Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H](OCC4C=CC=CC=4)C)[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.[C:51]([O:55]C(=O)N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1)(C)(C)[CH3:52]>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[CH2:52][CH2:51][OH:55])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCO)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
The title compound is prepared analogously to (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting {(R)-1-[9-[(1R,2S,3R,4S)-4-(3-tert-butoxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate ZG3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:34][CH3:35])[C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].[Br:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([C:45]2[N:46]=[CH:47][O:48][CH:49]=2)=[CH:39][C:38]=1[O:50][CH3:51]>>[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:34][CH3:35])[C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].[Br:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([C:45]2[N:46]=[C:47]([C:12](=[O:14])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[O:15][CH3:16])[O:48][CH:49]=2)=[CH:39][C:38]=1[O:50][CH3:51]
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Reactant: COC(C(=O)O)c1ccc(OC(C)C)cc1
Agent: COC(C(=O)N(C)OC)c1ccc(OC(C)C)cc1
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(OC(C)C)cc3)n2)cc(OC)c1Br

Procedure:
2-(4-Isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide was synthesized from 2-(4-isopropoxyphenyl)-2-methoxyacetic acid following the method used for the synthesis of Example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-(4-isopropoxyphenyl)-2-methoxyethanone was synthesized from 2-(4-isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used for the synthesis of Example 7. MS: m/z 490.1 [M+H]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:29])[C:25]([OH:28])([CH3:27])[CH3:26])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:29])[C:25]([CH3:27])([OH:28])[CH3:26])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(O)C(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.52 g), ammonium acetate (0.37 g) and acetic acid (4 mL) was stirred at 90° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.28 g, yield 56%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 531 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:22])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with piperazine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 630.3 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[CH:13][N:14]([CH3:16])C)[C:11]#[N:12].C([N:19](CC)CC)C.S(O)(O)(=O)=O.CNN>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:14]([CH3:16])[C:13]=1[NH2:19]
Reactant: CN(C)C=C(C#N)c1nc2ccccc2s1
Reactant: CCN(CC)CC
Agent: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc(-c2nc3ccccc3s2)c1N
Yield: 49 %

Procedure:
A mixture of the 2-benzothiazol-2-yl-3-dimethylaminoacrylonitrile prepared above (96 mg, 0.42 mmol) and triethylamine (0.3 mL) in EtOH (10 mL) was treated with methylhydrazine sulfate (180 mg, 1.25 mmol) and the mixture was heated to reflux for 2 days. The solution was concentrated in vacuo and the residue was purified by flash chromatography (hexanes:EtOAc=1:1) to yield 47 mg (49%) of the title compound as a yellow powder. MS (m/z, ES+): 231 (M+1, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:11][O:12][C:7]=2[C:6]=1[O:23][CH3:24].Cl[CH2:26][C:27]([OH:29])=[O:28]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:18]=3)=[CH:11][O:12][C:7]=2[C:6]=1[O:23][CH3:24]
Reactant: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1OC
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c(-c3ccc(OCC(=O)O)cc3)coc2c1OC

Procedure:
NaH is dissolved in dry dimethylformamide under nitrogen atmosphere at 0°. 7,8-Dimethoxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [cp. J. Inst. Chem. (Calcutta) 43, 234 (1971)], dissolved in dry dimethylformamide, is added slowly, then a solution of chloroacetic acid. The solution is heated at 70° for 5 h and evaporated under vacuum to about one third of its original volume. After cooling, water is added and a precipitate occurs which is filtered and crystallized in methanol to give 7,8-dimethoxy-3-(4-carboxymethoxyphenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: O=[Si]=O.C(O)C.[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si](OC)(OC)OC)(=[O:11])[C:8]([CH3:10])=[CH2:9]>O>[C:7]([O:12][CH2:13][CH2:14][CH3:15])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: O=[Si]=O
Solvent: CCO
Solvent: O
Product: C=C(C)C(=O)OCCC
Temperature: 50 °C
Reaction time: 20 h

Procedure:
100 g of Ludox TMA® [available from Helm AG; 34% nanosilica dispersion in water] is mixed with 100 ml of ethanol. To this mixture is added 11.7 g (25.6 mmol) of a photoinitiator [see reaction scheme] and 12.7 g (51 mmol) of 3-(trimethoxysilyl)propyl methacrylate at room temperature. The mixture is stirred at 50° C. for 20 hours. The amount of solvent is halved by evaporation in the rotary evaporator. By adding 150 ml of cyclohexane the product precipitates and is separated by centrifugation. After re-dispersing the product in butylacetate (BuOAc) a dispersion with 18.6 wt. % solid content is obtained. The ratio of photoinitiator to methacrylic groups is calculated based on analytical data to be 1 to 1.54. Thermographimetric analysis (TGA; heating rate: 10° C./min from 25° C. to 600° C.): Weight loss: 28.6%, corresponding to the organic material. Elemental analysis: found: C, 18.68%, H, 2.64%, O, 9.52%, S, 1.72: corresponding to an organic content of 32.6%. DLS: Average diameter d=54 nm.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:20]4[C:19](=[O:25])[NH:18][N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>CS(C)=O.C(OCC)(=O)C>[O:25]=[C:19]1[NH:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:28]3[CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27]3)=[O:26])=[CH:15][CH:14]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[C:20]12
Reactant: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)Oc1ccccc1
Reactant: c1ccc2c(c1)CNC2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)N1Cc2ccccc2C1
Temperature: 25 °C

Procedure:
40 mg [4-(1-Oxo-1,2-dihydro-pyrrolo[1,2-d][1,2,4]triazin-4-yl)-phenyl]-carbamic acid phenyl ester (0.115 mmol) were dissolved in 0.3 ml DMSO. A mixture of 15 mg isoindoline (0.121 mmol) in 0.2 ml DMSO was added at room temperature and the reaction was stirred at room temperature over night. The reaction mixture was diluted in ethyl acetate and washed with water, aqueous HCl, water, aqueous NaOH, and water. The solvent was evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[N:7][N:6]([CH3:10])[C:5](=[O:11])[C:4]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([C:4]2[C:5](=[O:11])[N:6]([CH3:10])[N:7]=[C:8]([CH3:9])[C:3]=2[O:2][CH3:1])[C:13]=1[CH3:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1c(C)nn(C)c(=O)c1-n1c(C)cc2ccccc21
Solvent: ClCCl
Product: COc1c(C)nn(C)c(=O)c1-n1c(C)c(Cl)c2ccccc21
Yield: 95.6 %

Procedure:
To a stirred solution of 5-methoxy-2,6-dimethyl-4-(2-methylindol-1-yl)pyridazin-3-one (147 mg, 0.52 mmol) in DCM (3 ml) at 0° C., was added dropwise a solution of sulfuryl chloride (70 mg, 0.52 mmol) in DCM (1 ml). Further DCM (1 ml) was added. After a reaction time of 1 h, the mixture was quenched by addition of sat. aqueous NaHCO3 (2 ml). The resulting mixture was filtered through solid MgSO4, washing with DCM. The filtration liquors were concentrated in vacuo to afford the title compound as a pale brown solid (158 mg, 96%). The material was used for subsequent reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CCCN1c1ccc(Br)cc1C=O
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (15 g, 73.8 mmol) in DMSO (150 mL) and water (40 mL) were added 2-methylpyrrolidine (9.8 mL, 96 mmol) and sodium carbonate (15.7 g, 148 mmol). The resulting mixture was heated at 110° C. for 8 hours. The reaction mixture was cooled at RT, diluted with water (1000 mL) and extracted with MTBE (2×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a yellow oil (17 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 9.94 (1H, s), 7.75 (1H, s), 7.51 (1H, d), 6.93 (1H, d), 3.92 (1H, m), 3.68 (1H, m), 2.97 (1H, t), 2.49-2.18 (1H, m), 1.88 (1H, m), 1.57-1.68 (2H, m), 1.10 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](Cl)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC

Procedure:
10.00 g (25.6 mmol) of 2-(4-Chloro-phenylsulfonylamino)4,5-dimethoxy-benzoyl chloride were mixed with 300 ml of toluene, 4.49 g (25.6 mmol) of 4-aminobenzenesulfonyl fluoride were added and the mixture was heated under reflux for 4 h. After cooling the precipitated solid was filtered off with suction and washed with toluene. 11.71 g (87%) of the title compound having a melting point of 216-219° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.C[O:34][B:35](OC)[O:36]C>C1COCC1>[C:16]1([C:12]2[C:11]3[C:6]([C:5]([C:4]4[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=4)=[C:22]4[C:23]=2[CH:24]=[C:25]([B:35]([OH:36])[OH:34])[CH:26]=[CH:27]4)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
In an argon atmosphere, 50 mL of dehydrated THF were added to 3.5 g (8.6 mmol) of 2-bromo-9,10-diphenylanthracene, and the temperature of the mixture was cooled to −78° C. Then, 6.0 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 2.9 mL (26 mmol) of trimethoxyborane were dropped. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 50 mL of 10-mass % hydrochloric were added, and the whole was stirred for 1 hour, followed by filtration. The resultant solid was washed with toluene to obtain 2.6 g of 9,10-diphenylanthracene-2-boronic acid (80% yield).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O.O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12 g (0.1 mole) of 4-tolualdehyde and 10.9 g (0.1 mole) of 2-aminophenol in toluene is heated at reflux with azeotropic removal of water. After 20 hours at reflux, the reaction is cooled to room temperature, 44.3 g (0.1 mole) of lead tetraacetate is added, and the mixture is stirred at room temperature overnight. The solids are removed by filtration, and the filtrate is swirled with basic alumina. Removal of the solvent in vacuo affords the solid product which is then purified by recrystallization from benzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>CC#N>[CH:27]([O:26][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([S:9][C:6]2[C:7]([CH3:8])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)[CH2:11][CH2:12]1)=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1c(Cl)ncnc1SC1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A mixture of 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine (HCl salt, 1.8985 g, 6.77 mmol) and triethylamine (2.825 mL, 0.02 mol) in 50 mL of CH3CN was stirred under room temperature. After 15 min, isopropyl chloroformate (1M in toluene, 8.13 mL, 8.13 mmol) were added slowly under 0° C. Mixture was stirred under room temperature. After 3 h, mixture was concentrated and residue was extracted with EtOAc and saturated NaHCO3. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester as yellowish oil (1.9143 g, 85%). Exact mass calculated for C14H20ClN3O2S 329.1, found 330.3 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(OC)c2)[nH]c1N

Procedure:
Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethan-1-one (2-bromo-3'-methoxy-acetophenone; Janssen) to form the title compound; m.p. 96-97oC; TLC-Rf =0.2 (hexane/ethyl acetate [2:1]).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26](OC(=S)C)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.OO.[S:48]([O-:51])([OH:50])=[O:49].[Na+]>C(O)(=O)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:24][CH2:25][CH:26]([S:48]([OH:51])(=[O:50])=[O:49])[CH2:27][CH2:28]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:45])([F:1])[F:44])[CH:8]=1
Reactant: O=S([O-])O
Reactant: CC(=S)OC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a suspension of 0.16 g (0.24 mmol) thioacetic acid 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl ester in 1 ml acetic acid were added 0.12 ml (1.2 mmol) of a 30% aqueous solution of hydrogen peroxide at room temperature. After heating to 60° C., a clear solution was obtained. Stirring was continued at this temperature for 20 h. After cooling to room temperature an aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Acidification with 1 N aqueous hydrochloride solution to pH 1 was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.13 g (83%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+].[ClH:30]>O.CO>[ClH:30].[CH2:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN)cc1
Reactant: CCCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCNCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 1 l. of methanol is added 10.0 g (0.0389 mole) of N-(2-aminoethyl)-4-[(methylsulfonyl)amino]benzamide. The suspension is refluxed for 1 hour, then cooled. To the suspension is added 4.66 g (0.0408 mole) heptaldehyde, the mixture is then stirred over ice for 30 minutes. To the chilled mixture is added 10.26 g (0.1632 mole) of sodium cyanoborohydride. The reaction is stirred at room temperature for 24 hours, conc. HCl is added to keep the pH at about 6.0. After about 24 hours the pH of of the reaction is adjusted to pH=1.0 and reduced to 1/3 volume. 100 ml of water is added and the solid is filtered. The resultant solid is suspended in 100 ml DMF, heated to 120° C. and filtered hot. The solution is cooled and the resultant solid is filtered and dried to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][NH2:15]>CO.[Pd]>[CH3:14][NH:15][CH2:5][C:4]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C=O)ccc2c1OCO2
Reactant: CN
Agent: [Pd]
Solvent: CO
Product: CNCc1ccc2c(c1OC)OCO2
Reaction time: 2 h
Yield: 100 %

Procedure:
5.0 g of 2-methoxy-3,4-methylenedioxybenzaldehyde was suspended in 30 ml of methanol, to which 4.31 g of 40% methylamine aqueous solution (2 equivalent) was added. 59 mg of 5% Pd/C catalyst (0.1 mol %) was added to the obtained reaction mixture and hydrogenation was carried out at ordinary temperature and atmospheric pressure. Absorption of hydrogen was completed in about 2 hours to quantitatively obtain N-methylbenzylamine derivative. The catalyst was filtered out and excessive methylamine, water formed and methanol solvent were distilled off to obtain an oily N-methyl-2-methoxy-3,4-methylenedioxybenzylamine. (Yield 100%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[C:19]([CH3:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[C:19]([CH3:25])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1c(N)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 57.5 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 3-amino-2-methylphenol (380 mg, 2.93 mmol), potassium carbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (454 mg, 58%) was obtained as a blackish brown powder.