Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)OC1.[CH3:20][N:21]1[CH2:26][CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]1.[Li+].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:20][N:21]1[CH:22]=[CH:23][CH:24]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)COB(c2cc(N)cc(C(F)(F)F)c2)OC1
Reactant: CN1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Product: CN1C=CC(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine (1.2 g) was added to trifluoro-methanesulfonic acid 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (1.0 g), LiCl (500 mg, Aldrich), PPh3 (300 mg, Aldrich) and 2M Na2CO3 aqueous solution (6 ml) and was bubbled with N2 for 5 min. Pd(PPH3)4 (300 mg, Aldrich) was added and the reaction was heated to 80° C. for 16 h. The reaction was cooled to RT and diluted with Et2O (100 mL). The mixture was filtered through Celite® and the filtrate was washed with NaHCO3 aqueous solution (25 ml) followed by brine (25 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The desired compound was isolated by silica gel column chromatography (EtOAc 10% (2M NH3) in MeOH/EtOAc) to provide yellow oil. M+H 257.2; Calc'd 256.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19](O)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[O:24]C1C=C(CCN)C=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:24])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(CCN)c1
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Product: Oc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1

Procedure:
1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-ol was prepared analogously to 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 82) using 2-(3-methoxyphenyl)ethanamine in place of 2-(4-methoxyphenyl)ethanamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=[O:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1

Procedure:
To a well stirred mixture of (3S,4S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8.2 g, 23.73 mmol) and Dess-Martin periodinane (10.06 g, 23.73 mmol) in CH2Cl2 (60 mL), slowly wet CH2Cl2 (0.47 mL of water in 60 mL of CH2Cl2) is added. The clear solution becomes cloudy toward the end of wet CH2Cl2 addition and is further stirred over-night. Then concentrated to a few mL of solvent by rotary evaporation and taken up in Et2O. A solution of 1:1 10% Na2S2O3/saturated aqueous NaHCO3 is added. The layers are separated and the organic extract is washed successively with H2O and brine. The aqueous washings are back-extracted with Et2O, and this organic layer is washed with H2O and brine. The combined organic layers are dried with Na2SO4, filtered and concentrated. The crude mixture is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.42. MS (LC-MS): 244.2 [M+H-Boc]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.45 min.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[C:23](=[O:24])[CH2:22][CH2:21][CH:20]1[C:25](O)=[O:26].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([CH:20]2[NH:19][C:23](=[O:24])[CH2:22][CH2:21]2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C1CCC(C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.00 g, 3.43 mmol), DL-pyroglutamic acid (0.49 g, 3.78 mmol), triethylamine (0.73 g, 7.20 mmol), EDCI (0.72 g, 3.78 mmol) and HOBt (0.58 g, 3.78 mmol) in acetonitrile (30 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The resulting white precipitate was collected by filtration and washed with diethyl ether to afford the title compound (1.03 g, 91%) as a off-white solid, mp 290° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Br[CH:21]([C:23]1[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][CH:28]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(Br)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2cccc(C(F)(F)F)c2)nc2nc(N)sc12
Yield: 81 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 0.1 mmol) with 3-(1-bromoethyl)trifluoromethylbenzene (15.5 μL, 0.1 mmol) to give 38 mg (81% yield) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[C:7]([C:6]1[C:4](=[O:5])[C:3]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:2]=2[O:1][C:14]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18])#[N:8]
Reactant: N#CCC(=O)c1ccc(O)cc1O
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#Cc1c(CCC(=O)O)oc2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8.85 g of 2,4-dihydroxybenzoyl acetonitrile, 25 ml of pyridine and 15 g of succinic anhydride was stirred at room temperature overnight. The next morning the solid was filtered and recrystallized from methanol, mp 300°-301° C.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N1C=C2C=NC=C(Cl)C2=N1)C#N.[N:21]([C:24]1[C:29]([Br:30])=[CH:28][N:27]=[CH:26][C:25]=1/[CH:31]=[N:32]/[C:33]1[C:40]([Cl:41])=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[Cl:42])=[N+]=[N-]>C1(C)C=CC=CC=1>[Br:30][C:29]1[C:24]2[C:25](=[CH:31][N:32]([C:33]3[C:40]([Cl:41])=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[Cl:42])[N:21]=2)[CH:26]=[N:27][CH:28]=1
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Br)c2N=[N+]=[N-])c(Cl)c1
Agent: N#Cc1cc(Cl)c(-n2cc3cncc(Cl)c3n2)c(Cl)c1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)c(-n2cc3cncc(Br)c3n2)c(Cl)c1
Yield: 70 %

Procedure:
Following the procedure described for 3,5-dichloro-4-(7-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile, 4-{[1-(4-azido-5-bromo-pyridin-3-yl)-meth-(E)-ylidene]-amino}-3,5-dichlorobenzonitrile was heated under reflux in toluene to afford the title compound as a beige solid (3.57 g, 70% yield). 1H NMR (300 MHz, methanol-d4): δ 9.26 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 8.20 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCl>[Br:1][C:2]1[C:3]2[CH2:12][CH2:13][C:14](=[O:15])[C:4]=2[CH:5]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: O=C(Cl)CCc1ccc2ccccc2c1Br
Agent: Cl
Agent: ClCl
Agent: [Al+3]
Product: O=C1CCc2c1cc1ccccc1c2Br
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To an ice cold, stirred solution of the above crude β-(1-bromo-2-naphthyl)propionyl chloride in 802 mL of dry CH2 Cl2 was added 26.11 g of anhydrous AlCl3 carefully. The reaction mixture was refluxed for 2 h, cooled to room temperature and treated carefully while stirring with 900 mL of ice-water followed by 75 mL of conc. HCl. The brown precipitate was filtered and washed five times with small portions of CH2Cl2. The aqueous layer was separated and extracted twice with 100-mL portions of CH2Cl2. The combined CH2Cl2 extracts were washed three times with small portions of H2O, dried (MgSO4) and evaporated from a water bath (50°-60° C.) with a rotary evaporator (7 mm) to give 30.1 g (80.1%) of the crude ketone as a yellow solid, mp 146°-149° C., which could be recrystallized from acetic acid to give 28.5 g (76%) of the pure ketone as colorless crystals, mp 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][NH:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CNCC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), methyl(cyclopropylmethyl)amine (1.02 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and concentrated in vacuo. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate and methylene chlorideethyl acetate to give 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 30 8 -Chloro-1-[[(cyclopropylmethyl)-methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Br[Zn][CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:35]1[CH2:36][CH2:37][O:38][CH:34]1[CH2:33][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: O=C1OCCc2cc(Br)ccc21
Reactant: Br[Zn]CC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: O=C1OCCc2cc(CC3OCCO3)ccc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
6-bromo-3,4-dihydro-1H-isochromen-1-one (10 g, 44 mmol) was combined with tri-t-butyl phosphonium tetrafluoroborate (256 mg, 0.881 mmol), palladium (II) acetate (99 mg, 0.44 mmol) and commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (0.5 M, 97 mL, 48 mmol) in DMF (100 mL), and the mixture was degassed three times by alternating vacuum and nitrogen purge. The mixture was then heated at 85° C. for 6 h, then was stirred at RT overnight. Ethyl acetate and ether were added and the mixture was washed with water. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed twice with water and once with brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by MPLC (silica) eluting with ethyl acetate in hexanes to afford the title compound. LCMS: m/z 235 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J31) (256 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (282 mg, 67%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[C:22]([CH3:23])=[C:21]([CH:24]([F:26])[F:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C>[F:25][CH:24]([F:26])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)ncnc1C(F)F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(difluoromethyl)-5-methylpyrimidine (ANICHEM CAS425394-59-8, 83 mg, 0.465 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N,N-dimethylformamide (5 mL) and the resulting mixture was stirred at room temperature for overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (38 mg);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:11].Cl[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:17]2[S:18][CH2:14][CH2:15][N:16]=2)=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: S=C=NCCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC2=NCCS2)cc1Cl

Procedure:
A mixture of 4-amino-2-chlorobenzoic acid methyl ester (0.5 g) and 2-chloroethylisothiocyanate (0.26 mL) in THF (20 mL) was refluxed for 24 h. THF was distilled and the residue was purified by column chromatography (silica gel: eluent: hexane/EtOAc 3:1-1:1) to yield 2-chloro-4-(2-thiazolinylamino)benzoic acid methyl ester (74 mg). ESMS: m/z 271 (MH+).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:28][OH:29]>C(O)C.N1C=CC=CC=1>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=[N:28][OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
A solution of 15.9 g (46 mmol) of 4-(quinolin-2-yl-methoxy)phenyl cyclohexyl ketone in 100 ml of ethanol and 33 ml of pyridine is stirred at room temperature for 18 h after addition of 4.77 g (68.6 mmol) of hydroxylamine hydrochloride. For working up, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated to dryness in vacuo.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=O)(=[O:5])=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(C3CCN(C)C3=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C3CCN(C)C3)c2c1
Yield: 44.1 %

Procedure:
A solution of the product of stage (ii) (450 mg) in dry tetrahydrofuran (20 ml) was added cautiously to a stirred suspension of lithium aluminium hydride (200 mg) in dry, freshly distilled tetrahydrofuran (20 ml) at 5°, under nitrogen. The reaction mixture was stirred and heated at reflux for 1 h; cooled to 5°, with stirring, and cautiously treated with a mixture of tetrahydrofuran (6 ml) and water (1 ml). The mixture was filtered through "hyflo". The residue was washed with ethanol. The combined filtrate and washings were evaporated to give a gum which was crystallised from a mixture of ethyl acetate and ether. The product was partitioned between ethyl acetate (30 ml) and 8% sodium bicarbonate (30 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organics were dried and evaporated to give a gum, which was crystallised from a mixture of ethyl acetate and cychlohexane to give the title compound (190 mg) as a cream powder, with m.p. 160° -162°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[OH-].[Na+].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=O.[Na+]>CCO>[S:4]1[C:3]2[C:2](=[N:1][C:12]([C:11]([OH:16])=[O:15])=[CH:14][CH:7]=2)[CH:6]=[CH:5]1
Reactant: Nc1ccsc1C=O
Reactant: CC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2sccc2n1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To a solution of 3-amino-2-formylthiophene (10 g, 78 mmol) in EtOH (50 mL) was added a mixture of aqueous NaOH (50 mL, 5%) and sodium pyruvate (17.16 g, 156 mmol). The mixture was heated to 60° C. for 2 hr. The mixture was cooled and washed with Et2O: EtOAc 1:1 and then acidified with 1 N HCl to pH 3 at 0° C. The mixture was filtered and the solid was air dried to give 10 g (71%) of the title compound.
Reaction SMILES: [N:1]([CH:4]1[C:9]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:17])([CH3:16])[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:9]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:17])([CH3:16])[CH2:5]1
Reactant: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(N)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A solution of 4-azido-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (2.00 g, 8.77 mmol), title C compound, in absolute ethanol (50 mL) was treated with 10% palladium on charcoal (0.25 g) and stirred under hydrogen for 90 minutes at room temperature. The catalyst was filtered off and the filtrate was acidified to pH 1-2 with concentrated HCl (0.85 mL) and concentrated under vacuum to a white solid. The residue was dissolved in 100 mL distilled water and extracted with ethyl acetate (discarded). The aqueous layer was adjusted to pH 11-12 with 50% sodium hydroxide solution and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solvent was evaporated under vacuum to provide the title compound (1.542 g, 87%) as a yellow oil which solidified upon standing. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]([C:20](N)=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25]
Reactant: C[C@@H](Nc1cc(N2CCN(C3CCCC(C(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](Nc1cc(N2CCN(C3CCCC(CO)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 3-(4-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperazin-1-yl)cyclohexanecarboxylic acid (prepared as illustrated in Example 15, 0.077 g, 0.15 mmol) in THF (1 mL) at 0° C. was added sodium borohydride (NaBH4) (0.017 g, 0.5 mmol) and boron trifluoride diethyl etherate (BF3.Et2O) (0.1 mL, 0.8 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 10-40% ethyl acetate in hexanes) to afford the desired product as a white solid (0.0074 g, 0.015 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.17 (dd, J=2.0, 8.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.17 (dd, J=2.8, 8.8 Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 4.90 (dd, J=5.6, 6.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.54 (d, J=7.2 Hz, 2 μl), 3.03-2.99 (m, 3H), 2.59 (m, 3H), 2.39-2.36 (m, 1H), 2.05-1.95 (m, 1H), 1.75-1.34 (m, 14H); MS: (ES) m/z calculated for C25H33Cl3N3O [M+H]+ 496.2. found 496.3.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[N:7]2[CH:11]=[CH:12][N:8]=[C:6]2[C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)nc1N
Reactant: O=CCCl
Product: Cc1ccc(Br)n2ccnc12
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 6-bromo-3-methylpyridin-2-ylamine (359 mg, 1.92 mmol) and chloroacetaldehyde (1 mL, 50 wt. % in water) in IMS (4 mL) was stirred at 100° C. in a sealed tube for 1.5 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-8-methylimidazo[1,2-a]pyridine as a beige solid (387 mg, 95%). 1H NMR (400 MHz, CHCl3-d): δ 7.79 (d, J=1.3 Hz, 1 H); 7.69 (d, J=1.3 Hz, 1 H); 6.96 (d, J=7.3 Hz, 1 H); 6.91 (dq, J=7.3, 1.1 Hz, 1 H); 2.61 (d, J=1.1 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([C:8]#N)[CH:7]=1.C(O)=[O:12]>O.C1(C)C=CC=CC=1.[Ni].[Al]>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH:8]=[O:12])[CH:7]=1
Reactant: O=CO
Reactant: N#Cc1cnc(Cl)c(Br)c1
Agent: [Ni]
Agent: [Al]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cnc(Cl)c(Br)c1
Reaction time: 48 h

Procedure:
3-Bromo-2-chloro-5-cyanopyridine (8.6 g) in 90% formic acid (40 ml) and water (10 ml) were treated with Raney nickel/aluminium alloy (8.0 g) and the mixture stirred and heated to 55°-60° for 6 hours. The mixture was left to stand for two days, and then filtered. The filtrate was diluted to 500 ml with water and extracted with ether (2×250 ml). The ether extract was washed with aqueous sodium carbonate, dried, and evaporated to give an oil. The oil was diluted with toluene which was then removed under reduced pressure. The residue was diluted with a little ether, the solution filtered, and the filtrate evaporated to give an oil identified as the required aldehyde.