Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O:15][CH2:16][CH3:17])=[O:18])[CH3:14]
Reactant: CCOC(=O)COCCCl
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)COCCP(=O)(OCC)OCC
Yield: 97.5 %

Procedure:
36.3 g (218 mmol) of ethyl chloroethoxyacetate and 37.4 ml (218 mmol) of triethyl phosphite are heated at 50° C. for 3 hours. The reaction medium is evaporated to dryness under vacuum. 57 g (100%) of crude ethyl (diethoxyphosphoryl)ethoxyacetate are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:59]([CH3:61])[CH3:60])[C:14]([N:16]1[C@H:21]([C:22]2[NH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]5[N:44]=[C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[N:46]6C(OC(C)(C)C)=O)[NH:42][C:41]=5[CH:58]=3)[CH:31]=[CH:30]4)=[CH:25][N:26]=2)[CH2:20][C@@H:19]2[C@H:17]1[CH2:18]2)=[O:15])=[O:11]>C(Cl)Cl>[C@@H:47]12[CH2:48][C@@H:49]1[CH2:50][C@@H:45]([C:43]1[NH:42][C:41]3[CH:58]=[C:37]([C:32]4[CH:33]=[C:34]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:24]4[NH:23][C:22]([C@@H:21]6[CH2:20][C@@H:19]7[C@@H:17]([CH2:18]7)[N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[CH:59]([CH3:61])[CH3:60])=[N:26][CH:25]=4)[CH:36]=[CH:35]5)[CH:38]=[CH:39][C:40]=3[N:44]=1)[NH:46]2
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)ccc3c2)[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6)[nH]c5c4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
TFA (2 mL) was added to a solution of (1R,3S,5R)-tert-butyl 3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (226 mg, 0.310 mmol) in DCM (5 mL) and the reaction was stirred for 2 h at room temperature. The solution was concentrated under vacuum and the residue was taken in MeOH (10 mL) and filtered through a Strata XC MCX cartridge and washed with methanol (25 mL). The compound was released from the cartridge by washing the column with a solution of 2M of ammonia/methanol (10 mL) and concentrated under reduced pressure to give a methyl(S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (131 mg, 0.208 mmol) as tan solid. LC-MS retention time 1.235 min; m/z 630.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.16 (s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.3, 6.3 Hz, 2H), 7.87 (s, 1H), 7.78-7.85 (m, 2H), 7.60-7.69 (m, 2H), 7.44 (s, 1H), 5.20 (dd, J=8.8, 4.8 Hz, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.28 (dd, J=9.8, 7.8
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([NH:18][NH2:19])=[O:17]>C1(C)C=CC(C)=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([N:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[NH2:19])=[O:17]
Reactant: NNC(=O)c1cccc(Br)c1
Reactant: Clc1nccc2ccccc12
Solvent: Cc1ccc(C)cc1
Product: NN(C(=O)c1cccc(Br)c1)c1nccc2ccccc12
Temperature: 150 °C
Yield: 90.6 %

Procedure:
To a 200-mL three-neck flask were added 3.3 g (20 mmol) of 1-chloroisoquinoline, 4.3 g (20 mmol) of 3-bromobenzoylhydrazine, and 80 mL of para-xylene. This mixture was refluxed at 150° C. for 14 hours under a nitrogen stream. After a predetermined time elapsed, this mixture was cooled to room temperature, and the precipitated solid was collected by suction filtration. The obtained solid was washed with toluene, a saturated aqueous solution of sodium hydrogen carbonate, and water. This solid was dried, so that the substance which was the object of the synthesis was obtained as 6.2 g of a pale yellow powder in 90% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:3]([NH2:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: CN1CCCC1=O
Product: Nc1cc([N+](=O)[O-])ccc1N1CCNCC1
Yield: 70.3 %

Procedure:
A solution of 2-fluoro-5-nitrobenzenamine (0.50 g, 3.2 mmol) and piperazine (0.83 g, 9.6 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. Red solids were filtered and dried under high vacuum. 5-Nitro-2-(piperazin-1-yl)benzenamine (0.50 g, 70%) was obtained by crystallization in acetyl acetate and hexanes. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.23 (s, 1H), 2.86 (m, 8H), 5.26 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.45 (dd, J=8.7, 2.8 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 270 mg (1.43 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 513 mg (2.67 mmol) of EDC and 241 mg (1.78 mmol) of HOBT are dissolved in 7.8 ml of DMF. After stirring for 15 min, 0.75 ml (5.4 mmol) of TEA and 510 mg (0.89 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 25f in 3.7 ml of DMF are added. After 20 hours, the mixture is worked up analogously to Example 25g to yield the title compound: HPLC20-100 : tRet =18.5; FAB MS (M+H)+ =743.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:3]1.O.[NH2:13][NH2:14]>CCO>[F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]2[NH:14][N:13]=[C:8]([NH2:9])[CH:7]=2)[CH2:3]1
Reactant: N#CCC(=O)C1CC(F)(F)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CC(F)(F)C2)[nH]n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile (12.5 g, 78.6 mmol) in EtOH (250 mL) was added hydrazine hydrate (5.9 g, 117.9 mmol) and the resulting mixture was stirred at 75° C. overnight. After concentrating the reaction mixture in vacuo, the residue was redissolved in EtOAc (500 mL) and washed with satd. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the combined extracts washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 3.46 g (39%) of 5-(3,3-difluoro-cyclobutyl)-1H-pyrazol-3-ylamine as a light yellow solid: 1H NMR (400 MHz, DMSO-do): δ 11.20 (br s, 1H), 5.23 (s, 1H), 4.65 (br s, 2H), 3.16-3.13 (m, 1H), 2.88-2.84 (m, 2H), 2.64-2.57 (m, 2H); MS (ESI+) m/z: 174 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:5]([NH2:14])=[C:4]([NH2:15])[C:3]=1[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[S:21](=NC1C=CC=CC=1)=O.Cl[Si](C)(C)C>N1C=CC=CC=1>[F:8][C:7]1[C:2]([F:1])=[C:3]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:4]2=[N:15][S:21][N:14]=[C:5]2[C:6]=1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S=Nc1ccccc1
Reactant: Nc1c(N)c(-c2cccs2)c(F)c(F)c1-c1cccs1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: Fc1c(F)c(-c2cccs2)c2nsnc2c1-c1cccs1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
2,3-difluoro-1,4-di(2-thienyl)-5,6-diamino-benzene (1.2 g, 3.9 mmol) was added into a small flask and purged with Ar three times. Then, dry pyridine (24 ml), N-thionylaniline (1.08 g, 7.8 mmol) and chlorotrimethylsilane (0.76 g, 7.0 mmol) were added. The mixture was stirred at 80° C. for 16 h before poured into ice water. The yellow precipitate was then filtered and washed with a mixture of ethanol and water (1:1 v/v) to afford 5,6-difluoro-4,7-di(2-thienyl)-2,1,3-benzothiadiazole as a yellow solid (1.3 g, 98%). 1H and 19F NMR spectra were as expected.
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH3:8][CH:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[OH:23])[CH3:10]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:23][C:12]1[C:13]([CH:20]([CH3:21])[CH3:22])=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=1[CH:9]([CH3:10])[CH3:8])[NH2:2]
Reactant: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
N-Chlorosulfonyl isocyanate (7.2 mL, 82.6 mmol) was added slowly to a warm solution of 2,6-bis(1-methylethyl)-4-nitrophenol (17.57 g, 78.7 mmol) in 400 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with 4×500 mL dichloromethane. The organic solution was dried over MgSO4, filtered, and concentrated to give a tan solid. Recrystallization from dichloromethane gave 14.18 g (60%) of the title compound as an off-white solid; mp 163-167° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35]C3)=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4ccccn4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using pyridine-2-yl-acetic acid and 6-((S)3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.76 min, [M+1]+ 494. Potency class C.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCS)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]1[C:40]([CH3:41])([CH3:2])[O:39][CH2:37][CH2:36][C:30]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: SCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93° - 95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyll chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1COCC1>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([OH:10])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:24])[CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:22][C@@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:24][C:43]2=[O:45])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](N)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)NC1=O
Reaction time: 0.75 h

Procedure:
A solution of (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in CH2Cl2 (15 mL) was cooled to 0° C. and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}4-phenylimidazolidin-2-one. The minor enantiomer was removed by chiral HPLC using an AD chiral column and 15% IPA/heptanes to afford enantiomerically pure product. Rf=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks observed) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H), 3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([N:11]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (658 mg) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil; 116 mg) at room temperature under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.286 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, ethyl acetate was added and the organic extract was washed with water and brine, after which it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[S:6][C:7]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[C:8]([Cl:10])[N:9]=1>CO>[Cl:10][C:8]1[N:9]=[C:5]([O:2][CH3:1])[S:6][C:7]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: C[O-]
Reactant: Clc1nc(Cl)c(C2OCCO2)s1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)c(C2OCCO2)s1
Yield: 57.1 %

Procedure:
Sodium methoxide (0.63 g, 11.66 mmol) is added to a solution of 2,4-dichloro-5-([1,3]dioxolan-2-yl)-thiazole (2.00 g, 8.85 mmol) in methanol (20 ml). The reaction is heated at reflux for 3.5 h, cooled, and concentrated. The residue is partitioned between aqueous saturated brine solution and ethyl acetate, separated, and the aqueous layer extracted with ethyl acetate. The ethyl acetate is dried over Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 12.5% ethyl acetate/hexanes to yield (1.12 g, 93%) of 4-chloro-5-([1,3]dioxolan-2-yl)-2-methoxy-thiazole: mass spectrum (ion spray): m/z=221.9 (M+1); 1H NMR (CDCl3): δ=6.05 (1H, s), 4.15-3.97 (7H, m).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=[C:33]([C:38]6[NH:42][C:41]([C@@H:43]7[CH2:47][CH2:46][CH2:45][N:44]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:40][CH:39]=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:106])[C@@H:94]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:107]1C=CC3N=C([C@@H]4CCCN4)N[C:111]=3[CH:120]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:44]1[CH2:45][CH2:46][CH2:47][C@H:43]1[C:41]1[NH:42][C:38]2[CH:33]=[C:107]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:106])[C@@H:94]([NH:101][C:102]([O:103][CH3:104])=[O:105])[CH:95]7[CH2:100][CH2:99][O:98][CH2:97][CH2:96]7)[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=6)=[CH:79][CH:78]=5)[C:70]([F:121])([F:69])[C:71]=4[CH:72]=3)[CH:120]=[CH:111][C:39]=2[N:40]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.94 [M+H]+. (52 mg, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:15])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1ccc(O)c(C(C)=O)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(CS(C)=O)ccc1O
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of 2'-hydroxy-5'-(methylthiomethyl)acetophenone (2.20 g, 11.0 mmol) in 70 mL MeOH cooled in an ice bath was added a solution of sodium metaperiodate (2.49 g, 12.1 mmol) in 115 mL water. The resulting cloudy mixture was stirred two hours with cooling then partially concentrated in vacuo to remove methanol. The remaining aqueous mixture was extracted with chloroform (3×125 mL). The extract was washed with 50 mL water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give crude product which was recrystallized from n-butylchloride to give 1.39 g (60%) product, as a pale yellow solid, mp 95°-97° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-fluorobenzoate (6.0 mL, 41 mmol), 1,4-dioxa-8-azaspiro(4,5)decane (13.5 mL, 102 mmol), and K2CO3 (5.7 g, 41 mmol) in NMP (35 mL) was stirred at 150° C. for 4 hours, cooled to room temperature, treated with water (0.5 L) and filtered. The filter cake was washed with water and dried briefly. The crude product was triturated with hexane, filtered, and dried under vacuum to provide the desired product. MS (DCI) m/e 292 (M+H)+.