Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:10]1>O1CCCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: Fc1ccc(-c2ccc(-c3ccc(CCC4CC[SiH](Cl)CC4)cc3)cc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)cc4)cc3)cc2)CC1

Procedure:
15.1 g (100 mmol) of n-pentyl bromide was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of tetrahydrofuran (hereafter referred to as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 40.9 g of 4-(2-(4-chloro-4-silacyclohexyl)ethyl)-4'-(4-fluorophenyl)biphenyl. The reaction mixture thus obtained was a mixture of trans isomers and cis isomers with respect to the silacyclohexane ring. After a conventional after treatment, they were separated by means of chromatography to obtain 38.1 g (yield 93%) of the target product.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1>CCOC(C)=O.[Pt]>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)C=Cc1ccc(Br)cc1O2
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)CCc1ccc(Br)cc1O2
Yield: 81.4 %

Procedure:
A solution of 2,7-dibromodibenzo[b,f]oxepine (10-2) (663 mg, 1.88 mmol) in EtOAc (40 mL) was degassed under N2. Pt/C 10% by wt (200 mg) was added and the reaction was evacuated and placed under H2 gas. After 2 h reaction mixture was degassed and filtered through Celite®545 (eluant EtOAc) and solvent was removed in vacuo to give a yellow oil. The compound was dissolved in petroleum ether and passed through a short pad of SiO2, eluting with isohexanes 400 mL. Solvent was removed in vacuo, to give 2,7-dibromo-10,11-dihydrodibenzo[b,f]oxepine (10-3) (542 mg, 81% yield) as a colorless oil. 1H NMR (CDCl3): δ 7.33-7.32 (1H, m), 7.29-7.24 (2H, m), 7.18-7.14 (1H, m), 7.04-6.96 (2H, m), 3.08 (4H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:14]([OH:16])[CH3:15])[C:3]=1[O:17][CH3:18].Cl.CN(C)CCCN=C=NCC.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:14]([O:16][C:31](=[O:33])[CH3:32])[CH3:15])[C:3]=1[O:17][CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C(C)O)cc2c(c1Br)C(C)(C)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C(C)OC(C)=O)cc2c(c1Br)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-bromo-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanol (Compound A-95, 12.3 g, 39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 11.2 g, 58.5 mmol) and 4-dimethylaminopyridine (DMAP, 9.5 g, 78 mmol) in dichloromethane (350 mL) at room temperature was added acetic anhydride (3.7 mL, 39 mmol). After stirring at room temperature for 16 h, the mixture was quenched with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([C:36](F)(F)F)[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
128 mg (0.500 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10]O>O>[C:1]1([S:7]([CH3:9])(=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CS(=O)c1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A complex (4) (1.9 mg, 1 mol %) was weighed out in a Schlenk flask, to which racemic phenylmethylsulfoxide (28 mg, 0.2 mmol) was added. Water (0.5 mL) was added, followed by stirring for 10 minutes at 20° C. A 30% hydrogen peroxide solution (9 μL, 0.4 eq) was added, followed by stirring the resultant mixture for 3 hours at room temperature. To the reaction mixture, water (5 mL) was added, followed by extraction using ethyl acetate. An organic phase was dried over anhydrous sodium sulfate, followed by filtration and then it was concentrated under reduced pressure. By purifying the concentrate using silica gel column chromatography (ethyl acetate), 6.5 mg (21% yield) of phenylmethylsulfone was obtained, and 22.1 mg of phenylmethylsulfoxide (79%) was recovered. Optical purity was determined to be 12% ee for a S form after measured by HPLC analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.[OH-].[K+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16]>CN(C)C=O.O>[CH3:1][C:2]1[N:3]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[CH2:21][CH2:22]2)=[O:16])[N:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Reactant: N#CC1CCN(C(=O)CCl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-5-trifluoromethylpyrazole (9.3 g, 62 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 mL) was cooled to 5° C., and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (i.e. the product of Example 1, Step A or A1) (11.2 g, 60 mmol) was added. The reaction mixture was stirred for 8 h at 5-10° C., then diluted with water (100 mL), and filtered. The filter cake was washed with water and dried at 50° C. in a vacuum-oven to give 15 g of the title compound as a solid containing 3% of its regioisomer, i.e. 1-[2-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]([NH:18]C(=O)C)=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])=[CH:7][C:6]([NH2:18])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1OCOCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(N)cc1OCOCC[Si](C)(C)C
Yield: 91 %

Procedure:
A mixture of Example 476D and K2CO3 (7.0 g, 50.6 mmol) in methanol (220 mL) was stirred at room temperature overnight, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum to produce 9.7 g (91%) of the desired product. MS (ESI) m/e 315 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 7.43 (br s, 2H), 7.37 (s, 1H), 6.66 (s, 1H), 5.28 (s, 2H), 3.69-3.75 (m, 2H), 3.73 (s, 3H), 0.89-0.94 (m, 2H), -0.01 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (172 mg, 0.97 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (289 mg, 0.97 mmol) by refluxing in xylene according to the general procedure M. Obtained as an off-white solid (310 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-(2,6-dimethoxyphenyl)piperidin-2-one (110 mg; 0.46 mmol) in anh. DMF (2 ml) was treated at rt with NaH (60% dispersion in mineral oil; 118 mg; 2.95 mmol), and with commercially available 1-(benzyloxy)-4-(chloromethyl)benzene (130 mg; 0.56 mmol). The resulting mixture was then heated to 60° C., under nitrogen, for 1 h. After cooling to rt, aq. sat. NaHCO3 was added, and this mixture was extracted with AcOEt (2×). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (AcOEt) afforded 1-(4-(benzyloxy)benzyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one as a yellow oil. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 432.24 g/mol.
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:19]=[C:18]([B:14]([OH:15])[OH:13])[CH:23]=[CH:22][CH:21]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCOB(c2cccc(S(=O)[O-])c2)OCC1
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Step 2) N-Chlorosuccinimide (1.015 g, 7.6 mmol) was added to a suspension of the above prepared lithium 3-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-benzenesulfinate (2 g, 7.27 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt. A solution of 25% ammonium hydroxide (1.09 mL, 14.5 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.38 g, 94%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 200.4 [(M−H)−].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:18][S:19]([CH2:22][CH2:23][NH2:24])(=[O:21])=[O:20].Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:24][CH2:23][CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCNc1cc(Cl)nc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30 %

Procedure:
In a 250 mL round-bottom flask was placed 4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 500 mg, 1.85 mmol) in dichloromethane (20 mL) to give a colorless solution. 2-(methylsulfonyl)ethanamine.HCl (325 mg, 2.04 mmol) was added followed by addition of triethylamine (0.77 mL, 5.55 mmol). The mixture was stirred at room temperature for 19 hours and was then refluxed for 21 hour. Excess potassium carbonate was added and heating under reflux was continued for 6 hours. The mixture was cooled to room temperature and stirred at room temperature for 2 weeks. The mixture was diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (20-100% ethyl acetate in hexanes) to give the title compound as a yellow solid (196 mg, 30%). HRMS: 357.0417 [M+H]+. For [M+H]+ mass error=−0.2 mDa or −0.60 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[NH:7][C:8]([C:12]3[CH:13]=[C:14]([S:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:33]([O-:35])=[O:34].[CH3:36]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[NH:7][C:8]([C:12]3[CH:13]=[C:14]([S:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)(=[O:23])=[O:24])[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][CH2:20][CH2:21][CH3:36])=[N:9]2)=[CH:4][C:3]=1[N+:33]([O-:35])=[O:34]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Reactant: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Yield: 68 %

Procedure:
Prepared using the above method for preparing 1-[[3-(7-chloro-3,4-dihydro-6-nitro-4-oxo-2-quinazolinyl)-4-propoxyphenyl]sulfonyl]-4-methylpiperazine, starting with 2-(2-butoxyphenyl)-7-chloro-6-nitro-4(3H)-quinazoline. Yield: 68%; LRMS [MH+] 536.2; HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.71 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[CH:18][CH:16]=[N:1]2
Reactant: O=CC=O
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1nc2cc(Cl)c3nccnc3c2nc1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 20 ml water was added 0,5 ml (3,36 mmol) 40% aqueous glyoxal and 0,35 g (3,36 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 3 h. After cooling to 25° C., the precipitate was filtered off. The crude product was stirred with water and added 1N hydrochloric acid to pH 2-3 to give 0,56 g (100%) 6-chloro-2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 9.0 (2H,s), 7.73 (1H,s).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
(R)-[3-[1-((S)-3-Fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, 0.24 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-((S)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 26 (140 mg, yield 94%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=[CH:19]2)[CH2:14][CH2:13]1.[Cl-].[NH4+].[CH2:27]1[CH2:31]OC[CH2:28]1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:13][CH2:14][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:28][CH2:27][CH3:31])([OH:24])[CH:20]=[CH:19]2)[CH2:16][CH2:17]1
Reactant: CCOc1ccc([C@H]2CC[C@H](C3C=CC(=O)CC3)CC2)c(F)c1F
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC1(O)C=CC([C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4.97 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-2-cyclohex enone (r-15) was dissolved into 60 mL of THF, 18.0 mL of propylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=6:4), and thus 3.79 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-1-propyl-2-cyclohexene-1-ol (compound (r-16)) was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:7][NH:8][C:9](=[O:34])[C:10]1[C:15]([I:16])=[C:14]([C:17](=[O:30])[NH:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[C:13]([I:31])=[C:12]([NH2:32])[C:11]=1[I:33])(=[O:3])[CH3:2].[C:39](Cl)(Cl)=[O:40]>O1CCOCC1.C1(C)C=CC=CC=1>[C:23]([O:22][CH2:21][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][NH:18][C:17](=[O:30])[C:14]1[C:13]([I:31])=[C:12]([N:32]=[C:39]=[O:40])[C:11]([I:33])=[C:10]([C:9](=[O:34])[NH:8][CH2:7][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=1[I:16])(=[O:25])[CH3:24]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Temperature: 60 °C

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-amino-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]-ethyl ester (4 mmol) in 1,4-dioxane (20 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (44 mL) at ambient temperature. The flask was sealed and the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid. The material was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH:3]2[C:4]3[C:12]4[CH:11]=[C:10]([CH3:13])[CH:9]=[CH:8][C:7]=4[NH:6][C:5]=3[CH2:14][CH2:15][N:2]2[CH3:1])=[CH:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)(C)Oc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)C(CCc1ccc(OC(C)(C)C)cc1)N(C)CC3
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassium hydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h. Reaction mass was cooled to RT and 1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was added at the same temperature and stir for 2 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (0.5% MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height of alumina—approx. 5 inch) then further purified by preparative TLC to provide the desired compound as light yellow oil (0.024 g, 6% yield). 5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.020 g, 67% yield).
Reaction SMILES: C[Sn](C)(C)[C:3]1([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4]1.Cl[B:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>>[CH2:16]([B:15]([CH2:18][CH3:19])[C:3]1([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:17]
Reactant: C[Si](C)(C)C1([Sn](C)(C)C)C=CC=C1
Reactant: CCB(Cl)CC
Product: CCB(CC)C1([Si](C)(C)C)C=CC=C1
Reaction time: 2 h

Procedure:
To 5.44 g (18.1 mmol) of colorless neat trimethyl(trimethylsilylcyclopentadienyl)tin is added 1.89 g (2.28 ml, 18.1 mmol) of colorless chlorodiethylborane at once at room temperature. An intense yellow color immediately appears. The mixture is stirred for 2 h and then subjected to fractional distillation. At a bath temperature of 60° C., the major part of the chlorotrimethylstannane can be separated off as the first fraction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C(O)C.[Pd]>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccsc1
Agent: [Pd]
Solvent: CCO
Product: COC(CNCc1ccsc1)OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 94 %

Procedure:
To 3-thiophenecarboxaldehyde (8.75 mL) cooled to 0° C. was added aminoacetaldehyde dimethylacetal (14.2 mL). The clear solution was stirred at room temperature for 60 h. The solution was diluted with ethanol and hydrogenated at 56 psi in the presence of 10% Pd/C (5 g) overnight. The catalyst was filtered off and washed with MeOH. The solvent was removed by rotary evaporation and co-evaporated with toluene to afford an oil (19 g, 94% yield).