Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1.[F:17][S:18]([F:29])([F:28])([F:27])([F:26])[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH3:15][S:12]([C:11]1[C:2]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18]([F:29])([F:17])([F:26])([F:27])[F:28])[CH:20]=2)=[CH:3][C:4]([CH3:16])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13]
Reactant: Oc1cccc(S(F)(F)(F)(F)F)c1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Yield: 27.6 %

Procedure:
600 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate, 700 mg of 3-pentafluorosulfanylphenol and 1.6 g of Cs2CO3 were stirred in 4 ml of anhydrous DMF at 100° C. for 3 h. The mixture was then cooled to RT, diluted with 100 ml of EA and washed 3 times with 20 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 300 mg of a colorless oil were obtained.
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C@H:22]3[C@H:27]([O:28]CC4C=CC=CC=4)[C@@H:26]([O:36]CC4C=CC=CC=4)[C@H:25]([O:44]CC4C=CC=CC=4)[C:24]([CH2:52][O:53]CC4C=CC=CC=4)=[CH:23]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1.CC1C(C)=C(C)C(C)=C(C)C=1.CO>C(Cl)Cl>[CH:5]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C@H:22]3[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C:24]([CH2:52][OH:53])=[CH:23]3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1
Reactant: C1=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1Oc1ccccc1Cc1ccc(C2CC2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: OCC1=C[C@@H](Oc2ccccc2Cc2ccc(C3CC3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
In a nitrogen stream, a boron trichloride 1.0 M methylene chloride solution (160 μL, 0.16 mmol) was added to a solution of 1-(4-cyclopropylphenyl)methyl-2-[(1R,4R,5S,6S)-4,5,6-tris-benzyloxy-3-(benzyloxymethyl)-cyclohex-2-enyloxy]benzene (12 mg, 0.016 mmol) and pentamethylbenzene (24 mg, 0.17 mmol) in methylene chloride (300 μL) at −78° C., and the mixture was stirred at the same temperature for 1.5 hours. After addition of methanol, the temperature of the resulting solution was raised to room temperature and the solvent was distilled under reduced pressure. The obtained residue was purified by preparative TLC [developing solution=methanol:methylene chloride (1:8)] to obtain the title compound (4.1 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C@H:12]([NH:18][S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[N:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][NH:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]1([S:19]([NH:18][C@@H:12]([CH2:11][N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:39]=[CH:40][C:41]4[CH2:42][CH2:43][CH2:44][NH:45][C:46]=4[N:47]=3)[CH2:34][CH2:33]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:21])=[O:20])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Reactant: CCOC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3.21 g of ethyl (2S)-3-(6-chloropurin-9-yl)-2-(naphthalene-1-sulfonylamino)propionate (Example 2) in 20 ml of abs. DMF were treated with 4.0 g of 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine and 3.88 g of diisopropylethylamine, and the mixture was stirred at 70° C. for 3 h. The solvent was distilled off in vacuo, the residue was taken up in EA and the mixture was extracted three times with water. The aqueous phases were extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (DCM/CH3OH/CH3COOH/H2O 95:5:0.5:0.5). Yield: 3.29 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([OH:26])=[N:18][CH:17]=1>>[OH:14][C@H:3]1[C@H:4]([O:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=[CH:17][N:18]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: Oc1ncnc2ccccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2ncnc3ccccc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and quinazolin-4-ol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[NH:22][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Temperature: 120 °C

Procedure:
A mixture of N2-benzyl-N2-methyl-4-(4-morpholinylmethyl)-1,2-benzenediamine (3.1 g, 10 mmol) and diethyl ethoxymethylenemalonate (4.2 g, 20 mmol) is heated at 120° C. until HPLC shows that the reaction is complete (20 min). The product is applied in 10% ethyl acetate/hexane to a silica gel column which is eluted with 20% ethyl acetate/hexane to remove excess diethyl ethoxymethylenemalonate and then with 50% ethyl acetate/hexane to elute 3.7 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>S(Cl)(Cl)=O>[NH:17]1[C:16]([NH:15][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=2)=[O:14])=[N:20][N:19]=[N:18]1
Reactant: CCCCOc1cccc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CCCCOc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 61 %

Procedure:
0.94 g of 6-n-butoxy-2-pyridinecarboxylic acid, 10 ml of thionyl chloride and 0.48 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.77 g of N-(5-tetrazolyl)-6-n-butoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.2 g, 0.72 mmol) in dry DCM (20 mL) were added (aminooxy)cyclohexane 21 (0.1 g, 0.86 mmol, US 2008/146625 A1), 1-hydroxybenzotriazole (0.14 g, 1.1 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.2 g, 1.1 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-N-(cyclohexyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 22 (0.24 g, 89.5%) as a clear thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 11, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:54]=[N+:55]=[N-:56].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][N:54]=[N+:55]=[N-:56])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:30]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18][C:19]=2[NH:27][O:28][CH3:29])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:10])[CH3:9]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCO)n2COCP(=O)(OC(C)C)OC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN=[N+]=[N-])n2COCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 36 (1.00 g, 1.48 mmol) in pyridine (20 mL) is treated with methanesulphonyl chloride (539 mg, 97%, 3.00 mmol) and the mixture is stirred for 20 h at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL), washed with water (2×) and brine and the organic layer dried over MgSO4 followed by filtration and concentration. The residue containing 37 is dissolved in DMF (9 mL), treated with sodium azide (260 mg, 3.96 mmol) and the mixture stirred for 4 h at 100° C. The reaction mixture is diluted with ethyl acetate (300 mL), washed with water (2×) and brine and the organic layer dried over MgSO4. After filtration, the filtrate is concentrated and the residue was purified on a silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent to give 458 mg (44%, two steps) of product as a colorless film: 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.89 (s, 1H), 7.40-7.18 (m, 13H), 6.79 (d, J=8.8 Hz, 2H), 4.87-4.76 (m, 1H), 4.73-4.60 (m, 2H), 4.19-3.68 (m, 4H), 3.77 (s, 3H), 3.41-3.32 (m, 1H), 3.22-3.10 (m, 1H), 2.47-2.32 (m, 1H), 2.24-2.12 (m, 1H), 1.29 (d, J=6.0 Hz, 6H), 1.24 (d, J=6.7 Hz, 6H). IR (neat, cm−1) 3017, 2103, 1605 and 1216. HRMS Calcd for C36H43N8O5P (M+H)+ 699.3172. Found: 699.3152.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)[CH3:11].C(OC(ON=C(C#N)C(N)=O)=O)C.O>O1CCCC1>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccccc1

Procedure:
To a solution of benzoic acid (1.22 g) and triethylamine (2.8 ml) in dry tetrahydrofuran (20 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.85 g) is added at room temperature while stirring, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is admixed with water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate, 1 N hydrochloric acid and water in order, dried and concentrated to give ethyl benzoate (1.3 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:33])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:24]=2)=[CH:16][CH:15]=1>>[CH3:33][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH3:32]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: CC(=O)c1ccccc1-c1ccc(-c2nc(CCN3CCC[C@H]3C)c(C)o2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-acetylphenyl boronic acid (235 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 94 mg (85%). MS (m/e) 389.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(N2CCN(c3ccccn3)CC2)nn1
Yield: 45.3 %

Procedure:
A mixture of 3.3 parts of 3,6-dichloropyridazine, 3.3 parts of 1-(2-pyridinyl)piperazine, 1.5 parts of sodium hydrogencarbonate and 120 parts of ethanol was stirred and refluxed over weekend. The reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and tetrahydrofuran, yielding 2.5 parts (45.3%) of 3-chloro-6-[4-(2-pyridinyl)-1-piperazinyl]pyridazine; mp. 194.7° C. (compound 213).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=2)[N:13]([CH3:21])[N:12]=1.[S:22](=O)(=[O:25])([OH:24])[OH:23]>>[NH2:20][C:16]1[N:15]=[C:14]2[N:13]([CH3:21])[N:12]=[C:11]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[CH:5]=3)[C:19]2=[CH:18][N:17]=1
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)c(OC)c1
Reactant: O=S(=O)(O)O
Product: COc1cc(OC)c(S(=O)(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 89) (1 g, 3.50 mmol) is dissolved in concentrated sulfuric acid (25 ml) to give a blood red solution. The reaction mixture is stirred at room temperature overnight, poured onto ice-water (200 ml) and the resulting solid is collected by filtration, washed with water and dried under vacuum to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:4]([CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:3]=1
Reactant: CS(=O)(=O)NCc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(CNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g, 29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K2CO3 (4.121 g, 29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68 h. The solids were removed by filtration and the solution was concentrated in vacuo. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title compound of Preparation 10 (5.637 g). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:19]=1[CH:20]=[N+:21]([CH3:23])[CH3:22].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:19]=1[CH:20]([N:21]([CH3:23])[CH3:22])[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenylindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]I.[N+]([O-])(O)=O>CCOC(C)=O>[I:16][C:8]1[C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][S:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sn1
Reactant: II
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1nsc(-c2ccccc2)c1I
Temperature: 80 °C
Yield: 21.4 %

Procedure:
To methyl 5-phenylisothiazole-3-carboxylate (500 mg, 2.280 mmol) in a tube were added iodine (579 mg, 2.280 mmol) and nitric acid (2.280 mmol). The resulting mixture was heated to 80° C. for 1 h. After the reaction was cooled to room temperature, EtOAc (50 mL) was added. The resulting mixture was washed with saturated Na2S2O3 solution until the brown color disappeared. The organic layer was concentrated. HPLC and flash chromatography yielded methyl 4-iodo-5-phenylisothiazole-3-carboxylate (168 mg, 0.487 mmol, 21.34% yield). The compound had an LC/MS M+1=345.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16]I>>[CH3:16][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CI
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccc(Cl)cc1

Procedure:
The α-cyano-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine is reacted with methyl iodide using the procedure of Example 2 to yield the α-cyano-m-phenoxybenzyl ester of N-methyl,N-(4-chlorophenyl)valine, MS m/e 448.1 (M+).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>C(#N)C>[F:27][C:28]([F:33])([F:32])[C@@H:29]([OH:30])[CH2:31][N:16]1[CH2:17][CH2:18][O:19][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)[CH2:15]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: Fc1ccc(C2CNCCO2)cc1
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@@H](CN1CCOC(c2ccc(F)cc2)C1)C(F)(F)F
Reaction time: 96 h
Yield: 72.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)morpholine oxalate (50 mg, 184 μmol) and triethylamine (128 μL, 922 μmole) in 2.5 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (82.6 mg, 737 μmol) at room temperature. The mixture was stirred at this temperature for 4 days. The solution was purified by reverse phase column chromatography (30-100% acetonitrile in water). The desired fractions were pooled and lyophilized to give (2S)-1,1,1-trifluoro-3-(2-(4-fluorophenyl)morpholino)propan-2-ol (39 mg, 73%). Used as is in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: COc1ccc(CCC(O)c2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(4-methoxy-phenyl)-propan-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1)[NH2:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=[C:3]([NH:1][NH:2][C:32](=[O:34])[CH3:33])[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2nc(C(F)(F)F)nc(NN)c2-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NNc1nc(C(F)(F)F)nc(-c2ccc(C)cc2)c1-c1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 4-hydrazino-6-(4-methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine (0.23 g, 0.66 mmol) (synthesized according to the procedure described in example 22) in dichloromethane (5 ml) and pyridine (0.06 g, 0.8 mmol), acetyl chloride (0.6 g, 0.7 mmol) was added dropwise at room temperature over a period of ten minutes under stirring. Stirring was continued for two hours and the resultant reaction mass was poured onto ice-water mixture and neutralised with hydrochloric acid. The reaction mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.2 g, 77.9%, HPLC purity 99.4%), mp: 147-152° C.