Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)[OH:4])#[CH:2].I[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>O.C(OCC)C.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>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[C:1]#[C:2][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(C#CC(O)c2cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6 g (15.4 mmol) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol, 4.1 g (15.4 mmol) of methyl 4-iodobenzoate and 50 ml of triethylamine are introduced into a three-necked flask. The reaction medium is degassed with nitrogen for 30 minutes and 820 mg (1.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 360 mg (1.9 mmol) of copper iodide are then added successively. The reaction medium is stirred at room temperature for four hours and evaporated to dryness, and the residue obtained is taken up in water and ethyl ether. The organic phase is separated out after settling has taken place, dried over magnesium sulphate and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (80/20% by volume); 6.7 g (84%) of methyl 4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoate are collected, with a melting point of 91-2° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([Cl:25])[CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:26].[C:28](O)(=[O:31])[CH2:29][OH:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:27])[CH2:2][NH:1][C:29](=[O:30])[CH2:28][OH:31])=[C:7]([CH3:26])[CH:8]=3)[N:17]=2)[CH:23]=[C:22]([CH3:24])[N:21]=1
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)cc(Cl)n1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (134 mg, 0.345 mmol) in DCM (10 mL), glycolic acid (54 mg, 0.707 mmol) and DIPEA (132 mg, 1.02 mmol) is added. The mixture is cooled to 0° C. and TBTU (134 mg, 0.416 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 16 h before it is diluted with EA (250 mL), washed with 1 N aq. NaOH solution (3×25 mL), 1 N aq. KHSO4 (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC to give N-((RS)-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (23 mg) as a colourless resin; LC-MS: tR=0.91 min, [M+1]+=447.44.
Reaction SMILES: N1[NH:2][C:3](=[O:7])[CH:4]=[CH:5]C=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1.N>>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([N:2]2[CH2:5][CH2:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2CCC2=O)cc1

Procedure:
The title compound was prepared using the procedure described in Example 35B substituting azetidin-2-one for pyridazin-3(2H)-one and substituting the product from Example 35A for the product from Example 34F. 1H NMR (300 MHz, CD3OD) δ 0.98-1.04 (m, 1H), 1.08-1.15 (m, 1H), 1.34 (d, J=6 Hz, 3H), 1.35 (m, 1H), 1.59-1.72 (m, 1H), 1.94-2.04 (m, 3H), 2.18-2.29 (m, 1H), 2.75 (q, J=6 Hz, 1H), 2.98-3.07 (m, 1H), 3.08 (t, J=6 Hz, 2H), 3.16-3.26 (m, 1H), 3.32-3.36 (m, 1H), 3.52-3.62 (m, 1H), 3.65 (t, J=6 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 299 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=1[OH:41]>ClCCl.O>[OH:41][C:33]1[C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (1.00 g) and 1,1'-carbonyldiimidazole (821 mg) in dichloromethane (5 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred solution of 2-amino-6-nitrophenol (723 mg) in dichloromethane (10 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1N HCl (50 ml) and brine (50 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (1.05 g, 68%) as an orange solid. δH (250 MHz;d6DMSO), 1.58-1.97 (8H,m,4 ×CH2), 3.73 (2H,s,CH2), 3.87 (3H,s,OMe), 4.79 (1H,m,CH), 6.78-6.93 (3H,m,ArH), 6.98 (1H,t,ArH), 7.78 (1H,dd,ArH), 7.95 (1H,bs,CONH), 8.71 (1H,dd,ArH), 10.5 (1H,bs,ArOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[NH:8])[NH2:7])[CH3:2].C(N(CC)CC)C.Br[CH:18]([CH3:22])[C:19](=O)[CH3:20]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:19]([CH3:20])=[C:18]([CH3:22])[NH:8][C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)CC(=N)N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N)[nH]c(C)c1C
Temperature: 5 °C
Yield: 35 %

Procedure:
To a solution of Carbamimidoyl-acetic acid ethyl ester (0.5 g) in ethyl acetate (6 mL) was added triethylamine (0.5 mL) and mixture was stirred at 5° C. Than 3-Bromo-butan-2-one (0.4 mL) was added under a nitrogen atmosphere and the mixture was refluxed for 1 h. The reaction mixture was then filtered through a medium porosity fitted glass funnel containing a thin layer of silica gel. The filtrate was washed with 100 mL of ethyl acetate and the combined washes were then evaporated under reduced pressure to give (0.25 g, 35%) of 2-Amino-4,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [MH]+=183.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[C:10](OC)=[C:9]([C:19]#[CH:20])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:35])[C:25]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(N(CC)CC)C.[C:43](OCC)(=[O:45])C>CCCCCC.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>[CH3:22][O:23][C:24](=[O:35])[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:20]#[C:19][C:9]2[CH:8]=[C:7]([O:45][CH3:43])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=3[CH:10]=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1OC)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.090 g, 0.32 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent-2, 0.097 g, 0.3 mmol), triethyl amine (8 mL) copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–20% ethyl acetate in hexane as the eluent, the title compound was obtained as a solid (0.09 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)C(Cc1cnc[nH]1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of [S-[R*,R*)]-[1-({2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclobutymethyl)-carbamoyl}-ethyl}-methyl-carbamoyl)-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (from Step 3, 1.28 g, 1.36 mmol) in methylene chloride (10 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and the solution was washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The residue was purified twice by chromatography (first: CH2Cl2:CH3OH 10:1; second: CH2Cl2:CH3OH 15:1) (0.23 g, 0.33 mmol; 24% yield); MS-APCI 700 (m+1).
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[NH2:16][C:9]1[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([NH:26][CH:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:29]3)([CH3:18])[CH2:7][C:6]=2[C:8]=1[CH3:17]
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 91.9 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), N-(diphenylmethyl)-4-piperidinamine (1.4 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) and recrystallized from hexane/ethyl acetate to afford 1.4 g of the title compound. Yield 91%.
Reaction SMILES: [CH2:1]([O:6][C:7](=O)[CH:8]([NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:9][C:8]1[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:4]2[CH2:3][CH2:2][CH2:1][O:6][C:7]=12
Reactant: C=CCCCOC(=O)C(C)NC(=O)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(c(C)n1)OCCC2
Temperature: 15 °C

Procedure:
Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)propanoate (1.05 g, 1 eq) and DCM (15 mL) were added to a vessel with stirring. Pyridine (0.39 g, 1.2 eq) was then added and the mixture was cooled to 15° C. Tf2O (1.7 g, 1.5 eq) was added to the mixture over 15 min and the mixture was warmed to ambient temperature to stir for 1.5 h. The reaction was quenched by the addition of DCM and 20 wt % aqueous NaOAc to form a biphasic mixture. The layers were separated and the organic layer was washed with water. The organic layer was then concentrated under reduced pressure to provide the title compound as yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.62 (s, 1H), 4.32 (q, J=7.12 Hz, 2H), 4.16-4.25 (m, 2H), 2.70 (t, J=6.44 Hz, 2H), 2.37 (s, 3H), 1.86-2.03 (m, 2H), 1.31 (t, J=7.12 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 165.15, 152.44, 147.98, 137.72, 128.73, 124.80, 66.85, 61.09, 23.98, 21.06, 18.98, 14.11; HRMS (M+H) m/z, calcd for C12H16NO3, 222.1130; found, 222.1133.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:18])[CH2:16][CH3:17].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:20](=[O:22])[O:18][CH:15]([CH2:16][CH3:17])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCC1OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the procedure of Example 9 from 1-(4-amino-3′-chloro-biphenyl-3-yl)-propanol and triphosgene. White solid: mp 146-148° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, J=8.22 Hz), 7.39 (d, 1H, J=8.28 Hz), 6.97 (d, 1H, J=8.22 Hz), 5.4 (t, 1H, J=10.9 Hz), 1.9 (m, 2H), 0.97 (t, 3H, J=7.68 Hz); MS (ESI) m/z 286 ([M−H]−, 100%)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)[N:22]2[N:21]=1)=O>>[CH3:34][N:32]1[CH:33]=[C:29]([C:28]2[N:22]3[C:23]([CH:24]=[N:25][C:20]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)=[N:21]3)=[CH:26][CH:27]=2)[CH:30]=[N:31]1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Product: Cn1cc(-c2ccc3cnc(Nc4cccc(OCCN5CCOCC5)c4)nn23)cn1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 10 (brs, 1H), 9.4 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.5 (brs, 1H), 7.3 (m, 2H), 7.06 (d, J=4.6 Hz, 1H), 6.9 (d, J=4.6 Hz, 1H), 6.7 (d, J=8.0 Hz, 1H), 4.3 (m, 2H), 4-3.1 (m, 10H), 3.9 (s, 3H); LC/MS (ESI+): 420 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])C#N)=[CH:4][CH:3]=1.OS(O)(=O)=O.O.[C:25]([O-:28])([O-])=[O:26].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[C:25]([OH:28])=[O:26])=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCC(C#N)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCC1CCC(C(=O)O)c1ccc(Br)cc1

Procedure:
The oily residue of 2-(4-bromo-phenyl)-4-(1-methyl-pyrrolidin-2-yl)-butyronitrile was hydrolyzed by refluxing for 2 h with concentrated H2SO4 and water (38:28) (4 mL). The mixture was neutralized with Na2CO3, then MeOH (20 mL) was added. The solid was filtered and washed with MeOH (3×10 mL). The combined methanol solution was evaporated to give an oil product. MS: calc'd 326 (MH+), exp 326 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)([OH:8])(=[O:7])=[O:6]>CCOCC.CN(C)C=O>[S:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([Cl:3])=[O:19])=[CH:12][CH:11]=1)([OH:8])(=[O:7])=[O:6]
Reactant: O=C(O)Cc1ccc(CS(=O)(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)Cc1ccc(CS(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of thionyl chloride in 20 ml of anhydrous ether is added p-sulfomethylphenylacetic acid. The mixture is stirred at room temperature until gas evolution ceases. Two drops of dimethylformamide is added, and the resulting mixture is stirred at 40° C. for 2.5 hours. The title compound is obtained after filtration and evaporation of the reaction mixture. The infrared spectrum of the product shows a characteristic acid chloride absorption at 1830 cm-1 whereas the starting acid shows a carbonyl absorption at 1740 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@@]1(O)CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (R)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The material was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.75 g, 69%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2,H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H) 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=2.00 min, M+H+=270.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)#[CH:20].[I-]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#Cc1cncnc1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (719 mg, 2.01 mmol) and triethylamine (3 mL, 0.015 mmol) in N,N-dimethylformamide (3 mL) was treated with 5-ethynyl-pyrimidine (230 mg, 2.21 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (92 mg, 0.48 mmol) and bis(triphenylphosphine)palladium (II) chloride (169 mg, 0.24 mmol). The reaction was stirred at 25° C. for 18 h and then heated at 67° C. for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid methyl ester (440 mg, 66%) as an orange oil: EI-HRMS m/e calcd for C21H22N2O2 (M+) 334.1681, found 334.1681.
Reaction SMILES: [H-].[Na+].CO[CH2:5][CH2:6][O:7][CH2:8][CH2:9]OC.[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15].[OH2:18]>>[CH3:15][C:14]([CH:13]([CH3:17])[CH3:12])=[CH:5][C:6]([O:7][CH2:8][CH3:9])=[O:18]
Reactant: O
Reactant: CC(=O)C(C)C
Reactant: COCCOCCOC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C(C)C(C)C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of sodium hydride (2.6 g) in diglyme (10 mL) triethylphosphonoacetate (24 g, 107 mmol) was added dropwise under nitrogen in an ice bath (ca. 0° C.). The mixture was stirred for 30 min. and then 3-methyl-2-butanone (XII, 4.3 g, 50 mmol) was added dropwise and the mixture stirred at ambient temperature for three hours. The mixture was cooled, diluted cautiously with a large excess amount of water, and extracted with ether. The ethereal extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to yield ethyl 3,4-dimethyl-2-pentenoate (XI, 7.1 g, 91%): NMR (Jeol C 60 HL, CDCl3) δ1.08 [6H, d, J=7 Hz, (CH3)2CH], 1.30 (3H, t, J=7 Hz, CH3CH2O), 2.15 (3H, d, J=1.5 Hz, CH3C=), 4.15 (2H, q, J=7 Hz, CH 3 CH2O), 5.68 (1H, br.s, CH=C); IR (neat) 1705 (C=O), 1640 (C=C), 1385 and 1365 [(CH3)2C] cm-1 ; GLC (2% OV-17, Chrom W 80/100, 2 mm×200 cm, 60° C., N2 30 cc/m) retention time, 9 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(NC3CCC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
To a mixture of 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (165 mg, 0.55 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (135 mg, 0.605 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.041 mL, 0.771 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (202 mg, 0.394 mmol, 71.6% yield). LC-MS (M+H)+=487.14. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.2 Hz), 7.28-7.33 (2H, m), 7.18-7.24 (3H, m), 7.13 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=1.2 Hz), 6.74 (1H, dd, J=8.5, 2.1 Hz), 4.64-4.80 (2H, m), 4.17-4.23 (1H, m), 3.49 (3H, s), 2.72-2.81 (1H, m), 2.61-2.71 (2H, m), 2.43-2.53 (2H, m), 2.09 (1H, td, J=8.0, 2.3 Hz), 1.92-2.04 (2H, m), 1.70-1.88 (2H, m).