Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH3:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[P:2]([Cl:5])([Cl:3])=[O:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNc1ccccc1
Solvent: CCOCC
Product: CN(c1ccccc1)P(=O)(Cl)Cl
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A 500 mL three-necked flask was fitted with an N2 inlet, thermometer and dropping funnel. The flask was flushed with nitrogen and charged with 150 mL dry ether and 31.1 g (0.203 mol) POCl3. In the dropping funnel was placed a solution of 21.4 g (0.20 mol) N-methylaniline in 5 mL ether. The amine solution was added to the solution of POCL3 (at -12° to -17° C.) over 40 minutes. The temperature was allowed to rise slowly to room temperature and stirring continued for 2 h thereafter. After filtering, volatiles were removed from the filtrate at reduced pressure. The 15.4 g (69% yield) of crude product was distilled (bp 96°-98° C. at 0.05 mm).
Reaction SMILES: [CH:1]1([C:6]([OH:34])([CH2:24][C:25]2[O:26]C(C)(C)O[C:29](=[O:31])[CH:30]=2)[C:7]#[C:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[N:18])=[C:11]([F:23])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[N:18])=[C:11]([F:23])[CH:10]=3)[CH2:24][C:25](=[O:26])[CH2:30][C:29](=[O:31])[O:34]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C#N)(CC)c1c(F)cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: CCC(C#N)(CC)c1c(F)cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to Example A (97), step 4, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-2-ethyl-butyronitrile (3.11 g, 6.55 mmol) from Step 2 below in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 1.52 g, 56%. 1H NMR (CDCl3) δ: 1.03 (t, J=3.65 Hz, 6H), 1.18–1.29 (m, 2H), 1.38–1 42 (m, 1H), 1.60–1.82 (m, 4H), 1.92–2.09 (m, 5H), 2.23–2.29 (m, 3H), 2.63–2.80 (m, 4H), 3.45 (d, J=3.6 Hz, 2H) 6.73 (d, J=10.8 Hz, 2H). MS (ESI): 416 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: N#Cc1cnc(N)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.00 g, 7.29 mmol) in DMA (18 ml) at room temperature was added tert-butylamine (2.4 ml, 22.03 mmol) and DIPEA (4.0 ml, 22.90 mmol). The reaction mixture was heated to 50° C. and stirred for one day. The temperature was increased to 70° C. and the reaction mixture was stirred for two days. The temperature was further increased to 120° C. and the reaction mixture was stirred for 8 h. The reaction mixture was then transferred into a sealed vial, additional tert-butylamine (1 mL, 9.18 mmol) was added and the mixture was continued to stir at 120° C. for another 4 days. The crude mixture was concentrated and purified by column chromatography on silica gel using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid mixed with a brown liquid. The material was dissolved in DCM and aqueous citric acid (<10%). Layers were separated, the aqueous layer was washed with DCM.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][OH:8].[ClH:9]>C1(C)C=CC=CC=1>[ClH:9].[CH3:7][O:8][C:5](=[NH:6])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC#N
Reactant: CO
Agent: Cl
Solvent: Cc1ccccc1
Product: COCCC(=N)OC
Temperature: 3 °C
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a 3-necked reaction vessel equipped with stirrer, gas delivery tube, thermometer and reflux condenser is charged 85.1 parts of 3-methoxypropionitrile, 32.0 parts of reagent grade methanol and 300 parts of toluene. The exit from the reflux condenser is connected to a drying tower filled with a commercially available drying agent and a bath is provided for cooling the vessel below 0° C. Hydrochloric acid gas flow is controlled by means of a rotameter and is passed through a calcium chloride filled trap which serves both as a means for drying the gas and as a receiver in case liquid is sucked back into the line. After charging the reagents and toluene, the solution is stirred and cooled to 3° C. and the HCl gas is then fed, while controlling the temperature to -4° to 1° C., until 38.0 parts have been added. The HCl gas is added as rapidly as possible commensurate with complete adsorption and good temperature control. The mixture is then stirred for 15 hours in an ice bath (maximum 10° C.). Crystals of methyl-3-methoxypropionimidate hydrochloride appear 2.25 hours after the HCl addition is complete. 46.5 Hours after the HCl addition is stopped, an 80% yield of methyl-3-methoxypropionimidate hydrochloride is formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[F:26])=[CH:9][C:8]([Br:27])=[C:7]([F:28])[CH:6]=2.CO.C(Cl)Cl.[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>>[Br:27][C:8]1[C:7]([F:28])=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:34]([CH3:35])[N:12]([C@H:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@@H:14]4[F:26])[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2c(N)cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cnc3cc(F)c(Br)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F

Procedure:
(3S,4S)-tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate (27 g, 0.059 mol) was heated in triethylorthoacetate (150 mL) under N2 atmosphere for 5 h at 120° C. The reaction was monitored by TLC (5% MeOH/DCM). The volatiles were concentrated under vacuum, the obtained crude product was purified by column chromatography on silica gel (0-3% MeOH/DCM) to afford (3S,4S)-tert-butyl 4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (15 g, yield from two steps). 1HNMR (CDCl3, 400 MHz): δ 9.28-9.23 (d, 1H), 8.43-8.34 (dd, 1H), 8.01-7.99 (d, 1H), 5.60-5.35 (m, 1H), 5.25-4.85 (m, 1H), 4.75-4.35 (m, 2H), 3.15-2.95 (m, 2H), 2.79 (s, 3H), 2.40-2.05 (m, 2H), 1.57 (s, 9H); LCMS: 100%, m/z=480.8 (M+); HPLC: 97.31%.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:31]
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 77 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 77% yield: nip 165-166° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.46 (d, J=4.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.29-7.14 (m, 5H), 6.46 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.56 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.4, 153.5, 149.0, 148.0, 135.8, 134.3, 129.6, 118.6, 117.0, 47.2, 42.0, 41.7, 41.3, 17.2; MS (ES+) m/z 492.3 (M+1).
Reaction SMILES: [CH:1]([S:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C([Li])CCC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([S:4][CH:1]([CH3:3])[CH3:2])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)SC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)SC1CCC(=O)N1S(=O)(=O)c1ccccc1
Yield: 46 %

Procedure:
To 2.5 g of 5-isopropylthio-pyrrolidin-2-one in 130 cm3 of tetrahydrofuran, there is added at -70° to -65° C., 10.48 cm3 of a 1.5M solution of butyllithium in hexane. This is maintained for 20 minutes at this temperature, then 2.76 g of benzenesulphonyl chloride is added in 25 cm3 of tetrahydrofuran. After allowing to return to ambient temperature, concentrating under reduced pressure, taking up with water, filtering and drying, 2.15 g of the expected product is obtained. m.p., 91°-93° C., crystallized from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O-:14])=[O:13]
Reactant: CCCCCCCCI
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A slurry of methyl 3-hydroxy-4-nitrobenzoate (5.5 g, 0.028 mol), iodooctane (10.0 g, 0.042 mol) and potassium carbonate (20 g) in 100 mL DMF was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with 500 mL H2O, then extracted with ether/ethyl acetate (9/1, 2×200 mL). The combined organic solution was washed with 400 mL H2O, dried over sodium sulfate, and concentrated to form methyl 4-nitro-3-octoxybenzoate as an off-white oil (8.7 g, 100%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In acetonitrile (80 ml), tert-butyl 1-piperazine carboxylate (2.50 g) was dissolved. Under ice cooling, benzyl bromide (1.59 ml) and triethylamine (1.87 ml) were added dropwise to the resulting solution, followed by stirring at room temperature for 90 minutes. After the solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethyl acetate:hexane=1:20 to 1:5), whereby the title compound (3.12 g, 84%) was obtained as colorless powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6]OS(=O)(=O)[N:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][NH:25]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[NH:25]1[C:26]2[C:22](=[C:21]([N:15]3[CH2:20][CH2:19][N:18]([CH2:6][C@@H:2]([CH3:1])[NH:3][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:17][CH2:16]3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Solvent: CC#N
Product: C[C@H](CN1CCN(c2cccc3[nH]ccc23)CC1)Nc1ccccn1
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A solution of (R)-4-methyl-3-pyridin-2-yl-[1,2,3]-oxathiazolidine-2,2-dioxide (4.04 g 0.019 moles) and 4-piperazinoindole (3.80 g 0.019 moles) in acetonitrile (200 ml) was heated to 60° C. for 0.5 h then evaporated in vacuo. The residue was taken up into dilute HCl (100 ml), warmed to 60° C. for 0.5 h, cooled, washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichioromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown glass. This was purified on a silica column eluting with 10% propan-2-ol in dichloromethane to give (R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl]piperazine (4.3 g) as a clear glass.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.C1CCCCC1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step A) (4.0 g, 16 mmol) in tetrahydrofuran (25 mL) was cooled to −78° C., and then treated dropwise with 2 M n-butyllithium in cyclohexane (8.6 mL, 17.2 mmol). The reaction mixture was stirred for a further 30 minutes, and then a solution of hexachloroethane (4.2 g, 18 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was stirred for 1 h, warmed to room temperature, and quenched with water (50 mL). The resulting solution was extracted with dichloromethane, dried (MgSO4), and concentrated under reduced pressure to give 4.38 g of title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Mg]Cl)C.C(O[CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1
Reactant: CC(=O)OC1CC(=O)N1
Reactant: C#C[Si](C)(C)C
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1CC(=O)N1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsilylacetylene (1715 ml) in tetrahydrofuran (18.0 l) was added ethyl magnesium chloride (2.0M solution in tetrahydrofuran; 6.19 l) was added dropwise below −30° C. under nitrogen atmosphere. The reaction mixture was allowed to 0° C. and stirred for 1 hour. After cooling to −30° C., 4-acetoxy-2-azetidinone (320 g) was added and warmed to room temperature, and stirred for 2 hours. After cooling to −20° C., saturated ammonium chloride (4.0 l) was added. Ethyl acetate (20 l) was added and washed with water (10 l×2) and brine. The organic layer was dried over magnesium sulfate, filtered off and evaporated in vacuo to give 4-(2-trimethylsilylethynyl)-2-azetidinone (425 g), which was essentially pure, so it was used to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), t-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DMF (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxy-1-[(t-butyldiphenylsilyloxy)methyl]benzene. ESMS: m/z 407 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C@H:8]2[CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:9]1)([CH3:16])[CH3:15]
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Yield: 56.1 %

Procedure:
A mixture of (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (0.04 g, 0.128 mMol), triethylamine (71 uL, 0.512 mMol) and 4-chloro-6-(trifluoromethyl)quinazoline (0.035 g, 0.192 mMol) were taken in EtOH and microwaved at 100° C. for 45 min. The reaction mixture was concentrated and chromatographed to yield (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonyl methyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one as a white solid (0.04 g). MS found: (M+H)+=557.2
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CN1CCOCC1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 161.2 %

Procedure:
With a waste gas absorption device, triphosgen (167 g, 0.56 mol, 0.5 eq) was dissolved in chloroform (500 mL). A solution of N-methyl morpholine (11.4 g, 0.11 mol, 0.1 eq) in chloroform (100 mL) was added dropwise into the above mixture at 5° C. After addition, a solution of 4-chloro-3-(trifluoromethyl)aniline (220 g, 1.13 mol, 1.0 eq) in chloroform (700 mL) was added dropwise at 10° C. The mixture was warmed to 40° C. and stirred for 15 hours, and then warmed to 50° C. and stirred for 5 hours, and then heated to 60-65° C. and refluxed for 5 hours. The solvent was removed under atmospheric pressure. The residue was distilled under vacuum (oil temperature 110-120° C., vacuum 200 Pa) and the fractions at 95-100° C. were collected to give the title compound (200 g, purity 98.7%, yield 84%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH:30]=[C:31]4[C:37]5[CH:38]=[CH:39][CH:40]=[N:41][C:36]=5[CH2:35][O:34][C:33]5[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN1C(=O)CN([C@@H]2CCNC2)Cc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)CN([C@@H]2CCN(CCC=C3c4cc(C(C)(C)O)ccc4OCc4ncccc43)C2)Cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of (R)-8-chloro-1-ethyl-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.121 g, 0.32 mmol) in acetonitrile/water (8:2) (3.2 mL) was added K2CO3 (0.368 g, 2.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.033 g, 21%). 1H-NMR (CDCl3): δ 1.17 (t, 3H), 1.55 (s, 6H), 1.73 (septet, 1H), 2.08 (m, 1H), 2.34 (pentet, 2H), 2.43-2.61 (m, 4H), 2.85 (t, 1H), 2.92 (d, 1H), 3.10 (q, 1H), 3.22 (m, 1H), 3.52 (q, 2H), 3.91 (septet, 2H), 5.29 (bs, 2H), 6.12 (t, 1H), 6.79 (dd, 1H), 7.15-7.28 (m, 5H), 7.44 (s, 1H), 7.56 (d, 1H), 8.47 (d, 1H). ESI-MS m/z: 587 (M+1), retention time 1.37.
Reaction SMILES: FC1C=C(C[C@H](N[C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.FC(F)(F)C1C2CCCCC=2N(CC(O)=O)N=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:38])([F:37])[F:39])=[N:28]2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 9.07 (d, J=8.1 Hz, 1H), 8.51 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.98 (t, J=9.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 2H), 5.41-5.30 (m, 1H), 4.80-4.64 (m, 2H), 3.35 (s, 2H), 3.25-3.12 (m, 1H), 3.07 (dd, J=13.4, 6.8 Hz, 1H), 2.33 (s, 1H), 2.23 (s, 1H), 1.63 (s, 4H). MS (m/z) 565.1 [M+H]+.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.[O-:13]CC.[Na+]>C1(C)C=CC=CC=1>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:13])[N:3]=1)[CH3:10]
Reactant: CC[O-]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml, three necked, flask equipped with an agitator and a condensor were added 3.0 g (0.014 mol) of 2-hydroxy-2-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 50 ml of toluene and 0.95 g (0.014 mol) of sodium ethoxide. The resulting solution was stirred at room temperature for 30 minutes. A 1 ml sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 6.6% of the thiazoline substrate had converted to the desired titled compound.