Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[N:20][CH:19]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cncc2ccccc12
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: Cc1cccc(C#CC=C2CCN(c3cncc4ccccc34)CC2)n1
Yield: 59.9 %

Procedure:
A mixture of the compound of Example 3 (0.076 g, 0.36 mmol), 4-bromoisoquinoline (0.064 g, 0.30 mmol), cesium carbonate (0.494 g, 1.5 mmol), 2,2′-bis(diphenylphosphino)-1,1′binaphthalene (0.011 g, 0.024 mmol), palladium(II)acetate (0.0027 mg, 0.012 mmol) in anhydrous and degassed toluene (3 mL) was heated at reflux under a nitrogen atmosphere for 18 h. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (CHCl3-1.4 N MeOH NH3 100:0.25) affording the title product (0.061 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[SH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[S:28][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Reactant: Oc1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 64 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (250 mg, 0.52 mmol) was treated with 2-mercaptophenol (80 μl, 0.80 mmol), potassium carbonate (110 mg, 0.8 mmol) and copper(I) iodide (150 mg, 0.79 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-25%, hexane-ethyl acetate) to give 252 mg (64% yield) to the title compound as an oil.
Reaction SMILES: [OH2:1].Cl.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH3:9][C:3]1[CH:8]=[CH:7][C:6]([C:4]2[C:3]([C:9]([OH:1])=[O:1])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: O
Agent: Cl
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
The resulting reaction solution was stirred at a temperature of 150° C. for 8 hours at a pressure of 1 to 2 kgf/cm2, and then cooled to 90° C. To this reaction solution was added dropwise 28.99 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 34.4 g (0.33 mol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75° C. to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand to separate into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and the solution was then gradually cooled to allow sedimentation of white crystals of 4′-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0° C., and its temperature was maintained for one hour, and then the crystals were filtered. The crystals were washed with 15 g of toluene at 0° C., and then air-dried to give 28.8 g of white crystals of 4′-methylbiphenyl-2-carboxylic acid (yield: 90.6% based on 2-cyano-4′-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.2° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=CC=[CH:3][CH:2]=1.[CH:8]([OH:11])([CH3:10])[CH3:9]>[Pt]>[CH:2]([CH:1]1[CH2:7][CH2:10][CH:8]2[O:11][CH:9]2[CH2:6]1)=[CH2:3]
Reactant: CC(C)O
Reactant: Cc1ccccc1
Agent: [Pt]
Product: C=CC1CCC2OC2C1
Temperature: 60 °C

Procedure:
Thereafter, 0.44 part of a 0.5% toluene solution of the platinum catalyst (supra) was added to the reaction mixture which was heated up to a temperature of 60° C. where the reaction mixture was admixed dropwise with a mixture of 14.7 parts of the Intermediate 1 obtained in Synthesis Example 3, 19.5 parts of 4-vinylcyclohexene oxide and 1.02 parts of isopropyl alcohol over a period of 1.5 hours during which the temperature of the reaction mixture was gradually increased to 65° C. After completion of the dropwise addition of the mixture, the reaction mixture in the flask was continuously agitated for further 6 hours at 65° C. and then admixed with 0.03 part of triphenyl phosphine to terminate the reaction followed by stripping of toluene and other volatile matters at 80° C. under a pressure of 5 Torr to obtain a light brown, cloudy liquid as the product, referred to as the Product 3 hereinafter, having a viscosity of 276 MPa·s and an epoxy equivalent of 1630.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][N:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[N:11]1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)NCc1cnn(C)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (1-methyl-1H-pyrazol-4-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (70%): mp 176-177° C. (N,N-dimethylformamide/water); 1H NMR (300 MHz, DMSO-d6) δ 8.28 (t, J=5.7 Hz, 1H), 7.56 (s, 1H), 7.36-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.57-4.50 (m, 1H), 4.42 (d, J=4.4 Hz, 2H), 4.19 (d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.63-3.57 (m, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ES+) m/z 443.1 (M+1).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2)([OH:14])=[O:13]>CO>[CH3:1][O:13][C:12]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Solvent: CO
Product: COC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
In the presence of an acid catalyst (p-toluenesulfonic acid), 1-carboxyadamantane obtained in Example 2 was allowed to react with an excess amount of methanol to give 1-methoxycarbonyladamantane.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.C(N(CC)CC)C.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59](Cl)=[O:60].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:59]([C:55]3[O:54][CH:58]=[CH:57][CH:56]=3)=[O:60])=[CH:42][CH:41]=2)=[N:20][CH:19]=[N:18]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1)c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
To a solution of 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol) was added tetrahydrofuran (4.50 mL), triethylamine (0.345 mL, 2.48 mmol), and 2-furoyl chloride (0.058 mL, 0.735 mmol). The mixture was stirred for 16 h at ambient temperature and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0086 g, 5% yield). 1H NMR (DMSO-d6) δ 8.75 (d, 1H), 8.10 (m, 6H), 7.74 (m, 1H), 7.39 (d, 1H), 6.75 (m, 1H). ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([N:22]([CH3:28])[CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:28][N:22]([CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1)[S:19]([NH:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)(=[O:21])=[O:20]
Reactant: CN(C1CCOC1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: CN(C1CCOC1)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 100 °C

Procedure:
N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-(tetrahydrofuran-3-yl)sulfamide Enantiomer B (0.070 g, 0.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.069 g, 0.33 mmol), Pd2(dba)3 (0.008 g, 0.0085 mmol), (tBu3)PBF4 (0.005 g, 0.017 mmol) and potassium fluoride (0.032 g, 0.56 mmol) were combined in a dry tube. 1.0 mL dry DMF was added and argon was bubbled through the solution for five minutes. The tube was sealed and heated in a Biotage Initiator series microwave reactor to 100° C. for 30 minutes. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by HPLC chromatography (20-100% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the crude compound. The crude material was purified by silica chromatography (0-100% ethyl acetate/hexanes gradient, followed by 0-20% methanol/dichloromethane gradient). The isolated material was dissolved in minimal 25% methanol/dichloromethane and hexanes were added until precipitation occurred. Precipitate was filtered to afford title compound. 1H NMR (600 MHz, D6-DMSO)□ 10.55 (s, 1H); 9.20 (d, 1H); 8.58 (d, 1H); 8.46 (s, 1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.75 (d, 1H); 7.52 (dd, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 4.48-4.53 (m, 1H); 3.88 (s, 3H); 3.74-3.80 (m, 1H); 3.42-3.54 (m, 3H); 2.68 (s, 3H); 1.93-2.00 (m, 1H); 1.65-1.72 (m, 1H). LRMS (APCI) calc'd for (C23H24N5O4S) [M+H]+, 466.2; found, 466.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:37]([N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[F-].[Cs+]>COCCOC.CO.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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:47]3[CH:46]=[N:45][N:44]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:48]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccccc2)c1

Procedure:
A mixture of EXAMPLE 1D (0.113 g), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.063 g), tetrakis(triphenylphosphine)palladium(0) (0.023 g) and CsF (0.091 g) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 120° C. for 30 minutes under microwave heating conditions. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 35% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:32][C:31]5[C:30]([F:29])=[CH:37][CH:36]=[CH:35][C:34]=5[F:38])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3c(F)cccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=1[NH2:14])([CH3:11])[CH3:10]>C(O)=O.CO>[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=1[N:14]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:11])[CH3:10]
Reactant: O=Cc1ccccn1
Reactant: Cc1cccc(C(C)C)c1N
Solvent: O=CO
Solvent: CO
Product: Cc1cccc(C(C)C)c1N=Cc1ccccn1
Reaction time: 5 h

Procedure:
A mixture of 2-pyridine-carboxaldehyde (8.5 ml, 0.052 mole), 2-iso-propyl-6-methylaniline (5 ml, 0.052 mole), 3 drops of formic acid and 30 ml methanol was stirred for five hours. The methanol was removed under vacuum. An oil-like residue was recrystallized from n-hexane. 2-(N-(2-iso-propyl-6-methylphenyl)-iminomethyl)-pyridine was isolated as yellow crystals. Yield: 10.25 g (82.8%). 1H NMR (200 MHz; CDCl3; δ, ppm; J, Hz): 1.18 d (6H, CH(CH3)2, J=6.9), 2.15 s (3H, CH3), 3.03 sept. (1H, CHMe2, J=6.9), 701-7.21 m (3H, C6H3), 7.41 d,d,d (1H, H(5) 3J4,5=7.5, 3J5,6=4.9, 4J3,5=1.3); 7.85 t,d,d (1H, H(4) 3J=7.7, 4J4,6=1.8, 5J=0.6); 8.28 d,t (1H, H(3) 3J3,4=7.9, J=1.1); 8.33 s (1H, HC═N); 8.73 d,d,d (1H, H(6) 3J5,6=4.9, 4J4,6=1.6, 5J3,6=1.0). 13C NMR, DEPT (50 MHz; CDCl3; δ, ppm): 18.6 (CH3), 23.3 (CH(CH3)2), 27.9 (CHMe2), 121.3 (C(3)H), 123.2 and 124.3 (C(3′)H and C(5′)H), 125.4 (C(5)H), 126.1 (C(6′)Me), 128.0 (C(4′)H), 136.7 (C(4)H), 137.9 (C(2′)i-Pr), 149.3 (C(1′)), 149.7 (C(6)H), 154.4 (C(2)), 163.4 (HC═N).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O:32][C:33](=[O:36])[CH2:34]Br.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:28]([CH:27]([C:26](=[O:30])[C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:18][C:19]=2[CH:25]=1)[CH2:34][C:33]([OH:36])=[O:32])[CH3:29]
Reactant: COC(=O)CBr
Reactant: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
625.00 μl (313 μmol) potassium bis(trimethylsilyl)amide 0.5M in toluene are placed in 15 ml THF and cooled to −78° C. 75.00 mg (283 μmol) 1-(2-phenyl-benzoxazol-6-yl)-butan-1-one, dissolved in 15 ml THF, are added dropwise to this solution and the mixture is stirred for 15 min at −78° C. Then 55 mg (360 μmol) methylbromoacetate, dissolved in 5 ml THF, are also added dropwise and the mixture is stirred for 30 min at −78° C., then 1N hydrochloric acid is added and the mixture is extracted with diethyl ether. The org. phase is dried on magnesium sulphate and the solv. is eliminated i.V.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38](=[O:45])[NH:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[OH:42][CH2:41][CH:40]([NH:39][C:38](=[O:45])[C:30]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([NH:27][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[CH:12]=[N:11][C:10]4[C:14]3=[N:15][CH:16]=[N:17][C:9]=4[NH:7][CH3:6])=[CH:19][CH:20]=2)=[O:26])[CH:29]=1)[CH2:43][OH:44]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To 40.8 mg (0.063 mmol) of [9-(4-{3-[3-(2-hydroxy-1-hydroxymethyl-ethyl-carbamoyl)-5-trifluoromethylphenyl]ureido}phenyl)-9H-purin-6-yl]-methyl-carbamic acid tert-butyl ester, 1 mL of trifluoroacetic acid was added and the mixture solution was stirred at room temperature for one hour. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was dissolved in methanol (1 mL) and water (60 μL), and 43.7 mg (0.315 mmol) of potassium carbonate was added thereto, and the mixture solution was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the obtained solid was collected by filtration and dried under reduced pressure to obtain 32 mg (93%) of a target product as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38](Br)[C:37]=1[OH:43])=[O:35])[CH3:32].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38]([N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[Cl:20])[C:37]=1[OH:43])=[O:35])[CH3:32]
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Reactant: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(N(CCOCc2ccccc2)c2cc(OC)ccc2Cl)CCC1
Temperature: 25 °C
Yield: 104.9 %

Procedure:
(2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) (10.0 g, 34.2 mmol) was stirred in dry THF (100 mL) at −40° C. under nitrogen and potassium bis(trimethylsilyl) amide (143.0 mL of a 0.5 M solution in toluene, 72.0 mmol) was added over 30 min. 3-bromo-2-hydroxycyclohex-1-enecarboxylic acid ethyl ester (4) (8.5 g, 34.2 mmol) in dry THF (10 mL) was then added and allowed to warm to RT over a period of 1.5 h. Acetic acid (10.0 g, 166 mmol, 10.0 mL) was added and concentrated in vacuo to remove the THF. Ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL) was added and the mixture vigorously shaken. The ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 16.5 g (quantitative) of 3[(2-Benzyloxy-ethyl)-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclohex-1-ene carboxylic acid ethyl ester (5) as a gum which was used crude in the next step. HPLC (Gemini 150×4.6 mm, 50-95% methanol/water over 20 min) of crude reaction mixture, 18.9 min (38%), 19.2 min (25%), 23.1 min (28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:4][C:3]=1[F:9]
Reactant: OC1CCOC1
Reactant: Oc1ccc(Br)c(F)c1
Product: Fc1cc(OC2CCOC2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (EI): 260 and 262 M+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:11]([C:12]([OH:14])=O)[CH:10]2[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1>CC(OC(C)=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:10]3[CH:11]2[C:12](=[O:14])[O:17][C:15]3=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2C(C(=O)O)C2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C2C3C(=O)OC(=O)C32)cc1

Procedure:
A mixture of 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid (crude product from the previous step) in Ac2O (20 mL) was heated under reflux for 1 h. Excess Ac2O was removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH3:53])[CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][C@@H:48]([CH3:49])[CH2:50][CH2:51][CH2:52][CH3:53])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCC[C@@H](C)N
Product: CCCC[C@H](C)NC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-2-aminohexane (Alfa) to give the title product. LC-MS (ES+) 748 [(M+H)+].