Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:57][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][N:69](COCC[Si](C)(C)C)[C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:55]2)[CH2:50][CH2:49]1>O1CCCC1>[F:16][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[CH2:55][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][NH:69][C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:57]2)[CH2:52][CH2:53]1)=[O:8]
Reactant: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)cc(C(F)F)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoic acid (14.0 mg, 0.0609 mmol, from Step D), Triethylamine (28.3 μL, 0.203 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 0.0558 mmol) in tetrahydrofuran (0.56 mL) was stirred for 15 minutes. {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25.0 mg, 0.0507 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic portion was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was stirred in 1:1 DCM:TFA for 1 hour, solvents were removed in vacuo, and the resulting residue stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a white powder. Yield: 0.012 g (40%); LC-MS: 574.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.46-7.41 (m, 2H), 7.07 (t, 1H), 7.07 (d, 1H), 4.17-4.03 (m, 1H), 3.75 (d, 2H), 3.62-3.25 (m, 7H), 3.22-3.03 (m, 2H), 2.58-2.51 (m, 1H), 2.15 (s, 6H), 1.85-1.55 (m, 2H), 1.33-1.12 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (12 g, 0.06 mol) in MeOH (150 mL) was added dropwise a solution of NaOH (9.8 g, 0.24 mol) in water (50 mL). The mixture was then stirred at RT for 1 h and concentrated in vacuo, the residue was acidified with HCl (IN) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (10 g, 67%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][CH3:2]
Reactant: CO
Reactant: CNCCCC(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNCCCC(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(methylamino) butyric acid HCl was dissolved in methanol and thionyl chloride in catalytic amount was added drop by drop. The reaction mixture was stirred at 0° C. for 30 min. Thereafter, the solvent was reduced in vacu, yielding a white solid.
Reaction SMILES: O=S(Cl)Cl.[NH2:5][CH:6]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:7][C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:5][CH:6]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: Cc1ccsc1C(N)CC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1sccc1C

Procedure:
To a 50 mL round bottom flask equipped with an electromagnetic stirrer and a drying tube, 15 mL of anhydrous methanol was added. The solution was cooled in an ice water-sodium chloride bath to minus 10° C., and 2 mL of SOCl2 was added slowly. The reaction mixture was allowed to react for an hour at room temperature. Then 1.85 g of 3-amino-3-(3-methyl-thiophene-2-yl)propionic acid was added. The mixture was allowed to react for 3 hours at room temperature, then refluxed for 40 minutes. After the solution was evaporated to remove the solvent, 100 mL of CHCl3 and 100 mL saturated NaHCO3 were added, and the layers were separated. The organic layer was washed successively with 30 mL of water and 30 mL of saturated brine, dried over anhydrous MgSO4, filtered, evaporated, and purified by column chromatography to give an oil-like product. MS (m/z): 200 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl.[CH3:13][NH:14][CH3:15].[OH-].[Na+].C([BH3-])#N.[Na+]>CO.O>[CH3:13][N:14]([CH3:15])[CH2:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1cnc2[nH]ccc2c1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)Cc1cnc2[nH]ccc2c1
Reaction time: 12 h
Yield: 33 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine-5-carbaldehyde (114 mg, 0.78 mmol), in methanol (10 ml) was added dimethylamine hydrochloride (127 mg, 1.56 mmol, NaOH (31.2 mg, 0.78 mmol), sodium cyanoborohydride (49 mg, 0.78 mmol) and the solution was stirred under nitrogen for 12 hr. Poured into water (50 mL), extracted with ethyl acetate, dried (Na2SO4) to afforded Dimethyl-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine (44 mg, 33% yield) used without purification. MS: m/e 176.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([CH:29]=[CH:30][C:31]=1[C:32]#[N:33])[C:5]([NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[Br:28])=[O:6].[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][N:37]=1.O.C(OCC)(=O)C>CN1C(=O)N(C)CC1>[Br:28][C:9]1[CH:10]=[C:11]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])[CH:12]=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=1[NH:7][C:5]([C:4]1[C:3]([F:34])=[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([Cl:35])=[N:37][CH:38]=2)[C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[O:6]
Reactant: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c(F)c1NC(=O)c1ccc(Cl)nc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 8.1 %

Procedure:
To a solution of 0.0500 g (0.0877 mol) of 3-amino-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-4-cyano-2-fluorobenzamide in 0.200 ml of DMI was added 0.0308 g (0.175 mmol) of 6-chloronicotinoylchloride, followed by stirring at 130° C. for 6 hours. To the reaction liquid were added water and ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=2:1) to prepare 0.0100 g (yield 16%) of a target compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:4]1[CH:3]=[C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccccn2)cc1F
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a suspension of EXAMPLE 50A (5 g), Pd2(dba)3 (1.5 g) and tri-2-furylphosphine (1.5 g) in DMF (100 mL) was added 2-trimethylstannyl pyridine (9.5 g) and triethylamine (2 mL). The reaction mixture was stirred at 80° C. for 18 hours, cooled and partitioned between ethyl acetate and brine. The ethyl acetate layer was separated and concentrated, and the concentrate flash chromatographed on silica gel with 1:2 ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:23])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35](Cl)=O.CN(C)C=O>ClCCl>[CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24])(=[O:17])=[O:18])[C:10]([O:12][CH2:34][CH3:35])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred 0° C. solution of (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoic acid (Example 8(a), Step 3) (0.8 g) in dichloromethane (10 mL), was added oxalyl chloride (0.28 mL) followed by a drop of N,N-dimethylformamide. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (10 mL), to which was added ethanol (2 mL). The reaction mixture was stirred overnight at room temperature. The volatiles were removed, and the residual material was purified by silica gel chromatography (hexanes/ethyl acetate 70:30) to afford ethyl (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoate (0.70 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.O=[S:10](Cl)Cl.S(=NS(C)(=O)=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[S:10][CH:8]=[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1N
Agent: CS(=O)(=O)N=S=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: c1ccc2nscc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene was added SOCl2 (12.1 g, 102 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in toluene (100 mL), then a solution of N-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise, followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated to reflux and stirred at that temperature overnight. Toluene was then removed under reduced pressure, the residue was dissolved in EtOAc (200 mL) and washed with water (2×200 mL). The organic layer was washed with brine, dried and evaporated to give the crude product. The crude product was purified by column chromatography (3% EtOAc/PE) to afford 6.2 g title compound as colorless oil. 1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5, 1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:18])[C@@H:11]([NH2:17])[CH2:12][O:13][CH2:14][CH2:15]Cl>CO>[CH3:8][O:9][C:10]([C@@H:11]1[CH2:12][O:13][CH2:14][CH2:15][NH:17]1)=[O:18]
Reactant: COC(=O)[C@@H](N)COCCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1COCCN1

Procedure:
Triethylamine (1.2 mL) was added to the above-obtained (2S)-2-amino-3-(2-chloroethoxy)propanoic acid methyl ester (726 mg) in methanol (10 mL), and the resultant mixture was refluxed under heat for 3 hours, and then cooled in air. The reaction solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and insoluble matter was removed by filtration. The solvent of the filtrate was removed under reduced pressure, to thereby give the title compound as an oily product (467 mg, 80%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>CN(C)C=O>[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40])=[O:25])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Triethylamine (0.63 ml, 4.52 mmol) is added to a solution of 6-(benzyloxycarbonylamino)hexanoic acid (1.00 g, 3.77 mmol) in dimethylformamide (20 ml) and the mixture is left to stir at ambient temperature and under argon for 30 minutes. The solution is cooled to 0° C. and ethyl chloroformate (0.43 ml, 4.52 mmol) is added dropwise. After two hours at ambient temperature, N-hydroxysuccinimide (0.52 g, 4.52 mmol) is added and the mixture is left to stir overnight at ambient temperature. The mixture is evaporated to dryness before taking up the residue in water to which ethyl acetate is added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated to dryness before purification on a silica gel column with an ethyl acetate/pentane mixture (75/25 v/v) as eluent. The fractions, once evaporated, give 1.13 g of succinimidyl 6(benzyloxycarbonylamino)hexanoate in the form of an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C([O:11][B:12](OC(C)C)[O:13]C(C)C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C.[K+]>C1COCC1>[C:6]([C:2]1[S:1][C:5]([B:12]([OH:13])[OH:11])=[CH:4][CH:3]=1)#[N:7]
Reactant: N#Cc1cccs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)s1
Reaction time: 1 h
Yield: 528.1 %

Procedure:
To a solution of compound thiophene-2-carbonitrile (10 g, 9.16 mmol, 1.0 eq) and tri-iso-propylborate (23 mL, 100 mmol, 1.09 eq) in dry THF (300 mL) under nitrogen at −78° C., potassium hexamethyldisilazide (1 M in THF, 100 mL, 100 mmol, 1.09 eq) was added dropwise. After 1 h, the reaction was quenched with 1 N HCl (200 mL), stirred for 30 min and extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4), filtered and evaporated and crystallized with petroleum ether/ethyl acetate to afford the product compound 5-cyanothiophen-2-ylboronic acid (7.4 g, 53%). LC-MS (m/z)=153.9 [M+H]+
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=2[S:14]([N:17]2[CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[F:33])[NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([O:4][CH:1]3[CH2:3][CH2:2]3)=[C:6]([S:14]([N:17]3[CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)c(Cl)c1)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a solution of 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid (170.00 mg, 475.68 umol, 1.00 eq) and 3-chloro-4-fluoro-aniline (69.24 mg, 475.68 umol, 1.00 eq) in DMF (5.00 mL) were added HATU (180.87 mg, 475.68 umol, 1.00 eq) and DIPEA (122.95 mg, 951.36 umol, 2.00 eq). The mixture was stirred at 25° C. for 16 hr. TLC detected the reaction was complete, the mixture was poured into water, extracted with EA, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was purified by prep-HPLC (FA) to afford product N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzamide (94.10 mg, 194.05 umol, 40.79% yield) as white solid. 1H NMR (400 MHz, MeOD) δ 8.48 (d, J=2.01 Hz, 1H), 8.23 (dd, J=8.66, 2.13 Hz, 1H), 7.96 (dd, J=6.78, 2.51 Hz, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.59-7.65 (m, 1H), 7.27 (t, J=8.91 Hz, 1H), 4.07-4.13 (m, 1H), 4.03 (t, J=6.53 Hz, 1H), 3.77-3.97 (m, 4H), 3.61-3.73 (m, 2H), 3.21-3.30 (m, 1H), 3.11 (dd, J=14.56, 7.53 Hz, 1H), 0.84-1.04 (m, 4H). LCMS: 485/487 [M+1].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1.Cl[C:47]1[S:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[S:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CNC4)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6s5)C4)cc3)cc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A solution of 0.835 g of benzyl 4-[4-(azetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 257c) and 0.233 g of 2-chlorobenzothiazole in 16 ml of N,N-dimethylformamide is admixed with 0.345 g of potassium carbonate. The mixture is stirred at 150° C. over 1 hour, cooled to room temperature and poured onto a mixture of 100 ml of brine, 50 ml of water and 150 ml of ethyl acetate. The phases are separated and the aqueous phase is extracted with 150 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a light yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (4:1 EtOAc-heptane); Rt=4.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9](C)([C:12](OC)=O)[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1(C)Oc2c(OC)cccc2C1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1OC(C)C2=O
Yield: 33.8 %

Procedure:
Methyl 7-methoxy-2-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (18.38 g) was dissolved in dioxane-water (5:1, 300 ml) and 0.5 N sulfuric acid (37 ml) was added to the solution, followed by refluxing the resulting solution for 16 hours. The reaction solution was concentrated and poured into water layer (300 ml), followed by extracting the resultant three times with ether (150 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1-5/1) using florisil to obtain the desired compound (4.69 g, yield: 36%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 67.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (213 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 194 mg (68%) of the title compound as a white solid. mp 110°-112°. FDMS: m/e=441 α[D]589 =+80.70 (c=1.05, methanol).
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[CH:32]([C:34]([CH2:36][CH3:37])=[O:35])=[CH2:33]>O1CCCC1>[C:1]([C:4]1([CH2:33][CH2:32][C:34](=[O:35])[CH2:36][CH3:37])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC(=O)CC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 52.3 g. of 9-carbamoylfluorene and 10 ml. of benzyltriethylammonium hydroxide in 700 ml. of tetrahydrofuran was heated at 45° C. for thirty minutes and then cooled to 25° C. The reaction mixture was diluted by addition in one portion of 25.2 g. of ethyl vinyl ketone. The reaction mixture was stirred at 25° C. for sixteen hours and at reflux for three hours. The mixture was cooled, added to 200 g. of ice and extracted with 50% ethyl acetate-diethyl ether. The organic extract was washed with water, with 10% sodium hydroxide, dried and the solvent was removed by evaporation under reduced pressure. The solid residue was crystallized from ethyl acetate and petroleum ether to afford 42.6 g of 9-carbamoyl-9-(3-oxopentyl)fluorene. m.p. 133°-135° C.