Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:27]=[C:28](C(O)=O)[C:29]3[C:34]([C:35]=2[C:36]=1[O:37][CH3:38])=[CH:33][C:32]([CH3:39])=[CH:31][CH:30]=3.[N-:43]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)C>[NH2:43][C:28]1[C:29]2[C:34]([C:35]3[C:36]([O:37][CH3:38])=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=3[CH:27]=1)=[CH:33][C:32]([CH3:39])=[CH:31][CH:30]=2
Reactant: COc1ccc2cc(C(=O)O)c3ccc(C)cc3c2c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(N)c3ccc(C)cc3c2c1OC
Reaction time: 0.17 h

Procedure:
A mixture of 400 ml (2.87M) of trifluoroacetic anhydride and 400 ml (5.22M) of trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 61.1 g (0.206M) of 3,4-dimethoxy-6-methyl-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. After the mixture has been cooled to -5°, 16.08 g (0.247M) sodium azide are carefully added in solid form. The mixture is stirred for 2 hours at 0°, poured onto ice, extracted three times with methylene chloride and washed with a solution 1N of sodium hydroxide. The aqueous phases are extracted twice with methylene chloride 2-propanol 8:2. The organic phases are combined, dried and evaporated, to give white crystals. 86 g of the resultant mixted anhydride are warmed for 2 hours under reflux in 800 ml of a solution 2N of sodium hydroxide and 800 ml ethanol and the mixture is evaporated. The residue is washed with water/ice and extracted three times with methylene chloride. The organic phases are combined, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7](OC(OCC)OCC)C.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20]>CN(C)C=O>[NH:3]1[C:2]([NH:1][CH:7]=[N:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([O:26][CH3:27])=[O:25])=[N:6][N:5]=[N:4]1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1ccccc1N
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture was prepared from 9.5 g of 5-aminotetrazole, 16.5 g of triethoxymethane and 50 ml of N,N-dimethylformamide and heated under nitrogen and a solution of 16.9 g of methyl anthranilate in 15 ml of N,N-dimethylformamide was added to the hot mixture and stirred for 15 minutes. The mixture was then cooled to room temperature and stirred for 16 hours. The white crystals which formed were separated by filtration, washed first with N,N-dimethylformamide and then with 2-propanol, and vacuum oven dried to give N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine which was identical with authentic material.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35]C(=O)OC(C)(C)C)O1>>[C:11]1([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]#[C:8][C:6]1[CH:5]=[N:4][C:3]2[C:2]([CH:7]=1)=[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]1=[N:35][C:19]=2[NH2:20]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Product: Cc1cc(C)c(C#Cc2cnc3c(N)nc4ccccc4c3c2)c(C)c1

Procedure:
2-(Mesitylethynyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 3-chloro-5-(mesitylethynyl)picolinonitrile (Example 77/Step 1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (commercially available) following the procedures described for Example 45/Step 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(OC(=O)NC2CCCCC2)N(c2nnc(SC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclohexyl isocyanate (3.5 ml); 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-(N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C3C=CC(C(F)(F)F)=CN=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:46][O:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[N:51][C:50]=1Cl.[CH2:58]1OCCOCCOCCOCCOCCO[CH2:59]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:50]3[C:49]([C:48]([O:47][CH3:46])=[O:57])=[CH:54][CH:53]=[C:52]([CH3:55])[N:51]=3)[CH:13]=2)[N:8]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:7]=1[CH2:36][C:37]([O:39][CH2:58][CH3:59])=[O:38])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3nc(C)ccc3C(=O)OC)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 90 °C

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)-indole-3-carboxylic acid ethyl ester (250 mg, 0.59 mmol, see (b) Example 12), K2CO3 (244 mg, 1.77 mmol), 2-chloro-6-methylnicotinic acid methyl ester (163 mg, 0.88 mmol), 18-crown-6 (16 mg, 0.06 mmol) and DMF (2 mL). The reaction mixture was heated at 90° C. for 4 d and worked-up as described before. Yield 80 mg (32%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].O[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)[CH3:14].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1(C)C=CC=CC=1>[CH:13]([O:7][CH:6]([CH3:5])[CH3:8])([CH3:15])[CH3:14].[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6](=[O:7])[C:8]=1[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)[CH3:14]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC(C)OC(C)C
Product: CCOC(=O)Cc1ccc(C(C)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To 100 ml of toluene were added 2.2 g (2 mmole) of trimethylhydroquinone and 3 g (1.5 mmole) of ethyl 4-(1-hydroxyethyl)phenylacetate, and after 0.2 g of D-camphorsulfonic acid was added, the reaction solution was stirred for 18 hours with heating at 60° C., cooled and evaporated under reduced pressure. The residue was dissolved in THF, and an aqueous solution of ferric chloride was added to the solution to carry out oxidation. Isopropyl ether (IPE) was added to the reaction solution, and the mixed solution was washed with water, dried and then evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using solution: IPE to give ethyl 4-[1-(3,5,6-trimethyl-1,4-benzoquinon-2yl)ethyl]phenylacetate. Hydrolysis of this compound with 6N hydrochloric acid in THF yielded 4-[1-(3,5,6-trimethyl-1,4-benzoquinon-2yl)ethyl]phenylacetic acid (1 g, uield of 31%). This compound was recrystallized from IPE, m.p. 142°-143° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](O)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:69]1[CH2:73][CH2:72][CH2:71][C@H:70]1[C:74]1[NH:78][N:77]=[N:76][N:75]=1>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](=[O:27])[N:69]3[CH2:73][CH2:72][CH2:71][C@H:70]3[C:74]3[NH:78][N:77]=[N:76][N:75]=3)[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C1CN[C@H](c2nnn[nH]2)C1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3c3nnn[nH]3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 193 mg 4-{2-[(5-Carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 2 ml DMF were added 150 mg HATU and 69 μl DIPEA. After 10 minutes a solution of 54 mg (S)-5-Pyrrolidin-2-yl-1H-tetrazole in 1 ml DMF was added and after 36 h the reaction mixture was diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and brine. The crude product thus obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were immediately lyophilized to yield the title compound
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:44])([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:44])([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:28])=[CH:21][CH:20]=1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yielded 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O[C@@H:32]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C.P(O)(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:32]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]3[O:34][C:35](=[O:37])[CH3:36])[C:6]=2[N:7]=1
Reactant: Nc1ncc2sc(=O)[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[N+]([O-])c1ccc(OP(=O)(O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 150 °C
Yield: 39.9 %

Procedure:
Compound 86 (62 mg, 0.4 mmol), 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose tetraacetate (128 mg, 0.4 mmol), and catalytic bis(p-nitrophenyl) hydrogen phosphate (13 mg, 0.04 mmol) were mixed and placed in a 500 ml flask. The reaction vessel was carefully placed under vacuum (˜5.0 mmHg) and lowered into an oil bath heated at 150° C. for 10 minutes. After cooling to room temperature, the solids were washed with ethyl acetate. The crude product was purified by flash column. (silica, 5 to 35% ethyl acetate gradient in chloroform) to yield 68 mg of compound 79 (40%) as a white solid as a white powder identical in all respects to material isolated in Example 38, step 2.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccc(Cl)cc2C=C3)cn1

Procedure:
The title compound was prepared from 9C and 2A by a route analogous to that used for the preparation of 2B. HPLC Rt=3.496 min; LCMS Found: (M+H)+=410.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=C[C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].[NH2:24]C1C(C(NC)=O)=NC(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[N:24][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1nc(Br)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D 700 mg, 3 mmol) to isolate 386 mg of the title compound as a hygroscopic foam (46%). 1H NMR (400 MHz, CDCl3) δ 8.11 (br. s., 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 5.95 (br. s., 2H), 4.34 (t, J=6.4 Hz, 2H), 3.68 (q, J=5.8 Hz, 2H), 3.02 (d, J=5.01 Hz, 3H), 2.58 (t, J=5.7 Hz, 1H), 2.11 (td, J=6, 12.3 Hz, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:22][C:9]2[C:10]([OH:21])=[C:11]([C:17](OC)=[O:18])[N:12]([CH3:16])[S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][C:29]2[O:33][C:32]([C:34]3[N:35]=[C:36]([NH2:39])[S:37][CH:38]=3)=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][C:29]2[O:33][C:32]([C:34]3[N:35]=[C:36]([NH:39][C:17]([C:11]4[N:12]([CH3:16])[S:13](=[O:15])(=[O:14])[C:8]5[CH:7]=[C:6]([C:2]6[O:1][CH:5]=[CH:4][CH:3]=6)[S:22][C:9]=5[C:10]=4[OH:21])=[O:18])[S:37][CH:38]=3)=[CH:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)C1=C(O)c2sc(-c3ccco3)cc2S(=O)(=O)N1C
Reactant: Nc1nc(-c2ccc(Oc3ccc(F)cc3)o2)cs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nc(-c3ccc(Oc4ccc(F)cc4)o3)cs2)=C(O)c2sc(-c3ccco3)cc2S1(=O)=O
Reaction time: 4.5 h

Procedure:
0.339 g (0.99 mmol) of methyl 6-(2-furanyl)-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylate 1,1-dioxide and 0.398 g (1.44 mmol) of 4-[5-(4-fluorophenoxy)-2-furanyl]-2-thiazolamine are heated to boiling in 3 ml of absolute xylene. After 4.5 h, the suspension is cooled, and the precipitated product is filtered off, digested several times with diethyl ether and recrystallized from dimethyl sulphoxide/acetone 10:1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([S:25]([NH:28][C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:27])=[O:26])[CH2:20]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[S:33]1[C:29]([NH:28][S:25]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[CH:24][C:15]=3[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH2:20]2)(=[O:26])=[O:27])=[N:30][CH:31]=[N:32]1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(Br)cccc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 120 °C

Procedure:
A vial charged with Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 9.43 μg, 0.013 μmol), (4-(trifluoromethyl)phenyl)boronic acid (0.200 μmol), 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.050 mg, 0.133 μmol), and potassium phosphate (0.085 mg, 0.400 μmol) was treated with 2 mL dioxane and 1 mL water. The reaction mixture was heated to 120° C. for 2 hours at which time the mixture was cooled to room temperature then concentrated and purified by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 75% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] to provide N-(1,2,4-thiadiazol-5-yl)-5-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=441.0. 1H NMR (400 MHz, MeOH-d4) δ ppm: 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.22-7.28 (m, 1H), 7.12 (dd, J=15.5, 7.1 Hz, 2H), 4.40 (s, 2H), 3.33-3.38 (m, 2H), 2.77 (m, 2H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].[Li+].CC([N-]C(C)C)C.[CH:22](OC)=[O:23]>O1CCCC1>[CH2:12]([O:11][P:6]([C:2]1[O:1][C:5]([CH:22]=[O:23])=[CH:4][CH:3]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:13]
Reactant: CCOP(=O)(OCC)c1ccco1
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C=O)o1
Reaction time: 1 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmol) in THF (tetrahydrofuran) was treated with LDA (1.12 mmol, lithium N,N-diisopropylamide) at −78° C. for 20 min. Methyl formate (1.5 mmol) was added and the reaction was stirred for 1 h. Extraction. and chromatography gave compound 1 as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: COCC(=O)OC
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 2.5 h

Procedure:
At room temperature, a solution of 16.6 g (0.107 mol) of racemic 1 -(4-chloro-phenyl)-ethylamine in 41 g of methyl methoxyacetate is mixed with stirring with 1.2 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at 40° C. and the progress of the reaction is monitored by gas chromatographic sample analysis. After 2.5 hours, the conversion is 54%. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 95.6%, while the (R)-enantiomer of N-(1-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 95.3%.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:12](O)[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:16][CH:12]([C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH2:13][CH3:14])[CH3:22]
Reactant: CCc1cc2c(cc1C(O)CC)OCO2
Reactant: CCOC(=O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CSC(CC)c1cc2c(cc1CC)OCO2
Yield: 68.8 %

Procedure:
3.9 g of 1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 3.35 g of ethyl mercaptoacetate were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. Water was added thereto. After extraction with benzene followed by drying over magnesium sulfate and concentration under reduced pressure, the product was purified according to silica gel column chromatography (ethyl acetate/hexane =1:9) to obtain 4.0 g of the intended compound in the form of a colorless, transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=[O:22].CC[O:32][CH2:33][CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:34](=[O:22])[C:33](=[O:32])[N:9]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2ccccc2)c1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)N(c1ccccc1)C(=O)C2=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of N-(3-methoxyphenyl)-N-phenylamine (1.14 g, 5.72 in ether (3 mL) was added to a solution of oxylyl chloride (728 g, 5.75 mmol)and heated at reflux for 1 hour. The resulting mixture was cooled to room temperature, concentrated to dryness, and redissolved in nitrobenzene (35 mL). The solution was added to a solution of AlCl3 in nitrobenzene (0.762 g, 5.72 mmol), and the resulting mixture was heated at 70° C. for 16 hours. The crude product was concentrated in vacuo and purified by column chromatography [eluent: EtOAc/hexane (1:1)], giving the desired product (60 mg, 50%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=4)[NH:22][CH:21]=3)[C:28]([C:30]3[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 489.16 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH2:18].[OH2:19].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].C(O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc(C#N)cc2)cc1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2ccc(C#N)cc2)cc1
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
6 g (0.0248 mol) of 4-[(4-methoxyphenyl)thio]benzonitrile and then 18.45 g of magnesium monoperoxyphthalate hexahydrate are added to a mixture of 120 ml of ethanol and 12 ml of water. The reaction medium is kept at 40° C. for 20 minutes. After hydrolysis in iced water, the solution is filtered and the white solid is washed with water. 5.2 g (yield: 77%) of the expected product are thus obtained.