Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:24][CH:12]([CH3:13])[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Product: CC(Oc1ccc(Cl)c(Cl)c1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 3,4-dichlorophenol. MS (m/e): 360.0 (M−H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=O)[CH2:4]1)[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][CH2:21][CH2:22][C:23]#[N:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(CCCC(N)=O)CC1c1nnc2cnc3[nH]ccc3n12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](CCCC#N)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Reaction time: 4 h
Yield: 15.3 %

Procedure:
To a solution of 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide (0.090 g, 0.264 mmol, Example #FFFF.1) in DCM (3 mL) was added TFAA (0.373 mL, 2.64 mmol). After about 4 h at ambient temperature the reaction mixture was concd in vacuo and purified by chiral preparative HPLC (Table 2, Method 33) to provide 4-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile (0.013 g, 15%) (rt=16.1 min, or =neg) LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 323 (M+H)+ and 4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile (0.010 g, 12%) (rt=13.7 min, or =neg) LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 323 (M+H)+ as solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]([O:15][CH3:16])=[O:14].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CO.N1CCCCC1>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](/[CH:26]=[C:8]2\[O:9][C:5]3[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:18]1
Reactant: COC(=O)c1c(OC)ccc2c1OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1c(OC)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of methyl 6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.070 g, 0.32 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.046 g, 0.32 mmol). Then, the mixture was added with 7 drops of piperidine, then the mixture was stirred at room temperature for 2 hours, and the solid formed was collected by filtration to obtain the objective substance. Further, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain the objective substance. Two portions of the objective substance was combined to obtain 0.090 g (80%) of methyl (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:13]([C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[C:5]2=[C:6]3[S:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=[C:4]2[N:3]=1.N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:21][CH2:20][C@H:17]2[CH2:16][CH2:15][C@H:14]([N:13]3[C:5]4=[C:6]5[S:12][CH:11]=[CH:10][C:7]5=[N:8][CH:9]=[C:4]4[N:3]=[C:2]3[CH3:1])[CH2:19][O:18]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c(C)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of [(2R,5S)-5-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]methanol (60.1 mg, 0.198 mmol) in methylene chloride (2.3 mL) and pyridine (51 μL, 0.62 mmol) was added p-toluenesulfonyl chloride (38.7 mg, 0.203 mmol) and 4-dimethylaminopyridine (1.2 mg, 0.010 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (50 mg, 55%). LCMS calculated for C22H24N3O4S2 (M+H)+: m/z=458.1. Found: 458.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[C:24]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3)CC2)c(C)c1
Reactant: BrCc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(Cc5ccccc5)C4=O)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (100 mg) described in Example 401 and benzyl bromide (35 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (63 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:17]#[N:18])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N:25]([Sn](C)(C)C)=[N+:26]=[N-:27]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:6]([C:17]1[NH:27][N:26]=[N:25][N:18]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: Cc1ccccc1C
Product: Clc1ccc2nc(N3CCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 20.5 %

Procedure:
6-Chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carbonitrile (25 mg, 74.9 μmol, Eq: 1.00) and azidotrimethyltin (30.8 mg, 150 μmol, Eq: 2) were dissolved in xylene (1 ml) and the reaction mixture was heated to 120° C. for 40 h. The mixture was allowed to cool to RT and the solid was filtered off, washed with boiling toluene and suspended in water. The pH was adjusted to 1 by addition of 0.1N HCl and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried with Na2SO4 and evaporated and the remaining residue was purified by column chromatography (silica gel, DCM/MeOH 9:1) to afford the title compound as yellow solid (5.8 mg). MS (ESI): 377.3 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:15])[CH2:13]I)[CH2:3]1.[N:26]1([C:31]2[N:36]=[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:34]=[C:33]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[N:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:15])[CH2:13][N:40]2[CH2:41][CH2:42][N:37]([C:35]3[CH:34]=[C:33]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[N:32]=[C:31]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:36]=3)[CH2:38][CH2:39]2)[CH2:3]1
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
3β-Hydroxy-21-iodo-16α-methylpregn-5-en-20-one (10 g) is added all at once to 4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]piperazine (16 g) in DMF (400 ml) at 65° and then concentrated to 50 ml under reduced pressure. The concentrate is added to sodium dihydrogen phosphate (0.3M, 400 ml) and ethyl acetate (500 ml). The pH is adjusted to 4.5 with 0.3M phosphoric acid. The ethyl acetate layer is separated and extracted with sodium dihydrogen phosphate (0.3M, 2×200 ml). The ethyl acetate extract is then washed with phosphoric acid (0.3M, 400 ml). The acid extract is stirred and the ph is adjusted to 3.5 with sodium hydroxide (10%). The resulting precipitate is filtered, washed with water (200 ml) and dried to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[NH4+].[Cl-].O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2)=NN1c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
The product from step 1 (1.25 g, 4.4 mmol) in DCM (30 mL) was added BBr3 (30 mL, 1 M in DCM) dropwise at 0° C. After stirring 4 h at rt, the mixture was cooled to 0-5° C. on an ice-bath while saturated NH4Cl solution (30 mL) was added dropwise. Additional water was added and the DCM was removed at reduced pressure. The solid was collected and dried to give 1.1 g (93%) of a tan solid; Mp>220° C.; MS m/z 268 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:15])[CH3:16])=[C:5]3[NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)CC(C)C)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, 1-{6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}-3-methylbutan-1-one (13 mg, 0.030 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (21 mg, 0.075 mmol) to afford the desired product (8.8 mg, 58%) as a yellow solid: NMR (500 MHz, CD3OD) δ 8.94 (s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 4.24 (t, J=10.8 Hz, 1H), 3.99 (s, 3H), 2.94 (d, J=7.0 Hz, 2H), 2.82 (s, 1H), 2.53 (s, 6H), 2.42 (d, J=12.0 Hz, 2H), 2.33-2.21 (m, 1H), 2.14 (d, J=12.0 Hz, 2H), 1.72-1.53 (m, 4H), 1.03 (d, J=6.7 Hz, 6H); ESI MS m/z 510 [C29H36ClN3O3+H]+; HPLC>99% (AUC), tR=11.38 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:25][CH3:26])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37].[OH-].[Na+]>C(#N)C.CO>[C:36]([N:1]1[CH2:2][CH:3]([C:5]2[C:6]([O:25][CH3:26])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of N-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine (25 mg, 0.064 mmol, from Example 194, Step 8) in acetonitrile (0.3 mL) was treated with DIPEA (28 μL, 0.16 mmol) followed by acetyl chloride (5.4 μL, 0.076 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated with 1N sodium hydroxide (200 μL) and heated briefly with a heat gun. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6.3 mg, 23%). 1N NMR (300 MHz, DMSO-d6) δ 8.15-8.06 (m, 2H), 7.72 (s, 1H), 5.82-5.61 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.30 (m, 1H), 4.29-4.17 (m, 1H), 4.14-4.03 (m, 0.5H), 3.86 (s, 3H), 1.84-1.71 (m, 5H), 1.45 (d, J=6.8 Hz, 3H). LCMS for C19H21Cl2N6O2 (M+H)+: m/z=435.1. Found: 435.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:10]=1/[CH:11]=[CH:12]/[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16](Cl)=[N:17][C:18]=2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([P:29]([CH3:32])([CH3:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:10]=1/[CH:11]=[CH:12]/[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[N:17][C:18]=2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([P:29]([CH3:32])([CH3:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(-n3ccnc3)nc21
Temperature: 25 °C

Procedure:
Imidazole (0.16 g, 2.36 mmol) was dissolved in DMF (1.0 mL) in a CEM 10 mL microwave tube and to this was added NaH (0.09 g, 60% dispersion in mineral oil). The content was stirred at room temperature until no more bubbling was observed (˜10 min). Then (E)-9-(2,6-dimethylstyryl)-2-chloro-N-(4-(dimethylphosphoryl)phenyl)-9H-purin-6-amine (0.12 g, 0.236 mmol) was added. The reaction was heated with microwave (120° C., 10 min). Solvent was removed on rotavapor and the residue was partitioned between EtOAc/water, and the organic layer was separated and dried Na2SO4. The product was purified on ISCO combiFlash (12 g silica gel column, 5% MeOH/DCM): MS [M+H]+ 484.
Reaction SMILES: [H-].[Na+].C#CCCCC.FC1C=CC(C2C=CC(C(=O)C)=CC=2)=CC=1.FC1C=CC(C2C=CC=CC=2)=CC=1.C(Cl)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([O-:67])([C:61]#[C:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH3:60])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1.[Na+].[Cl-].[NH4+]>C1COCC1>[F:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([OH:67])([C:61]#[C:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH3:60])=[CH:55][CH:54]=2)=[CH:51][CH:52]=1
Reactant: CCCCC#CC(C)([O-])c1ccc(-c2ccc(F)cc2)cc1
Agent: C#CCCCC
Agent: CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Fc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCCCC#CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
2.43 g. of sodium hydride in added portionwise to a solution of 8.2 g. of 1-hexyne in 30 ml. of dry THF and then, under a stream of nitrogen, a solution of 21.4 g. of 4'-fluoro-4-acetylbiphenyl, preparable from 4-fluorobiphenyl and acetyl chloride in the presence of AlCl3, in 60 ml. of THF is added thereto. The reaction mixture contains sodium 2-(4'-fluoro-4-biphenylyl)-3-octyn-2-olate. It is hydrolyzed with an aqueous 15% ammonium chloride solution and worked up as usual. There is obtained 2-(4'-fluoro-4-biphenylyl)-3-octyn-2-ol; m.p. 62°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([N:10]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:7]([CH3:17])=[C:6]([N:18]3[CH2:21][CH:20](C)[CH2:19]3)[N:5]=2)[CH2:3][CH2:2]1.N1(C2N=C(C3CC3)N=C(N3CC(O)C3)C=2C)CCCCCC1.C1(C2N=C(N3CCCCCC3)C=C(N3CC(C)C3)N=2)CC1.N1(C2N=C(C3CC3)N=C(N3CCCCCC3)C=2)CCC1.C1(C2N=C(N3CCCCCC3)C(C)=C(N3CC(F)C3)N=2)CC1>>[N:18]1([C:6]2[N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=[C:8]([N:10]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:7]=2[CH3:17])[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(C)C1
Agent: CC1CN(c2cc(N3CCCCCC3)nc(C3CC3)n2)C1
Agent: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(F)C1
Agent: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(O)C1
Product: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CCC1

Procedure:
1-[2-cyclopropyl-5-methyl-6-(3-methylazetidin-1-yl)pyrimidin-4-yl]azepane; 1-(6-azepan-1-yl-2-cyclopropyl-5-methylpyrimidin-4-yl)azetidin-3-ol; 1-[2-cyclopropyl-6-(3-methylazetidin-1-yl)pyrimidin-4-yl)azepane; 1-(6-azetidin-1-yl-2-cyclopropylpyrimidin-4-yl)azepane and 1-[2-cyclopropyl-6-(3-fluoroazetidin-1-yl)-5-methylpyrimidin-4-yl]azepane, or pharmaceutically acceptable salts thereof.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:13]([CH3:30])[C:12]1=[O:31].[OH-].[Na+]>CO>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:14]1[N:13]([CH3:30])[C:12](=[O:31])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)CCCCCCCn1c(-c2ccccc2F)c(-c2ccccc2F)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccccc2F)c(-c2ccccc2F)n(CCCCCCCC(=O)O)c1=O

Procedure:
The product is produced as described in example 18 from 5.2 g of 8-[4.5-bis-(2-fluorophenyl)-3-methyl-2-oxo-4-imidazolin-1-yl] caprylic acid methyl ester and 0.53 g of NaOH in 25 cc. of methanol. Recrystallization from ether/hexane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[C:16]1([C:12]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:1])[CH:11]=2)[OH:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(O)nc2ccccc12
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(C(O)(c2ccccc2)c2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.3 %

Procedure:
A solution of methyl 2-hydroxy-4-quinolinecarboxylate (406 mg, 2 mmol) in THF (20 mL) at 0° C. was treated with a solution of phenyl lithium (1.8-M in THF, 2.3 mL, 4.2 mmol), stirred at room temperature for 2 h, poured into water (100 mL), the resulting precipitate filtered and dried to give the title compound (636 mg, 97%) as a cream solid: mp>350° C.; IR νmax (Nujol)/cm−1 3550-3300,3085, 3059, 2924, 2854, 1652, 1461, 1377, 759, 750 and 698; NMR δH (400 MHz, ?) 5.66 (1H, s), 6.88 (1H, t, J 7.6 Hz), 7.28-7.39 (11H, m), 7.47 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 8.6 Hz), 7.81 (1H, d, J 7.6 Hz) and 11.63-11.88 (1H, s); M/Z 328 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>C(O)CCC>[CH2:3]([O:29][C:28](=[O:30])[CH2:27][CH2:26][C:25]([NH:24][C@H:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)[CH2:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[O:31])[CH2:2][CH2:7][CH3:6]
Reactant: CS(=O)(=O)NC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)NS(C)(=O)=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
To a solution of N—[(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-succinamic acid (50 mg, 0.107 mmol) in n-butanol (2 mL) is added thionyl chloride (9.38 μL, 0.128 mmol). The reaction mixture is warmed to 50° C. and stirred for 1 h. After cooling to room temperature, the reaction mixture is concentrated and purified by reverse phase HPLC (SunFire C18, 0.1% TFA in H2O/CH3CN) to give N—[(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-succinamic acid butyl ester (32 mg). HPLC retentions time=1.56 minutes (condition A); MS (m+1)=523; 1H NMR (400 Mz, DMSO-d6) δ ppm 0.86 (t, 3H, J=7.33 Hz), 1.22-1.34 (m, 2H), 1.45-1.55 (m, 2H), 2.23-2.33 (m, 2H), 2.35-2.44 (m, 3H), 2.45-2.55 (m, 3H), 2.71-2.83 (m, 1H), 3.18 (s, 3H), 3.96 (t, 2H, J=6.57 Hz), 4.27-4.38 (m, 1H), 7.28 (d, 2H, J=8.08 Hz), 7.37-7.43 (m, 1H), 7.48 (t, 1H J=7.83 Hz), 7.62 (d, 3H, J=8.34 Hz), 7.70 (s, 1H), 7.91 (d, 1H, J=8.34 Hz), 11.71 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].[K].Cl[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.C(O)C>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:7]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: NC(=S)c1cccs1
Agent: [K]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cccs2)s1
Reaction time: 20 h
Yield: 62.5 %

Procedure:
Acetic acid (3.78 ml) was added to a stirred mixture of 2-thiophenecarbothioamide (3.15 g), ethyl chloroformylacetate potassium salt (6.23 g) and ethanol (60 ml). Afte refluxing for 4 h, ethyl chloroformylacetate potassium salt (4.15 g) and acetic acid (2.52 ml) were added, and then the refluxing was continued for further 20 h. The reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to give an oil which was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v) the crystals of ethyl 2-(2-thienyl)-5-thiazolecarboxylate (3.29 g, 63%) were obtained. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 61-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C.C(OCC)(=O)C.O>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Reaction time: 0.25 h

Procedure:
Under argon, 213 mg (1.13 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT are placed in 18 ml of DMF. After 15 min, 627 μl (4.5 mmol) of TEA and 0.75 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane are added. After 2 hours, water and ethyl acetate are added; the aqueous phase is separated off and extracted a further 2× with ethyl acetate. The organic phases are washed 2× with water, sat. NaHCO3 solution, 2× water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/THF 5:1) and crystallisation from ether yield the title compound: m.p: 200-201° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.