanol (12 mL) at room temperature was added formaldehyde (0.345 mL, 37% water solution, 4.6 mmol) followed by sodium borohydride (261 mg, 6.9 mmol). The reaction mixture was stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The aqueous layer was back extracted with CH2Cl2 three times, and the combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield (3S,5S)-3,4,5-trimethyl-2-piperazinone (128 mg, 39%). LCMS: (M+H)+: 143.1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C#N)cn2)CC1
Yield: 73.3 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (198 mg, 0.697 mmol), 2-chloro-5-cyanopyridine (90 mg, 0.65 mmol) and diisopropylethylamine (400 μL) in dioxane (2 mL) in a sealed tube was heated to 170° C. under microwave conditions for 20 minutes. The reaction mixture was cooled, concentrated and then purified by chromatography (silica gel, eluting with 10% hexane/ethyl acetate to 60% ethyl acetate/hexane) to provide the titled compound (167 mg) as a white foam. MS (CI) m/z 380 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 7.80 (dd, 1H), 7.37 (m, 5H), 7.18 (s, 1H), 6.93 (d, 1H), 5.00 (s, 2H), 4.00-3.95 (m, 2H), 3.35-3.26 (m, 2H), 2.19-2.07 (m, 2H), 1.49-1.43 (m, 2H), 1.27 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([C:11](O[C@H]2CC[C@H](C3C=C(F)C(C#N)=C(F)C=3)CC2)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(OCC1C=CC(C(O)=O)=CC=1)CCC.S(Cl)([Cl:49])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([Cl:49])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(C(=O)O[C@H]2CC[C@H](c3cc(F)c(C#N)c(F)c3)CC2)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCOCc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOCc1ccc(C(=O)Cl)cc1
Reaction time: 2 h

Procedure:
Preparation of trans-4-(3,5-difluoro-4-cyanophenyl)-cyclohexyl 4-(butoxymethyl)benzoate (in the formula (1), R=C4H9, l=1, m and n=both, 1, o=0, A1 =1,4-phenylene group, A2 =trans-1,4-cyclohexylene group, Z1 =--COO--, Z2 =covalent bond, X=CN, and Y1 and Y2 =both, F) (Compound No. 148) 4-(butoxymethyl)benzoic acid (1.5 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.8 mmol) pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C., for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(butoxymethyl)benzoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:46][S:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Yield: 98.3 %

Procedure:
Suspend trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (12.5 g, 24 mmol) in dry methylene chloride (100 ml). Add diisopropylethylamine (8.3 mL, 48 mmol). Slowly add methanesulfonyl chloride (2.7 mL, 36 mmol). Pour reaction into saturated aqueous sodium bicarbonate after 20 minutes and extract with methylene chloride. Wash the organic layer with water, dry with sodium sulfate, filter and concentrate in vacuo to yield 14.2 g (99%) of the title compound.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29](Cl)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CCC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 108.3 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 1.0 g of 6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.97 g of the title compound, melting at 275°-278° C. (dec.).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][C:29](=[O:39])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][OH:38])[CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]([NH:28][C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])=[O:39])[CH2:32][CH:33]2[CH2:37][OH:38])=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: Cc1cccc(Cl)c1NC(=O)CN1CCNC(CO)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(CO)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7.4 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 5.5 parts of N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide, 4.0 parts of N,N-diethylethanamine and 68 parts of N,N-dimethylformamide was stirred for 4 hours at about 70° C. The reaction mixture was cooled overnight to room temperature and the solvent was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.21 parts (33.1%) of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide; mp. 149.8° C. (compound 51).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]2[C:10]([C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=3)=[CH:11][N:12]=[C:13]2[CH:18]=1
Reactant: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(-c2ccccc2)n1

Procedure:
[6-Chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine (1 eq, 0.19 mmol, 56 mg) and phenylboronic acid (1.1 eq, 0.21 mmol, 25.6 mg) are dissolved in DME (2 ml) and water (0.5 ml) and Na2CO3 (1.5 eq, 0.29 mmol, 35.5 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.019 mmol, 13.4 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-6-phenyl-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=335
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][O:10]2)=[CH:5][N:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[N:12]([C@@H:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:11][OH:10])=[N+:13]=[N-:14]
Reactant: COc1ccc([C@@H]2CO2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc([C@@H](CO)N=[N+]=[N-])cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-2-methoxy-5-(oxiran-2-yl)pyridine (1.02 g, 6.75 mmol) in acetonitrile (100 mL) were added sodium azide (1.8 g, 27 mmol) and lithium perchlorate (11 g, 0.10 mol) and the mixture was stirred at 60° C. for 4 h. TLC indicated completion of the reaction. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was treated with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-50% EtOAc/hexane) to give a light yellow oil (0.9 g, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.Cl.[OH-].[Na+]>Cl.ClCCl>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:11][CH2:10][CH2:9][C:6]1[C@@H:7]2[CH2:8][C@H:3]([CH2:4][CH:5]=1)[C:2]2([CH3:12])[CH3:1]
Reactant: CC1(C)[C@H]2CC=C(CCO)[C@@H]1C2
Reactant: C1=COCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)[C@H]2CC=C(CCOC3CCCCO3)[C@@H]1C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A solution of 2-{(1R,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl}ethanol (61.6 g) in a minimum of dichloromethane (20 ml) was acidified by treatment with concentrated hydrochloric acid (2 drops). The solution was then treated with 2,3-dihydropyran (56 g), dropwise, at such a rate that the temperature rose to 60° C. and remained at 60° C. During the addition of the 2,3-dihydropyran the acidic nature of the mixture was maintained by the addition of one or more further small quantities of concentrated hydrochloric acid. The mixture was stirred at 60° C. for a further period of 3 hours, and was then added dropwise to a vigorously stirred, ice-cooled, aqueous sodium hydroxide solution (2 N; 91 ml). The resulting mixture was extracted with diethyl ether and the ethereal extract was dried over sodium sulphate, and concentrated and distilled in vacuo, to give 2-{(1R,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl}ethyl tetrahydropyran- 2-yl ether (74 g), b.p. 160°-167° C./14 mmHg [νmax (liquid film): 978, 998, 1038 cm-1. N.M.R. (10% w/v solution in deuterochloroform): multiplets at 5.3δ, 4.55δ, 2.25δ, 1.6δ, broad multiplet at 3.6δ, singlets at 1.3δ, 0.83δ. C16H26O2 requires C, 76.75%; H, 10.47%; found C, 76.75%; H, 10.6%].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:38])[NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[CH:6][N:5]=2)[CH2:35][CH2:36]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(NC(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and (trans-4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Astatech) to give [4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-carbamic acid tert-butyl ester as a white solid. MS (M+H)+, 474
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccccc1OC
Reactant: C1COCCN1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)N2CCOCC2)ccc1C(C)(C)C)c1ccccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Preparation 74F) and morpholine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1COCC1.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)I>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#CCO)cc1
Temperature: 35 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (120 mg; 0.171 mmol) was added to a stirred solution of propargyl alcohol (5.38 g; 95.88 mmol, 1.02 eq), 1-iodo-4-methylbenzene (20.50 g; 94.0 mmol, 1 eq), triethylamine (18.99 g; 188 mmol, 2 eq), and copper iodide (60 mg; 0.32 mmol) in THF (50 mL). The mixture was stirred at 35° C. for 12 h under a nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate. The filtrate was then concentrated at 35° C. (vac.=28 in Hg) using a rotary evaporator. The residue was purified using a silica gel column (4:1 heptane/ethyl acetate→2:1 heptane/ethyl acetate) to give the desired product as a light yellow oil (9.62 g; 65.8 mmol; 70%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 4.48 (s, 2H) 7.11 (d, 2H) 7.33 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:3]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(N)c1C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 99.5 %

Procedure:
A mixture of diethyl [3-amino-2-(methoxycarbonyl)-4-nitrophenyl]malonate (4.80 g, 13.6 mmol), 10% Pd/C (0.72 g) in MeOH (70 mL) and EtOAc (70 mL) was stirred under H2 atmosphere (balloon) at room temperature for 21 h. The catalyst was removed by filtration through diatomaceous earth. The cake was washed with EtOAc and the filtrate was concentrated to give the title compound (4.39 g, 100% yield) as a brown solid.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][N:14]([CH:16]=[O:17])C>N1C=CC=CC=1>[CH3:13][NH:14][C:16]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:17]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 60 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and one drop of pyridine were dissolved in 10 ml of DMF. To the mixture, 10 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-(N-methylcarbamoyloxy)-3-adamantanol (yield 85%) was formed.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)[OH:24])[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33].[CH3:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([OH:24])[C:25]4[CH:30]=[CH:29][C:28]([C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:44]=5)=[CH:27][N:26]=4)[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: NC(=O)c1sc2nc(N3CCC(NCC(O)c4ccc(Br)cn4)CC3)cc(C(F)(F)F)c2c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(C(O)CNC3CCN(c4cc(C(F)(F)F)c5c(N)c(C(N)=O)sc5n4)CC3)nc2)c1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
A N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (60 mg, 0.107 mmol), (3-methylsulfonylphenyl)boronic acid (24 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and potassium carbonate (30 mg, 0.214 mmol) in dry DMF (4 ml) and water (1 ml) was sealed and heated to 85° C. for 18h. The crude reaction mixture was applied to a celite plug and purified by SiO2 chromatography (0–25% MeOH/CH2Cl2 with 1% NH4OH). Fractions containing product were pooled and concentrated. The solid yellow residue was dissolved in 1 ml DMF, applied to a 2 mm prep plate (Merck) and eluted twice with 10% MeOH/CH2Cl2 with 1% NH4OH. The recovered yellow residue was dissolved in 0.5 ml water, 2 ml MeOH, 10 ml CH2Cl2, and 10 ml EtOAc and crystallized by the addition of 50 ml hexanes to give 29.0 mg, 42.3% of 3-Amino-6-(4-{2-hydroxy-2-[5-(3-methanesulfonyl-phenyl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide product. ES+ 635.1 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Oc3ccc4ccccc4n3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenoxy)quinoline (2.4 mmoles, 0.56 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (2.4 mmoles, 0.57 g) were reacted according to procedure C to yield the title compound, 0.8 g. 70%. Mass Spec (FD) 473. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.47; H, 3.48; N, 8.85.