Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:37]=[C:38]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)[CH:39]=[CH:40][CH:41]=1)(=[O:35])[NH2:34]>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:38]4[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=4)[C:33]([NH2:34])=[O:35])=[O:44])=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccc(C(N)=O)c4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 13 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([I:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1I)C(C)CNCC2
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0.058 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 18 mg of a white solid. MS calculated for C14H18INO+H: 344, observed: 344.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11]
Reactant: COC(=O)CN1C(=O)c2cccc(O)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)c2cccc(OC)c2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-(4-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (160 mg, 0.680 mmol) in DMF (5 ml), K2CO3 (94 mg, 0.680 mmol) and iodomethane (88 μl, 1.361 mmol) were added, and the mixture was stirred under microwave irradiation at 100° C. for 1 hour. The insoluble inorganic salts were filtered off, the solvent was removed and the resulting crude product (130 mg, 0.522 mmol, 77% yield) was used in the following step without further purification. MS/ESI+ 250.1 [MH]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylene chloride (anhydrous, 2 mL) and cooled to 0° C. followed by the addition of triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL, 1.14 mmol). The reaction mixture was stirred for 16 h while gradually warming to ambient temperature. The reaction was quenched with water, diluted with methylene chloride (20 mL), and the resulting layers were separated. The organic layer was washed with water (2×2 mL) and the combined aqueous phases were extracted with methylene chloride (2×3 mL). The combined organic phases were washed with brine (2×2 mL), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH:24]=1)[CH2:30][O:31][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: OCc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1OCc1cc(F)ccc1O
Temperature: 100 °C
Yield: 3.6 %

Procedure:
To a solution of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (211.2 mg, 0.70 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (100 mg, 0.70 mmol) in N-methyl pyrrolidinone (3 mL) was added cesium carbonate (687.8 mg, 2.1 mmol) and the mixture was heated at 100° C. for 2 hours. The reaction was cooled to 25° C., filtered and purified by reverse phase HPLC using a gradient of acetonitrile/water (10 to 99%) and HCl as a modifier to yield 2-[(5-fluoro-2-hydroxy-phenyl)methoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (159) (10.5 mg, 3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.49 (s, 1H), 10.04 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.05-6.91 (m, 2H), 6.91-6.79 (m, 2H), 6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. ESI-MS m/z calc. 422.09. found 423.3 (M+1)+; Retention time: 1.83 minutes (3 minutes).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([C:28]([F:31])([F:30])[F:29])[C:22]([F:27])([F:26])[C:23](Cl)=[O:24].Cl>ClCCl>[F:26][C:22]([F:27])([C:21]([F:20])([F:32])[C:28]([F:29])([F:30])[F:31])[C:23]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6])=[O:24]
Reactant: N#CCc1ccccc1N
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccccc1NC(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 2-aminobenzylcyanide (15 g) [Rousseau et al., JACS 72, 3047 (1950)], diisopropylethylamine (16 g) and dichloromethane (400 mL) was cooled in an ice bath under a nitrogen atmosphere. Heptafluorobutyryl chloride (28.9 g) in dichloromethane (100 mL) was added dropwise and the reaction was left to warm gradually to room temperature overnight. A 10% aqueous HCl solution was added and the organic phase was separated and dried over MgSO4. After filtration and concentration with a rotary evaporator, the crude, orange oil (42 g) was purified by high pressure liquid chromatography to give 35.4 g of 2,2,3,3,4,4,4-heptafluoro-N-[2-(cyanomethyl)phenyl]butanamide as a white solid, m.p. 76°-79° C.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([OH:6])=[O:5])C.[OH-].[K+].Cl>O>[CH2:19]([O:18][C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=1[CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cccc(O)c1CCC(CC)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cccc(O)c1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-[2-ethoxycarbonyl-6-hydroxyphenyl]butanoic acid (9.06 g, 32.4 mmol) was dissolved in a room temperature solution of potassium hydroxide (3.62g, 64.6 mmol) in water (68 ml). The solution was stirred at room temperature for 2 hr, and then made acidic with 12N HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined and extracted with 10% aqueous potassium carbonate three times. These aqueous extracts were made acidic with 12N HCl and extracted twice with ethyl acetate. The ethyl acetate extracts were concentrated in vacuo to a white solid (6.4 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)Cl
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: C1CCOC1
Product: CCOC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added ethyl chloroformate (97.5 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 10%-35%, 25 min) to give the title compound (240 mg, 58%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.99 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.42 (q, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 4.00 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][OH:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH2:35]Br)[CH:26]=1.CC(C)([O-])C.[Na+].CO>O1CCCC1.C(=O)(O)[O-].[Na+]>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:35][O:23][CH2:22][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2F)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220 mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooled to 0° C. The reaction was treated with sodium tert-butoxide (75 mg, 0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treated with another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol), allowed to warm to room temperature, and stirred for 30 min. The reaction was diluted with 10% sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%). Mass spec.: 586.04 (MH)+ LC tr=2.552 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[N:19]=[C:20](Cl)[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][NH2:47].CO>>[NH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][NH:47][C:20]1[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=[C:18]([CH2:17][C:16]2[CH:36]=[CH:37][CH:38]=[C:14]([CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]([F:13])([F:12])[F:11])[CH:15]=2)[N:19]=1
Reactant: CN(CCCN)CCCN
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(Cl)c12
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(NCCCN(C)CCCN)c12
Temperature: 140 °C
Yield: 63.9 %

Procedure:
A mixture of methyl 2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.375 g, 0.695 mmol) and N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (0.784 mL, 4.86 mmol) in MeOH (9.83 mL, 243 mmol) was heated in a microwave oven to 140° C. for 30 minutes. Then, after concentration to dryness under reduced pressure the resulting brown oil was purified by flash chromatography to afford methyl 4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (288 mg, 63.9% yield) as a yellow foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (dt, J=14.0, 6.9 Hz, 2H) 1.75 (quin, J=6.7 Hz, 2H) 2.14 (s, 3H) 2.24-2.42 (m, 4H) 2.52-2.60 (m, 2H) 3.61 (q, J=6.3 Hz, 2H) 3.88 (s, 3H) 4.10 (s, 2H) 4.49 (s, 2H) 5.17 (q, J=7.0 Hz, 1H) 7.18-7.30 (m, 5H) 7.31-7.36 (m, 1H) 7.39 (t, J=7.6 Hz, 1H) 7.44-7.53 (m, 2H) 7.58 (t, J=5.3 Hz, 1H) 7.84 (dd, J=8.2, 1.4 Hz, 1H) 8.00 (d, J=1.4 Hz, 1H) 8.28 (d, J=8.2 Hz, 1H); MS m/z 649.3 (M+H)+; HPLC 97.6% @ 220 nm and 95.5% @ 254 nm, RT=1.96 minutes.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cccc2c1-c1ccccc1C2

Procedure:
A partial solution of 196.2 mg (1 mmol) of 4-hydroxy-fluoren-9-one in 2 mL EtOAc and 3 mL EtOH with 40 mg 10% Pd/C was stirred under a balloon of hydrogen for 27.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated. The residue was purified by plate layer chromatography with CH2Cl2-EtOAc(50:1) to give 102.7 mg of the title substance.
Reaction SMILES: Cl.[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:6])[CH2:4][CH2:3]1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:12][CH2:13]2)=[O:6])[CH2:3][CH2:4]1
Reactant: O=C(NC1(c2ccccc2)CCNCC1)C1CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccccc2)CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C1CC1
Yield: 102.1 %

Procedure:
A mixture of 0.565 g of 4-(cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride in 50 ml of DCM is cooled to +5° C., 0.565 g of trityl chloride is added followed by 0.7 ml of triethylamine and the mixture is kept stirring while allowing the temperature to rise to RT. The reaction mixture is washed with water, the organic phase dried over MgSO4 and the solvent evaporated under vacuum. 1 g of the expected product is obtained after crystallization from ether.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][C:13]3=[O:18])[N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][C:13]3=[O:18])[N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(O)cc2)CC[C@]12CCCNC2=O
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCCNC2=O

Procedure:
The title compounds were prepared (D52: 20 mg, 76%; D53: 3 mg, 11%) using a similar procedure to that set out earlier in Description 11 starting from 1,1-dimethylethyl (5S)-2-(4-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylate (D51) and 2-fluorobenzyl bromide. D52: Rt (HPLC) 5.92 min; MS: (ES/+) 909 [dimerH+]. D53: Rt (HPLC) 5.73 min; MS: (ES/+) 909 [dimerH+].
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:12](=[O:13])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cnc2[nH]ccc2c1)OCc1ccccc1
Temperature: 0 °C
Yield: 76.8 %

Procedure:
1H-pyrrolo[2,3-b]pyridin-5-amine (9.45 g, 71.05 mmol) was dissolved in THF (150 mL) and stirred at 0° C. under an atmosphere of nitrogen. Benzyl chloroformate (20.3 mL, 142.10 mmol, 2.0 Eq) was added dropwise over a period of 15 minutes and the mixture allowed to stir at room temperature for 30 minutes. The mixture was treated with 4M NaOH (aq) (53.3 mL, 213.16 mmol, 3.0 Eq) over a period of 15 minutes and the resultant brown solution left to stir for 16 hours. The reaction mixture was taken to pH 4 (125 mL of 10% aq. citric acid) and the 2 layers were separated. The aqueous layer was back extracted with EtOAc and the combined organics were dried over magnesium sulphate, filtered and dried under vacuum. The crude product was purified by column chromatography (50% EtOAc/Petroleum Ether) to give 14.59 g (77%) of pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:14]([C:17]([NH2:18])=[O:34])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: COc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: COc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-methoxyphenylamino)pyrazine-2-carbonitrile (43 mg, 0.115 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 393.3 (M+H); UV 206.0, 251.1, 297.8 nm; t 0.471 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:48]4[N:53]=[CH:52][CH:51]=[CH:50][N:49]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Product: COc1c(Cc2ccc(-c3ncccn3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxylnaphthalene obtained in Example 265-(3) and 2-tributylstannylpyrimidine were treated in a manner similar to Example 128-(5) and (6) to give 1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienyl-methyl)-4-methoxylnaphthalene. APCI-Mass m/Z 495 (M+H).
Reaction SMILES: C([NH:4][C:5]1([CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.Cl.[OH-].[Na+]>>[NH2:4][C:5]1([CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)NC1(C)CCN(c2cccc3c2OCCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(N)CCN(c2cccc3c2OCCO3)CC1
Yield: 73.2 %

Procedure:
0.51 g (1.76 mmol) of the product obtained in Step 2 is treated at reflux for one night with 3 ml of 3N HCl. 1 ml of concentrated HCl is added and the whole is heated at reflux for 24 hours, allowed to cool, rendered basic with 2N NaOH and extracted 3 times with 30 ml of CH2Cl2 each time. The organic phases are washed and then dried. 0.32 g of the expected product is obtained. Yield: 73%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: NO
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (63.3 g, 495 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (66.8 g, 97%) which was obtained as a light yellow solid. MS m/e (EI): 139.0 [M].
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C1(C)C=CC=CC=1.ClCCl>[Cl:22][CH2:23][C:24]1[N:21]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[O:20][CH:26]=1
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc2c(-c3nc(CCl)co3)cn(CC3CCCCC3)c12
Yield: 81.1 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 30 minutes. The resulting black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate solution (5×20 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown oil was purified by flash column chromatography using 5% (v/v) acetone in petroleum ether 40-60 to give 3-(4-chloromethyl-oxazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (510 mg, 1.42 mmol) as a white solid.