Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2nccs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH:13][CH:14]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1)[OH:16])=[O:12].[C:33]([OH:42])(=[O:41])[CH:34]([CH:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>C(O)(C)C.CO>[C:38]([CH:36]([CH:34]([C:33]([OH:42])=[O:41])[OH:35])[OH:37])([OH:40])=[O:39].[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH:13][C@H:14]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1)[OH:16])=[O:12]
Reactant: O=C(CC1Cc2ccccc2C1)NC(CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: O=C(CC1Cc2ccccc2C1)N[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (compound 3h) (0.15 g, 0.34 mmol) in isopropanol (10 ml) was added a solution of (+)-tartaric acid (0.05 g, 0.34 mmol) in MeOH (5 mL). The resulting mixture was stirred 30 minutes, then concentrated in vacuo. EtOAc was added followed by diethyl ether (excess). The resulting solid was stirred 30 minutes, then allowed to set overnight. The solid was filtered, washed with diethyl ether, and dried overnight under high vacuum to yield 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide tartrate, 0.16 g, 79% desired white solid. ESI-MS m/z 437.2 (M+H+). mp=174-175° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH:13]3[O:17][CH2:16][CH2:15][O:14]3)[C:6]=2[N:18]=1.[F-:19].[Cs+].C(OCC)(=O)C.O>CN(C)C=O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[N:10][C:5]2[CH:4]=[CH:3][C:2]([F:19])=[N:18][C:6]1=2
Reactant: O=c1cnc2ccc(Cl)nc2n1CC1OCCO1
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cnc2ccc(F)nc2n1CC1OCCO1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To a solution of 0.10 g of 6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one in 3 mL of N,N-dimethylformamide, 0.57 g of cesium fluoride was added, and the mixture was stirred at 90 to 100° C. for 1 hour 10 minutes. Thereto was further added 0.57 g of cesium fluoride, and the mixture was stirred at 90 to 100° C. for 1 hour 30 minutes. Thereto were added ethyl acetate and water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=50:1 to obtain 60 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-one as a light yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:4]5[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@@H](C)CS3(=O)=O)cc2)CC1
Yield: 34.4 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (91 mg) described in Preparation Example 7 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (200 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (70 mg) was obtained.
Reaction SMILES: [CH2:1]([C:8]1([OH:31])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]>CO.C(OCC)(=O)C.[Pd]>[ClH:32].[CH2:1]([C:8]1([OH:31])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2ccccc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(OCCN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 72 %

Procedure:
4-Benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidin-4-ol (1.35 g, 3.2 mmol) was dissolved in a mixture of MeOH (75 ml) and ethyl acetate (75 ml) and hydrogenated in the presence of Pd on C at room temperature and atmospheric pressure. After filtration and evaporation of the solvent, the residue was dissolved in ethanol (2 mnl) and ethyl acetate (10 ml). 1.1 equivalent of ethanolic HCl were added to give 4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidin-4-ol hydrochloride (0.85 g, 72%) as colorless solid, m.p. 161°-163° C. and MS: m/e=328.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light brown solid (0.47 g, 73%), MS (ISP) m/z=298.4 [(M+H)+], mp 176° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-cyano-phenylboronic acid (0.36 g, 2.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4.5 g. of ethyl 4-{[3-(4-chlorophenoxy)propyl]amino}benzoate 4.5 g. of potassium hydroxide and 100 ml. of 95% ethanol is refluxed for 3 hours. The solution is acidified with hydrochloric acid and the mixture is diluted with 100 ml. of water to give 3.7 g. of solid. Recrystallization by dissolving in a mixture of chloroform-ethyl acetate and diluting with hexane gives 3.3 g. of product as off-white crystals, m.p. 180°-181° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[N:29]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[N:29]1([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH:1][C:2]3[N:6]([C@@H:7]4[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]4[OH:9])[C:5]4[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=4[N:3]=3)=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](n2c(NCc3ccc(-n4ccnc4)cc3)nc3ccccc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (94 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (41 mg) were suspended in tetrahydrofuran (3 mL), and the mixture stirred at room temperature for 2 hours. To the reaction mixture was added acetic acid (200 μL), and then was added sodium triacetoxyborohydride (56 mg). The mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 mL). To the mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (67 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N+:14]([O-])=O)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])[CH3:2].CN(C=O)C>C(O)C.[Pd]>[NH2:14][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:13])[CH:6]=1
Reactant: CCOc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)O)c(F)cc1N
Yield: 40.3 %

Procedure:
5-ethoxy-2-fluoro-4-nitrobenzoic acid (Intermediate 172; 1.24 g, 5.40 mmol) was stirred and dissolved in ethanol:DMF (50 mL:5 mL) over 5% Pd/C (125 mg) and hydrogenated at ambient temperature for 4 hours. The catalyst was filtered and washed with ethanol and the solvent evaporated. The resultant material was purified on a silica column, eluting with 0-5% MeOH/DCM. Product containing fractions were combined and evaporated to yield the title compound as a pale brown solid (433 mg, 40%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42]>CN(C=O)C.CCCCCC.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(Cl)nc1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-5-iodopyridine(37.7 g) in DMF (300 mL) was added palladium(II) acetate (1.77 g), tri-o-tolylphosphine (7.19 g), diisopropylethylamine (82 mL), and ethyl acrylate (17.9 mL), and the mixture was heated at 100° C. for 10 hours. Resulting mixture was poured into water and extracted with AcOEt. The organic layer was washed with water and brine and dried over Na2SO4, and the solvent was removed in vacuo. Obtained brown solid was suspended in a mixture of hexane and AcOEt(4:1), and the precipitate was filtered off. The filtrate was concentrated in vacuo, and residual brown oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:4-1:2). Resulting solid was triturated with IPE to give ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate as pale yellow powder (20.58 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(Cl)(Cl)Cl>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[S:19]
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Reactant: CN=C=S
Solvent: ClC(Cl)Cl
Product: CNC(=S)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C

Procedure:
1.3 g. (6.3 mmol) 7-Amino-4,4-dimethyl-isoquinolin-1,3-dione were dissolved in 30 ml. chloroform, mixed with 1.4 g. methyl isothiocyanate and boiled under reflux for 6 hours. The reaction mixture was then cooled and the precipitate was filtered off with suction and recrystallised from ethanol. Yield: 0.8 g. (46% of theory); m.p. 206°-207° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C[C@@H](F)[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D+22.67° (c=0.935, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitarily. Contains 17% of trans (−) diastereomer.
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:41])[N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])=[CH:27][CH:26]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].C(N(CC)CC)C.[CH3:49][Si:50](Cl)([CH3:52])[CH3:51].C(OCC)(=O)C>O1CCCC1>[NH2:1][C@H:2]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33](=[O:41])[N:34]([CH2:38][CH2:39][O:40][Si:50]([CH3:52])([CH3:51])[CH3:49])[CH2:35][CH2:36][O:37][Si:50]([CH3:52])([CH3:51])[CH3:49])=[CH:29][CH:30]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO)CCO)cc1)c1nc2ccc(I)cc2[nH]1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO[Si](C)(C)C)CCO[Si](C)(C)C)cc1)c1nc2ccc(I)cc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
(R)-2-Amino-2-(4-{[bis-(2-hyd roxy-ethyl )-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide (170 mg, 0.253 mmol) was dissolved in dry tetrahydrofuran (3.4 mL) and cooled in an ice bath. To this solution was added triethylamine (176.3 μL, 1.265 mmol) followed by trimethylsilyl chloride (132 μL, 1.012 mmol). After 0.5 hours another 2.5 equivalents of triethylamine (88 μL, 0.63 mmol) and 2 equivalents of trimethylsilyl chloride (66 μL, 0.506 mmol) were added. The reaction mixture was stirred at 0° C. for an additional 1.5 hours then the reaction mixture was poured into ethyl acetate (40 mL) and washed with brine (3×25 mL). The combine aqueous washes were then extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-2-amino-2-(4-{[bis-(2-trimethylsilanyloxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide (190 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OC(N1C[C@H](O)C[C@H]1C(=O)N[C@@]1(C(OCC)=O)C[C@@H]1C=C)=O)(C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Agent: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of compound 63 (50 mg, 37 mmol) with (1R,2S)-1-amino-2-vinyl-cyclo-propane carboxylic acid tert-butyl ester according to the method described for the preparation of 59 provided the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:32]=[O:33])C>>[CH2:17]([O:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:32]=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 63 %

Procedure:
12 g of chloro-3,5-dibenzyloxybenzene are dissolved in 40 ml of DMF. 12 ml of POCl3 are slowly added dropwise at 5-10°. The mixture is allowed to react further for 90 min at room temperature, then overnight at 80° C. The solution is evaporated in a Rotavapor, then added to 200 ml of icewater. The mixture is extracted 3× with EtOAc, washed with water, dried and evaporated. Silica gel chromatography gives 8.2 g (63%) of 2,4-bisbenzyloxy-6-chlorobenzaldehyde, which crystallises from (Me2C)2O, m.p. 85-86°.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[NH:11][C:10]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][C@H:14]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]3)=[N:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Xe](F)[F:33]>C(#N)C>[CH:1]1([C:5]([C:7]2[NH:11][C:10]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:30][CH2:31]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][C@H:14]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]3)=[N:9][C:8]=2[F:33])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: F[Xe]F
Reactant: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ncc(C(=O)C3CCC3)[nH]2)C1
Solvent: CC#N
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2nc(F)c(C(=O)C3CCC3)[nH]2)C1
Temperature: 0 °C
Yield: 4.7 %

Procedure:
To a solution (16 mL) of (3R)-3-{2-[5-(cyclobutylcarbonyl)-1H-imidazol-2-yl]-2-[4-(cyclopropylsulfonyl)phenyl]ethyl}cyclopentanone (0.720 g) in acetonitrile was added xenon difluoride (0.552 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio), and recrystallized from diethyl ether-hexane to give the title compound (0.035 g, yield 5%) as colorless crystals. melting point 85-88° C.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C@H:8]([C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:13]([CH3:23])=[N:12][N:11]=2)[N:7]([C:24](=[O:40])[NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=3)[O:29][CH2:28][CH2:27]2)[CH2:6]1)(=O)C.[K]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:13]([CH3:23])=[N:12][N:11]=[C:10]2[C@H:8]2[CH2:9][C@@H:5]([OH:4])[CH2:6][N:7]2[C:24]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][C:32]([C:36]([F:37])([F:39])[F:38])=[CH:33][CH:34]=3)[O:29][CH2:28][CH2:27]2)=[O:40])=[CH:17][CH:18]=1
Reactant: CC(=O)O[C@@H]1C[C@H](c2nnc(C)n2Cc2ccc(Cl)cc2)N(C(=O)N[C@H]2CCOc3cc(C(F)(F)F)ccc32)C1
Agent: [K]
Solvent: CO
Product: Cc1nnc([C@H]2C[C@@H](O)CN2C(=O)N[C@H]2CCOc3cc(C(F)(F)F)ccc32)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude (3R,5R)-1-(((S)-7-(trifluoromethyl)chroman-4-yl)carbamoyl)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetate from Step F (120 mg, 0.21 mmol) in aqueous MeOH (2.0 ml, 1:1 water:MeOH) was added potassium carbonated (116 mg, 0.84 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue dissolved in EtOAc, washed with 1N HCl and then concentrated. Preparative HPLC purification provided the desired compound as a white fluffy solid (47 mg, 72% over 3 steps).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[C:59]([CH3:64])=[N:60][O:61][C:62]=1[CH3:63])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[C:59]([CH3:64])=[N:60][O:61][C:62]=2[CH3:63])=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1noc(C)c1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as starting materials in 30% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.41 (m, 2H), 9.00 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.02 (m, 2H), 2.98 (m, 4H), 2.80 (m, 2H), 2.32 (m, 2H), 2.20 (s, 3H), 2.12 (m, 4H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C30H33ClN9O3 (M+H)+: m/z=602.2.