Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH2:26][CH3:27])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[O:6]1)=[O:4].[I:28]Cl.C(=O)(O)[O-].[Na+].COC([C@H]1[C@H](C(OC)=O)OCO1)=O>ClCCl>[CH3:13][O:12][C:10]([C@H:9]1[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[O:6][C:7]([CH:26]([I:28])[CH3:27])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[O:8]1)=[O:11]
Reactant: ClI
Reactant: CCC1(c2ccc3cc(OC)ccc3c2)O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Agent: COC(=O)[C@@H]1OCO[C@H]1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1OC(c2ccc3cc(OC)ccc3c2)(C(C)I)O[C@H]1C(=O)OC

Procedure:
A solution of 2 -ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (0.935 g, 2.5 mmol) and of iodine monochloride (0.81 g, 5 mmol) in dichloromethane (5 ml) is kept under nitrogen and at 15° C. for 24 hours. The reaction mixture is poured into a 10% aqueous solution of sodium bicarbonate, and extracted with additional dichloromethane. The combined organic extracts are washed with a 5% aqueous solution of sodium thiosulphate, with water, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (silical gel, eluent hexane:diethyl ether=7:3) gives the diastereoisomeric mixture of 2-(1-iodoethyl)-1-iodoethyl)-2-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 15 and 16 in ratio 15:16=60:40 (determined by 1H-NMR).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl>>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1[N:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc2ccccc2n1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Product: O=S(=O)(c1ccc2ccccc2n1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 15.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 2-(piperidin-4-ylsulfonyl)quinoline (150 mg, 0.51 mmol) was reacted with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title compound (34 mg), an off-white solid, in 16% yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]1[C@H:18]3[CH2:19][C@H:15]([CH2:16][CH2:17]3)[C@@H:14]1[CH2:20][N:21]([CH3:23])[CH3:22])[CH:7]=[CH:6]2.O>CN(C=O)C>[CH3:23][N:21]([CH2:20][C@H:14]1[C@@H:15]2[CH2:19][C@@H:18]([CH2:17][CH2:16]2)[C@@H:13]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2)[CH3:22]
Reactant: COc1ccc2cc([C@H]3[C@@H]4CC[C@@H](C4)[C@@H]3CN(C)C)ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C[C@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2cc(O)ccc2c1

Procedure:
To a stirred solution of [(1S,2S,3S,4R)-3-(6-methoxy-2-naphthyl)bicyclo [2.2.1]hept-2-yl]-N, N-dimethyl methanamine in DMF was added sodium ethane thionyl. The mixture was heated to 100 C for 40 hours. When cool, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated in-vacuo. Purification was achieved by column chromatography, using flask silica and DCMM/eOH(M/eOH,NH40H at 10%) in a ration of 10/1/0.1 for eluant. Yield (10%). ME 296 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17])C>>[F:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)cc1F
Yield: 83 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-[3-fluoro-4-hydroxy-phenyl]-cyclopropane carboxylic acid ethyl ester (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.060 g, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[S:19][CH:20]=[CH:21][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[N:11]1([C:14]2[C:18]3[S:19][CH:20]=[CH:21][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccsc23)CC1
Agent: Cl
Product: c1cc2onc(N3CCNCC3)c2s1
Yield: 97.3 %

Procedure:
4-Thieno[2,3-d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 16.2 mmol) was stirred at room temperature in a solution of HCl (25 mL, 4N HCl in dioxane) for 4 hours. The volatiles were removed in vacuo and the residue was triturated with ether (twice) to yield off white solids 3.3 g (84%) as the desired hydrochloride salt.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH:7]=[C:8](SC)[S:9]([CH3:11])=O)([O-:6])=[O:5].Br.[Br:15][CH2:16][CH2:17][NH2:18]>CO>[N+:4]([CH:7]=[C:8]([S:9][CH3:11])[NH:18][CH2:17][CH2:16][Br:15])([O-:6])=[O:5]
Reactant: NCCBr
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCBr
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
(b)(i) A solution of sodium methoxide (sodium (0.3 g, 0.013 mol) in methanol (10 ml)) was added dropwise, over a period of 10 minutes to a stirred mixture of 1-nitro-2-methylthio-2-methylsulphinylethylene (2 g, 0.011 mol) and 2-bromoethylamine hydrobromide (2.7 g, 0.013 mol) in methanol (25 ml), cooled to 0°. The solution was stirred at 0° for a further 15 minutes, and then it was allowed to attain room temperature. After 1 hour, the solvent was removed in vacuo, and the semi-solid residue was extracted with hot chloroform (2×25 ml). The extracts were combined and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2-bromo-ethylamino)ethylene (1.85 g, 71%) m.p. 123°14 126°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH3:20][Mg]Br>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([OH:16])[CH3:20]
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone (0.67 g, 2.5 mmol) in anhydrous THF (10 mL) at −78° C. was added a solution of methylmagnesium bromide (3.0 M in diethyl ether, 2.5 mL, 7.5 mmol) under nitrogen. The reaction mixture was slowly warmed to rt, stirred under nitrogen for 12 hours, and quenched with a saturated aqueous ammonium chloride solution (40 mL). Ethyl acetate (50 mL) was added, the organic layer was separated, and dried (MgSO4). After removal of the solvent, the residue was purified via silica gel chromatography (hexane:ethyl acetate/7:1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol as yellow oil: MS (EI) m/z 287/289 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9][C:10]=2[C:11]=1[F:12].[CH:23]#[C:24][CH:25](O)[CH2:26][CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:24]([CH:25]([O:22][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:12])[C:2]=1[F:1])[CH2:9][CH:8]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)[CH2:26][CH2:27][CH3:28])#[CH:23]
Reactant: CCCC1CCC(C2CCc3cc(O)c(F)c(F)c3C2)CC1
Reactant: C#CC(O)CCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CCC)Oc1cc2c(c(F)c1F)CC(C1CCC(CCC)CC1)CC2
Reaction time: 19 h

Procedure:
7.0 g (22.7 mmol) of 3,4-difluoro-6-(4-propylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol are initially introduced in 90 ml of THF together with 2.70 ml (24.0 mmol) of 1-hexyn-3-ol and 6.60 g (25.2 mmol) of triphenylphosphine. 5.3 ml (46.8 mmol) of DIAD in 10 ml of THF are added over the course of 20 min with ice-cooling. After 19 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane MTBE=2:1), giving 6-(1-ethynylbutoxy)-7,8-difluoro-2-(4-propylcyclohexyl)-1,2,3,4-tetrahydronaphthalene as a colourless solid.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([NH:18][C:19]([C:21]1[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])[CH:12]=2)=[O:7])C>C(O)C.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([C:19]([NH:18][C:13]3[CH:12]=[C:11]4[C:16]([CH:17]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]4)=[CH:15][CH:14]=3)=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(C)(C)C)cc3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccccc2C(=O)Nc2ccc3cc(C(=O)O)cnc3c2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Lithium hydroxide (20.0 mg, 0.48 mmol) was added to a mixture of 7-[(4′-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (99 mg, 0.22 mmol) in 6 ml ethanol and 3 ml water. The reaction mixture was heated under reflux for 1.5 hr, then cooled to room temperature. The ethanol was removed in vacuo and aqueous hydrochloric acid solution was added (0.46 ml of 0.961 M solution, 0.44 mmol) to the resulting aqueous solution. The precipitate that formed was filtered, washed with water and air dried to yield the title compound as a white solid (75.1 mg, 80.8% yield).
Reaction SMILES: Cl.[C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)([OH:4])=[O:3].Cl.[C:29]([C@H]1C[C@H](NC(C2C=CC=C(CN)C=2)=O)C2C(=CC(Cl)=CC=2Cl)N1)(O)=O>CS(C)=O>[ClH:26].[CH3:29][O:3][C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)=[O:4]
Reactant: NCc1ccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)cc1
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(CN)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given for Example 82 using trans-2-carboxy-5,7-dichloro-4(4-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride, Example 83, in place of trans-2-carboxy-5,7-dichloro-4(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride to give the title compound as a colourless crystalline solid m.p. 238°-240° C. δ (DMSO, 360 MHz), 1.80 (1H, ddd, J=13.0, 12.5 and 4.1 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.71 (3H, s, CH3), 4.07 (3H, m, CHACHBHCCHD and CH2NH2), 5.26 (1H, m, CHACHBHCCHD), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.95 (1H, s, NH), 7.53 (2H, d, J=8.2 Hz, Ar-H), 7.91 (2H, d, J=8.2 Hz, Ar-H), 8.38 (2H, br s, NH2), 8.73 (1H, d, J=7.2 Hz, NHCO); m/e (CI+ , NH3), 408 (M+1), 15 (100%; Found C, 48.87; H, 4.37; N, 8.95; C19H19Cl2N3O3.1.6 HCl requires C, 48.91; H, 4.45; N, 9.10%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[OH-].[Na+]>O1CCOCC1.CO>[OH:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 68.3 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-hydroxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (35 mg, 0.060 mmol) in dioxane (1 mL) was added NaOH (1N) (0.298 mL, 0.298 mmol). The mixture was heated to 85° C. for 15 h then was cooled to rt. The mixture was diluted with MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound (25 mg, 0.041 mmol, 69.5% yield) as a white solid. LCMS: m/e 574.5 (M+H)+, 1.69 min (method 2). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 5.37 (1H, d, J=4.6 Hz), 4.86 (1H, s), 4.75 (1H, s), 3.95-4.11 (2H, m), 3.25-3.43 (2H, m), 2.90-2.98 (1H, m), 1.77 (3H, s), 1.21 (3H, s), 1.14 (3H, s), 1.09 (3H, s), 1.02 (3H, s), 1.00 (3H, s), 0.97-2.32 (22H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[C:12]([Cl:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(Cl)Cl.O=[Mn]=O>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1 g of 1-(4-nitrobenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole and 5 g of activated MnO2 in CH2Cl2 was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a thick oil which was purified by flash column chromatography on silica gel (Hexane:ethyl acetate-1.5:1 elution). The desired compound was obtained as a colorless solid, 0.76 g; m.p. 88°-89°; NMR (200 MHz, CDCl3): δ 9.74 (2, 1h); 5.64 (s, 2H); 2.63 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Br-:1].O=[S:3]1(=O)[CH:8]([CH3:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.C([O-])(=O)C.[Na+].II>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[CH:13][C:5]2[O:4][S:3][CH:8]([CH3:9])[CH2:7][C:6]=2[CH:10]=1
Reactant: CC1Cc2ccccc2OS1(=O)=O
Reactant: [Br-]
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2cc(Br)ccc2OS1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
6.7 g of bromide are added dropwise to a mixture of 7.92 g of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiine, 6.5 g of sodium acetate, 0.1 g of iodine and 60 ml of glacial acetic acid, which is then stirred for 24 hours at a temperature of 40° C. The mixture is concentrated and taken up with a mixture of water and ethyl acetate. The organic phase is separated, twice washed with an aqueous solution of sodium hydrogen-carbonate, dried and evaporated. The oily residue is introduced into the following reaction step without further purification operations.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1ccc(C2C=Cc3cc(Br)cnc3O2)cc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccc(C2=CCc3cc(Br)cnc3O2)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2.9 g of 6-bromo-2-(3,4-dichlorophenyl)-2H-pyrano[2,3-b]pyridine in 40 ml of tetrahydrofuran was added 0.5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 1 hour at 25° C., the reaction mixture was partitioned between ethyl acetate and aqueous saturated ammonium chloride solution. The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated to leave a solid residue. This was recrystallized from ethanol to give 6-bromo-2-(3,4-dichlorophenyl)-4H-pyrano[2,3-b]pyridine melting at about 138°-139.5° C.
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:19])C(C)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[CH2:28](Cl)[CH3:29]>C(O)C>[NH2:1][C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:19][CH2:28][CH3:29]
Reactant: CCCl
Reactant: CC(=O)Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc2cc(S(=O)(=O)O)ccc2c1N
Temperature: 120 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
98.1 g of 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid (71.7% pure=50.4 g of 100% pure=0.25 mol), prepared according to Example 4, are introduced into a 1.3 l autoclave. 34.6 g (0.25 mol) of potassium carbonate suspended in 500 ml of ethanol are added thereto. After heating the mixture to 120° C., 115 ml of 2 N potassium hydroxide solution and 54 ml (74 g=0.75 mol) of ethyl chloride are simultaneously pumped in. The reaction mixture is allowed to cool somewhat, the salt residue is filtered off and, after adding 100 g of water, 460 g of ethanol (water-containing) are distilled off from the filtrate. 50 ml of 50% strength sodium hydroxide solution are added dropwise to the mixture at a temperature of 98° C. After 2 hours, the reaction mixture is cooled to room temperature and the product which has precipitated is filtered off and washed with 100 ml of saturated sodium chloride solution. After filtering off and drying, 76.1 g of 1-amino-2-ethoxy-naphthalene-6-sulphonic acid (78.3% pure=60.0 g of 100% pure=90% of theory, relative to 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid, or 69.4% of theory, relative to 2-hydroxy-naphthalene-6-sulphonic acid) are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH2:19][OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:30][C:31]([O:20][CH2:19][C@H:10]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC[C@@H](COCc1ccccc1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)OC[C@@H](COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200 %

Procedure:
A mixture consisting of 0.50 ml (1.98 mmol) of (S)-(−)-1,2-dibenzylglycerol and 0.69 ml (3.96 mmol) of N,N-diisopropylethylamine was dissolved in 5 ml of dichloromethane. The obtained solution was added dropwise to 5 ml of a dichloromethane solution containing 294 mg (0.99 mmol) of triphosgene under cooling on ice. The obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was concentrated, and the concentrate was then dissolved in 5 ml of dichloromethane, so as to obtain a dichloromethane solution of (R)-2,3-bis-benzyloxy-propyl chloroformate (1.98 mmol/5 ml).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: Cc1cc2c(C)noc2cc1-c1cnc(N)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(C)noc2cc1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 5-(3,5-dimethylbenz[d]isoxazol-6-yl)pyrazine-2-ylamine (109) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.09 mmol) followed by addition of DIEA (47 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (90 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7.3 mg (yield: 63.8%, purity>95%) (2,6-difluorophenyl)-N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)pyrazin-2-yl]carboxamide (110) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2c[nH]nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(380 mg, 0.573 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 200 mg of (±)-5-bromo-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (81%). The crude amine (200 mg, 0.463 mmol) in dichloromethane (4 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (202 mg, 0.925 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (1%→30% EtOAc/Hex) to give 200 mg (81%) as clear oil. LC/MS (HPLC method 3): tR=4.046 min, 532.27(MH)+.