Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>[Cu]I.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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), CuI (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CC1O[CH:34]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[N:36]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:52][N:53]=[C:54]=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[CH:34]=[CH:52][N:53]([CH3:54])[N:36]=6)[CH2:38][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1nc(C2(N)CC2)co1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine (0.066 g, 0.47, 1.2 eq), HOBT (0.092 g, 0.68 mmol, 1.7 eq), EDC.HCl (0.14 g, 0.73 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.26 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM as an eluent followed by preparative HPLC. Yield: 0.02 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.10-1.13 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.33 (s, 3H), 2.81-2.82 (d, 3H, J=4.6 Hz), 7.38-7.43 (m, 4H), 7.57 (s, 1H), 7.61 (s, 1H), 7.75-7.71 (d, 1H, J=8.4 Hz), 7.80-7.81 (s and m, 2H), 7.97-8.01 (m, 2H), 8.47-8.48 (d, 1H, J=4.76 Hz), 9.1 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H). LCMS Method: Chromolith SpeedROD C18 (4.6×3.0 mm-5.0 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: CC[O-].[Na+].O=[C:6]([CH2:13][C:14](=O)[CH2:15][CH2:16]C)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:19][NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH3:19][N:20]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:13]([CH2:14][CH2:15][CH3:16])=[N:21]1
Reactant: CCCC(=O)CC(=O)CC(=O)OCC
Reactant: CNN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1cc(C(=O)OCC)n(C)n1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
76.5 g of 20% strength by weight sodium ethylate solution were initially introduced into a 250 ml 4-necked flask and 41.9 g of ethyl 2,4-diketoheptanecarboxylate were added in the course of 15 minutes. The solution thus prepared was added to a mixture of methylhydrazine (10.4 g), acetic acid (13.5 g) and ethanol (20 ml) at an internal temperature of 30 to 40° C. in the course of 45 minutes. When the addition was complete, the mixture was subsequently stirred at room temperature for a further hour and the ethanol was then distilled off. 100 ml of toluene and 100 ml of water were then added, the phases which form were separated and the aqueous phase was extracted twice more with 50 ml of toluene each time. The combined toluene extracts were reextracted with 100 ml of water, dried and concentrated under a slight vacuum. 31 g of isomer-free ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate having a boiling point of 125 to 128° C. under a pressure of 13 mm were obtained by fractional distillation. This corresponds to a yield of 75% of theory. The undesirable isomer ethyl 1-methyl-5-n-propyl-pyrazole-3-carboxylate was obtained as a second fraction in a yield of 6.2 g (=15% of theory). The boiling point of this isomer was 166 to 168° C. under a pressure of 13 mm.
Reaction SMILES: [CH2:1](N(CC)CC)C.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:23]([N:30]1[CH2:37][C@@H:36]([N:38]=[N+:39]=[N-:40])[CH2:35][C@H:31]1[C:32]([OH:34])=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClC(Cl)C.CSC>[CH3:1][O:33][C:32](=[O:34])[C@@H:31]1[CH2:35][C@H:36]([N:38]=[N+:39]=[N-:40])[CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CSC
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-(2-(S)-4-(S)-(Azido)-N-pyrrolidin-2-yl-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide. To 2b (R9′=H) (200 mg, 0.788 mmol) in DMF (5 mL) at 0° C., triethylamine (0.164 mL, 1.18 mmol) and bis-(trimethylsilyl)trifluoroacetamide (0.93 mL, 3.94 mmol) were added and then left stirring at room temperature overnight. After which, N-Boc-(2S,4S)-4-azidoproline (300 mg, 1.18 mmol) and HATU (444 mg, 1.18 mmol) was added at 0° C. and then left stirring for four hours. At the end, DMF was removed and the residue was taken in ethyl acetate (100 mL) and washed with citric acid (10%, 30 mL), saturated sodium bicarbonate (30 mL) and brine (30 mL). After drying the organic portion with sodium sulfate, the solvent was removed to obtain the crude product which was taken as such for the next deprotection step. To the crude product in dichloroethane 30% trifluoroacetic acid (10 mL) and dimethylsulfide (0.5 mL) was added and the reaction mixture was stirred for an hour. The solvent was removed and the crude product obtained was chromatographed on silica gel column using 20% methanol in DCM to obtain the title compound as a white solid (278 mg, 90%): TLC: Rf=0.38 (40% methanol in DCM); 1H NMR (300 MHz, CD3OD) δ 4.24 (d, J=5.4, 1), 4.16 (s, 1), 4.03–4.13 (m, 3), 3.95 (d, J=3.6, 1), 3.80 (dd, J=4.5, 9.9, 1), 3.51–3.56 (dd, J=3.3, 10.2, 1), 3.13–3.22 (m, 1), 2.95–3.00 (m, 1), 2.35–2.45 (m, 1), 2.08 (s, 3), 1.93–2.04 (m, 1), 1.29 (t, J=7.2, 1), 0.97 (m, 3); MS (ESPOS): 392 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].[CH3:23][C:24](CC(C)C)=O.O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[O:12][CH2:24][CH2:23][N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: CCCCNc1cc(C(=O)OC)cc(Br)c1O
Reactant: CC(=O)CC(C)C
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1CCOc2c(Br)cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of Methyl 3-bromo-5-(butylamino)-4-hydroxybenzoate (440 mg) and sodium bicarbonate (280 mg) in 1:1 isobutyl methyl ketone/water (10 mL) was added chloroacetyl chloride (226 mg). The mixture was stirred for 1 h, warmed to room temperature, and heated at reflux for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and the layer separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give a white solid: 1H NMR (300 MHz, CDCl3) δ 7.94, 7.62, 4.76, 3.98, 3.93, 1.65, 1.43, 0.97, which was used in the next step without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][NH:38][CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]([CH3:39])[CH3:37])=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (93 mg, 540%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.ClC1C=C(C2C(CO[C:38]3[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=CN=3)=C(C)ON=2)C=CC=1.FC(F)(F)C[NH2:51]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:51])=[O:21])=[C:17]([CH:45]4[CH2:46][CH2:38][O:43][CH2:42][CH2:41]4)[N:16]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(F)cn2)nc1
Product: NC(=O)c1ccc(OCc2conc2-c2ccc(F)cn2)nc1C1CCOCC1
Yield: 79 %

Procedure:
As described for example 98b, 6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79 mg, 0.25 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using 4-aminotetrayhdropyran instead of 2,2,2-trifluoroethylamine, to the title compound (79 mg, 79%) which was obtained as an off white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8]C(=O)[CH2:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([Mg]Br)C.Cl.C([O:23][CH2:24][CH3:25])(=O)C>O1CCCC1.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]([CH3:13])([CH3:14])[CH2:6][C:24]([OH:23])([CH3:25])[CH3:15])[CH:3]=1
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Reactant: CC[Mg]Br
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1 g, 3.92 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with 3M solution of ethyl magnesium bromide (2.6 mL) and stirred at ambient temperature for 2hours. The reaction mixture was poured into cold dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow solid (1.1 g, 100%).
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[NH:25]N>>[ClH:1].[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[C:19]2[C:20]=1[C:4]([CH2:5][CH2:6][NH2:7])=[CH:3][NH:25]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1ccc(C)c(NN)c1
Agent: Cl
Product: Cc1ccc(C)c2c(CCN)c[nH]c12

Procedure:
4,7-dimethyltryptamine hydrochloride was prepared (0.94 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,5-dimethyl-phenylhydrazine hydrochloride (16.8 g) as starting material. ##STR64##
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][CH:42]=1)[CH2:26][N:27]([CH3:39])[C:28](=[O:38])[CH2:29][NH:30]C(=O)OC(C)(C)C.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C(Cl)(Cl)Cl.O>[CH3:39][N:27]([CH2:26][C:25]1[CH:40]=[CH:41][CH:42]=[C:23]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH:24]=1)[C:28](=[O:38])[CH2:29][NH2:30]
Reactant: CC1(C)OB(c2cnc(N3CCCCC3)nc2)OC1(C)C
Reactant: CN(Cc1cccc(Br)c1)C(=O)CNC(=O)OC(C)(C)C
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: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCCCC3)nc2)c1)C(=O)CN
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a mixture of 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (14 mg), tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (9 mg), and DMF (0.2 ml) were added tetrakis(triphenylphosphine)palladium (3 mg), sodium carbonate (5 mg), and water (0.1 ml), followed by stirring at 60° C. overnight. After cooling to room temperature, to the reaction mixture was added CHCl3 (2 ml), and the reaction mixture was filtered in a column preconditioned by the addition of 0.8 ml of water to a diatomaceous earth column (manufactured by Varian Inc., ChemElute 1 ml). The obtained filtrate was concentrated, and then to the residue were added MeOH (0.5 ml) and a 4 M hydrogen chloride/EtOAc solution (0.5 ml), followed by leaving to stand for 30 minutes. Thereafter, the reaction mixture was concentrated and the compound was purified by preparative liquid chromatography (MeOH/0.1% aqueous formic acid solution) to obtain N-methyl-N-{3-[2-(piperidin-1-yl)pyrimidin-5-yl]benzyl}glycinamide (3.8 mg).
Reaction SMILES: [CH:1]1([CH:7]([OH:16])[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>ClCCl.O>[CH:1]1([CH:7]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(O)C2CCCCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1ccc(C#N)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Dissolve 4-(cyclohexyl-hydroxy-methyl)-benzonitrile (1 g, 4.66 mmol), and triethylamine (1.3 mL, 9.3 mmol) in dichloromethane (20 mL). Cool the mixture to 0° C., add methanesulfonyl chloride (1.49 mL, 5.34 mmol) and stir the solution for 2 h at 0° C. Add water (10 mL) and saturated aqueous NaHCO3 (10 mL). Separate the layers and extract back the aqueous phase with dichloromethane (3×20 mL). Combine the organic layers, wash with water (20 mL), dry over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as a yellow oil (1.29 g, 94%). MS (APCI) m/z: 294 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:28][CH2:29][OH:30])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)cc2c1cnn2C1CCCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OCCCO)cc2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
To a stirred solution of methyl 1-cyclopentyl-6-(4-hydroxyphenyl)-1H-indazole-4-carboxylate (0.5 g, 1.48 mmol) in DMF (15 mL), 3-bromopropane-1-ol (0.616 g, 4.46 mmol) and K2CO3 (0.306 g, 2.23 mmol) were added, resulting reaction mass was heated at 100° C. for 4 h. On completion, water was added to reaction mass and extracted with ethyl acetate. Combined organic layers were dried and concentrated under reduced pressure giving crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford methyl 1-cyclopentyl-6-(4-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxylate (0.4 g, 68.2%).
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].[NH2:13][C:14]([NH2:16])=[S:15].[Na+].[Cl-]>CN(C=O)C.CC#N>[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[S:15][C:14]([NH2:16])=[N:13][C@@H:12]12)=[O:6]
Reactant: NC(N)=S
Reactant: COC(=O)N1C=CC=CC1
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)N1CC=C[C@H]2SC(N)=N[C@H]21

Procedure:
A solution of Br2 (0.71 ml, 13.9 mmol, 1 equiv.) in DMF (5 ml) is added over 10 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (1.92 g, 13 mmol, 1 equiv.) and of thiourea (3.95 g, 52 mmol, 4 equiv.) in DMF (15 ml)/CH3CN (5 ml) at ambient temperature and under argon. The reaction being complete from the end of the addition of the bromine, the reaction mixture is concentrated approximately twofold, poured onto ice-cold water (200 ml) and then filtered through a Buchner funnel. The filtrate is basified (5% Na2CO3) until a pH of greater than 10 is obtained and is then saturated with NaCl. After extracting with DCM, drying over MgSO4 and evaporating the solvent, the liquid obtained (10.8 g) is chromatographed on silica gel using DCM (sat. NH3) and then DCM (sat. NH3)/MeOH, 2%. The product 6 (Rf=0.39, DCM/MeOH(NH3), 98:2) is obtained in the form of a white solid (0.32 g, 11%).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH3:8][C:9]1[C:14](/[CH:15]=[CH:16]/[N+:17]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=1[O:20][CH3:21].CO>C1COCC1>[CH3:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][NH2:17]
Reactant: COc1cccc(/C=C/[N+](=O)[O-])c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CCN)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To lithium borohydride (2M in THF; 2.0 ml; 4.0 mmol) (cloudy) at room temperature was added dropwise over 0.5 min chlorotrimethylsilane (1.02 ml; 8.00 mmol). A precipitate was formed and after ca. 3 min, 2-methyl-1-(methyloxy)-3-[(E)-2-nitroethenyl]benzene (Preparation 9, 193 mg; 1.0 mmol) in THF (4 ml) was added dropwise via syringe over 5 min, making sure that the temperature remained at ca. 25° C. (using a water cold bath). The solution was stirred at room temperature overnight. The mixture was cooled with an ice bath, methanol was added slowly, and the solvent removed in vacuo. The residue was partitioned between 25% aqueous sodium hydroxide and dichloromethane. The aqueous phase was separated and extracted three times with dichloromethane and the combined organic layers evaporated. Purification of the residue by solid phase extraction (SCX column), eluting with methanol followed by 2N ammonia in methanol, followed by evaporation of the ammonia containing fraction gave the title compound (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=O)[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[CH2:8][C:7]=2[CH:24]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[CH2:8][C:7]=2[CH:24]=1
Reactant: CCOC(=O)CC1C(=O)c2ccc(OC)cc2Cc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-methoxy-11-oxo-5H-dibenzo[a,d]cycloheptene-10-acetate (0.3 g., 0.93 mmol) and 10% Pd/C (0.3 g) in glacial acetic acid (25 mL) was hydrogenated at 50 psi for 18 hours. The mixture was filtered using celite® and washed with acetic acid. The filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 0.25 g of the title compound: 1H NMR (400 MHz, CDCl3) δ1.28 (t, 3H), 2.60 (m, 2H), 2.90 (m, 1H), 3.30 (m, 1H), 3.80 (s, 3H), 3.85 (d, 1H), 4.18 (q, 2H), 4.30 (d, 1H), 6.70 (m, 2H), 7.0 (d, 1 H), 7.22 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:24])([F:25])[F:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21

Procedure:
A mixture of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (27 mg, 0.07 mmol) and palladium on carbon (10 mg, 10 wt %; Aldrich) in methanol (1 mL) was subjected to 1 atmosphere of hydrogen for 50 min. The reaction was then filtered, concentrated, and the resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (25 mg, 91%). MS (ESI) 399.4 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([CH3:18])[C:13](=O)[NH:14]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:12]([CH3:18])=[N:11][C:10]2[C:15]([N:14]=1)=[CH:16][C:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[CH:8][CH:9]=2
Reactant: Cc1nc2ccc(Cn3ccnc3)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(Cn3ccnc3)cc2nc1Cl
Reaction time: 2 h
Yield: 59.4 %

Procedure:
A mixture of 6 parts of 7-(1H-imidazol-1-ylmethyl)-3-methyl-2(1H)-quinoxalinone and 40 parts of phosphoryl chloride was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated to dry. The residue was taken up in 300 parts of ice water and the whole was neutralized with potassium carbonate. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.6 parts (59.4%) of 3-chloro-6-(1H-imidazol-1-ylmethyl)-2-methylquinoxaline; mp. 115.8° C. (comp. 22).