Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:33])[CH:23]=[CH:24][C:25]=1[CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ClCl>ClCCl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:33][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[CH2:26][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CN2CCCCC2)c(Cl)c1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-piperidin-1-ylmethylphenylamine. Yield: 0.1 g (22% of theory); melting point: 277° C.-281° C.; C27H24Cl2N2 0 (M=463.4); calc.: molecular ion peak (M+H)+: 463/5/7 (Cl2); found: molecular ion peak (M+H)+: 463/5/7 (Cl2); Rf value: 0.50 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: ClB.CSC.C[SiH](C[CH2:10][Si:11]([CH3:19])([CH3:18])[CH2:12][CH2:13]CCC=C)C.OO.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:19][Si:11]([CH3:18])([CH2:10][Si:11]([CH3:18])([CH3:12])[CH3:10])[CH2:12][CH2:13][CH2:24][CH2:23][CH2:22][CH2:26][OH:25]
Reactant: C=CCCCC[Si](C)(C)CC[SiH](C)C
Reactant: C1CCOC1
Agent: BCl
Agent: OO
Solvent: CSC
Product: C[Si](C)(C)C[Si](C)(C)CCCCCCO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Monochloroborane-methyl sulfide (2.03 ml, 2.15 g, 19.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of compound 10 (2.96 g, 13.0 mmol) in THF (20 ml). The reaction mixture was stirred at 0° C. for 24 h, and a solution of hydrogen peroxide (13 ml, 30% in water) added dropwise and the reaction mixture stirred at 0° C. for 4 h, washed with water and the organic layer extracted into hexane/ethyl acetate (3×30 ml, 1:1). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield colorless oil. The crude product was purified by column chromatography [silica gel eluted with hexane/ethyl acetate (4:1)] to yield a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1>CN(C=O)C.[Cu]I>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=3[CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1cccc2c1cnn2-c1ccc(F)cc1
Yield: 369.1 %

Procedure:
A mixture of 1H-indazol-4-amine (750 mg, 5.64 mmol), copper (I) iodide (247 mg, 1.3 mmol), potassium carbonate (1.56 g, 11.28 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.321 g, 2.26 mmol) and 4-fluoro-1-iodobenzene (0.78 ml, 6.77 mmol) in dry DMF (2 ml) was heated in a microwave reactor at 140° C. for 20 minutes (potassium carbonate was placed in the tube first and care was taken to avoid any particles of potassium carbonate being left on the side of the tube above the level of the liquid (in order to avoid any superheating). Three identical reactions plus two using 500 mg input of 1H-indazol-4-amine were then combined and partitioned between water and dichloromethane. The organic layer was evaporated and the residue purified by silica gel chromatography using the Flashmaster II (2×100 g cartridges) eluting with a 0 to 50% dichloromethane:ethyl acetate gradient over 60 minutes to give the title compound (4.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Br:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)nccc12
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nccc3c(CBr)cccc23)cc1
Yield: 68.8 %

Procedure:
1-(4-Chlorophenyl)-5-methylisoquinoline (10.2 g) was dissolved in 50 ml of carbon tetrachloride. While the solution was heated under reflux and light was irradiated on it, 7.5 g of N-bromosuccinimide was added. The mixture was heated with stirring. After the reaction, the reaction mixture was cooled. The insoluble matter was removed by filtration. The filtrate was washed in water, dried, and concentrated to remove the solvent. Recrystallization from cold methanol afforded 9.2 g of 1-(4-chlorophenyl)-5-bromomethylisoquinoline as colorless needles having a decomposition point of 116° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15])#[CH:5]
Reactant: CCC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccccc1C(CC)C(N)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2-((trimethylsilyl)ethynyl)phenyl)butanamide (I3) (149 mg, 0.574 mmol) in DCM (10.0 mL) at 0° C. under nitrogen was added TBAF (1.0 M in THF, 0.86 mL, 0.86 mmol). The resulting mixture was stirred at 0° C. for 5 minutes then poured into water (50 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×40 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4 and the solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-75% EtOAc in petroleum benzine 40-60° C.) to give the title compound K1 as an off-white solid (104 mg, 97%); 1H NMR (400 MHz, d6-DMSO) δ 7.50-7.43 (m, 2H), 7.35 (td, J=7.7, 1.5 Hz, 1H), 7.31 (s, 1H), 7.23 (td, J=7.5, 1.3 Hz, 1H), 6.93 (s, 1H), 4.37 (s, 1H), 3.85 (dd, J=8.6, 6.4 Hz, 1H), 1.97-1.83 (m, 1H), 1.61 (J m, 1H), 0.84 (t, J=7.3 Hz, 3H). LCMS-A: rt 5.265 min; m/z 188 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][N:6]4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2ccccc2n1
Agent: Cl
Product: Clc1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Yield: 51 %

Procedure:
Following the general procedure of Example 38, Step 2, and making non-critical variations, 2-(chloromethyl)imidazo[1,2-a]pyridine (Example 2, Step 1; 0.25 g) and 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.45 g) give 0.25 g of the title compound after chromatography on silica gel using methanol/dichloromethane (4/96), pooling of the appropriate fractions, and crystallization from dichloromethane/ethyl ether; mp 138-139° C.; IR (mineral oil) 1339, 1498, 765, 814, 1223 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.20, 3.79, 6.79, 7.17, 7.56, 7.57, 8.08.
Reaction SMILES: [OH:1][C:2]1([C:23]2[C:32]([OH:33])=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:22].Cl[CH2:35]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[F:19][C:18]([F:20])([F:21])[C:17]1[C:12]([CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]3([C:23]4[CH:24]=[C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]5=[CH:31][C:32]=4[O:33][CH2:35][O:1]3)[C:3]2=[O:22])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12OCOc1cc3c(cc12)OCCO3
Temperature: 25 °C
Yield: 34 %

Procedure:
A 100 mL flask was charged under argon with 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-{[3-(trifluoromethyl)pyridine-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (0.46 g, 1.0 mmol), chloroiodomethane (0.36 g, 2.0 mmol), cesium carbonate (1.3 g, 4.0 mmol) and anhydrous tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4-dioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1H)-one (0.16 g, 34%) as an off-white solid: mp>250° C. (methanol); 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.35-7.14 (m, 3H), 6.95-7.03 (m, 1H), 6.68 (s, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 5.70 (ABq, 2H), 5.21 (ABq, 2H), 4.25-4.01 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.3, 152.3, 152.2, 147.8, 144.1, 143.3, 138.9, 134.3, 134.2, 134.2, 134.1, 130.7, 130.2, 129.2, 125.6, 125.2, 124.8, 124.4, 124.0, 123.5, 122.2, 122.0, 114.9, 114.2, 108.7, 105.3, 88.3, 77.2, 64.5, 64.0, 41.8, 41.7.
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)C1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCC(C)C>>[CH2:6]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH3:15])=[CH:24][CH:23]=2)[C:19](=[O:26])[C:20]1=[O:25])[CH:7]([CH3:12])[CH3:8]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CC(C)CBr
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CC(C)C

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione using 5-methyl isatin (purchased from Fisher Scientific) and 1-bromo-2-methyl propane (purchased from Fisher Scientific). 1H NMR δ 7.42 (m, 2H), 6.79 (d, 1H), 3.52 (d, 2H), 2.33 (s, 3H), 2.08 (m, 1H), 0.99 (d, 6H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.[I-].[K+]>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
Carbazole (1.0 g, 6.0 mmol) and sodium hydride (60 wt. % in mineral oil, 0.14 g, 6.0 mmol) were placed under argon and dissolved in 5 mL of DMF. The mixture was stirred at room temperature for 30 min, followed by addition of 4-bromomethylbenzoic acid methyl ester (1.4 g, 6.0 mmol) and 5 mg of potassium iodide. The reaction was heated to 80° C. for 2 h upon which a precipitate formed and the reaction turned from dark brown to dark orange. The reaction was then quenched with water (30 mL) and ethyl acetate (30 mL). The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.95 g, 50%) as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 8.19 (d, 2H, J=7.7 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.41 (m, 4H), 7.23 (m, 4H), 5.74 (s, 2H), 3.79 (s, 3H). 13C NMR (100 MHz, DMSO): δ 166.4, 143.8, 129.9, 127.3, 126.4, 125.9, 120.8, 119.6, 118.9, 111.4, 109.9, 52.5, 45.8. ESI-HRMS (m/z): [M+H]+ calcd. for C21H17NO2, 316.1323. found, 316.1314.
Reaction SMILES: Br[C:2]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:20][O:21]3)=[CH:16][C:15]=2[Cl:29])=[CH:11][CH:10]=1)=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:58]2[CH2:63][CH2:62]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:29][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:2]=3[CH:62]3[CH2:63][CH2:58]3)=[CH:10][CH:11]=1)[O:21][CH2:20][CH2:19][CH:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Br)cc3)c(Cl)cc21
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4C4CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Yield: 172.1 %

Procedure:
To a stirred suspension of ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (129 mg; 0.22 mmol) in 2 mL toluene was added successively water (0.1 mL), potassium phosphate (138 mg; 0.65 mmol), tricyclohexylphosphine (24 mg; 0.087 mmol), and cyclopropylboronic acid (0.435 mmol) at ambient temperature with stirring. A balloon of nitrogen with a three-way purge valve was attached, and the flask was evacuated and refilled five times with nitrogen. Palladium (II) acetate (10 mg; 0.043 mmol) was added, and again the flask was evacuated and refilled five times with nitrogen. The mixture was stirred in an oil bath set to 100° C. under the nitrogen balloon. After 4 hours the mixture was cooled to ambient temperature. The mixture was diluted with 10 mL EtOAc and 5 mL water. The mixture was transferred to a separatory funnel and after shaking, the organic layer was separated, dried over sodium sulfate and evaporated to give a brown oil. This material was purified by silica gel chromatography on a Biotage 25S column, eluting with 75/25 hexane/EtOAc to provide 83 mg of ethyl 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless oil. MS (apci, pos) m/z=554.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1)=[O:4].[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([N:6]3[CH2:7][CH2:8][C@H:5]3[C:3]([N:2]([CH3:15])[CH3:1])=[O:4])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@@H]1CCN1C1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H]1CCN1C1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of (2S)—N,N-dimethyl-1-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)azetidine-2-carboxamide (682 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) is in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (590 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]([C:10]([CH:13](Br)Br)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)(O)[O-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+]>CC(N(C)C)=O.O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:13][C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:16][CH3:17])[C:2]([Br:1])=[CH:12][CH:11]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C(Br)Br)ccc(Br)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(Cl)cc2)ccc(Br)c1OC
Temperature: 90 °C
Yield: 57.7 %

Procedure:
A mixture of ethyl 3-bromo-6-(dibromomethyl)-2-methoxybenzoate (Intermediate 88, 0.25 g), sodium bicarbonate (0.122 g) and sodium 4-chlorobenzenesulphinate (0.29 g) in dimethylacetamide (4 ml) and water (1 ml) was stirred and heated at 90° C. for 5 hours. After cooling, the mixture was diluted with water and loaded onto a water washed C-18 column which was then flushed with water and eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give ethyl 6-(4-chlorobenzenesulphonylmethyl)-3-bromo-2-methoxy-benzoate (0.15 g) as a gum.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]C)[CH2:10][CH2:9]1.Br>C(O)(=O)C>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:12][CH2:13]1
Reactant: COc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxyphenyl)piperidine (compound no. 397) (2.000 g, 6.21 mmol) was dissolved in acetic acid (33 mL) and treated with aq. HBr 48% (33 mL). After refluxing for 4 h the solvent was evaporated under reduced pressure, and the residue was azeotroped with dichloromethane (3×30 mL) to eliminate most of the acetic acid. Diethyl ether (100 mL) was added to the residue, and the mixture was shaken with saturated K2CO3 (100 mL) until most solids disappeared. The layers were separated, and the aqueous layer was extracted with diethyl ether (4×100 mL). The combined ethereal extracts were dried over Na2SO4 and concentrated. The crude product was dissolved in diethyl ether (40 mL) and treated with excess 1 N HCl in ether (20 mL). The pink precipitate was collected by filtration and dried under vacuum to provide 2-(1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenol (compound no. 229) as a white solid. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 272.0 [M+H]+, retention time 1.83 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:30](=O)[CH:31]([CH3:33])[CH3:32])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:9][C:30]=1[CH:31]([CH3:32])[CH3:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C(=O)C(C)C)C(C(=O)c1ccccc1)c1ccc(F)c(Oc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)C)oc(-c2ccccc2)c1-c1ccc(F)c(Oc2ccccc2)c1

Procedure:
185 g (0.4 mmol) of the compound from Example 22 are boiled in a water separator for 2.5 hours with 15.2 g (0.05 mol) of p-toluenesulphonic acid hydrate in 2 l of toluene. 7 ml of water separates from the mixture. After cooling, the mixture is washed twice with saturated bicarbonate solution and once with sodium chloride solution, dried over sodium sulphate and concentrated to dryness. The residue is recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=S)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:27]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccccc2)cc1
Reactant: N
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.51 g, 0.0069 mol), N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2.14 g, 0.0058 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.27 g (62%), m.p. 141°-143 ° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([NH:9][C:10]1[S:11][C:12]([S:15]CC2C=CC=CC=2)=[CH:13][N:14]=1)(=[O:8])=[O:7]>C1(C)C=CC=CC=1>[CH3:5][S:6]([NH:9][C:10]1[S:11][C:12]([SH:15])=[CH:13][N:14]=1)(=[O:7])=[O:8]
Reactant: CS(=O)(=O)Nc1ncc(SCc2ccccc2)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1ncc(S)s1
Yield: 30.6 %

Procedure:
To a mixture of aluminum chloride (510 mg.) and dried toluene (15 ml.) was added 2-methanesulfonamido-5-benzylthiothiazole (560 mg.) over 5 minutes at 110° C. with stirring, and the mixture was further stirred for 1 hour at the same temperature. After the reaction, toluene was removed by decantation. To the residue was added a mixture of water (20 ml.) and methylene chloride (20 ml), and the mixture was stirred for 30 minutes. Thus obtained insoluble material was collected by filtration, washed with water and then dried to give 2-methanesulfonamidothiazole-5-thiol (120 mg.), mp 185° to 192° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=O.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH2:18]
Reactant: COc1cccc2c(NC(C(N)=O)c3ccccc3)cc(C)nc12
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc2c(NC(CN)c3ccccc3)cc(C)nc12
Reaction time: 1 h
Yield: 20.3 %

Procedure:
2-(8-Methoxy-2-methylquinolin-4-ylamino)-2-phenylacetamide (example 74, 430 mg, 1.33 mmole) was suspended in tetrahydrofurane (20 mL) and BH3xSMe2 (2M in tetrahydrofurane) was added dropwise. The mixture was refluxed under stirring for 1 h and then stirred at RT for 12 hrs. The content of the flask was carefully mixed with 2N HCl and refluxed for 2 hrs. The reaction mixture was alkalized and extracted with dichloromethane. The organic phases were dried and concentrated. The residue thus obtained was purified using HPLC (RP-18, eluting with water/acetonitrile) to obtain the product (12%, 83 mg). ESI-MS [M+H]+=294.1 calculated for C22H21F6N3O5=293 g/mole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:6]#[N:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].[ClH:19].CCOCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[CH2:6][NH2:7].[ClH:19]
Reactant: CCc1ccc(C#N)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(CN)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxy-4-ethyl-benzonitrile (7-2, 1.5 g, 9.31 mmol) in THF (45 mL) at 0° C. was added LAH (40 mL, 40.0 mmol, 1M in THF) and stirred at 0° C. for 0.5 h. Quenched carefully over a period of 0.5 h with EtOAc at 0° C. and stirred for 15 minutes. Following this, water (1.5 mL) was added to this mixture and stirred for 15 minutes followed by 15% NaOH (1.5 mL) and again stirred for 15 minutes. Lastly, water (4.5 mL) was added and stirred for 15 more minutes. The mixture was dried over Mg2SO4, filtered and concentrated to yield a clear semi-solid. This semi-solid was treated with 2.0M HCl in ether (4.65 mL, 9.3 mmol) and the reaction contents were concentrated to afford the desired product as a white powder (7-3) in the form of a mono HCl salt. ESI+MS [M+H]+ C8H12N2O2: M-16 (—NH2), 149.1 found, 149.2 required.