Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH2:23]C#C>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][C:22]#[CH:23])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: C#CCCCl
Product: C#CCCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1

Procedure:
In analogy to the procedure described in example 5A], (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) and 4-chloro-but-1-yne gave the title compound as orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([OH:34])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:44][C@H:45]([OH:47])[CH3:46]>CN(C)C(=O)C>[CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([O:34][CH2:44][C@H:45]([OH:47])[CH3:46])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: C[C@@H](O)CI
Reactant: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)COc1cc(F)c(Nc2ncc(C#N)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 100 °C
Yield: 23.8 %

Procedure:
4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)-2-fluoro-4-hydroxyl-phenylamino)pyrimidine-5-carbonitrile (467 mg, 1.0 eq.) was added to N,N-dimethylacetamide (4.7 ml, 0.2M), followed by Cs2CO3 (922 mg, 3.0 eq.) and 3-iodo-2-(R)-propanol (0.88 g, 5.0 eq.) and heated at 100° C. under nitrogen overnight. It was cooled to room temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate (10 ml) and treated with saturated NaHCO3 (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml), and the combined organic solution was washed with brine (10 ml), and dried with Na2SO4. Solid was filtered off, and the organic solution was concentrated under reduced pressure. 5 ml of ethyl acetate was added to the residue, silica gel was added to form a thick paste, and was concentrated under reduced pressure. This silica gel mixture was loaded onto the Combiflash chromatography and product was eluted using 2N NH3 in MeOH (0-20%)/Ethyl Acetate (100%-80%) gradient to yield 124 mg of product as a light beige solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCNCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.104 g, 0.35 mmol) in methylene chloride (3.5 mL) was added N-(2,4-difluorobenzyl)-N-heptylamine hydrochloride (0.098 g, 0.35 mmol) and DMAP (0.094 g, 0.77 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.067 g, 0.35 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.066 g (36%) of a colourless oil.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:16])[CH:12]=2)[C:7]=1[CH2:17]N(C)C)(=O)C.[BH4-].[Na+].O.Cl>C(O)C>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:17])=[C:6]([OH:5])[CH:15]=[CH:14]2
Reactant: CC(=O)Oc1ccc2cc(Br)ccc2c1CN(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-1-[(dimethylamino)methyl]-2-naphthyl acetate hydrochloride (6.4 g, 0.0179 mol) was stirred in ethanol (250 mL). Sodium borohydride (3.0 g, 0.078 mol) was added portion-wise. The mixture was heated at reflux for 2 hours, then cooled to room temperature and water (100 mL) was added. The mixture was stirred for ½ hour then acidified with 2N hydrochloric acid. The ethanol was evaporated and the mixture was extracted with ethyl acetate. The extracts were washed with 2N hydrochloric acid, then with water, dried over anhydrous magnesium sulfate and solvent evaporated to give the title compound as a solid, mp 127-129° C. 1HNMR (500 MHz, DMSO-d6): δ9.66 (s, 1H), 8.01 (s, 1H), 7.80 (d, 1H, J=9.2 Hz), 7.60 (d, 1H, J=8.7 Hz), 7.53 (d, 1H, J-9.0 Hz), 7.19 (d, 1H, J=8.9 Hz), 2.80 (s, 6H), and 2.39 ppm (s, 3H). Elemental Analysis for C11H9BrO: Calculated: C, 55.72; H, 3.83; N, 0.00. Found: C, 55.81; H, 3.82; N, 0.00.
Reaction SMILES: C([O:5][P:6]([O:41]C(C)(C)C)([O:8][CH:9]([O:11][C:12](=[O:40])[N:13]([C:37](=[O:39])[CH3:38])[CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:34][C:33]4[C:29](=[N:30][N:31]([CH3:35])[CH:32]=4)[CH2:28]3)=[C:23]([F:36])[CH:22]=2)[CH2:16]1)[CH3:10])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[P:6]([O:8][CH:9]([O:11][C:12](=[O:40])[N:13]([C:37](=[O:39])[CH3:38])[CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:34][C:33]4[C:29](=[N:30][N:31]([CH3:35])[CH:32]=4)[CH2:28]3)=[C:23]([F:36])[CH:22]=2)[CH2:16]1)[CH3:10])([OH:7])([OH:41])=[O:5]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 17b (1 equiv) in dichloromethane is added TFA (3 equiv) and the reaction mixture is stirred at rt for 3 h. The reaction mixture is concentrated in vacuo, and purified directly by HPLC (C-18 column, 10-100% gradient elution, MeCN:H2O) to give the title compound. Theoretical MS 542 (M+1)+
Reaction SMILES: C([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[C:6](=[O:15])[NH:7][S:8]2(=[O:10])=[O:9])(C)C.ClCS[C:19]1[CH:24]=CC=C[CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:19]([N:7]1[C:6](=[O:15])[C:5]2[C:11](=[CH:12][CH:13]=[CH:14][CH:4]=2)[S:8]1(=[O:9])=[O:10])([CH3:24])[CH3:20]
Reactant: CC(C)c1cccc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)c2ccccc2S1(=O)=O
Yield: 141.2 %

Procedure:
A mixture of 4-isopropylsaccharin (37.9 g), phenyl chloromethyl sulfide (33.3 g), tetrabutylammonium bromide (5.4 g) and toluene (200 mL) was heated under reflux for 24 hours, then stripped of volatiles. Column chromatography of the residue on silica gel (485 g) and elution first with hexane, then hexane-dichloromethane (1:1), then dichloromethane gave in the hexane-dichloromethane eluate 2-phenylthiomethyl-4,-isopropylsaccharin as a pale yellow oil (53.5 g, 92% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CN2CCC(Cc3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 124.5 %

Procedure:
To a stirred solution of ((1R,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 4-benzylpiperidine (0.17 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.45 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3: 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[CH3:32][NH2:33]>CCO>[CH2:11]([C:9]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]([CH3:31])=[C:5]2[N:10]=1)[CH3:12]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CN
Solvent: CCO
Product: CCc1nc2c(C)cc(NC)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 180 °C
Yield: 51.9 %

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (74 mg), methylamine (0.6 g), and EtOH (2 mL) was heated in a bomb at 180° C. for 16 hours. Concentration and purification (SiO2, 90/9/1 CH2Cl2 /MeOH/NH4OH) gave 34.4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34](Br)[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:41]#[N:42])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(Br)cc(C)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-bromo-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (40 mg, 0.064 mmol) in DMF (3 mL) was added zinc cyanide (8.3 mg, 0.071 mmol) and Pd(Ph3P)4 (22.3 mg, 0.019 mmol). The resulting reaction mixture was stirred at 110° C. for 24 hours, then concentrated. The resulting residue was purified by preparative TLC eluting with 40% EtOAc/hexanes afforded a 9:1 mixture of naphthyl regioisomers. The residue was purified by preparative HPLC (Chiralcel OD column) eluting with 5% EtOH/heptane to afford the major diastereomer of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.65 (d, J=7.5 Hz, 1H); 7.63 (s, 1H); 7.48 (d, J=8.5 Hz, 2H); 7.42 (m, 1H); 7.36 (d, J=8.5 Hz, 2H); 7.26 (d, J=8.0 Hz, 2H); 7.20 (d, J=8.5 Hz, 2H); 6.66 (m, 1H); 5.00 (d, J=11.5 Hz, 1H); 4.13 (q, J=7.2 Hz, 2H); 3.62 (q, J=11.8 Hz, 2H); 3.56 (m, 1H); 2.54 (q, 14.5 Hz, 2H); 2.54 (s, 3H); 1.62-1.51 (m, 2H); 1.25 (t, J=7.3 Hz, 3H), 1.06-1.00 (m, 2H); 0.74 (t, J=7.2 Hz, 3H). LC3 4.06 min. [M+H]+ 567.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31]C1=O.[OH-].[Na+].Cl>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][NH:29][CH2:33][CH2:32][OH:31])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: O=C1OCCN1CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCNCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 50 mg (0.34 mmol) of 3-(2-chloroethyl)oxazolidin-2-one. The protecting group was cleaved off using a 1N sodium hydroxide solution. The product is in the form of the hydrochloride.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[C@H:3]([NH:17]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:17][C@H:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:8][CH:9]=1)[C:2]([CH3:26])([OH:1])[CH3:25]
Reactant: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(C)(C)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@@H](N)C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of t-butyl (1R)-2-hydroxy-2-methyl-1-(4-(2-methylpentyloxy)phenyl)-propylcarbamate (340 mg, 0.930 mmol) in dichloromethane (1 mL) was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was transferred to a separatory funnel containing saturated aqueous K2CO3 solution. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated to afford (1R)-1-amino-2-methyl-1-(4-(2-methylpentyloxy)phenyl)propan-2-ol.TFA (350 mg, 99% yield) as a colorless oil which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 3.78 (dd, J=9.1, 5.8 Hz, 1H), 3.73 (s, 1H), 3.68 (dd, J=8.9, 6.7 Hz, 1H), 1.86-1.97 (m, 1H), 1.27-1.51 (m, 4H), 1.17 (s, 3H), 1.01 (s, 3H), 0.99 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=O.CO.Cl>O1CCCC1>[N+:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:3][OH:2])[NH:6][CH2:7]2)=[CH:12][CH:11]=1)([O-:17])=[O:16]
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CNC(CO)C2
Yield: 38.7 %

Procedure:
To 7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (5.0 g, 21.2 mmol) in dry tetrahydrofuran (18.5 ml) was added 10M borane-methyl sulfide complex (2.4 ml). The mixture was heated at reflux for 1.5 h while distilling off the methyl sulfide formed. The reaction mixture was cooled and methanol (2.7 ml) was added cautiously followed by 6N hydrochloric acid (5.4 ml). The mixture was then refluxed for 2.5 h and concentrated to dryness under reduced pressure. The solid residue was dissolved in water, the solution basified with 2.5N sodium hydroxide solution and the product extracted into dichloromethane. The crude product was purified by chromatography using silica gel and 5% methanol saturated with ammonia in dichloromethane to yield 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-methanol (1.71 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[C:4](=O)[NH:3]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:4]1[C:5]2[C:6](=[CH:9][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc2c1=O
Product: Cn1nc(Cl)c2cn(Cc3cccc4ccccc34)cc2c1=O

Procedure:
A suspension of 2,3-dihydro-2-methyl-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazine-1,4(6H)-dione (0.10 g) in phosphorus oxychloride (1 ml) was heated at reflux for 30 minutes and then allowed to cool. The solvent was evaporated, water (25 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The organic extracts were dried, filtered and evaporated to give the sub-title compound (0.095 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH:6]([O:8][C:9](=[O:36])[CH2:10][CH:11]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=2)[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=2)[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3]1.[C:40](O)(=[O:42])[CH3:41]>C(OC(=O)C)(=O)C>[C:40]([N:3]1[C:2]([CH3:39])([CH3:1])[CH2:7][CH:6]([O:8][C:9](=[O:36])[CH2:10][CH:11]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=2)[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=2)[CH2:5][C:4]1([CH3:38])[CH3:37])(=[O:42])[CH3:41]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C(CC(=O)OC1CC(C)(C)NC(C)(C)C1)c1cc(C(C)(C)C)c(O)cc1C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(C)(C)CC(OC(=O)CC(c2cc(C(C)(C)C)c(O)cc2C)c2cc(C(C)(C)C)c(O)cc2C)CC1(C)C
Temperature: 25 °C

Procedure:
10 g of 2,2,6,6-tetramethyl-4-[3,3-bis-(3-tert.-butyl-6-methyl-4-hydroxyphenyl)-propionyloxy]-piperidine are stirred in 25 ml of acetic anhydride at 110° for 6 hours. The acetic acid formed and excess anhydride are then distilled off under vacuum as completely as possible. The residue is cooled down to room temperature, 100 ml of water are added and are mixed in efficiently, and the precipitate is filtered off, is washed with water and is dried. Crystallising from acetonitrile gives 1-acetyl-2,2,6,6-tetramethyl-4-[3,3-bis-(3-tert.-butyl-6-methyl-4-hydroxyphenyl)-propionyloxy]-piperidine having a melting point of 270° (optical stabiliser No. 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of (S)-1-(7-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 19 (482 mg, 1.77 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (466 mg, 1.95 mmol) and DIPEA (0.91 mL, 5.32 mmol) in IMS (3.5 mL) was stirred in a sealed vial for 48 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The product containing fractions (basic and methanolic) were combined and concentrated in vacuo. Purification by Isolute® SCX-2 was repeated a second time and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The basic fractions were combined and concentrated in vacuo and the residue was refluxed in MeOH. After cooling to RT the solid was filtered off and washed with EtOAc affording 138 as a white solid (379 mg, 55%). LCMS: RT 3.65 min [M+H]+ 390.0. 1H NMR (DMSO, 400 MHz): δ 8.20-8.06 (2H, m), 7.94 (1H, s), 7.69-7.36 (6H, m), 7.24-7.19 (2H, m), 5.26 (1H, bs), 1.10 (3H, d, J=7.00 Hz)
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].O.[F:14][C:15]([F:27])([F:26])[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[CH:24]=[O:25])[CH:21]=[CH:20][S:19]2>CC(O)(C)C>[F:27][C:15]([F:26])([F:14])[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]([OH:5])=[O:25])[CH:21]=[CH:20][S:19]2
Reactant: O
Reactant: O=Cc1c(C(F)(F)F)nc2sccn12
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: O=C(O)c1c(C(F)(F)F)nc2sccn12
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of sodium chlorite 418.986 mg (4.633 mmol) and sodium dihydrogen phosphate dihydrate 553.971 mg (3.551 mmol) in water 3.94 mL (218.895 mmol) was added dropwise to a solution of 6-trifluoromethyl-imidazo[2,1-b]thiazole-5-carbaldehyde 119 mg (0.54 mmol) in t-BuOH (3.94 mL). The mixture was stirred for 2 h30 at RT. The mixture was then concentrated in vacuo to remove t-BuOH, a white precipitate was formed and filtered to give the title compound as a white solid (70 mg, 55%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1(Cl)[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][C:5]1([F:17])[F:16]>C(O)C>[Cl:3][C:4]1[C:5]([F:16])([F:17])[CH2:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=C(Cl)C(F)(F)C2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3.2 g. (0.049 mole) of 85% potassium hydroxide in 60 ml. of absolute ethanol there is added 10.7 g. (0.04 mole) of 2,2-dichloro-1,1-difluoro-3-(p-methoxyphenyl)cyclobutane. The mixture is heated at reflux for 1 hr. and then cooled to room temperature. Precipitated potassium chloride is removed by filtration and the filtrate concentrated to about 20 ml. About 70 ml. of water is added and the mixture is extracted with three 50 ml. portions of ether. The extract is washed (water 70 ml.), dried and the solvent distilled. The residual material constitutes a 96% yield of desired intermediate suitable for use in the next step. A small sample was distilled for analysis, b.p. 67°C. (0.02 mm) ND27 1.5597.
Reaction SMILES: [CH2:1]([N:4]([CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][CH2:13]1)[CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CCCCCCOC1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
3 g of allyl-methyl-[6-(piperidin-4-yloxy)-hexyl]-amine (Ex. 49.1) are dissolved in 50 ml of methylene chloride and treated with 5.3 ml of Hünig Base (di-isopropyl-ethylamine) and 1.9 g of 4-bromo-phenylsulphonyl chloride. The reaction mixture is stirred at room temperature for 3 hours, treated with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and concentrated. The brown oil is purified on silica gel with ethyl acetate/methanol (9:1). There are obtained 2.6 g of allyl-[6-[1-(4-bromo-phenylsulphonyl)-piperidin-4-yloxy]-hexyl]-methyl-amine which are converted into the fumarate, MS: m/e 473 (M+H+, 1Br).