Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Nc1cccc(Cl)c1O
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cccc(Cl)c6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-chlorophenol (0.053 g, 0.367 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4052419F). The compound was formed as an off-white solid (0.018 g, 13%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.78 min., 94%; m/z 558 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].F[B-](F)(F)F.C(C1C=CC=C(C(C)C)C=1[N+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.CC(C)([O-])C.[K+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:18][C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=3)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=[N:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cccc(C(C)C)c1N1C=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3cccc(OCCNC(=O)OC(C)(C)C)c3)n2)c1
Yield: 42.4 %

Procedure:
Using Method O, 2-(3-acetamidophenyl)-6-chloropyrazine (150 mg, 0.61 mmol), tert-butyl 2-(3-aminophenoxy)ethylcarbamate (CJS 700, 190 mg, 0.753 mmol), tris(dibenzylideneacetone) dipalladium (0) (28 mg, 0.030 mmol), 1,3-bis(2,6-di-i-propylphenyl)-4,5-dihydro-imidazolium tetra-fluoroborate (29 mg, 0.061 mmol) and potassium tert-butoxide (102 mg, 0.91 mmol), and dioxane (3.5 mL) were reacted at 100° C. for 20 minutes with microwave heating. The reaction mixture was filtered and washed with ethyl acetate (45 mL). The resulting liquid was dried under vacuo to give a paste that was chromatographed using a mixture of ethyl acetate:dichloromethane (1:1) as eluent to furnish 120 mg of the title compound. Yield: 43%. 1H NMR (250 MHz, DMSO-d6) δ 1.37 (s, 9 H), 2.09 (s, 3 H), 3.32 (m, 2 H), 3.98 (m, 2 H), 6.56 (dd, 1 H, Ja=8.0 Hz, Jb=2.4 Hz), 7.01 (bt, 1 H), 7.25 (t, 1 H, J=8.1 Hz), 7.36 (bd, 1 H, J=8.4 Hz), 7.45 (t, 1 H, J=7.9 Hz), 7.59 (bs, 1 H), 7.66 (bd, 1 H, J=9.2 Hz), 7.74 (bd, 1 H, J=8.0 Hz), 8.19 (s, 1 H), 8.34 (bs, 1 H), 8.42 (s, 1 H), 9.60 (s, 1 H), 10.09 (s, 1 H). 13C NMR (62.5 MHz, DMSO-d6) δ 23.99, 28.18, 66.23, 77.77, 103.95, 107.82, 110.74, 117.11, 120.07, 121.24, 129.24, 129.66, 130.08, 133.66, 137.10, 139.90, 141.88, 147.96, 151.44, 155.65, 158.87, 168.53. m/z 364.2 [(M-Boc+H)+ calc for C20H21N5O2 363.2].
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.[Cl:23]N1C(=O)CCC1=O>N1C=CC=CC=1.O>[Cl:23][C:20]1[S:21][CH:22]=[C:8]2[C:7](=[O:6])[N:12]3[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3c(Cl)scc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.4 ml, 0.03 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (0.75 g., 0.03 mol) in pyridine (5 ml) under nitrogen. The mixture is stirred at ice bath temperature for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (0.8 g., 0.06 mol) is added and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with water (3 ml) and stirred for 15 minutes. The precipitate is filtered off, dried and recrystallized from ethanol to give the product (0.5 g.), mp 285° C. (dec).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[N:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:14][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6]
Reactant: NN1CCCCC1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCCCl)NN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
Add 4-chloro-butyryl chloride (5 mL, 43 mmol) to piperidin-1-ylamine (4.3 g, 43 mmol) in dichloromethane (100 mL) at room temp. Stir the reaction mixture at room temp for two hours. Add the reaction mixture into ice and saturated sodium bicarbonate solution. Extract the mixture with dichloromethane (100 mL). Wash the organic layer with saturated sodium bicarbonate solution (50 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to obtain 5 g (57%) of the title compound as a white solid: Mass spectrum (ion spray): m/z=205.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1)=[O:41]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:49][C:46]1[CH:45]=[CH:44][C:43]([NH:42][C:40](=[O:41])[CH3:39])=[CH:48][CH:47]=1)=[N:6]2
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 31.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 4-aminoacetanilide (26 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-{4-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]phenyl}acetamide (19 mg) as a yellow solid. MS m/z 359 (M+1).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][C:42]=1[F:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[CH:23][CH:22]=1>>[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]1[C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[CH:23][CH:22]=2)[N:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)NCCNc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCNC(C)=O)n2)cc1
Yield: 11 %

Procedure:
In the reaction of N-[2-(2-chloro-5-(2-thienyl)-pyrimidine-4-ylamino)ethyl]-acetamide (150 mg, 0.51 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxy-carbonyl)-S-methylsulfoximide (111 mg, 0.46 mmol) according to procedure 5a, the desired product is obtained in 11% yield (28 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-10% methanol)).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1cccc(N2CCN(CC(=O)O)CC2)c1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COc1cccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)c1
Yield: 32 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(3-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 42, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (15.7 mg, 32%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.01 (d, 1H), 7.60 (d, 2H), 7.26 (m, 7H), 7.11 (t, 1H), 7.01 (m, 4H), 6.50 (d, 1H), 6.43 (s, 1H), 6.37 (d, 1H), 4.70 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.73 (m, 4H), 3.13 (m, 4H), 3.06 (s, 2H), 2.61 (m, 4H). MS (EI) for C35H37FN4O5: 613.7 (MH+).
Reaction SMILES: C([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.[ClH:18]>O>[ClH:18].[NH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: Cl
Solvent: O
Product: NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Temperature: 95 °C
Yield: 78 %

Procedure:
To a 3-neck 5-L flask equipped with a reflux condenser, a mechanical stirrer and a temperature probe was added 3-acetylamino-adamantane-1-carboxylic acid (432 g, 1.82 mol), water (1.00 L) and concentrated hydrochloric acid (2.44 L), and the resulting mixture was heated at 95° C. for 6 days. During this time, solid material precipitated from the solution. After cooling at 0° C., the solids were filtered and washed with acetone. The solid was then dried under high vacuum at 50° C. for about 2 hours to afford 328 g (78%) of the title compound, 3-amino-adamantane-1-carboxylic acid hydrochloride, as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.35 (br s, 1H), 8.27 (br s, 3H), 2.22-2.12 (m, 2H), 1.92-1.85 (m, 2H), 1.83-1.71 (m, 6H), 1.69-1.48 (m, 4H).
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[C:10](=[O:26])[CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[CH2:14]([C@H:13]1[CH2:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[C:10](=[O:26])[CH2:9][NH:8]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1
Temperature: 0 °C

Procedure:
A solution of the product from Step D (0.570 g, 1.58 mmol) in ethyl acetate (50 mL) was cooled to −15° C. under nitrogen. HCl gas was bubbled through for 15 min, and the reaction solution warmed to 0° C. for 2h. The solvent was removed in vacuo to provide the titled product.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:38]#[N:39].[K+].O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:38]#[N:39])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=1
Reactant: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 7-(bromomethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (122 mg, 0.40 mmol) in N,N-dimethylformamide (1.5 mL) was added 18-crown-6-ether (202 mg, 0.80 mmol) and potassium cyanide (131 mg, 2 mmol). The reaction mixture was allowed to stir for 2 h and then poured into water and extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (50%-60% EtOAc/petroleum ether) gave (80 mg, 75% yield) of the product as a gray solid, m.p. 170-180° C.; MS m/e 265 (M−H)+. Analysis for C15H10N2O3×1.5H2O
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=[C:14]2[C:34]2[CH:35]=[N:36][C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][C:39]=2[O:40][CH2:41][CH3:42])=[O:12])[CH2:7][CH2:6]1.[OH-].[Li+].Cl>CO.O1CCCC1.O>[C:43]([C:37]1[N:36]=[CH:35][C:34]([C:14]2[N:13]([C:11]([N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:47])=[O:2])[CH2:10][CH2:9]3)=[O:12])[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=2)=[C:39]([O:40][CH2:41][CH3:42])[CH:38]=1)([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reaction time: 3 h
Yield: 94.9 %

Procedure:
{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 methyl ester (519 mg, 0.763 mmole, example 162) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with lithium hydroxide (36 mg) in water (4 mL) and allowed to stir at room temp. for 3 h. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give {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 (482 mg) which was used without purification.
Reaction SMILES: Br[C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:5]2[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.Cl.[O:25]1[CH2:30][CH2:29][NH:28][CH:27]2[CH2:31][CH2:32][CH2:33][CH:26]12.[F-].[K+].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:11][C:6]1[C:5]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:2]([N:28]3[CH2:29][CH2:30][O:25][C@@H:26]4[CH2:33][CH2:32][CH2:31][C@@H:27]34)=[N:3][C:4]=2[CH:9]=[C:8]([Cl:10])[N:7]=1
Reactant: FC(F)(F)c1ccc(Cn2c(Br)nc3cc(Cl)nc(Cl)c32)cc1
Reactant: C1CC2NCCOC2C1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)cc1
Temperature: 90 °C

Procedure:
To a vial were added 2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (200 mg, 0.47 mmol), octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine); 147 mg, 0.9 mmol), potassium fluoride (81 mg, 1.41 mmol), DIEA (246 μL, 1.41 mmol), and DMSO (2 mL). The vial was sealed and heated to 90° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes, linear gradient) to afford 4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemate). MS APCI calc'd. for C21H19Cl2F3N4O [M+H]+ 471. found 471.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1F
Solvent: CSC
Solvent: CC(=O)Cl
Product: O=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1F
Temperature: 40 °C
Reaction time: 96 h
Yield: 54 %

Procedure:
To the mixture of (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol (0.726 mmol), freshly fused zinc chloride (2.17 mmol), dimethyl sulphide (3.2 mmol), acetyl chloride (2.17 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 54% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:15]=2[O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].O1CCCC1.C(O)(C)C.[BH4-].[Na+]>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([NH:20][C:16]2[C:15]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=3)=[C:14]([O:13][CH2:12][CH2:11][O:10][C:7]3[N:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][N:6]=3)[N:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)=O)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)O)cn2)c1
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a mixture of N-[6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (756 mg), tetrahydrofuran (10 ml) and isopropyl alcohol (10 ml) is added with stirring sodium borohydride (48 mg) under ice-cooling, and the mixture is stirred for 40 minutes under ice-cooling. To the reaction solution is further added sodium borohydride (14 mg), and the mixture is stirred for 30 minutes. The mixture is diluted with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=40:1~20:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (571 mg) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][C:6]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:7]1([F:10])[F:9].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])=[CH:25][CH:24]=1.N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([CH2:5][C:6]2([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][C:7]2([F:10])[F:9])=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C@H:29]([C:26]1[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=1)[C@@H:33]([CH3:38])[C:34]([F:35])([F:36])[F:37]
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1(F)F
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1.15 g (3.62 mmol) of (+/−)-tert-butyl 1-(3-amino-4-chlorobenzyl)-2,2-difluorocyclopropane-carboxylate were dissolved in 5 ml of DMF, and 1.49 g (5.43 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 2.5 ml of pyridine and 1.79 g (4.71 mmol) of HATU were added at RT. The reaction mixture was then stirred at 40° C. overnight. After cooling, the mixture was diluted with ethyl acetate and the solution was washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1). This gave 1.82 g of the title compound (88.8% of theory).