Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)=[O:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:22].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:22]
Reactant: COc1ccccc1C(=O)Cn1cccc2c(C)c(C)nc1-2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2n(CC(=O)c3ccccc3O)cccc-2c1C
Yield: 62.4 %

Procedure:
A solution of 2,3-dimethyl-7-(o-methoxyphenacyl) pyrrolo[2,3-b]pyridine (75 mg, 0.2 mmol) in 20 ml CH2Cl2 was cooled to 0° C. and treated with 1M BBr3 in CH2Cl2 (200 μl, 0.2 mmol). After reacting for an additional hour the reaction mixture was poured into a stirred solution of 5% NaHCO3. The aqueous layer was attracted with 50+10 ml CH2Cl2 and the combined organic layers washed With 50 ml 2M HCl (reextraction trice with 10 ml CH2Cl2). The combined organic layers were dried over MgSO4 and evaporated. The residue was chromatographed (silica, CH2Cl2 /MeOH; 9/1) affording 35 mg (62%) pure title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:22].S(=O)(=O)(O)O.Cl([O-])=O.[Na+]>O.C(#N)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([C:13]([OH:22])=[O:14])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: COc1cc(C=O)c(I)cc1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde (reference example 1-1) (20 g), dimethylsulfoxide (19 mL), concentrated sulfuric acid (3 mL), water (30 mL) and acetonitrile (181 mL) was added a mixture of sodium chlorite (9.8 g) and water (30 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (20.3 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])CC1.BrC1C=C(C=CC=1C)C(O)=O.BrC1C=C(C=CC=1C1CC1)C(O)=O>>[CH3:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Agent: Cc1ccc(C(=O)O)cc1Br
Agent: O=C(O)c1ccc(C2CC2)c(Br)c1
Product: CCC(=O)c1cc(C(=O)O)ccc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 10.6, except 3-bromo-4-methylbenzoic acid was used in place of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O1CCCC1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (33.42 g) in methanol (150 ml)-tetrahydrofurane (30 ml), sodium borohydride (4.31 g) was added in portions at 0° C. After stirring for 30 minutes at room temperature, water was added to the reaction mixture, and the mixture was stirred for 1 hour. The crystals of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (32.85 g, yield 98%) was isolated by filtration. Recrystallization from ethyl acetate-diethylether gave pale-yellow crystals. m.p. 128-129° C.
Reaction SMILES: CC(C[NH:5][C:6](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/C1C=CC2OCOC=2C=1)=O)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][C:32]([OH:34])=O)=[CH:29][C:24]=2[O:23][CH2:22]1.N1CCCCC1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][C:32]([N:5]3[CH2:6][CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:34])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CC(C)CNC(=O)/C=C/C=C/c1ccc2c(c1)OCO2
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: CS(=O)(=O)Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc2c(c1)OCO2)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
The method was adapted from that reported for piperlonguminine (section 2.2) but utilising 3-benzo-1,3-dioxol-5-ylpropionic acid and piperidine as the acid and amine components respectively. A mixture of 3-benzo-1,3-dioxol-5-ylpropionic acid (200 mg, 0.0026 mole, 1 eq) and triethylamine (0.27 ml, 0.002 mole, 2 eq) in dichloromethane (50 ml) was stirred for 15 min at 0° C. To this mixture methanesulfonyl chloride (0.11 ml, 0.0015 mole, 1.5 eq) was added and stirred for further 30 min at 0° C. Piperidine (0.15 ml, 0.0015 mole, 1.5 eq) was added to the mixture and stirred for 1 h at 0° C. and 1 h at room temperature. Dichloromethane (50 ml) was added to the mixture which was then washed with 5% HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml) and water (3×100 ml). The organic fraction was dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield brown oil (65% yield).
Reaction SMILES: [O:1]=[C:2]([C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]([C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C=Cc1cccc(CC(O)c2ccc(-c3ccccc3)o2)c1

Procedure:
To ketone (27) (33 mg; 0.10 mmol) dissolved in MeOH (2 mL) was added sodium borohydride (8 mg, 0.21 mmol). Subsequent additions of sodium borohydride (2 mg) were added until the reaction was complete. The reaction mixture was acidified to pH 5 by dropwise addition of 1N HCl and extracted with TBME (×3). The organic layer was dried (MgSO4) and the solvent concentrated in vacuo to give the title compound as a white solid. Yield: 20 mg, 61%; LC-MS tr 2.02 min; HPLC Purity: 100%; MS (ES+) m/z 335 (M+H), 317 (M−H2O+H); 1H NMR (400 MHz; CDCl3): δ 3.20-3.30 (d, 2H), 5.0 (t, 1H), 6.3 (d, 1H), 6.40 (d, 1H), 6.60 (d, 1H), 7.20-7.50 (m, 7H), 7.65-7.80 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([S:9][CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[S:9][CH3:10]
Reactant: CSc1cc(O)c(Cl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1cc(O)c(Cl)cc1N
Reaction time: 0.25 h

Procedure:
The 6-chloro-3-methylthio-4-nitrophenol prepared in the preceding stage is added to a solution of 32 g of NaOH pellets in 270 ml of water, and 100 g of sodium hydrosulphite are then added rapidly without exceeding a temperature of 70° C. The mixture is stirred for a further 15 minutes after the addition is complete.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH2:8])[N:3]=[CH:2]1>CO.[Pd]>[NH:1]1[CH:5]=[C:4]([CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH3:8])[N:3]=[CH:2]1
Reactant: C=CC(Cc1ccccc1)c1c[nH]cn1
Agent: [Pd]
Solvent: CO
Product: CCC(Cc1ccccc1)c1c[nH]cn1
Reaction time: 12 h

Procedure:
3 mmol of (1H-imidazol-4-yl)-4-phenyl-1-butene (Example 51) are dissolved in 50 ml of methanol. 70 mg Pd/C (10%) are added, and reduction is carried out for 12 hours at a pressure of 10 bar under hydrogen.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:42])[C:14]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:31]=4[CH3:41])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:43])[CH2:3]1.[C:44]([NH2:48])(=[O:47])[CH:45]=[CH2:46].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C.CS(C)=O>[NH2:48][C:44](=[O:47])[CH2:45][CH2:46][N:7]1[CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:42])[C:14]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:32][C:31]=4[CH3:41])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:43])[CH2:3][CH:2]1[CH3:1]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Reactant: C=CC(N)=O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1c(N2CC(C)N(CCC(N)=O)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 70 °C

Procedure:
A few drops of acetonitrile are added at room temperature to 55 mg of the compound of Example 52, 18 mg of acrylamide and 35 mg of lithium perchlorate, so that a stirrable suspension results. The mixture is heated to 70° C. over night and left to cool. After the addition of DMSO the whole mixture is separated by preparative HPLC (Method 5). After concentrating the suitable fractions and drying under high vacuum 30 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH2:2])=[O:15])[CH3:5]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1ccsc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (20 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (600 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the precipitated solid was filtered and dried to give crude product, which was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (400 mg, 72%), mp 168-170° C. IR (neat) νmax 3337, 3172, 2923, 1636, 1599, 1348, 1219, 1117, 884, 771 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.28 (2H, br s), 7.35 (1H, d, J=5.6 Hz), 7.31 (1H, d, J=5.6 Hz), 3.58 (3H, br s), 3.20 (3H, br s); LC-MS (positive ion mode): m/z 221 (M+Na)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 2-fluorobenzenesulfonylchloride (91 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (120 mg, 80%). 1H NMR (400 MHz, CDCl3) δ7.86-7.82 (t, 1H), 7.58-7.52 (m, 1H), 7.28-7.24 (m, 1H), 7.13-7.12 (m, 3H), 6.90-6.88 (m, 2H), 4.19 (m, 1H), 4.05-4.02 (t, 2H), 3.73-3.70 (m, 2H), 3.56-3.51 (t, 2H), 3.10-3.08 (d, 2H), 2.66-2.62 (t, 2H), 2.54 (m, 4H), 2.06-1.99 (m, 4H), 1.85-1.8 (m, 6H).
Reaction SMILES: C(O)(=O)C.[O-:5][C:6]#[N:7].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[NH:24][C:25](=[O:36])[C@:26]([O:32][C:33](=[O:35])[CH3:34])([CH3:31])[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[Cl:9][C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:6]([NH2:7])=[O:5])=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]=1[NH:24][C:25](=[O:36])[C@:26]([O:32][C:33](=[O:35])[CH3:34])([CH3:31])[C:27]([F:30])([F:28])[F:29]
Reactant: N#C[O-]
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl)C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(NC(N)=O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Water (0.34 ml), acetic acid (0.54 ml) and sodium cyanate (0.104 g dissolved in 0.3 ml of water) were added to a solution of (R)-N-[2-chloro-4-{4-aminophenylsulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (0.432 g) (Method 22) in THF (0.8 ml. The mixture was stirred for 2 hours then diluted with water (5 ml) and extracted with ethyl acetate (2×20 ml). The extracts were poured onto a Varian Chem Elut column and eluted with ethyl acetate. Volatile material was removed by evaporation and the residue was triturated with ether to give the title compound (0.31 g) as a solid. NMR: 1.8 (s, 3H), 2.2 (s, 3H), 5.9 (s, 2H), 7.1 (s, 3H), 7.4 (d, 2H), 7.5 (d, 2H). 8.8 (s, 1H), 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH3:24]>>[CH2:22]([C:21]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=1[CH:18]=2)[CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CCCC(=O)Cl
Product: CCCc1nc2cc3c(cc2o1)CCNCC3

Procedure:
The title compound was prepared as described in General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and butyryl chloride.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][NH:5][C:6](=[O:29])[CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:15])[S:11][CH:12]=1.C(OC1C=C(C)C=CC=1NC(=O)NC1SC=C(CC(O)=O)N=1)C(C)C.Cl.COC(=O)CN>>[CH2:25]([O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:14](=[O:15])[NH:13][C:10]1[S:11][CH:12]=[C:8]([CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])[N:9]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)CNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC(C)C)n1
Agent: COC(=O)CN
Agent: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OCC(C)C)c1
Agent: Cl
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)NCC(=O)O)cs2)c(OCC(C)C)c1
Yield: 85.6 %

Procedure:
(2-{2-[3-(2-Isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetylamino)-acetic acid (90 mg, 86%) was prepared from (2-{2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetylamino)-acetic acid methyl ester (108 mg, 0.25 mmol) following the general procedure J. (2-{2-[3-(2-Isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetylamino)-acetic acid methyl ester (150 mg, 70%) was in turn prepared from {2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (181 mg, 0.5 mmol) and glycine methyl ester hydrochloride following the general procedure K.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH:1][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of Boc-Phe-OH 5.1 (2.0 g, 7.53 mmol) and N,O dimethylhydroxylamine (808 mg, 8.29 mmol) in DCM (38 ml) was added TEA (2.2 ml, 15.8 mmol) and HOBT (1.27 g, 8.29 mmol). After cooling to 0° C., EDCI (1.59 g, 8.29 mmol) was added in one portion, and the reaction was stirred overnight, warming to room temperature. The reaction was concentrated in vacuo, diluted with EthOAc (150 ml), and washed with H2O, 1 N KHSO4, 1 N NaHCO3 and brine. After drying over Na2SO4, filtering, and concentrating in vacuo, the residue was purified by flash chromatography to give the title compound as an oil in 88% yield. Rf=0.35 (50% EthOAc/hexane). 1H NMR (300 MHz, CDCl3) δ7.28 (d, 2H, J=7.4 Hz), 7.24 (t, 1H, J=6.8 Hz), 7.17 (d, 2H, 7.1 Hz), 5.18 (d, 1H, J=7.4 Hz), 4.9 (dd, 1H, J=7.0, 11.9 Hz), 3.66 (s, 3H), 3.16 (s, 3H), 3.05 (dd, 1H, J=6.0, 13.6 Hz), 2.87 (dd, 1H, J=7.0, 13.6 Hz), 1.39 (s, 9H).
Reaction SMILES: C([O:8][C:9](=[O:35])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[O:24])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH:16]([NH:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][CH2:30][CH2:29]2)=[O:24])[C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:35])=[O:8])=[CH:15][CH:14]=1
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
10% Palladium-carbon (0.10 g) was added to a solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5-yl)ureidomethyl]benzoic acid benzyl ester (Reference Compound No. 12-1, 0.97 g, 2.1 mmol) in methanol (20 mL), and then the reaction mixture was stirred at room temperature for 29 hours under hydrogen atmosphere. The insoluble materials were filtered out and the filtrate was evaporated under reduced pressure. The obtained solid was filtered with ethyl acetate to give 0.78 g of the title reference compound as a white solid quantitatively.
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=3)=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:1])[CH3:29])=[CH:25][CH:26]=3)=[O:19])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: C=O
Reactant: CNCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Solvent: O=CO
Product: CN(C)Cc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.00 mL formaldehyde (37% in water) was added at 0° C. to a solution of 0.100 g (0.280 mmol) (E)-3-(4′-chloro-biphenyl-4-yl)-N-(4-methylaminomethyl-phenyl)-acrylamide (Example 180) in 1 mL formic acid and the mixture was stirred for 1 h at RT and 2 h at 90° C. The reaction mixture was poured onto ice water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried i. vac. at 100° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5][C:4]([CH3:16])([CH3:15])[O:3]1.C1C(=O)N([Br:25])C(=O)C1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:25][C:12]1[C:11]([NH2:14])=[CH:10][CH:9]=[C:8]([CH:6]2[CH2:7][C:2]([CH3:17])([CH3:1])[O:3][C:4]([CH3:16])([CH3:15])[CH2:5]2)[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CC(c2ccc(N)cn2)CC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(N)c(Br)n2)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-ylamine (as prepared in the previous step, 13.5 g, 0.057 mol) in DCM (100 mL) was added a solution of freshly recrystallized NBS (10.2 g, 0.0570 mol) in DCM (300 mL) dropwise at 0° C. for 1 h. The reaction mixture was allowed to warm to RT, stirred for 30 min and then treated with satd aq Na2CO3 (300 mL). The organic phase was washed with 10% Na2S2O3 (300 mL) and water (300 mL), dried (Na2SO4) and concentrated to obtain the title compound as red solid (17.1 g, 95%) which was directly used in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 6.95 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, j=8.1 Hz), 4.03 (br s, 2H), 3.08 (m, 1H), 1.73 (m, 2H), 1.44 (m, 2H), 1.28 (s, 6H), 1.26 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C14H21BrN2O, 313.2 and 315.2 (M+H), found 313.2 and 315.1.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([C:17]([S:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:52][CH2:53][CH:54]1[CH2:56][CH2:55]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][S:19][C:17](=[O:18])[C:16]1[CH:50]=[CH:51][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.046 g, 0.053 mmol) in DCM (2 ml), HCl 4M in dioxane (0.013 ml, 0.053 mmol) was added and the resulting mixture was stirred at RT overnight. Three more additions of HCl 4M in dioxane (0.265 ml, 1.06 mmol) over five days were performed. The volatiles were removed under vacuum and the crude was purified by filtration through a silica gel cartridge (DCM:Et2O=7:3) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzoylthio)acetoxy)ethyl)pyridine 1-oxide as a colorless oil (0.032 g, 0.042 mmol, 79% yield, MS/ESI+ 761.26 [MH]+, [αD]=−46.44, c=0.5, MeOH).