Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+].[N+]([C:20]1[CH:21]=[C:22]([C:28]#[N:29])[C:23](=[CH:26][CH:27]=1)[C:24]#[N:25])([O-])=O.[Na][Na]>O.C1C=CC=CC=1.CS(C)=O>[C:24]([C:23]1[CH:26]=[C:27]([CH:20]=[CH:21][C:22]=1[C:28]#[N:29])[O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]#[N:29])[CH:21]=1)#[N:25]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: OCCCCCCCCCCCCO
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: N#Cc1ccc(OCCCCCCCCCCCCOc2ccc(C#N)c(C#N)c2)cc1C#N
Temperature: 140 °C
Yield: 43.6 %

Procedure:
A mixture of 1,12-dodecanediol (10.2 g, 0.051 mol), sodium hydroxide (4.6 g, 0.11 mol), 120 ml of dimethyl sulfoxide, 20 ml of benzene and 6 ml of water was stirred at reflux under a nitrogen atmosphere for 12 hours. The water was azeotroped from the mixture with a Dean-Stark trap. After cooling, 17.5 g (0.11 mol) of 4-nitrophthalonitrile was added to the disodium salt of 1,12-dodecanediol prepared above. The resulting mixture was slowly heated to 140° C. and stirred at this temperature for 8 hours. The cooled reaction mixture was poured into 400 ml of cold water. The aqueous solution was extracted with three, 75 ml portions of methylene chloride. The combined extract was washed with water, charcoaled, and dried over anhydrous sodium sulfate and concentrated at reduced pressure. Recrystallization from ethanol-water yielded 10.1 g (45%) of 1,12-bis(3,4-dicyanophenoxy) dodecane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([C:18]4([C:21]([OH:23])=O)[CH2:20][CH2:19]4)[N:17]=[C:13]3[C:12]([O:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.C[N:33](C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[N:15]=[C:16]([C:18]4([C:21]([NH2:33])=[O:23])[CH2:20][CH2:19]4)[N:17]=[C:13]3[C:12]([O:24][CH3:25])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(-c2ccc(C#N)cc2)n2nc(C3(C(=O)O)CC3)nc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C#N)cc2)n2nc(C3(C(N)=O)CC3)nc12
Reaction time: 0.08 h

Procedure:
1-[5-(4-Cyano-phenyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-cyclopropanecarboxylic acid (27 mg, 0.08 mmol) was dissolved in DCM (0.3 mL). Oxalyl chloride (0.008 mL, 0.09 mmol) and drop of DMF was added. Stirring for 5 min. Oxalyl chloride (0.003 mL) was added. After 20 min the suspension was concentrated and re-suspended in dioxan (0.3 mL). Aq. NH3 (25%, 0.1 mL) was added. The suspension was stirred at rt for 2 h after which it was concentrated in vacuo. The crude product was mixed with aq. Na2CO3 and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as a slightly coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCc1ccc(Br)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 177 %

Procedure:
A solution of BH3 (34 mL, IM in tetrahydrofuran) was added dropwise to the solution of 4-bromo-3-chlorobenzoic acid (2.5 g, 11.4 mmol) in tetrahydrofuran at 0° C. The mixture was stirred at 40° C. overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-3-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (s, 1H), δ 4.48 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:24]([CH3:26])[CH3:25])[CH2:11][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@H:13]1[CH2:15][O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-]>CO>[NH2:27][CH2:15][C@H:13]([OH:14])[C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: [NH4+]
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl (1S,3S)-3-(benzyloxymethyl)-4-methyl-1-((R)-oxiran-2-yl)pentylcarbamate (500 mg, 1.38 mmol) in MeOH (5 mL), was added NH4OH (5 mL). The mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptan-3-ylcarbamate (510 mg, 97.3%). 1H NMR (400 MHz, CD3OD): 0.86 (m, 6H), 1.41 (s, 12H), 1.82 (brs, 1H), 2.50 (m, 1H), 3.42 (m, 2H), 3.61 (m, 2H), 3.71 (m, 3H), 3.90 (m, 4H), 6.61 (m, 1H), 7.31 (m, 5H), 7.71 (m, 1H); MS: 381 (M++1)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)(=[O:16])=[O:15].[C:34]([C:37]([CH3:49])([CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)([OH:36])=[O:35].C(OCC)(=O)C>O.C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:34]([C:37]([CH3:49])([CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:8]2[C:9]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:41][CH:40]=1)([OH:36])=[O:35]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Reactant: CC(C)(Cc1ccccc1B(O)O)C(=O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(CC(C)(C)C(=O)O)cc1
Yield: 33 %

Procedure:
A solution of sodium carbonate (2.86 g) in water (4 ml) was added to a soultion of 2-iodo- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)benzenesulphonamide (6.2 g), (2-carboxy-2-methylpropyl)benzeneboronic acid (3.0 g) and tetrakis(triphenylphosphine)palladium(O) (235 mg) in toluene (30 ml) and ethanol (20 ml). The mixture was stirred vigorously and heated under reflux for 18 hours under an atmosphere of argon. Water (100 ml) and ethyl acetate (100 ml) were added and the organic layer was separated. The organic phase was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phases were combined. The solution was acidifed with 6M hydrochloric acid and extracted with ethyl acetate (3×50 ml). The extracts were washed with water (50 ml) and saturated sodium chloride solution (50 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with etherexane (1:1 v/v) to give 4'-(2-carboxy-2-methylpropyl)- N-(isobutoxycarbonyl)- N-(3-methoxy-5 -methylpyrazin-2-yl)-2-biphenylsulphonamide (2.25 g); 1H NMR (d6 -DMSO): 0.6 (d, 6H), 1.1 (s, 6H), 1.5-1.7 (m, 1H), 2.52 (s, 3H), 2.85 (s, 2H), 3.8 (d, 2H), 3.95 (s, 3H), 7.15 (d, 2H), 7.25 (d, 2H), 7.3-7.4 (m, 1H), 7.7-7.8 (m, 2H), 8.15 (s, 1H), 8.5-8.6 (m, 1H), 12.3 (s, 1H).
Reaction SMILES: ClO.[CH2:3]([N:6]1[CH2:25][CH2:24][C@:13]23[C:14]4[C:15]5[O:23][C@H:12]2[C:11](=[O:26])[CH2:10][CH2:9][C@@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:7]1[CH2:20][C:19]=4[CH:18]=[CH:17][C:16]=5[O:21][CH3:22])[CH:4]=C.C([O-])([O-])=O.[K+].[K+].C(I)C>O>[O:23]1[C@@H:12]2[C@@:13]34[CH2:24][CH2:25][N:6]([CH2:3][CH3:4])[C@@H:7]([C@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:9][CH2:10][C:11]2=[O:26])[CH2:20][C:19]2=[C:14]4[C:15]1=[C:16]([O:21][CH3:22])[CH:17]=[CH:18]2
Reactant: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Agent: O=C([O-])[O-]
Agent: OCl
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-[(3-phenylpropyl)oxy]morphinan-6-one hydrochloride (see Example 1) (4.0 g, 8.77 mmol), K2CO3 (8.0 g, 57.89 mmol), ethyl iodide (0.99 ml, 12.40 mmol) and 50 ml of water-free N,N-dimethylformamide was stirred for 5 h under N2 at 80° C. (bath temperature). After filtration from the inorganic residue, the filtrate was evaporated down and the residue (4.7 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH: 8 l: (250/2/0.5)); 0.5 l: (250/3/0.5), (250/4/0.5), (250/6/0.5), (250/8/0.5), (250/10/0.5)). The evaporation residue (1.3 g of bright yellow oil) was crystallised out of MeOH. Yield: 1.2 g (30%) of compound 19. Fp. 95-101° C.; IR (KBr): 1719 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 7.30-7.13 (m, 5 arom. H), 6.73 (d, J=8.2 Hz, 1 arom. H), 6.64 (d, J=8.2 Hz, 1 arom. H), 4.76 (s, 1H, C5—H), 3.78 (s, 3H, OCH3), 0.96 (t, 3H, N—CH2—CH3), J=7 Hz); MS (CI): m/z 448 (M++1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: COc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 37 %

Procedure:
A solution of 5-chlorosulfonyl-2-oxindole (3 g), o-anisidine (1.8 mL) and pyridine (2.1 mL) in dichloromethane (20 mL) was stirred at room temperature for overnight at which time the red color solid was present. The solid was filtered, washed with ethanol and dried under vacuum to yield 1.5 g (37%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (2-methoxy-phenyl)-amide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[C:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].OC1C=C(OC)C=CC=1C(=O)C(C1C=CC(OC)=CC=1)(C)C>>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([CH3:14])[CH3:13])=[C:3]([OH:2])[CH:8]=1
Reactant: COc1ccc(C(C)(C)C(=O)c2ccc(OC)cc2OC)cc1
Agent: COc1ccc(C(C)(C)C(=O)c2ccc(OC)cc2O)cc1
Product: COc1ccc(C(C)(C)Cc2ccc(OC)cc2O)cc1

Procedure:
Synthesized from 1-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)-2-methylpropan-1-one according to an analogous synthetic method to Preparation Example 192 described below, 1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)-2-methylpropan-1-one (2.9 g) was used according to an analogous synthetic method to Preparation Example 185 described below to provide the title compound (1.9 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CCOC(=O)NC
Reactant: CC(C)Oc1ccccc1O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)Oc1ccccc1OC(C)C

Procedure:
To a solution of 2-isopropoxyphenol (1.52 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in dichloroethane (10 ml, was added phosphoryl chloride (1.54 g, 0.01 mole) and refluxed for six hours. The reaction mixture was worked up as described earlier to give 2-isopropoxyphenyl N-methylcarbamate of the formula (VI) as a solid, crystallised from pet. ether, m.p. 89° C. to 90° C.
Reaction SMILES: [CH:1]([P:3](=[O:14])([CH:12]=[CH2:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[CH2:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([N:22]1[CH2:13][CH2:12][P:3](=[O:14])([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:1][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CP(=O)(C=C)Cc1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=P1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 82 °C
Yield: 77.5 %

Procedure:
Divinyl-(4-Fluorophenylmethyl)-phosphine oxide (0.719 g, 3.42 mmol) and benzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15 mL) and deionized water (15 mL). The reaction mixture was heated at 82° C. for 22 hours. The reaction was not complete and so an additional 0.04 mL of benzylamine was added and the reaction mixture was heated for an additional six hours at 90° C. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was taken up in 1:1 ethyl acetate:dichloromethane and passed through a plug of silica. The product was then eluted from the silica with a solution of 10% methanol in ethyl acetate. The solvents were removed by rotary evaporation to yield 0.84 g of 1-benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide (2.65 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H); 7.25-7.20 (m, 2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m, 2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([O:12]C)=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]=1)[CH3:2].CO.C1COCC1.[Li+].[OH-].Cl>CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)O
Temperature: 60 °C
Reaction time: 120 h
Yield: 38.5 %

Procedure:
A solution of 440 mg (1.3 mmol) methyl 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylate in a MeOH/THF mixture (6 ml, 1:1 v/v) was treated with a 2M aq. LiOH sol. (3 ml) and was then stirred at 60° C. for 5 d. After cooling to RT the RM was acidified with a 2M aq. HCl sol. to pH 2. Upon dilution with EtOAc the precipitate formed was filtered off to give 176 mg (0.5 mmol, 42%) 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl>N1C=CC=CC=1>[O:16]=[C:14]1[NH:13][C:9]2=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:26]([NH:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:27])=[CH:3][CH:4]=3)=[C:8]2[NH:15]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Temperature: 50 °C
Yield: 68.7 %

Procedure:
Method H1 (in Pyridine). 7-(4-Aminophenoxy)-2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridine (65 mg, 0.27 mmol) was suspended in dry pyridine (3 mL) and heated at 50° C. Phenyl isocyanate (30 μL, 0.28 mmol) was added; the solution became clear. The reaction mixture was heated at reflux for 2 hours, then it was allowed to cool at room temperature. DCM (20 mL) was added, the precipitate formed was recovered by filtration and washed with more DCM, to afford 1-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl-oxy)phenyl)-3-phenyl-urea (67 mg, 69%). 1H-NMR (δ, ppm, DMSO-d6): 6.34 (d, 1H, HPy,5, J=7.5 Hz), 6.98 (t, 1H, Harom,Ph′,4, J=7.5 Hz), 7.13 (d, 2H, Harom,Ph,3+5, J=8.75 Hz), 7.29 (t, 2H, Harom,Ph′,3+5), 7.46 (d, 2H, Harom,Ph′,2+6), 7.53 (d, 2H, Harom,Ph,2+6), 7.76 (d, 1H, HPy,6) 8.67 (s, 1H, NHurea,1), 8.76 (s, 1H, NHurea,3), 11.19 (s, 1H, NHPy3), 11.35 (s, 1H, NHPy2). LC-MS (m/z): 362 (M+H, 100).
Reaction SMILES: [OH-].[Na+].C(Cl)Cl.[CH:6]1[CH:15]=[N:14][C:13]2[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][C:12]=2[OH:16])[CH:7]=1.[CH2:18](Br)[CH:19]=[CH:20][CH3:21]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:17][C:9]1[CH:10]=[CH:11][C:12]([O:16][CH2:18][CH:19]=[CH:20][CH3:21])=[C:13]2[C:8]=1[CH:7]=[CH:6][CH:15]=[N:14]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: CC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC=CCOc1ccc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.6 g (0.09 mol) of NaOH pellets are dissolved in 300 ml of water, and 300 ml of methylene chloride are added; there are subsequently added 10.8 g (0.06 mol) of 5-chloro-8-oxyquinoline, 16.2 g of 2-butenyl bromide (0.12 mol) and 0.5 g of tetra-n-butylammonium bromide, and the mixture is stirred for 5 hours at room temperature. The organic layer is separated, and the aqueous layer is extracted twice with methylene chloride. The organic solvents are combined and concentrated by evaporation. The residue is taken up in water and methylene chloride; the organic layer is then extracted by shaking three times with 2N NaOH, separated, dried with Na2SO4 and concentrated by evaporation; crude yield 15.5 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28](=[O:29])[N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCCC1
Yield: 63 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with pyrrolidine (0.35 ml, 4.2 mmol) to give the title compound as a solid (135 mg, 62%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.07 (br s, 1H); Mass spectrum 511.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C]=O.[CH:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Agent: Cl
Agent: [C]=O
Product: O=C(O)C=Cc1ccccc1
Yield: 81 %

Procedure:
A mixture of 129 g of 1,1,1,3-tetrachloro-3-phenylpropane and 100 g of 85% formic acid is heated to 100° to 106° C. for 10 h. Te reaction is accompanied by evolution of hydrogen chloride and carbon monoxide. Cooling the reaction mixture, filtration of the crystals and their washing with water affords 60 g of cinnamic acid in 81% yield (melting point 126° to 132° C., purity over 97per cent).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C/C=C/c1ccccc1)[C@@H](C)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCc1ccccc1)[C@@H](C)O
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A solution of methyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxybutanoate (42.0 g, 179.5 mmol) in 400 mL of methanol is treated with 400 mg of 10% palladium on carbon. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 16 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide methyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoate as an oil (42.2 g, 100% yield).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])=[C:8](/[CH:10]=[CH:11]/[CH:12]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH:9]=1.Cl>C1COCC1.O>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH:12](/[CH:11]=[CH:10]/[C:8]2[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)([OH:21])=[O:20]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
18 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150 mg (0.25 mmol) of methyl 4-[(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-{2-[4-(methoxycarbonyl)-phenyl]ethyl}pent-4-en-1-yl]benzoate in 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and concentrated. The residue obtained is purified directly by preparative HPLC. This gives 130 mg (content 96%, 0.22 mmol, 87% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1.C(ON=O)(C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)nc2cnc(Oc3ccc(F)cc3F)cc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Fc1ccc(Oc2cc3cnc(Cl)nc3cn2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
Compound (1F) (1.8 g, 5.83 mmol) was taken up in THF (100 mL) and tert-butylnitrite (Aldrich Chemical Co.) was added. The resulting mixture was heated to reflux with stirring for 48 hours and additional tert-butyl nitrite was added in portions (total 5 mL). By TLC, the reaction was complete. After cooling to room temperature, the solvent was removed under reduced pressure at 55° C. EtOAc (180 mL) and water (60 mL) were added to the residue, and the layers were partitioned and separated. The organic layer was washed with water (3×60 mL) and brine (1×60 mL). After drying over magnesium sulfate, the organic layer was filtered, concentrated and pumped to give a crude oil (3.14 g). Purification by column chromatography eluting on 68 g of silica gel with 5% EtOAc in hexanes afforded the title compound (1G) as a yellow powder (0.546 g, M+=293).