Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.Cl.[CH3:25][O:26][C:27]([C:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:25][O:26][C:27]([C:29]1([NH:35][C:19]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][Cl:13])=[CH:23][CH:22]=2)=[O:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
Under ice-cooling, 9.96 g (52 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 8.8 g (52 mmol) of 4-(chloromethyl)benzoic acid, 10 g (52 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 15 g (152 mmol) of triethylamine and 8.63 g (56 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 8.5 g (53%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[CH3:57])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[CH3:57])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)c(Cl)c4)c4ccccc43)cn12
Yield: 68.1 %

Procedure:
A solution of Intermediate 50a (280 mg, 0.345 mmol) and TBAF (1M in THF, 0.41 mL, 0.41 mmol) in THF (3 mL) was stirred at RT for 0.5 h. Water was added and the mixture extracted with DCM (3×15 mL). The combined organics were concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound (154 mg, 68%). LCMS (Method 5): Rt 3.52 min, m/z 655.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.82-2.26 (11H, m), 2.31-2.39 (1H, m), 3.10-3.16 (1H, m), 3.99 (1H, d, J=8.2 Hz), 4.77-4.85 (1H, m), 5.35-5.42 (1H, m), 6.28 (1H, s), 7.03-7.10 (2H, m), 7.22-7.38 (6H, m), 7.43 (1H, d, J=2.5 Hz), 7.75 (1H, dd, J=9.9 Hz), 7.99 (1H, s), 8.24 (1H, br d), 10.56 (1H, v br).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCCCO)c12
Yield: 60.7 %

Procedure:
To a solution of N-{3-amino-2-[(5-hydroxypentyl)amino]phenyl}-N′-(2,4-dichlorophenyl)thiourea (Reference Example 111; 554 mg, 1.34 mmol) in tetrahydrofuran (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (771 mg, 4.02 mmol) at room temperature. The resultant mixture was stirred at 40° C. for 2.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-90% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (308 mg, 0.813 mmol, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:3])=[O:2].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])([O-:3])=[O:2]
Reactant: N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A solution of 11.60 g (48 mmol) of S-(o-nitrophenyl)-D-cysteine in 36 mL of 4N sodium hydroxide (NaOH) was cooled to 0° C. To this solution was added dropwise 6.85 mL (48 mmol) of carbobenzyloxychloride, and the mixture was stirred at room temperature for 2.5 hours. The pH was maintained at 10.8 with the addition of 4N NaOH as needed. The solution was then extracted with ether and the pH adjusted to 1.0 with 12N HCl. The resulting precipitate was dissolved in CH2Cl2, dried with Na2SO4 and evaporated to yield 17.0 g of product as a yellow gum. This material was used as is in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CS(O[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O>>[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCCCCOCc1ccccc1
Product: O=Cc1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde (11) with 4-(benzyloxy)butyl methanesulfonate following the method used in Example 149 gave 3-(4-(benzyloxy)butoxy)benzaldehyde (137) as a clear oil. Yield (1.5 g, 80%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.46 (m, 2H), 7.33-7.38 (m, 5H), 7.28-7.31 (m, 1H), 7.14-7.18 (m, 1H), 4.53 (s, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.4 Hz, 2H), 1.88-1.98 (m, 2H), 1.80-1.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:37]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:38])=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cn(C(=O)N2CCCCC2)c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of piperidine-1-carbonyl chloride. The crude reaction mixture was purified by preparative HPLC to afforded 21 mg of the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:19]([S:22][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccc([N+](=O)[O-])c(NC(=O)C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 88.1 %

Procedure:
A mixture of N-(5-chloro-2-nitropheny)-2,2-dimethylpropanamide (Step A, 1.54 g, 6.0 mmol), 2-methyl-2-propanethiol (675 μL, 6.0 mmol) and potassium carbonate (993 mg, 7.2 mmol) in N,N-dimethylformamide (25 mL) was stirred in a sealed tube at 100° C. for 17 h. Water (20 mL) was added and precipitate was collected by filtration and dried in vacuo at 50° C. to afford the title compound (1.64 g, 88%) as an orange solid.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:35])[C@H:17]([NH:31][C:32](=[O:34])[CH3:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:32]([NH:31][C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 91.5 %

Procedure:
1-(2-(R)-Acetylamino-3-biphenyl-4yl-propionyl)-pyrrolidine-2-(S)-carboxylic acid benzyl ester (0.50 g) were dissolved in 30 mL of methanol and hydrogenated for 4 h at room temperature using 0.3 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.37 g (91%) of the title compound as a white solid. (+)-APCI-MS: 381 (MH+).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][N:25]=[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])[C:27]([O:29][CH3:30])=O>C1(C)C(C)=CC=CC=1>[CH3:23][O:24][N:25]=[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])[C:27]([O:29][CH3:30])=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON=C(C(=O)OC)c1ccccc1COc1ccccc1C
Solvent: Cc1ccccc1C
Product: CON=C(C(=S)OC)c1ccccc1COc1ccccc1C
Reaction time: 24 h
Yield: 58 %

Procedure:
16.6 g (41 mmol) of Lawesson's reagent were added to 10.2 g (33 mmol) of 2-[2-methylphenoxymethyl]-phenylglyoxylic acid methyl ester O-methyloxime in 50 ml of xylene. Refluxing was carried out for 24 hours and the solvent was removed under reduced pressure. Chromatography over silica gel using ethyl acetate/hexane gave 6.3 g (59%) of the compound as a black oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (14.0 g, 58.3 mmol) in toluene (250 mL), was added hexane-2,5-dione (7.05 mL, 60.1 mmol) and pTSA (0.22 g, 1.20 mmol). The flask was fitted with a Dean Stark trap and reaction mixture was heated at reflux for 1 h. The mixture was allowed to cool to rt and concentrated. The residue was purified by filtration through a pad of silica to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole as an orange solid (18.g g, 97.8%). 1H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 5.92 (s, 2H), and 2.05 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][N:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline, prepared as in STEP 3 above (2.33 g, 7 mmol, 1 equiv), 1-methylpyrazole-4-boronic acid pinacol ester (1.75 g, 8.4 mmol, 1.2 equiv), K2CO3 (3.86 g, 28 mmol, 4.0 equiv), and Pd(PPh3)4 (809 mg, 0.7 mmol, 0.1 equiv). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (30 mL/6 mL) was added and the resulting mixture was heated at 100° C. for 3 h. The resulting mixture was poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator, and the resulting residue was purified by column using EtOAc as the eluent to yield the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1)[CH2:3][CH3:4].B.[OH:18]O.[OH-].[Na+]>C1COCC1.O>[NH2:1][CH:2]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH:8]([OH:18])[CH2:9]1)[CH2:3][CH3:4]
Reactant: OO
Reactant: CCC(N)C1(c2ccc(F)cc2)CC=CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)C1(c2ccc(F)cc2)CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopent-3-ene (118, 348 mg, 1.6 mmol) was dissolved in THF at 0° C. under argon. Borane (1.75 mL, 1.75 mmol, 1M in THF) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature before stirring overnight. After cooling to 0° C., water was added (4 mL), followed by hydrogen peroxide (0.61 mL, 30% solution in water) and sodium hydroxide solution (1.75 mL, 1M aqueous solution). After stirring for 5 minutes the mixture was extracted with ethyl acetate, dried over sodium sulphate and evaporated to give 458 mg of desired product, which was stirred for 15 minutes with dilute hydrochloric acid (10 mL, 2M aqueous solution). Evaporation, followed by freeze drying gave 514 mg of the desired product as mixture of four stereoisomers as a colourless hydrochloride salt. Rt=1.83, 1.99, 2.36, 2.86 min (Method 2). Detected mass: 203.1 (M—NH3—H2O+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][O:21][CH2:22][CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH2:22][O:21][CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COCCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (400 mg, 1.22 mmol) and 2-methoxyacetaldehyde (1.3 mg, 17.56 mmol) in 7 ml of dichloroethane, acetic acid (0.42 mL, 7.33 mmol) was added and stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (777 mg, 3.66 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was then neutralized with sat. NaHCO3 and extracted with DCM, and the organic layer was dried over Na2SO4, concentrated under reduced pressure to get 260 mg of crude product.
Reaction SMILES: C(O)C.O.[OH-].[Li+].C([O:9][C:10]([C:12]1[NH:38][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[O:29])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])C.Cl>O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[C:14]4[CH:13]=[C:12]([C:10]([OH:11])=[O:9])[NH:38][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:22][CH:23]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(C(=O)O)cc23)cc1
Temperature: 42.5 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
After adding 7 ml of ethanol, 7 ml of water and 31 mg of lithium hydroxide monohydrate to 75 mg of the 4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester synthesized in Example 163 and stirring the mixture at 40-45° C. for 24 hours, it was neutralized with 2N HCl and concentrated to dryness to obtain 40 mg of the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:7]([O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:9]=1[O:10][CH2:15][CH:14]=[CH2:13])[CH:2]=[O:1])[CH3:8]
Reactant: C=CCBr
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1OCC

Procedure:
Ethyl vanillin (21.6 g, 0.130 mol) and allyl bromide (19.9 g, 0.160 mol) were heated under reflux together with potassium carbonate (27.3 g, 0.200 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. A yellow oil was obtained after a thorough concentration of the organic phases.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:25][C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:33]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]([CH3:23])([CH3:22])[C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:24])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:34])[CH:29]=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]
Reactant: C[C@@H]1NCCN(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 53 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3,3-dimethyl-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 28) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 53% yield as off-white foam. MS: 559.23 (MH+, Cl).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[OH:14]O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])=[O:14]
Reactant: CSCCOc1cccc(C=O)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)CCOc1cccc(C=O)c1

Procedure:
A solution of 1.6 g (8.15 mmol) 3-(2-methylsulphanyl-ethoxy)-benzaldehyde and 1 ml (9.78 mmol) hydrogen peroxide solution in 30 ml acetic acid is stirred for 2 h at room temperature. Then the reaction mixture is poured onto 4N NaOH and extracted with ethyl acetate. The combined organic layers are washed with sodium bisulphite solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colorless solid, sufficiently pure for the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5].[H][H]>>[CH:8]1([CH2:7][CH2:6][CH:2]([CH3:1])[CH2:3][CH2:4][OH:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CCO)CCc1ccccc1
Reactant: [H][H]
Product: CC(CCO)CCC1CCCCC1
Reaction time: 15 h
Yield: 97 %

Procedure:
1200 g of 3-Methyl-5-phenyl-pentanol (Phenoxanol™, supplier: IFF) combined with 10.5 g Ru on aluminium oxide (Ru content 5 wt. %) were hydrogenated at a hydrogen pressure of 25 bar and at a temperature of 110° C. After 15 hours the reaction was finished. The catalyst was removed and the product distilled. 1204 g (content 99.7%) of 5-cyclohexyl-3-methyl-pentanol were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl.O>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2-tert-butylaniline (2.0 g, 2.1 mL, 13.4 mmol) and TEA (2.8 mL, 20.1 mmol) in DCM (100 mL) was cooled to 0° C. Acetyl chloride (1.0 mL, 14.7 mmol) was added dropwise. The resulting solution was allowed to stir and warm to rt over 2 h. The reaction mixture was diluted with water and DCM. The organic phase was washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (2.73 g, >100%). 1H NMR (400 MHz, CDCl3) δ: 7.51-7.53 (m, 1H), 7.39-7.41 (m, 1H), 7.14-7.24 (m, 2H), 2.21 (s, 2.2H), 1.92 (s, 0.9H), and 1.41 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:32][C:33]1[C:34]([CH3:40])=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[C:41]([N:48]1[CH2:51][CH2:50][C@H:49]1[CH2:52]O)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C1COCC1>[C:41]([N:48]1[CH2:51][CH2:50][C@H:49]1[CH2:52][O:39][C:37]1[CH:36]=[N:35][C:34]([CH3:40])=[C:33]([Br:32])[CH:38]=1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Cc1ncc(O)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Triphenylphosphine (6.3 g, 24 mmol) was dissolved in THF (100 mL), cooled to 0° C. and treated with diethylazodicarboxylate (3.8 mL, 24 mmol) for 15 min. Then the compound of 196d (3 g, 16 mmol) followed by 1-BOC-2-(S)-azetidinemethanol (3.4 g, 18 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After 3 days, the solvent was evaporated and the crude residue was chromatographed (silica gel; hexanes/ EtOAc, 4:1) to provide an oil. The product was contaminated with a byproduct related to the DEAD reagent and was taken forward as is; the subsequent allowed isolation of the byproduct and revealed ˜35 wt % contamination therefor the calculated yield was 70% (4.0 g, 11.2 mmol): TLC Rf 0.6 (1:1 hexanes/EtOAc); MS (CI/NH3) m/z 357 (M+H)+.