Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C[Li].CCOCC.[O:20]1[C:25]2[C:26]([C:33](OCC)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3>C1COCC1>[O:20]1[C:25]2[C:26]([C:33]([O:12][CH2:11][CH:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]3)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3
Reactant: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Reactant: CCCCN1CCC(CO)CC1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCN1CCC(COC(=O)c2c3c(n4ccccc24)CCCO3)CC1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
A stirred solution of (1-butyl-4-piperidinyl)methanol (125 mg, 0.72 mmole) in dry THF (5 ml) at 5° C. under argon was treated with 1.5M methyllithium in ether (0.35 ml, 0.50 mmole). After 10 minutes, a solution of ethyl 3,4-dihydro-2H-pyrano[2,3-b]indolizine-10-carboxylate (55 mg, 0.22 mmole) in dry THF (5 ml) was added and the mixture heated under reflux for 3 h. The mixture was then allowed to cool and concentrated in vacuo. The residue was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×40 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform to afford the title compound as a pale pink oil (65 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11](OCC)=[O:12])[CH3:10])[C:5]([N+:16]([O-])=O)=[CH:4][C:3]=1[C:19]1[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.[Sn].Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:19]2[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=2)=[CH:4][C:5]2[NH:16][C:11](=[O:12])[CH:9]([CH3:10])[O:8][C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CC1Oc2cc(Cl)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc2NC1=O
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To 10 ml of ethanol, 0.90 g (2.0 mmol) of 3-[2-chloro-4-(1-ethoxycarbonylethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1 g (8.5 mmol) of tin were added, and 2 ml of concentrated hydrochloric acid was added thereto with stirring at room temperature, followed by stirring for 1 hour. After completion of the reaction, excess ethanol was distilled off under reduced pressure, and the residue was neutralized with a saturated sodium hydrogencarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure to obtain 0.7 g (yield: 91%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 1.63(3H,d), 3.70(3H,d), 4.67(1H,q), 6.77(1H,d), 6.83(1H,s), 7.08(1H,s), 7.35(1H,d,J=7.80)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:10](=[O:12])[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Br:1])([CH3:14])[CH3:13])[CH2:43][CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C(=O)O)c1cc(F)ccc1Br
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)NC1CCN(Cc2ccccc2)CC1)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-bromo-5-fluorophenyl)-2-methylpropanoic acid (510 mg, 1.95 mmol, EXAMPLE 44, Step 1) in tetrahydrofuran (20 mL) were added triphosgene (197 mg, 0.66 mmol) and triethylamine (0.288 mL, 2.05 mmol). The mixture was stirred at room temperature for 30 min and was filtered. The filtrate was added drop-wise into a solution of 1-benzyl-4-aminopiperidine (372 mg, 1.95 mmol) and triethylamine (0.288 mL, 2.05 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for overnight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24][CH2:25]O)=[CH:22][CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:25][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)=[CH:21][CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(O)cccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(OCCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cccc21

Procedure:
In analogy to the procedure described in example 5 f], (4-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 8 e]) in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(#N)C>[F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC#N
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
6.24 g (40 mmol) of 5-fluoro-salicylic acid is dissolved in 62.4 ml of acetonitrile with warming, the solution is cooled to 0° C. and, with this temperature being maintained a solution of 2.96 ml (44 mmol) of 65% HNO3 in 14.8 ml of acetonitrile is instilled. The reaction mixture is stirred for 24 hours at 0° C., then filtered over 7.5 g of silica gel 60 and evaporated to dryness 6.1 g =75.8% of the theoretical yield is obtained of the crude product, which is used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 0° C. (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J=8.0 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Cl:13]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(C)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 300 mL three-necked, round-bottomed flask fitted with a magnetic stirrer, condenser equipped with nitrogen inlet, and thermometer were placed 5.68 (25 mmole) of methyl 4-amino-3-methylbenzoate and 35 mL of acetonitrile. The flask was immersed in a preheated oil bath (oil bath temperature 70° C.) and 5.15 g (37.8 mmole) of N-chlorosuccinimide was added all at once. The resulting mixture was refluxed for 2 hours then cooled to room temperature to stand overnight. The reaction mixture was concentrated by removing solvent using a rotary evaporator and the resulting residue was partitioned between a mixture of 100 ml of ethyl ether and 100 ml of water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed using a rotary evaporator, yielding 6.05 g methyl 4-amino-3-chloro-5-methylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[O:35][CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cccnc2c1=O
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ncccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 ml round bottomed flask charged with (2,4-Dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-acetic acid t-butyl ester (14.9 mg, 0.054 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (26.5 mg, 0.06 mmol), and Cs2CO3 (50.9 mg, 0.11 mmol) is treated with DMF (3 ml) and the solution stirred at RT. After 2 hours, the reaction mixture is treated with water and stirred for 10 minutes. The product is extracted into EtOAc and washed with water (3×10 ml). The organic portions are dried (MgSO4), filtered and concentrated to give the title compound, [M+H]+ 505
Reaction SMILES: O=S(Cl)[Cl:3].[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:3][CH2:15][CH:12]1[CH2:13][CH2:14][C:9]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:10][CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCC2(CC1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCC1CCC2(CC1)OCCO2
Yield: 88.1 %

Procedure:
SOCl2 (37.1 mL, 509 mmol, 1.3 equiv) was slowly added to a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (67.3 g, 391 mmol) and pyridine (94.8 mL, 1175 mmol, 3 equiv.) in CHCl3 (400 mL) Caution: The reaction is exothermic. The resulting yellow mixture was heated at reflux for 1.5 h and concentrated. The residue was partitioned between water (500 ml) and ether (500 ml). The layers were separated and the aqueous layer was re-extracted with ether (200 ml). The combined ether layers were washed with 1N HCl (2×100 ml), water (200 ml) followed by brine (200 ml), then dried (MgSO4), filtered and concentrated to give the title compound as a dark amber oil (65.7 g, 88% yield). 1H NMR (500 MHz, CDCl3) δ: 3.94 (4 H, t, J=2.9 Hz), 3.41 (2 H, d, J=6.4 Hz), 1.83-1.88 (2 H, m), 1.75-1.79 (2 H, m), 1.63-1.73 (1 H, m), 1.55 (2 H, td, J=4.3, 13.2 Hz), 1.29-1.39 (2 H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([P:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: CCOP(OCC)OCC
Product: CCCCCCC(C(=O)OCC)P(=O)(OCC)OCC
Yield: 80.6 %

Procedure:
2-Bromo octanoic acid ethyl ester (50 g, 0.2M) was heated at 150° with triethyl phosphite (75 g, 0.44M) and the distillate, Bpt 37°-60° condensed as the temperature was raised to 200° over 6 h. The reaction mixture was cooled and distilled under high vacuum (1.00 mm Hg) to afford 2 main fractions (a) Triethyl phosphite b.p. 40°-70° and (b) 2-(diethylphosphono)octanoic acid ethyl ester (49.5 g, 0.16M); b.p. 120°-130° at 0.5 mm Hg. (Found: C, 52.9; H, 9.4. C14H29O5P+0.5H2O requires: C, 53.0; H, 9.5%; δ(CDCl3) 0.88 (3H, m, CH3); 1.32 (17H, m, (CH2)4, 3×CH3); 1.9 (2H, m, CH2); 2.92 (1H, d, d, d, J= 22 Hz, J=10 Hz; J=4 Hz, CH--P); 4.18 (6H, m, 3×CH2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1(Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: BrC1CCCCC1
Product: COc1ccc(CC2c3c(OC4CCCCC4)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclohexyl bromide
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of triethylamine and 239.93 mg of dimethylaminopyridine in 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined filtrates evaporated to give the desired product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[F:18][CH:19]([F:21])Cl>O.O1CCOCC1>[F:18][CH:19]([F:21])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(OC(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
100 g of 4-hydroxybenzophenone and 200 g of sodium hydroxide are dissolved in a mixture of 1 l of water and 500 ml of dioxane. The mixture is heated to 70° C. and a vigorous stream of difluorochloromethane (Frigen 22) is introduced. After 2 hours, the mixture is cooled to room temperature and 1 l of water is added to the contents of the flask. The mixture is extracted three times using 1.2 l of chloroform each time, the chloroform phase is extracted by shaking with 1N sodium hydroxide solution, washed with water and the organic phase is dried using potassium carbonate. After stripping off the solvent and subsequent distillation under vacuum, 60 g (48%) of 4-difluoromethoxybenzophenone are obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[NH:7][C:8](=[O:10])[CH3:9].CN(C)[C:16]1[O:17][C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1>C(O)(=O)C.O>[Cl:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([N:1]2[C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[NH:21][C:16]2=[O:17])=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc(N)c(F)cc1Cl
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Yield: 78.1 %

Procedure:
A mixture of 5′ -amino-2′-chloro-4′-fluoroacetanilide (1.0 g, 4.9 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (1.0 g, 4.9 mmol) in acetic acid is refluxed for 90 minutes and diluted with water. The resultant aqueous mixture is filtered to obtain the title product as an off-white solid (1.4 g, mp 264-266° C.) which is identified by 1H, 13C and 9F NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=[O:46])[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[CH3:3][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[C:9]([N:40]1[C@H:41]([C:45]([NH2:47])=[O:46])[CH2:42][C@H:43]2[C@@H:39]1[CH2:44]2)=[O:10])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C(N)=O)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (S)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula VI) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-Cl)(13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH2:20])[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[C:30](Cl)([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH:20][C:30](=[O:31])[O:32][CH2:33][CH:34]3[C:46]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:40]4[C:35]3=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2c([C@H](C)N)cc3cccc(Cl)c3c2=O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2c([C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc3cccc(Cl)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(4-methoxybenzyl)-3-(1-aminoethyl)-8-chloroisoquinolin-1(2H)-one (343) (20 g, 58.3 mmol, 1.0 eq) and NaHCO3 (12.7 g, 291.51 mmol, 5.0 eq) in DCM (120 mL) and water (60 mL) at RT, Fmoc-Cl (15.7 g, 61.22 mmol, 1.05 eq) was slowly added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford (S)-(9H-fluoren-9-yl)methyl 1-(2-(4-methoxybenzyl)-8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (344).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=2)[O:21][C:20]([CH3:29])([CH3:28])[CH2:19][C:18]3([CH3:31])[CH3:30])[CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:25]([C:23]1[CH:24]=[C:15]([C:14]#[C:13][C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:28])([CH3:29])[CH2:19][C:18]2([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1cc(C#Cc2cccc(C=CC(=O)O)c2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 3-[3-(8-isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 33, 0.058 g, 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 5N solution of potassium hydroxide (2 mL, 10 mmol) and the reaction mixture was stirred at ambient temperature overnight. The Volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound (0.036 g, 66%).
Reaction SMILES: [N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH:28][C:33]([NH:34][C:35]5[N:36]([C:44]6[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=6)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=5)=[O:32])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCCC5)n4c3)c3ccccc32)cc1
Yield: 10 %

Procedure:
A solution of Intermediate 67b (173 mg, 0.458 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 186 mg, 0.458 mmol) in 1,4-dioxane (3 mL) and DIPEA (122 μL, 0.700 mmol) was stirred at 95° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM. Further purification by FCC, using 0-10% MeOH in DCM, gave impure product. This was further purified by HPLC (C18X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give impure product. Further purified by HPLC (XBridge column, 35-98% MeCN in H2O, 0.1% NH4OH) to give an off-white powder after freeze-drying (50 mg). This material was further purified by MDAP (Method 7) to give the title compound as a white solid (28 mg, 10%). LCMS (Method 5): Rt 4.77 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d5-DMSO): 1.27 (9H, s), 1.64-1.71 (4H, m), 1.74-1.97 (6H, m), 1.99-2.18 (2H, m), 2.36 (3H, s), 3.38-3.43 (4H, m, under water signal), 4.77-4.85 (1H, m), 5.47 (1H, t, J 4.3), 6.32 (1H, s), 7.07-7.14 (2H, m), 7.25-7.40 (8H, m), 7.55-7.59 (2H, m), 8.06 (1H, s).