Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20](Cl)=[N:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:15]1[C:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: Clc1nccnc1Cl
Reactant: CON(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON(C)C(=O)c1ccc(Oc2nccnc2Cl)cc1

Procedure:
A mixture of 4-hydroxy-N-methoxy-N-methylbenzamide (6.50 g, 35.9 mmol), 2,3-dichloropyrazine (6.95 g, 46.6 mmol), and potassium carbonate (12.40 g, 90 mmol) in acetonitrile (70 mL) was heated at reflux in 18 h. The reaction mixture was cooled, concentrated, taken up in H2O, extracted with EtOAc, dried over MgSO4, concentrated and purified by ISCO (50% EtOAc/Hexanes) to give the titled compound. MS [M+1]: 294.1.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]5[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[I-:40].[Na+].CN(C)[C@@H]1CCCC[C@H]1N(C)C>O1CCOCC1.[Cu](I)I>[Si:30]([O:29][CH2:28][C@H:27]1[O:26][C:25]([CH3:37])([CH3:38])[O:24][C@@H:23]1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:39])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([I:40])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32]
Reactant: [I-]
Reactant: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: I[Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N(C)C
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(I)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 110 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
Under nitrogen atmosphere, 3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T22-1, 300 mg, 0.47 mmol), sodium iodide (147 mg, 0.94 mmol) and copper iodide (9.40 mg, 0.047 mmol) were dissolved in dioxane (1.00 ml), added with (1R,2R)—N,N,N′,N′-tetramethyl-cyclohexane-1,2-diamine (15.4 μl, 0.094 mmol), and then stirred at 110° C. for 16 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (220 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[C:11]3[S:10][C:9]([NH:8][CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:13][C:12]3=[O:14])[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16]
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4sccc4C)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 56.5 mg (80.4%), MS: m/e 440 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)Cl>C(#N)C>[C:1]([NH:4][C:5]1[N:14]=[C:13]([C:21]2[N:20]=[CH:19][NH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(Br)ccc2n1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a mixture of 2-acetamido-6-bromo-4-hydroxy-quinazoline (2.82 g, 10 mmol) and 1,2,4-triazole (6.9 g, 100 mmol) in acetonitrile (100 ml) was added diisopropylethylamine (3.5 ml, 30 mmol) and POCl3 (2.8 ml, 30 mmol). The mixture was stirred at room temperature for 12 hours. The precipitate was collected, washed with ethanol, diethylether, and dried over P2O5 in a vacuum dessicator to yield the title compound as yellow solid (3.3 g). The crude product was used in the following reaction without further purification and was characterized by its mass spectrum as follows: MS (m/z): 333 ([M+H]+, 100).
Reaction SMILES: Br[CH:2]=[CH:3]Br.[O:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[C@:24]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:33])[CH2:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[C@@:24]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:2][CH2:3][NH:14][CH2:13][CH2:12][CH2:11][N:8]4[CH2:9][CH2:10][O:5][CH2:6][CH2:7]4)[C:25]3=[O:33])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: BrC=CBr
Reactant: NCCCN1CCOCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C1N(CCNCCCN2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 81 starting from dibromo ethylene, 3-morpholinopropan-1-amine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C25H30ClN3O2: 439, observed (M+H)+: 440.1 1HNMR (400 MHz, MeOD-d4) δppm 2.07-2.32 (m, 6 H) 3.26 (s, 8 H) 3.47 (t, J=5.94 Hz, 3 H) 4.24 (d, J=28.55 Hz, 3 H) 6.12 (d, J=7.07 Hz, 1 H) 6.81 (t, J=7.07 Hz, 1 H) 7.14 (d, J=7.58 Hz, 1 H) 7.19-7.29 (m, 3H) 7.30-7.39 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[CH3:13][C:14](O)([CH3:16])[CH3:15].OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:14]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)([CH3:16])([CH3:15])[CH3:13]
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnnc1-c1ccccc1Br
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 5-(2-bromophenyl)-1H-tetrazole (7.9 g, 0.035 mol) in trifluoroacetic acid (35 mL) was added tBuOH (5.2 g, 0.070 mol) and H2SO4 (1.0 mL, 0.0175 mol). After 18 h, the solution was concentrated and the residue was taken up in EtOAc. The mixture was washed with water, 2.5N NaOH, water, dried (MgSO4), and concentrated. Purification by flash chromatography (20% EtOAc/hexane) gave 6.6 g (67%) of product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 52.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.073 mL (0.78 mMol) propyl isocyanate, 0.107 gm (52%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=O.[OH-].[Na+]>C(O)=O>[CH3:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 18 grams of commercially available 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine, 18 grams of an aqueous solution containing 37% of formaldehyde and 4 milliliters of formic acid containing 1% water is placed in a 100-ml., round-bottomed flask and heated on a steam bath for 7 hours. The contents are cooled, made basic with sodium hydroxide and extracted with ether. The ether extract is dried using anhydrous magnesium sulfate and the ether evaporated. The residue, a white solid, is purified by sublimation at 90°C. at 0.05 torr. The purified 1, 2, 2, 6, 6-pentamethyl-4-hydroxypiperidine has a melting point of 70°-71°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([C:8]1[N:9]=[C:10]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:11][CH:12]=1)=[N:6][OH:7])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].O.C(O[CH2:45][CH3:46])(=O)C>CN(C)C=O.C(I)(C)C>[C:14]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:5](=[N:6][O:7][CH:45]([CH3:46])[CH3:34])[C:4]([O:3][CH2:1][CH3:2])=[O:33])[N:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CC(C)I
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl-2-(2-tritylamino-4-thiazolyl)-2hydroxyiminoacetate of Example 14, 3.51 g of potassium carbonate in 15 ml of dimethylformamide and 7.7 ml of isopropyl iodide was held under an argon atmosphere and stirring for 41/2 hours and then 250 ml of distilled water and 150 ml of ethyl acetate were added there with stirring. The mixture was decanted and the aqueous phase was washed with water and was extracted with ethyl acetate. The organic phase was dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallization started after seeding. The mixture was vacuum filtered and the precipitate was rinsed with ethanol and empasted with petroleum ether to obtain 3.26 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate melting at 182° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[C:24]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=2[S:22](=[O:31])(=[O:30])[N:21]=1.[K+].[Br-]>C(Cl)(Cl)Cl>[ClH:19].[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=3[S:22](=[O:30])(=[O:31])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)N=C(Cl)c2cc(F)ccc21
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=S1(=O)N=C(NCCCOc2cccc(CN3CCCCC3)c2)c2cc(F)ccc21
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (0.870 g, 3.503 mmoles) in dried chloroform (35 ml) under dry nitrogen is added over 45 minutes a solution of 3-chloro-5-fluoro-1,2-benzisothiazole 1,1-dioxide (0.808 g, 3.679 mmoles) in dried chloroform (20 ml) while maintaining reflux. After the addition is complete refluxing is continued for 15 minutes and the solution allowed to come to room temperature. Evaporation in vacuo gives an orange solid. Recrystallization from isopropanol gives a light tan solid. m.p. 224°-226° after softening from 200° C. IR (KBr) 2950, 1600, 1302, 1171 cm-1 ; NMR (in DMSO) 1.76 (6H,s), 2.2 (2H,t), 2.8 (2H,m), 3.3 (3H,m), 3.6 (2H,t), 4.2 (3Hm,), 7.0-8.5 (7H,m), 10.1 (1h,s), 10.6 (1H,m).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:20]3[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=3)[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cccc(C)c42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([F:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=[O:42])C=2C(F)=CN=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=O)C=2C(Br)=CN=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[OH:42][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([F:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(F)c23)C1
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)ncc(F)c12
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)ncc(Br)c12
Product: CNC1CCN(S(=O)(=O)c2cccc3c(O)ncc(F)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1-chloro-4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 27) can be prepared by using 1-chloro-4-fluoro-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 35-1, Step A instead of 1-chloro-4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 35-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]I.C([O:7][C:8]1[C:9](/C(/CC)=C(/F)\C=C\C(\C)=C\C(OCC)=O)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)C.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH3:1]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
N-Propyl iodide (4.9 mL, 50 mmol) was added to a stirring suspension of 6-hydroxy-1,2,3,4-tetrahydronaphthalene (Intermediate 1, 2.07 g, 10 mmol), potassium carbonate (6.9 g, 50 mmol), in acetone (50 mL), and the mixture was stirred at reflux for 14 h. The solution was poured into a separatory funnel, water was added, and the products were extracted three times with hexane. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O-].[Na+].Cl.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]=1>COCCO.COC(O)C.C1COCC1>[CH2:20]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]=[C:10]2[CH2:9][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc2c(c1)C(CCl)=NCC2
Reactant: COCC[O-]
Agent: COC(C)O
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(CCCOC)=NCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Under cooling in an ice bath, a mixture of sodium hydride (suspension of 8 g of sodium hydride in mineral oil (60%) washed with hexane) in THF (10 mL) was added to methoxyethanol (100 mL) under stirring over 20 minutes to produce sodium 2-methoxyethoxide, followed by further stirring for 2 hours. A solution of sodium 2-methoxyethoxide in 2-methoxyethanol (55 mL) was added with stirring to a solution of 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g) in methoxyethanol (50 mL) under cooling in an ice bath, for 5 minutes. The reaction mixture was heated at 60° C., followed by stirring for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and diluted with THF (150 mL), followed by filtration. The filtrate was concentrated under reduced pressure. To the resulting residue was added a saturated aqueous ammonium chloride solution and the residue was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain 7-ethyl-1-[(2-methoxyethyl)methyl]-3,4-dihydroisoquinoline (2.13 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].O1CCOCC1.[I-:33].[Na+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([I:33])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Oc2cncc(Br)c2)SC[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(I)c1
Temperature: 130 °C
Yield: 85 %

Procedure:
1.34 g (3 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-α-D-xylo-pyranoside, 10 ml of dioxane, 0.057 g (0.3 mM) of copper(I) iodide, 0.899 g (6 mM) of sodium iodide and 0.085 g (0.6 mM) of (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine are mixed under an argon atmosphere in a reactor adapted for microwaves and the mixture is heated for 3 h 30 min at 130° C. 100 ml of water are added to the cooled reaction mixture and extraction is then carried out with ethyl acetate. The organic phase is washed with 1 N sodium thiosulfate solution and with water, dried over sodium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (1/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 85%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C.CCOC(C)=O>[CH:22]1([CH2:21][N:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([OH:1])[C:3]2=[O:13])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cc[nH]c(=O)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CC2CC2)c(=O)c1O
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a solution of Intermediate 1B (250 mg, 1.370 mmol) in DMF (2 mL) was added cesium carbonate (1.12 g, 3.41 mmol) and (bromomethyl)cyclopropane (553 mg, 4.09 mmol). The reaction was heated at 80° C. for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in a small amount of DCM and charged to a 24 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 11 (82 mg, 0.350 mmol, 25.3% yield) as an oil. HPLC/MS (Method D) RT=1.64 min, [M+1]+ 238.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (1H, d, J=7.28 Hz), 6.30 (1H, d, J=7.03 Hz), 4.21 (2H, q, J=7.03 Hz), 3.65-3.66 (2H, m), 1.29 (1H, m), 1.19 (3H, t, J=7.04 Hz), 0.78 (2H, m), 0.61 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:28])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(C1C=CC(C)=CC=1)(O[C:33]#[C:34][CH3:35])(=O)=O.C[O-].[Na+].[Cl-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:28])[C:10]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:35][C:34]#[CH:33])=[C:21]([O:26][CH3:27])[CH:20]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC#COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
A solution of 0.6 g (1.4 mmol) of 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(4-hydroxy-3-methoxy-phenyl)-cyclohexyl]-acetamide and 0.4 g (1.9 mmol) of propynyl tosylate and 2.7 ml of 1 M solution of sodium methoxide in 10 ml methanol is heated to reflux for 3 hours. The reaction mixture is cooled and poured into 30 ml of aqueous saturated sodium chloride solution and finally extracted with two 100 ml portions of ethyl acetate. The combined organic extract is concentrated under reduced pressure to a residue, which is subjected to column chromatography on silica gel, with 1:1 ethyl acetate/isohexane as the eluant to obtain 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-cyclohexyl]-acetamide.
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O)([F:4])[F:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[N:17][OH:18])([F:4])[F:3]
Reactant: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Trifluoromethyl(3,4-methylenedioxyphenyl) methanone (1.46 g, 0.0067 mole), hydroxylamine hydrochloride (1.06 g), 0.015 mole) and sodium acetate (0.86 g, 0.010 mole) were dissolved in a mixture of methanol (4 ml) and water (4 ml) and heated to reflux for 4.5 hours. After cooling to room temperature, water (10 ml) was added and the mixture extracted with ether (3×15 ml). The combined extracts were washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the solvent in vacuo the residue was recrystallized from a mixture of dichloromethane and petroleum spirit (40°-60° C.) to give trifluoromethyl(3,4-methylenedioxyphenyl)methanone-oxime (1.2 g), (76.9%) m.p. 96.0° C.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[CH:10]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([S:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6]
Reactant: O=C(Cl)CCC(F)(F)Cl
Reactant: SC1CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC(F)(F)Cl)SC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
4.0 g of 4-chloro-4,4-difluorobutyryl chloride are added dropwise over the course of 30 minutes to a solution of 2.6 g of cyclohexyl mercaptan and 4.5 g of pyridine in 50 ml of toluene at 0° C. The reaction mixture is stirred at RT for 16 hours and then diluted with 150 ml of diethyl ether and subsequently washed with 50 ml each of 1N HCl, saturated NaHCO3 and saturated NaCl solution. The organic phase is then dried over MgSO4, filtered and evaporated. The resulting crude product is distilled at +90° C./5 mbar. 3.8 g of S-cyclohexyl 4-chloro-4,4-difluorothiobutyrate are obtained as an oil, nD23 : 1.4748.