Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:24][CH2:23][C:13]3([O:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)[CH2:12][CH2:11]2)[CH3:9])=[C:4]([F:25])[CH:3]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B(O)O)[CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:20]1([N:15]2[CH2:14][C:13]3([CH2:23][CH2:24][N:10]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:34]=[C:35]6[C:30]([CH:29]=[CH:28][CH:27]=[N:26]6)=[CH:31][CH:32]=5)=[CH:3][C:4]=4[F:25])[CH3:9])[CH2:11][CH2:12]3)[O:18][CH2:17][C:16]2=[O:19])[CH2:22][CH2:21]1
Reactant: CC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: OB(O)c1ccc2cccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 24.8 %

Procedure:
A solution of 9-(1-(4-bromo-2-fluorophenyl)ethyl)-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.438 mmol) in 1,4-dioxane (2 mL) was treated with quinolin-7-ylboronic acid (0.481 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.022 mmol), and 2M aq potassium carbonate (1.313 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 130° C. for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The aqueous layer was further diluted with brine (50 mL) and was then extracted with tetrahydrofuran. The organic layers were combined and were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (4-10% methanol/dichloromethane) followed by resolution of the product by chiral HPLC (Lux Cellulose-2 column, acetonitrile:methanol 85:15) afforded the title compound as a white solid (50 mg, 23%). MS(ES)+ m/e 460.2 [M+H]+, >99% ee, αD=+38 deg (c=0.02, acetonitrile:methano185:15).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:48])[CH2:6][N:7]([CH2:43][C:44]([O:46]C)=[O:45])[C:8](=[O:42])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:10]=1>>[C:5]([CH2:6][N:7]([C:8](=[O:42])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:10]=1)[CH2:43][C:44]([OH:46])=[O:45])([OH:48])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine methyl ester gave N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine, mp 93°-95°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH:14]1([C@H:17]2[CH2:22][NH:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:18]2[OH:31])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH:14]1([C@H:17]2[CH2:22][N:21]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]4[CH2:11][CH2:12][CH2:13][C:3]=34)[CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:18]2[OH:31])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.094 g, 0.47 mmol), tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate (0.13 g, 0.51 mmol), and triethylamine (0.26 mL, 1.9 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. for 2 days. The desired product partially precipitated from the reaction mixture and was collected by filtration, washed with hexanes and dried under reduced pressure to afford pure sub-title compound (0.080 g). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (20 g silica gel column, eluting with 0-15% MeOH/DCM) to afford further sub-title compound (0.034 g, total 0.114 g, 58%). LCMS (ESI) m/z calc. for C21H31N4O5 419.2 [M+H]+. found 419.1.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[O:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=C(O)c1ccncc1F
Product: Cc1ccc(CNc2cnccc2C(=O)O)o1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from 5-methylfurfurylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.35 (s, 1H), 7.86 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.24 (d, 1H, J=2.9 Hz), 6.00 (d, 1H, J=2.0 Hz), 4.50 (s, 2H), 2.23 (s, 3H). [M+H] calc'd for C12H12N2O3, 233. found 233.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a nitrogen-saturated solution of 2-amino-3-nitrobenzoic acid methyl ester (Chess GmbH, 50 g, 0.26 mol) in absolute ethanol (800 mL) was added palladium hydroxide (Degussa, 20% w/w on carbon, 58.75% w/w water, 10 g). The slurry was degassed then shaken vigorously under hydrogen (4 atm) at room temperature for 48 h. The catalyst was filtered and the filtrate concentrated in vacuo to afford 2,3-diaminobenzoic acid methyl ester as a dark orange oil that solidified on standing (43 g, 0.26 mol, 100%). (m/z): [M-OCH3]+ calcd for C8H10N2O2 135.05. found 135.3. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 3.74 (s, 3H), 4.80 (br s, 1H), 6.20 (br s, 1H), 6.38 (t, 1H), 6.70 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][C:8](=[O:43])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:32]=[CH:31][C:25]3[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=3[C:23]=2[CH2:33][CH2:34][CH3:35])=[C:11]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH:10]=1)C.O.O.[OH-].[Li+].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C>[C:38]([CH2:37][CH2:36][C:11]1[CH:10]=[C:9]([C:8](=[O:43])[CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=2[C:23]=1[CH2:33][CH2:34][CH3:35])([OH:40])=[O:39]
Reactant: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 19.3 h
Yield: 76.6 %

Procedure:
To a mixture of 0.442 g (0.73 mmol) of 4-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester from the preceding example, in 7 mL of tetrahydrofuran and 7 mL of water was added 91.7 mg (2.19 mmol) of lithium hydroxide monohydrate and the reaction was stirred at room temperature for 19.3 hr. After being acidified with 16 mL of 3N aqueous sulfuric acid, the mixture was worked-up with ethyl acetate in the usual manner. The crude product thus obtained was recrystallized from hexane-ethyl acetate to give 0.309 g (77%) of the title compound as a white solid, mp 136°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[I:14](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([I:14])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Product: COC(=O)c1nc(Cl)c(I)c(N)c1Cl
Temperature: 60 °C
Yield: 208.7 %

Procedure:
Methyl 4-amino-3,6-dichloropicolinate (10.0 g, 45.2 mmol), periodic acid (3.93 g, 17.2 mmol), and iodine (11.44 g, 45.1 mmol) were dissolved in methanol (30 mL) and refluxed at 60° C. for 27 h. The reaction mixture was concentrated, diluted with diethyl ether, and washed twice with saturated aqueous sodium bisulfite. The aqueous layers were extracted once with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. The product was concentrated and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide the title compound as a pale yellow solid (12.44 g, 35.9 mmol, 79%): mp 130.0-131.5° C.; 1H NMR (400 MHz, CDCl3) δ 5.56 (s, 2H), 3.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.80, 153.00, 152.75, 145.63, 112.12, 83.91, 53.21; EIMS m/z 346.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])(=[O:24])=[O:25])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cc1ccccc1F)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3ccccc3F)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:12])[CH:9]1[O:11][CH2:10]1>[Pt](=O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:12])[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCC(=O)C1CO1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)CCO
Reaction time: 16 h
Yield: 66.9 %

Procedure:
A 100 ml autoclave was charged under argon with 9.4 g (50 mmol) of 7,8-epoxy-6-oxo-octanoic acid methyl ester, with 0.4 g of platinum(IV) oxide catalyst, and with 50 ml of ethyl acetate. The hydrogenation was carried out for 16 hours at 20° C., at a constant pressure of 50 bar pure H2 and with intensive stirring. When the reaction was complete, the catalyst was filtered off and the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 6.3 g (67%) of 8-hydroxy-6-oxo-octanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[C:10]([CH:17]3[C:19]4([C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]4([CH3:28])[CH3:27])[O:18]3)[CH:9]=2)=[C:4]([F:29])[CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.Cl([O-])(=O)(=O)=O.[Li+]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:15][CH2:16]3)=[C:10]([CH:17]3[C:19](=[O:18])[C:20]([CH3:27])([CH3:28])[O:21][C:22]([CH3:25])([CH3:26])[C:23]3=[O:24])[CH:9]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.2 %

Procedure:
To a mixture of 2-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (18.20 g, 0.044 mol) and ytterbium triflate (2.40 g, 4.40 mmol) is added a solution of 5M lithium perchlorate (prepared from 46 ml diethyl ether and 24.40 g lithium perchlorate). The resulting suspension is stirred at room temperature for 3 days, then is diluted with diethyl ether (85 ml) and additional ytterbium triflate (7.80 g, 0.014 mol) is added. After stirring at room temperature for a further 3 days additional ytterbium triflate (13.63 g, 0.025 mol) is added, and the reaction mixture is stirred for 11 days. Finally, extra lithium perchlorate (24.40 g, 0.23 mol) is added in one portion, and the mixture is heated at 27° C. (internal temperature) for 1 day. The reaction mixture is partitioned between diethyl ether and distilled water, the two phases separated, and the aqueous phase is extracted with diethyl ether (×2). The organic fractions are combined, washed with brine then dried over magnesium sulphate. The suspension is filtered and the filtrate concentrated in vacuo. The crude material purified by flash column chromatography (10% ethyl acetate in hexanes as eluant) to afford an oil which is triturated with hexanes to afford 4-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (4.78 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[N:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 88 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.67 (t, 1H, J=7.6 Hz), 7.33–7.27 (m, 4H), 6.88 (d1H, J=7.2 Hz), 6.57 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.58–2.53 (m, 2H), 2.37 (t, 2H, J=6.4 Hz), 1.97 (t, 2H, J=11.2 Hz), 1.87 (d, 2H, J=13.2 Hz), 1.67–1.58 (m, 4H), 1.57 (s, 6H), 1.28 (d, 6H, J=7.2 Hz); ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]3=[O:31])=[CH:10][C:4]=2[O:3]1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]3[O:32][CH2:34][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=5)[C:12]4=[O:31])[C:9]3=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ncccc1C(F)(F)F
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OC(F)(F)O3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (23%) as a colorless solid: mp 200-201° C. (ether/hexanes); 1H NMR (300 MHz, acetone-d6) δ8.75 (d, J=4.1 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.62-7.55 (m, 1H), 7.30-7.22 (m, 2H), 7.10-6.84 (m, 4H), 5.42 (d, J=17.4 Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 5.01 (d, J=9.2 Hz, 1H), 4.91 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, acetone-d6) δ177.6, 158.1, 153.5, 153.4, 144.9, 144.0, 138.6, 135.7, 132.8, 129.9, 126.9, 125.3, 124.9, 124.6, 124.0, 123.7, 123.3, 109.9, 106.6, 98.4, 81.3, 58.7, 42.9; MS (ES+) m/z 477.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Li]C(C)(C)C.CCCCC.C(Br)C[Br:29]>C1COCC1>[Br:29][CH2:16][Si:13]([CH3:15])([CH3:14])[C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: BrCCBr
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CBr
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 17.9 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) in THF (30 mL) at -78° C. was added a 1.7 M solution of t-BuLi in pentane (6.5 mL, 11 mmol, 2.2 eq) such that the temperature was less than -70° C. The reaction was stirred at -78° C. for 1.5 h and ethylene dibromide (0.52 mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min at -78° C. and worked up in the usual manner. The crude product was purified by RC and recrystallized from aq methanol to afford the title compound as white needles (0.30 g, 18%). m.p. 98-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:20]2[CH:15]=[CH:16][C:17]([NH2:22])=[CH:18][CH:19]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(N)cc1
Solvent: ClCCl
Product: Nc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2Cl2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CH2Cl2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with a 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to afford impure N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl)urea (3.3 g): TLC (100% EtOAc) Rf 0.72.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:9]=1Cl.[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.CCCCCCC.C(OC(=O)C)C.O>[Br:3][C:4]1[C:9]([O:18][CH2:17][CH:14]2[CH2:16][CH2:15]2)=[N:8][CH:7]=[C:6]([CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Yield: 69.3 %

Procedure:
Potassium hydroxide (3.8 g, 51 mmol) was added to a solution of 5-bromo-6-chloro-3-pyridinecarboxylic acid (CAS 29241-62-1; 3 g, 13 mmol) and cyclopropanemethanol (1.5 mL, 19 mmol) in dimethylsulfoxide (12 mL). The mixture was microwaved at 100° C. for 4 min and poured into a mixture of water (50 mL) and citric acid (150 mL, 10%). The precipitating solid was collected by filtration, washed with water, dissolved in ethyl acetate and dried with Na2SO4. The solvent was removed to yield a solid which was stirred with a mixture of heptane/ethylacetate (40 mL, 1:1), filtered, washed with heptane and dried to yield 2.45 g of the title compound as colorless solid, MS (ISP) 270.1, 272.1 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-])=O.[OH2:13]>CN(C=O)C>[O:13]1[CH2:6][CH2:5][C@@H:4]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7]2)[CH2:12]1
Reactant: O
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Solvent: CN(C)C=O
Product: Nc1cccc2c1ccn2[C@@H]1CCOC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (2.5 g) and (S)-tetrahydrofuran-3-yl methanesulfonate obtained in the above-described Step (1.01 g) were added to a solution of 4-nitro-1H-indole (980 mg) in DMF (10 mL), and the reaction solution was stirred at 100° C. for 24 hours. Water was added to the reaction solution, the reaction solution was extracted with ethyl acetate twice, and then washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate). THF (10 mL) was added to the resultant residue, 10% palladium on carbon (100 mg) was added, and the reaction solution was stirred under hydrogen atmosphere at room temperature for 14 hours. The insolubles were filtrated with celite, and the solvent was evaporated under vacuum. Thereafter, the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 1-((R)-tetrahydrofuran-3-yl)-1H-indol-4-amine as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[H-].[Na+].[CH3:14]I.CO>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(NC#N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(N(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of m-ethylphenylcyanamide (1.46 g, 10 mmol) and sodium hydride (480 mg, 20 mmol, prewashed thrice with hexane) in anhydrous THF (10 ml) was heated at 80°-85° C. for 2.5 hours. After it was allowed to cool to room temperature, methyl iodide (3.5 g, 25 mmol) was added and stirring continued at room temperature for 2 hours. Methanol (10 ml) followed by water (20 ml) was added and the reaction mixture was extracted with dichloromethane (3×25 ml) . Concentration of the organic layer followed by flash chromatography on SiO2 afforded N-(m-ethylphenyl)-N-methylcyanamide (960 mg, 60%) as a colorless liquid: IR (film): 2220, 3400cm-1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.N1CCOCC1.[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23](Cl)=[O:24])[C:19](=[O:26])[O:18]1>C(Cl)Cl>[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[C:19](=[O:26])[O:18]1
Reactant: NCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)cc2)O1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 4-fluorobenzylamine (37.5 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture shaken for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (84.4 mg, 100% yield). MS calc for C14H14FNO4 (M+Na): 302.29; found: 302.29.
Reaction SMILES: [Na].[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5](Cl)[N:4]=1.[CH2:12]([OH:14])[CH3:13]>>[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5]([O:14][CH2:12][CH3:13])[N:4]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: CCO
Agent: [Na]
Product: CCOc1cc(N)[n+]([O-])c(N)n1
Temperature: 120 °C

Procedure:
1.8 g of sodium are dissolved in 100 ml of ethanol. 10 g of 2,4-diamino-6-chloropyrimidine 3-oxide are added. The reaction mixture is refluxed until the starting material has disappeared and is heated to 120° C. in an autoclave for 7 hours. It is returned to ambient temperature and the insoluble material is filtered off and washed with ethanol.