Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Cl-].[Cl-].[Al+3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])(O)[CH3:20]>C1COCC1.C(OCC)C.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH2:11])=[C:13]([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH3:20])[CH:14]=1
Reactant: CC(O)(c1cc(Cl)ccc1N)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(c1cc(Cl)ccc1N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.9 %

Procedure:
To 54 ml of a 1M solution of lithium aluminium hydride in THF are added portionwise 7.1 g of aluminium trichloride. To this solution are added 4 g of 1-(2-amino-5-chlorophenyl)-1-(2-chlorophenyl)ethanol, obtained in Example 25.1, dissolved in diethyl ether, and the mixture is stirred for 18 hours at room temperature and then refluxed for 4 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 40/60 (v/v) dichloromethane/cyclohexane mixture to give 0.9 g of the expected product.
Reaction SMILES: C1OC1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](=[O:15])([OH:14])[OH:13].C=CCCCCCCCC>>[CH2:10]1[CH:9]([C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:14][C:12](=[O:13])[O:15]1
Reactant: CCCCCCCCC1CO1
Reactant: O=C(O)O
Agent: C=CCCCCCCCC
Product: O=C1OCC(c2ccccc2)O1

Procedure:
Decene oxide (8.98 mins), decene carbonate (13.40 mins)
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:22])[CH2:20][OH:21])[N:17]=[C:16]([CH3:23])[N:15]=1)[N:7]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:34]1(B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1>O1CCCC1.O.C(Cl)Cl.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>[CH:34]1([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:10]([CH:9]=[C:8]([C:14]5[N:18]([CH:19]([CH3:22])[CH2:20][OH:21])[N:17]=[C:16]([CH3:23])[N:15]=5)[N:7]=4)[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:36][CH2:35]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)CO)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CC4)cc2OCC3)n(C(C)CO)n1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A microwave vial was charged with a solution of 2-[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-3-methyl-[1,2,4]triazol-1-yl]-propan-1-ol (0.140 g, 0.000346 mol) and Potassium phosphate (0.220 g, 0.00104 mol) in Tetrahydrofuran (2.0 mL) and Water (2.0 mL). The mixture was thoroughly purged with N2. 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.189 mL, 0.00104 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.0400 g, 0.0000346 mol) were added and the vial was sealed immediately. The reaction was heated in the microwave to 120° C. for 20 minutes. The reaction was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 35 mg of 270 as a white solid. MS (ESI+) 366.2. 1H NMR (500 MHz, DMSO) δ 8.26 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.75 (d, J=1.7 Hz, 1H), 5.73-5.57 (m, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.50-4.43 (m, 4H), 3.76 (ddd, J=10.7, 7.5, 6.0 Hz, 1H), 3.68-3.62 (m, 1H), 2.24 (s, 3H), 1.97-1.85 (m, 1H), 1.39 (d, J=6.7 Hz, 3H), 1.02-0.93 (m, 2H), 0.75-0.67 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][C:33]([S:36](=[O:38])(=[O:37])[NH2:39])=[CH:32][CH:31]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1ccccc1-c1ccc(S(N)(=O)=O)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccccc4-c4ccc(S(N)(=O)=O)cc4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[2-(4-sulphamoylphenyl)phenyl]-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(2-aminophenyl)phenylsulphonamide using method I. LCMS; retention time 3.16 min, MH+ 525.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](/[CH:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]C)=[O:36])[CH:30]=2)[N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[C:35]([C:31]1[CH:30]=[C:29](/[CH:28]=[CH:27]\[C:8]2[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:39])=[O:2])[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:34]=[CH:33][CH:32]=1)([OH:37])=[O:36]
Reactant: COC(=O)CCc1nc(/C=C\c2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(/C=C/CCCCOc2ccc(/C=C\c3cccc(C(=O)O)c3)nc2CCC(=O)O)cc1
Yield: 88.9 %

Procedure:
Under the conditions of example 3 C, 82 mg of 3-{6-[2-(3-methoxycarbonyl-phenyl)-(1Z)-1-ethenyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester in 2.5 ml of methanol and 1 ml of tetrahydrofuran is saponified with 2 ml of 2n sodium hydroxide solution and worked up. 69 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[NH:13][N:12]=[C:11]([C:14]2[N:15]([CH2:25][CH3:26])[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.COC(N1C=CN=C1)=O>C(Cl)Cl.C(OCC)(=O)C.OS([O-])(=O)=O.[Na+]>[CH3:1][O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[NH:13][N:12]=[C:11]([C:14]2[N:15]([CH2:25][CH3:26])[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH:10]=1
Reactant: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Agent: COC(=O)n1ccnc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of the above-prepared (2′-ethyl-5′-phenyl-1H,2′H-[3,3′]bipyrazolyl-5-ylmethyl)-carbamic acid tert-butyl ester (25 mg, 68 μmoles) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL, excess). The resulting solution was stirred at room temperature for one hour, then concentrated and azeotroped with acetonitrile (3×) in vacuo. To the resulting crude deprotection product in acetonitrile was added triethylamine, then 1-methoxycarbonyl imidazole (26 mg, 204 μmoles) and the mixture was heated to 90° C. for two hours. The reaction was then cooled to room temperature, diluted with ethyl acetate and 1 M NaHSO4, and stirred vigorously for 20 minutes. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): 7.87 (d, 2H); 7.41 (dd, 2H); 7.37 (dd, 1H); 6.75 (s, 1H); 6.42 (s, 1H); 5.30 (dd, 1H); 4.68 (q, 2H); 4.40 (d, 2H); 3.73 (s, 3H); 1.51 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@:16]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C@H:20](O)[CH:19]2[CH:17]1[CH:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:14])([CH3:11])([CH3:10])[CH3:9].O1CCCC1.CC(C)([O-])C.[K+]>CC(C)=O.O>[C:8]([O:12][C:13]([NH:15][C@@:16]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[CH:20][C@@H:19]2[C@H:17]1[C@H:18]2[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)C2C(C(=O)OC(C)(C)C)C21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C=C[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 23 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
Triethylamine (735 mL, 5.30 mol) is added dropwise at 0° C. under N2 over 40 minutes to a solution of di-tert-butyl(2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (995.4 g, 2.41 mol) in dry tetrahydrofuran (8.4 L) Methanesulfonyl chloride (373 mL, 4.82 mol) is added at 0° C. over 50 minutes. The reaction is warmed to 23° C. After 3 hours, the reaction if filtered to remove triethylamine hydrochloride salt. Wash the filter cake with dry tetrahydrofuran (2×2 L). The filtrate (13 L) is split into two equal parts. To one half of filtrate, add 1M potassium tert-butoxide in tetrahydrofuran (3.6 L, 3.6 mol) dropwise to the solution obtained in previous step (Crude V=6.5 L, 1.2 mol) at 15° C. over 2 hours 15 minutes then allow to warm to 23° C. After 2 hours 30 minutes the reaction is quenched by pouring into 10% aqueous acetic acid (950 mL). Separate the layers and extract the aqueous layer with ethyl acetate (1.7 L). The organic layers are combined and concentrated in vacuo to obtain a solid which is dissolved in acetone (1.45 L) and added to water (7.3 L). Stir the resulting suspension overnight at 23° C. Filter off the precipitate, wash with water (2×1 L), and dry in the vacuum oven at 40° C. to obtain the title compound (450.67 g, yield 95%). MS (m/z): 418 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:49]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([N:58]2[CH2:59][CH2:60][CH:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:56][CH2:57]2)=[O:23])=[CH:25][CH:26]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(OCC(=O)N4CCC(c5ccccc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}acetic acid (100 mg), WSC.HCl (81 mg), and HOBT.H2O (57 mg) were dissolved in chloroform (3 ml) to prepare a solution. 4-Phenylpiperidine (54 mg) was then added to the solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (42 mg, yield 30%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[F:14])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.[Cu]I.O>[C:1]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:9][C:8]=1[F:14])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(N)C(=O)O
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Temperature: 100 °C
Yield: 108.9 %

Procedure:
The title compound, made in accordance with General Method 3, may be used to prepare compound 3 in accordance with General Method 1. N-tert-Butyl-4-bromo-2-fluorobenzamide (850 mg, 3.1 mmol), 2-aminoisobutyric acid (450 mg, 4.36 mmol), CuI (100 mg, 0.5 mmol), TEA (0.2 mL) and K2CO3 (1.0 g, 7.2 mmol) were charged in DMF (8 mL) and water (2 mL) and stirred at RT for 5 min. 2-Acetylcyclohexanone (100 mg, 0.7 mmol) was added and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was acidified with 1 M citric acid (pH 4) and extracted with ethyl acetate (50 mL, 2 times). The combined organic layer was dried over Na2SO4 and concentrated to obtain 1.0 g of 2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[C:21](=S)=[S:22].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:13]([CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:21]=[S:22]
Reactant: S=C=S
Reactant: COc1cc(CCN)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CCN=C=S)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of 1.0 mL (1.0 g, 5.5 mmol) of 2-(3,5-dimethoxyphenyl)ethanamine (8) in 30 mL of THF was added dropwise 2.5 mL (1.8 g, 18.2 mmol) of triethylamine at 0° C. After stirring for 5 min, a solution of 420 mg (5.52 mmol) of carbon disulfide in 5 mL of THF was added dropwise at 0° C. The resulting solution was slowly warmed to room temperature, stirred for 1.5 h and then cooled to 0° C. To the reaction mixture was added 1.16 g (6.07 mmol) of tosyl chloride in one portion and solution stirred at room temperature for an additional hour. The reaction was quenched by slowly adding 30 mL of saturated NH4Cl(aq). The layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was taken up in methylene chloride and filtered through a plug of silica gel (eluted with methylene chloride) and concentrated in vacuo to afford 1.2 g (100%) of 9 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 3H), 3.80 (s, 6H), 3.71 (t, J=7.0 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:19]1[C:23]2[CH:24]=CC=C[C:22]=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[CH:23]([NH:19][C:15](=[O:17])[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[1-(Tert-butoxycarbonyl)piperidin-4-yl]acetic acid 46-1 (0.20 g, 0.82 mmol), 1-hydroxybenzotriazole (0.15 g, 0.99 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g, 1.07 mmol), 4-methylmorpholine (0.33 g, 3.29 mmol) and isopropyl amine (0.053 g, 0.90 mmol) were dissolved in DMF and stirred at 25° C. for 18 hours. Evaporated off the DMF and partitioned between ethyl acetate and dilute KHSO4. The aqueous was drawn off and the organic was washed with dilute NaHCO3, brine, dried, filtered and evaporated to afford 46-2. 1H-NMR (CD3OD): 4.03(d, 2H); 3.95(m, 1H); 2.75(br s, 2H); 2.06(d, 2H); 1.91(m, 1H); 1.64 (d, 2H); 1.44(s, 9H); 1.12(complex, 8H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[C:19]([CH3:26])[CH:18]=1
Reactant: CSc1nc(Cl)c(C=O)c(NC(C)C)n1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1nc(NC(C)C)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-(4-fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.21 (s, 3H), 2.59 (s, 3H), 4.52 (m, 1H), 7.90-7.15 (m, 2), 7.18-7.25 (m, 1H), 9.06 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=320 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CO>C1(C)C=CC=CC=1>[CH2:16]([O:15][P:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:9]=[CH:8][CH:7]=1)([O:12][CH2:13][CH3:14])=[O:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CCOP(=O)(Cc1cccc(CCN)c1)OCC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCc1cccc(CP(=O)(OCC)OCC)c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of diethyl [[3-(2-aminoethyl)phenyl]methyl]phosphonate (Example D) (3.6 g, 13.2 mmol) in toluene (15 ml) and triethylamine (2.7 g, 26.4 mmol) is cooled in an ice/salt bath and a solution of ethyl bromoacetate (2.2 g, 13.2 mmol) in toluene (8 ml) is added dropwise over 20 minutes. A gum forms and methanol (5 ml) is added and stirred an additional two hours. After evaporation of the solvent, the residue is dissolved in ethyl acetate (75 ml) and washed with water (20 ml, and 10 ml) and then saturated sodium chloride solution (10 ml). The organic layer is dried over magnesium sulfate, filtered, and evaporated to give an oil (4.3 g). Chromatography over silica gel gives an analytical, colorless oil. 1H-NMR: 4H, m, 7.33-7.0 ppm; 6H, m, 4.33-3.86; 2H, s, 3.40; 2H, d, 3.13; 4H, m, 2.90-2.70; 1H, s, 1.8; 9H, m, 1.33-1.10.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CNCCN1
Reactant: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)Cl)cc1
Product: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)N2CCNC(=O)C2)cc1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12c) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 573.5 [(M+H)+]
Reaction SMILES: [C:1]([CH2:8][C:9]([OH:11])=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C([Cl:15])=O>CCCCCC>[C:1]([CH2:8][C:9]([Cl:15])=[O:11])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(=O)CC(=O)O
Solvent: CCCCCC
Product: CCCCCC(=O)CC(=O)Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
8.7g (0.05 m) of hexanoylacetic acid and 12.7 g (0.10m) of oxalyl chloride were mixed together at room temperature. The reaction was heated gradually over one hour to 50-60° C., then to 60-70° C. under aspirator pressure for one hour. The reaction mixture was diluted with 125 ml hexane, washed with 3×100 ml ice water, dried over 20 g MgSO4, and roto-vapped at 50° C. to yield an oil (9.4 g, 98% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[NH:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[H-].[Na+].[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27]Cl)[CH3:23].C(O)(=O)/C=C\C(O)=O>CN(C=O)C.CC(C)=O.CCOCC>[CH3:1][N:2]1[C:8]([S:9][CH2:27][CH2:26][CH2:25][N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])=[N:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: CCN(CC)CCCCl
Reactant: CN1Cc2ccccc2C(c2ccccc2)NC1=S
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCN(CC)CCCSC1=NC(c2ccccc2)c2ccccc2CN1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A solution of of 12 g (45 mmol) of 1,2,4,5-tetrahydro-4-methyl-1-phenyl-3H-2,4-benzodiazepin-3-thione of Example 152 in 100 mL of DMF was treated with 1.24 g (50 mmol) of sodium hydride at 70° and 7.5 g (50 mmol) of 3-diethylaminopropyl chloride was added dropwise at 70°. The reaction was stirred at 70° for five hours and then at room temperature for two days. The reaction was poured into 250 mL of ice water and extracted twice into ethyl acetate. The product was extracted into 150 mL of 2N HCl, washed with ethyl acetate, made basic, and extracted back into ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, stripped, and the residue was dissolved in acetone. Two equivalents of maleic acid in 40 mL of acetone was added, followed by a small amount of ether. The resulting precipitate was recrystallized from acetone/ether to provide 13.2 g of product as the dimaleate salt, mp 95-97.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.CN([C+](N(C)C)N1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)O
Agent: CN(C)[C+](N(C)C)n1n[n+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 411 mg (1 mmol) 4-(6-Bromo-8-isobutylamino-imidazo[1,2-a]pyrazin-3-yl)-2-methyl-benzoic acid which was prepared according to intermediate example 49b in 4 mL 1-methylpyrrolidin-2-one were added 114.9 mg cyclopropanamine, 760 mg bis(dimethylamino)(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methylium hexafluorophosphate and 685 μL N-ethyl-N-isopropylpropan-2-amine and the mixture was stirred overnight at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to give 65.5 mg (15%) of the title compound.