Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C

Procedure:
2-(4-Bromophenoxy)-5-(trifluoromethyl)pyridine (2) was prepared by heating a mixture of 4-bromophenol (1.0 eq, Aldrich), 2-chloro-5-(trifluoromethyl)pyridine (0.9 eq, Aldrich), and K2CO3 (2 eq) in 25 mL of CH3CN at 80° C. under argon for 14 hours. After cooling to room temperature, water (30 mL) was added, extracted with EtOAc (2×100 mL), concentrated and purified by column (silica gel, Hexanes, then Hexanes/EtOAc 10/1) to give compound 2: 1H-NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.94 (ddd, 1H, 0.6, 2.6 & 8.6 Hz), 7.56 (d, 2H, 8.9 Hz), 7.05-7.08 (m, 3H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.[CH2:28]([CH:30]1[S:34][C:33](=[S:35])[N:32]=[N:31]1)[CH3:29].Cl>O.C(=O)(O)[O-].[Na+]>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:35][C:33]1[S:34][C:30]([CH2:28][CH3:29])=[N:31][N:32]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([OH:27])=[O:26]
Reactant: CCC1N=NC(=S)S1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 60 °C
Yield: 23.8 %

Procedure:
3-Acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (7 g.) is dissolved in distilled water (100 cc.) and sodium bicarbonate (1.46 g.). A solution of 5-ethyl-2-thioxo-1,3,4-thiadiazoline (2.63 g.) in distilled water (60 cc.) and sodium bicarbonate (1.46 g.) is added and the resulting solution is heated to 60° C. for 6 hours. After cooling, it is acidified to pH 5.5 by adding 4 N hydrochloric acid and is then extracted twice with ethyl acetate (100 cc.). The organic extracts are discarded. The acidification is continued in the presence of ethyl acetate (300 cc.) until the pH is 2. After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The combined organic extracts are washed twice with water (200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and then filtered and concentrated to dryness under reduced pressure (20 mm.Hg). The residue obtained is recrystallised from methanol (100 cc.) to give 2-carboxy-3-[(5-ethyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2 g.) m.p. 155° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].N(C(C)(CC)C#N)=NC(C)(CC)C#N.[C:30]([O:33][CH2:34][CH3:35])(=O)C>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7][CH2:8][CH3:9].[C:10]([O:15][CH2:35][CH:34]1[O:33][CH2:30]1)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: C=CC(=O)OCCCC
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1CO1
Temperature: 60 °C

Procedure:
The following were added to a 946 mL bottle: 72.0 g of butyl acrylate (Dow Chemical Co., Midland, Mich.), 48.0 g of glydicyl methacrylate (Sartomer Co. Inc., Easton, Pa.), 0.18 g of 2,2′-azobis(2-methylbutanenitrile) (DuPont, Wilmington, Del.), 140 g of ethyl acetate, and 140 g of toluene. The solution was purged with nitrogen for two minutes at a rate of one liter per minute. The bottle was sealed and placed in a water bath that was maintained at 60° C., for 24 hours. The reaction mixture was 29.5 wt % solids, had a measured inherent viscosity of 0.78 dL/g and a Brookfield viscosity of 0.7 Pascal-seconds.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:35][CH:36]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:37]([OH:42])[C:38]([F:39])([F:40])[F:41])=[O:22])[C:15]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:35][CH:36]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:39])([F:40])[F:41])=[O:21])[C:15]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-2-(3,5-dinitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)-acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(3,5-dinitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 16, mixture with diethyl ether, 3.74 g, 7.08 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.78 g, 8.12 mmol), WSCI hydrochloride (1.63 g, 8.50 mmol) and HOBT (1.91 g, 14.1 mmol) in DMF (25 mL) to give 4.06 g (86%) of the target compound as a dark-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)=O.CC(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:34]1[CH:35]=[N:36][CH:28]=[CH:29][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80 mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) via addition funnel, at a rate that kept the internal temp below −59° C. (˜2 h). After final addition, the yellow-green slurry was stirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0 g, 56.69 mmol). The bath was not removed, but the contents were allowed to slowly warm to room temp. After 4 days, the dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL). The aqueous layer was separated and the organics were again extracted with base (1000 mL). The pH of the two aqueous layers was adjusted to −2 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered. The resultant yellow cake was washed with water (2×400 mL) and dried under high vacuum at 40° C. (17-19 g). LC/MS [(5.2 min; 359 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30].C(OCC)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:19])=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:25]([F:27])([F:26])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of the benzoxazinone product of Step D (124 g, 300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine (76 mL, 900 mmol) at room temperature. The temperature of the reaction mixture rose and the suspension thinned during the addition. The reaction mixture was then warmed to reflux for 1.5 h. A new suspension formed. The reaction mixture was cooled to room temperature and diethyl ether (1.3 L) was added and the mixture stirred at room temperature overnight. The solids were collected and washed with ether. The solids were air-dried and then dried in vacuo at 90° C. for 5 h to yield 122 g of the title compound, a compound of the present invention, as a fluffy white solid, melting at 194-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C([O-])([O-])=O.[K+].[K+].[CH3:26][C:27]([CH3:29])=O>>[CH2:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[C:13]([CH2:29][CH:27]=[CH2:26])[C:12]=1[OH:15])[CH:17]=[CH2:18]
Reactant: C=CCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Temperature: 25 °C

Procedure:
To a solution of starting 4-benzyloxyphenol (20 g) in acetone (800 mL) were added allylbromide (50 mL) and K2CO3 (60 g). The reaction mixture was refluxed overnight. After cooling to the room temperature, the insoluble materials were removed by filtration. The filtrate was concentrated in vac. The residue was partitioned between ethyl ether (500 mL) and 2N aqueous NaOH (200 mL). The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vac. to give the desired product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:24](=O)[CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:22][C:20]1[CH:21]=[C:12]([N:11]([CH2:24][CH3:25])[CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[C:13]([CH3:23])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a stirred solution of methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)-5-chloro-2-methylbenzoate (6.6 g, 19 mmol) and acetaldehyde (2.56 g, 58.4 mmol) in dichloroethane (70 mL) was added acetic acid (7.0 g, 120 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (12 g, 57 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (4.0 g, 56%).
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>CO>[CH2:11]([N:21]1[CH2:26][CH2:25][N:24]([C:3]2[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1
Reactant: COc1cccccc1=O
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: CO
Product: O=c1cccccc1N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-methoxytropone (1.36 g, 10.0 mmol) (Pietra, F. Chem Review, 1973, 73:293) and 1-piperonylpiperazine (6.61 g, 30.0 mmol) in methanol (50.0 mL) was refluxed for 16 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to column chromatography using ethyl acetate as the eluent. The title compound was obtained as a yellow oil (1.24 g, 38%). MS (FAB) 325 (M+ +1).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C.O>[CH:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[C:4]([O:3][CH3:16])=[O:15])=[O:1]
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(O)c2cccc(C(F)(F)F)c21
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(C=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of (±)-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1 (3H)-one, from Example 1, Part B, (3.31 g, 15.2 mmol) in 20 mL of DMF was added potassium carbonate (4.2 g, 30.4 mmol) followed by iodomethane (1.04 mL, 16.7 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was cooled to 0° C. and carefully acidified with 6N HCl, diluted with water and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.1 g (89%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 10.05 (s, 1H), 8.12 (d, 1H, J=7.7 Hz), 7.95 (d, 1H, J=7.7 Hz), 7.76 (t, 1H, J=7.7 Hz), 4.02 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([N:38]([CH2:39][CH3:40])[C:19](=[O:20])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1)[CH3:37]
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.0312 mole), 1,1'-carbonyldiimidazole (6.1 g, 0.0374 mole), and dry tetrahydrofuran (250 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. An additional 6.1 g (0.0374 mole) of 1,1'-carbonyldiimidazole was added, and the suspension was stirred at room temperature under nitrogen overnight. The suspension was heated at 50° C. for 2 hours and then treated with diethylamine (7.07 g, 0.097 mole) in dry tetrahydrofuran (10 ml). The reaction mixture was heated at 50° C. for 5 hr and allowed to stand at room temperature over the weekend. The solvent was evaporated under reduced pressure, the resulting solid was triturated in water (200 ml) and filtered. The solid was dissolved in hot isopropyl alcohol, treated with charcoal and filtered while hot. Upon cooling, a solid precipitated. The solid was filtered and rinsed with isopropyl ether to give 6.4 g (55%) of white solid, mp. 140.5°-142.5° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[C:34]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31])[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c(Cl)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1>COCCOC.C(OCC)(=O)C>[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:17]#[N:18])[CH2:27][CH2:26]2)[CH2:22][CH2:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(SCC2CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#CC1CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
Potassium-t-butoxide (16.10 g, 144 mmol) was added to a stirred, cooled (0° C.) mixture of TOSMIC (15.84 g, 81 mmol) and 4-[(cyclopropylmethyl)thio]cyclohexanone (11.5 g, 62.4 mmol) in DME (125 ml) and the mixture was stirred at room temperature for 3 h. The mixture was cooled, diluted with ethyl acetate, washed with brine, dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give two separated isomers. Combined yield of 4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (7.1 g, 36.3 mmol, 58.3% yield)
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:25]=[C:26]([N:32]2[CH:40]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[CH:39]3[C:34]([C:35]4[CH:51]=[CH:50][C:49]([C:52]([OH:54])=O)=[CH:48][C:36]=4[CH2:37][CH2:38]3)=[N:33]2)[CH:27]=[CH:28][C:29]=1[C:30]#[N:31].C(O)C.C(N(CC)CC)C.[N:65]1([CH2:70][CH2:71][NH2:72])[CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([N:32]2[CH:40]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[CH:39]3[C:34]([C:35]4[CH:51]=[CH:50][C:49]([C:52]([NH:72][CH2:71][CH2:70][N:65]5[CH2:69][CH2:68][CH2:67][CH2:66]5)=[O:54])=[CH:48][C:36]=4[CH2:37][CH2:38]3)=[N:33]2)[CH:27]=[CH:28][C:29]=1[C:30]#[N:31]
Reactant: NCCN1CCCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)NCCN5CCCC5)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Reaction time: 0.17 h
Yield: 42 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (77 mg, 0.24 mmol) was added to a solution of (±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 2 (89 mg, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol), and dimethylformamide (2.0 mL) at room temp. After 10 minutes, 2-(pyrrolidin-1-yl)ethanamine (0.051 mL, 0.40 mmol) was added. After 40 minutes, the reaction was quenched with 0.30 mL 3N hydrogen chloride and purified by reverse-phase HPLC (20 to 90% acetonitrile/water/0.05% trifluoroacetic acid). The purified fractions were combined, neutralized with saturated sodium bicarbonate solution, and concentrated until a precipitate formed. The precipitate was filtered, washed with water, and dried to give the title compound (yellow solid, 45.5 mg, 0.084 mmol, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 1H), 1.64 (m, 4H), 1.79 (m, 1H), 2.46 (m, 4H), 2.54 (t, J=7.03 Hz, 2H), 2.91 (m, 2H), 3.35 (q, J=6.64 Hz, 2H), 3.95 (ddd, J=13.57, 11.03, 5.08 Hz, 1H), 5.92 (d, J=11.33 Hz, 1H), 7.15 (m, 6H), 7.65 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.75 (dd, J=8.20, 1.56 Hz, 1H), 8.10 (d, J=8.20 Hz, 1H), 8.47 (t, J=5.86 Hz, 1H). ES-MS m/z 542 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]=[C:20]=[O:21])=[CH:14][C:13]=1[Cl:22].CCCCCC>C1COCC1>[Cl:22][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[Cl:11])[CH2:18][NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94; H, 3.68; N, 11.97.
Reaction SMILES: [CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>CC(=O)CC>[CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:36][CH2:35][CH2:34][CH2:33][Br:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: CN1C(=O)C(Cc2ccccc2)(c2ccccc2O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1C(=O)C(Cc2ccccc2)(c2ccccc2OCCCCBr)c2ccccc21
Yield: 83.1 %

Procedure:
16.5 g (0.05 mol) of 3-benzyl-3-(2-hydroxyphenyl)-1- methylindolin-2-one in 250 ml of 2-butanone are stirred under reflux with 20.7 g (0.15 mol) of ground anhydrous potassium carbonate and 17.2 ml (0.15 mol) of 1,4-dibromobutane for 5 hours. The hot mixture is filtered with suction, and the filtrate is concentrated in vacuo. The crystalline residue is triturated with petroleum ether, and the product is isolated after removal of the solvent with suction. 19.3 g of product of melting point 174°-5° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([O:15]C(C)(C)C)=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc2[nH]c(=O)nc(N)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)sc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of tert-butyl 4-amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (example 64a) (10.7 g, 38.03 mmol) in CH2Cl2 (25 mL), was added trifluoroacetic acid (25 mL, 324.5 mmol). The reaction mixture was stirred at rt overnight. The precipitated solid was collected by filtration, and washed with CH2Cl2 to yield 4-Amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (6.98 g, 82%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 2.78 (s, 3H). MS 226.0 (MH+).